dosing and administration of anti-c5 antibodies for the treatment of paroxysmal nocturnal hemoglobin

专利摘要:
  These are methods for the clinical treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) and Atypical Hemolytic Uremic Syndrome (aHUS) using an anti-C5 antibody, or antigen-binding fragment thereof.
公开号:BR112020008182A2
申请号:R112020008182-5
申请日:2018-10-26
公开日:2020-10-27
发明作者:Lori Shafner；Scott T. ROTTINGHAUS；Rajendra Pradhan；Andrew Damokosh；Xiang Gao
申请人:Alexion Pharmaceuticals, Inc.；
IPC主号:

专利说明:

[0001] [0001] This application claims priority and benefit from Interim Application US 62/685,505 filed June 15, 2018 Interim Application US 62/685425 filed June 15, 2018 Interim Application US 62/662503 , filed April 25, 2018, Interim Application No. US 62/643,608, filed March 15, 2018, Interim Application No. US 62/643,056, filed March 14, 2018, and Interim Application No. on October 26, 2017. The entire contents of the aforementioned requests are incorporated herein by reference. SEQUENCE LISTING
[0002] [0002] This application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated in its entirety by reference. Said ASCII copy, created on October 25, 2018, is named AXJ-224PC_SL.txt and is 59,066 bytes in size. BACKGROUND
[0003] [0003] The complement system works in conjunction with other immune systems in the body to defend against the intrusion of cellular and viral pathogens. There are at least 25 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors. Plasma proteins constitute about 10% of the globulins in vertebrate serum. Complement components achieve their defensive immune functions by interacting in a series of intricate but precise enzymatic cleavage and membrane-binding events. The resulting complement cascade leads to the production of products with opsonic, immunoregulatory, and lytic functions. A concise summary of the biological activities associated with complement activation is provided, for example, in The Merck Manual, 16th Edition.
[0004] [0004] Although a properly functioning complement system provides a robust defense against microbial infection, inappropriate regulation or activation of complement pathways has been implicated in the pathogenesis of several disorders, including paroxysmal nocturnal hemoglobinuria (PNH) and hemolytic uremic syndrome. atypical (aHUS). PNH and aHUS are both ultra-rare disorders triggered by chronic uncontrolled complement activation. The resulting inflammation and cell damage lead to devastating clinical manifestations of these diseases.
[0005] [0005] PNH is a condition in which uncontrolled complement activity leads to systemic complications, primarily through intravascular hemolysis and platelet activation (see Socié G, et al., French Society of Haematology. Lancet. 1996;348(9027) ):573 to 577 and Brodsky, R., Blood. 2014;124(18):2804 to 2811). Persistent intravascular hemolysis can be triggered by various stressors, such as infection or physical exertion, and this leads to mild muscle contraction (free hemoglobin), chronic anemia, and an increased risk of severe thromboembolism. Thromboembolism is the most common cause of mortality in PNH patients, and pulmonary hypertension and target organ damage to vital organs, such as the liver, kidneys, brain, and intestines, are sequelae of such events (Hillmen, P., et al. J. Ammatol. 2010;85(8):553 to 559). Due to these adverse pathological processes, PNH patients have a reduced quality of life (QoL), which can include debilitating fatigue, chronic pain, poor physical function, shortness of breath, abdominal pain, erectile dysfunction, need for anticoagulation, blood transfusions, blood and in some cases, need for dialysis (Weitz, IC., et al, Thromb Res. 2012;130(3):361 to 368).
[0006] [0006] Hemolytic-uremic syndrome (HUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. HUS is classified as one of two types: diarrhea-associated (D+HUS; also known as E. coli (STEC)-HUS or typical HUS or HUS), and non-diarrheal or atypical HUS (aHUS). D+ HUS is the most common form, accounting for more than 90% of cases and is caused by a previous illness with a shiga-like toxin-producing bacterium, eg E. coli O157:H7.
[0007] [0007] aHUS can be genetic, acquired, or idiopathic. Inherited forms of aHUS can be associated with mutations in numerous human complement components including, for example, complement factor H (CFH), membrane cofactor protein (MCP), complement factor I (CFI), C4b binding protein (C4BP), complement factor B (CFB), and complement component 3 (C3). See, for example, Caprioli et al. (2006) Blood 108:1267 to 1279. Certain mutations in the CD55 gene encoding, although not yet implicated in aHUS, are associated with the severity of aHUS. See, for example, Esparza-Gordillo et al. (2005) Hum Mol Genet 14:703 to 712.
[0008] [0008] aHUS is rare and has a mortality rate of up to 25%. Many patients with this disease will experience permanent neurological or renal impairment, for example, at least 50% of aHUS patients progress to end-stage renal failure (ESRF). See, for example, Kavanagh et al. (2006) British Medical Bulletin 77 and 78:5 to 22. Until recently, treatment options for patients with aHUS were limited and often involved plasma infusion or plasma exchange. In some cases, aHUS patients undergo uni or bilateral nephrectomy or kidney transplantation (see Artz et al. (2003) Transplantation 76:821 to 826). However, recurrence of the disease in treated patients is common.
[0009] [0009] Patients with PNH or aHUS are at risk of substantial morbidity and mortality. Therefore, it is an object of the present invention to provide improved methods for treating patients with PNH or aHUS. SUMMARY
[0010] [0010] Compositions and methods for treating PNH or aHUS in a human patient are provided herein, which comprise administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is for administration) according to a particular clinical dose administration regimen (i.e., in a particular dose amount and according to a specific dose administration schedule) .
[0011] [0011] Any suitable anti-C5 antibody, or antigen-binding fragment thereof, may be used in the methods described herein. An exemplary anti-C5 antibody is ravulizumab (also known as Ultomiris™, ALXN1210 and BNJ441 antibody) which comprises heavy and light chains having the sequences known in SEQ ID Nos: 14 and 11, respectively, or antigen-binding fragments and variants thereof. In other embodiments, the antibody comprises the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of ravulizumab. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the ravulizumab heavy chain (VH) variable region having the known sequence in SEQ ID NO:12, and the CDR1, CDR2 and CDR3 domains of the region light chain variable (VL) of ravulizumab having the known sequence in SEQ ID NO:8. In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions that have the amino acid sequences set forth in SEQ ID NO:12 and SEQ ID NO:8, respectively. In another embodiment, the antibody comprises a heavy chain constant region as set forth in SEQ ID NO:13.
[0012] [0012] In another embodiment, the antibody comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions. at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering.
[0013] [0013] In another embodiment, the antibody comprises CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs. : 4, 5 and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-
[0014] [0014] In another embodiment, the antibody binds to human C5 at pH 7.4 and 25 °C with an affinity dissociation constant (KD) that is in the range 0.1 nM ≤ KD ≤ 1 nM. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25 °C with a KD ≥ 10 nM. In yet another embodiment, the [(KD of antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25°C)/(KD of antibody or antigen-binding fragment thereof for human C5 in pH 7.4 and at 25 °C)] of the antibody is greater than 25.
[0015] [0015] Another exemplary anti-C5 antibody is antibody 7086 described in U.S. Patents 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patents 8,241,628 and 8,883,158). In another embodiment, the antibody, or antigen-binding fragment thereof, comprises the heavy chain domains CDR1, CDR2 and CDR3 having the sequences set forth in SEQ ID NOs: 21, 22 and 23, respectively, and light chain domains CDR1, CDR2 and CDR3 which have the sequences set forth in SEQ ID NOs: 24, 25 and 26, respectively; In another embodiment, the antibody, or antigen-binding fragment thereof, comprises the VH region of antibody 7086 which has the sequence set forth in SEQ ID NO: 27, and the VL region of antibody 7086 which has the sequence set forth in SEQ ID NO: 28.
[0016] [0016] Another exemplary anti-C5 antibody is the 8110 antibody also described in U.S. Patents 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises the heavy chain domains CDR1, CDR2, and CDR3 that have the sequences set out in SEQ ID NOs: 29, 30 and 31, respectively, and CDR1, CDR2 and CDR3 light chain domains having the sequences set out in SEQ ID NOs: 32, 33 and 34, respectively; In another embodiment, the antibody comprises the VH region of the 8110 antibody which has the sequence set forth in SEQ ID NO: 35,
[0017] [0017] Another exemplary anti-C5 antibody is the 305LO5 antibody described in US2016/0176954A1. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises heavy chain domains CDR1, CDR2 and CDR3 having the sequences set forth in SEQ ID NOs: 37, 38 and 39, respectively, and light chain domains CDR1, CDR2 and CDR3 having the sequences set forth in SEQ ID NOs: 40, 41 and 42, respectively; In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence set out in SEQ ID NO: 43, and the VL region of the 305LO5 antibody having the sequence set out in SEQ ID NO: 44.
[0018] [0018] Another exemplary anti-C5 antibody is the SKY59 antibody described in Fukuzawa T., et al., Rep. Apr 2017 24;7(1):1080 ). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.
[0019] [0019] Another exemplary anti-C5 antibody is antibody REGN3918 (also known as H4H12166PP) described in US20170355757. In one embodiment, the antibody comprises a heavy chain variable region comprising SEQ ID NO:47 and a light chain variable region comprising SEQ ID NO:48. In another embodiment, the antibody comprises a heavy chain comprising SEQ ID NO:49 and a light chain comprising SEQ ID NO:50.
[0020] [0020] In another embodiment, the antibody competes for binding with, and/or binds to the same epitope on C5 as, the antibodies mentioned above (e.g., eculizumab, ravulizumab, antibody 7086, antibody 8110, antibody 305LO5, antibody SKY59 or antibody REGN3918). In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity to the antibodies mentioned above (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% variable region identity).
[0021] [0021] In one embodiment, the dose of the anti-C5 antibody, or antigen-binding fragment thereof, is based on the weight of the patient. For example, in one embodiment, 2400 mg or 3000 mg of the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 to < 60 kg. In another embodiment, 2700 mg or 3300 mg of the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 60 to < 100 kg. In another embodiment, 3000 mg or 3600 mg of the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 100 kg. In certain embodiments, dose administration regimens are adjusted to provide the optimal desired response (eg, an effective response).
[0022] [0022] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered for one or more cycles of administration. In one embodiment, the administration cycle is 26 weeks. In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered once on Day 1 of the administration cycle, once on Day 15 of the administration cycle, and every eight weeks thereafter. In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered every eight weeks following the administration cycle for an extension period of up to two years (e.g., at a dose of 3000 mg, 3300mg or 3600mg).
[0023] [0023] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered for one or more cycles of administration. In one embodiment, the administration cycle is 26 weeks. In another embodiment, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 cycles. In another embodiment, treatment is continued throughout the life of the human patient.
[0024] [0024] In another embodiment, a method is provided for treating a human patient with PNH or aHUS, the method comprising administering to the patient during one cycle of administration an effective amount of an anti-C5 antibody, or DNA-binding fragment. antigen thereof, comprising heavy chain sequences CDR1, CDR2 and CDR3 as set out in SEQ ID NOs: 19, 18 and 3, respectively, and light chain sequences CDR1, CDR2 and CDR3 as set out in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered: (a) once on Day 1 of the administration cycle at a dose of: 2400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg, or 3000 mg for a patient weighing ≥ 100 kg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing ≥ 40 to < 60 kg,
[0025] [0025] In another embodiment, a method is provided for treating a human patient with PNH or aHUS, the method comprising administering to the patient during one cycle of administration an effective amount of an anti-C5 antibody, or DNA-binding fragment. antigen thereof, comprising heavy chain sequences CDR1, CDR2 and CDR3 as set out in SEQ ID NOs: 19, 18 and 3, respectively, light chain sequences CDR1, CDR2 and CDR3 as set out in SEQ ID NOs: 4, 5 and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues that correspond to the methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered: (a) once on Day 1 of the administration cycle at a dose of: 2,400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg, or 3000 mg for a patient weighing ≥ 100 kg; and
[0026] [0026] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 to < 60 kg: (a) once on Day 1 of the administration cycle in a 2400 mg dose; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg.
[0027] [0027] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 60 to < 100 kg: (a) once on Day 1 of the administration cycle in a 2700 mg dose; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3300 mg.
[0028] [0028] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 100 kg: (a) once on Day 1 of the administration cycle at a dose of 3,000 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3600 mg.
[0029] [0029] In some modalities, the patient has not been previously treated with a complement inhibitor (eg, the patient is a patient who has never received treatment with a complement inhibitor). -C5, or antigen-binding fragment thereof, and is switched to another anti-C5 antibody during the course of treatment. For example, in certain embodiments, different anti-C5 antibodies are administered during the course of treatment. In one embodiment, different anti-C5 antibodies are administered during separate treatment and extension periods. For example,
[0030] [0030] Exemplary alternative anti-C5 antibodies include, but are not limited to, (i) ALXN1210, (ii) an antibody, or antigen-binding fragment thereof, comprising the heavy chain domains CDR1, CDR2, and CDR3 that comprise SEQ ID NOs: 21, 22 and 23, respectively, and light chain domains CDR1, CDR2 and CDR3 which comprise SEQ ID NOs: 24, 25 and 26, respectively, (iii) an antibody, or DNA-binding fragment antigen thereof, comprising a heavy chain variable region comprising SEQ ID NO: 27 and a light chain variable region comprising SEQ ID NO: 28, (iv) an antibody, or antigen-binding fragment thereof , which comprises the heavy chain domains CDR1, CDR2 and CDR3 which comprise SEQ ID NOs: 29, 30 and 31, respectively, and light chain domains CDR1, CDR2 and CDR3 which comprise SEQ ID NOs: 32, 33 and 34 , respectively, (v) an antibody, or antigen-binding fragment thereof, which comprises a variable region chain comprising SEQ ID NO: 35 and a light chain variable region comprising SEQ ID NO: (vi) an antibody, or antigen-binding fragment thereof, comprising the heavy chain domains CDR1, CDR2 and
[0031] [0031] In some modalities, the patient has been pretreated for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months with an anti-C5 antibody, or antigen-binding fragment thereof, ( e.g. eculizumab) before switching to another anti-C5 antibody, or antigen-binding fragment thereof (eg, ravulizumab). In one particular modality, the patient was pretreated for at least 6 months with eculizumab.
[0032] [0032] In another embodiment, where a patient (e.g., PNH or aHUS patient) is treated with a first anti-C5 antibody and then switched to treatment with a different second anti-C5 antibody, especially where the second different anti-C5 antibody binds to a different epitope on C5 than the first anti-C5 antibody, administration schedules take into account the half-life of the first anti-C5 antibody. For example, to ensure that the first anti-C5 antibody is extracted (e.g., “cleared”) from the patient before the second (different) anti-C5 antibody is administered (e.g., to avoid issues associated with aggregation, formation of immune complex, etc.), the half-life of the first anti-C5 antibody is taken into account. In one embodiment, the second (different) anti-C5 antibody is not administered until a duration of time corresponding to 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, or 7.5 times the half-life of the first anti-C5 antibody has passed after the final administration of the first anti-C5 antibody.
[0033] [0033] In another embodiment, the patient was pretreated with eculizumab and then switched to treatment with a second (different) anti-C5 antibody (e.g., ravulizumab, antibody 7086, antibody 8110, antibody 305LO5, SKY59 antibody, or antibody REGN3918). In an embodiment where eculizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, for example, until at least 36, 45, 54, 63, 72, 81, 90, 99, 108, 117 or 126 days have passed after the final administration of eculizumab.
[0034] [0034] In another embodiment, the patient was pretreated with ravulizumab and then switched to treatment with a different anti-C5 antibody (e.g. eculizumab, antibody 7086, antibody 8110, antibody 305LO5, antibody SKY59, or antibody REGN3918) . In an embodiment where ravulizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, for example, until at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325 , 375 or 400 days have elapsed after the final administration of ravulizumab.
[0035] [0035] Additionally or alternatively, techniques are used to extract or enhance the extraction of the first anti-C5 antibody before switching to treatment with a second (different) anti-C5 antibody. Exemplary techniques include, but are not limited to, plasma exchange or blood transfusions. In another embodiment, an antibody against the first anti-C5 antibody (e.g., an anti-eculizumab antibody, an anti-ravulizumab antibody, an anti-7086 antibody, an anti-8110 antibody, an anti-305LO5 antibody, an anti- -SKY59, or an anti-REGN3918 antibody) is administered to extract or boost extraction of the first anti-C5 antibody before a second (different) anti-C5 antibody is administered.
[0036] [0036] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ALXN1210), is administered to a patient, wherein the administration cycle begins at least about two weeks, at least about three weeks, at least about four weeks, at least about six weeks, at least about seven weeks, or at least about eight weeks after the patient's last dose of eculizumab. In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ALXN1210), is administered to a patient, wherein the administration cycle begins at least two weeks after the patient's last dose of eculizumab. .
[0037] [0037] In some embodiments, patients treated according to the methods described herein were vaccinated against meningococcal infections within 3 years before or at the time of initiating treatment. In one embodiment, patients who received treatment less than 2 weeks after receiving a meningococcal vaccine are also treated with appropriate prophylactic antibiotics for up to 2 weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135 and/or B.
[0038] [0038] In another aspect, the treatment regimens described are sufficient to maintain particular trough serum concentrations of the anti-C5 antibody, or antigen-binding fragment thereof. For example, in one embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 µg/ml or greater. In one embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 100 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 150 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 200 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 250 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 300 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, between 100 µg/ml and 200 µg/ml. In another embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of about 175 µg/ml.
[0039] [0039] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain at least 50 μg, 55μg, 60 μg, 65 μg, 70 μg, 75 μg , 80µg, 85µg, 90µg, 95µg, 100µg, 105µg, 110µg, 115µg, 120µg, 125µg, 130µg, 135µg, 140µg, 145µg, 10µg, 145µg, 1µg μg¸ 165 μg, 170 μg¸ 175 μg, 180 μg, 185 μg, 190 μg¸ 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 240 μg 245 μg, 250 μg, 255 μg, or 260 μg antibody per milliliter of patient blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain between 50 µg and 250 µg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain between 100 µg and 200 µg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain about 175 µg of antibody per milliliter of the patient's blood.
[0040] [0040] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain a minimum concentration of free C5. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain a free C5 concentration of 0.2 µg/ml, 0.3 µg/ml, 0.4 µg /ml, 0.5 µg/ml or below. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain a free C5 concentration of 0.309 to 0.5 µg/ml or below. In another embodiment, the treatment described herein reduces the concentration of free C5 by more than 99% over the entire treatment period. In another modality, the treatment reduces the free C5 concentration by more than 99.5% for the entire treatment period.
[0041] [0041] Anti-C5 antibodies, or antigen-binding fragments thereof, may be administered to a patient by any suitable means. In one embodiment, the antibodies are formulated for intravenous administration.
[0042] [0042] The effectiveness of the treatment methods provided in this document can be evaluated using any suitable means. In one embodiment, for a PNH patient, the treatment produces at least one therapeutic effect selected from the group consisting of a reduction or cessation of fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction. In another embodiment, for an aHUS patient, the treatment produces at least one therapeutic effect selected from the group consisting of a reduction or interruption in severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impairment. of renal function (eg, acute renal failure).
[0043] [0043] In other modalities, treatment results in terminal complement inhibition.
[0044] [0044] In other modalities, treatment produces a shift toward normal levels of a hemolysis-related hematologic biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, erythrocyte PNH clone (RBC) and dimer D. In another embodiment, the treatment produces an increase in hemoglobin stabilization from the patient's pretreatment baseline.
[0045] [0045] In other modalities, treatment produces a shift toward normal levels of a biomarker associated with chronic disease selected from the group consisting of estimated glomerular filtration rate (eGFR) and spot urine albumin:creatinine and brain natriuretic peptide in plasma (BNP).
[0046] [0046] In other modalities, the treatment produces a reduction in the need for blood transfusions. In another modality, treatment produces a greater than 70% increase in transfusion prevention.
[0047] [0047] In other modalities, treatment results in a reduction in sudden hemolysis relative to eculizumab treatment. In another embodiment, the treatment results in a sudden elimination of hemolysis during the treatment period. In another modality, the treatment results in a reduction in sudden hemolysis compared to the baseline amount of sudden hemolysis pretreatment.
[0048] [0048] In other modalities, treatment produces a reduction in major adverse vascular events (MAVEs).
[0049] [0049] In other modalities, the treatment produces a change from the baseline in quality of life as assessed using the Functional Assessment Fatigue Scale for Chronic Illness Therapy (FACIT), version 4 and the Quality of Life Questionnaire. Life Scale Core 30 of the European Organization for Research and Treatment of Cancer. In another modality, the treatment produces a change from the baseline in quality of life, evaluated using the Functional Assessment Fatigue Scale for Chronic Illness Therapy (FACIT), version 4 and the Quality of Life Questionnaire Core Scale 30 of the European Organization for Research and Treatment of Cancer by at least 7 points from the baseline score of untreated patients.
[0050] [0050] In another modality, the treatment does not result in a change in quality of life (QoL) as assessed using the Chronic Illness Therapy Functional Assessment Fatigue Scale (FACIT), version 4, Baseline-to-Day
[0051] [0051] In other modalities, lactate dehydrogenase (LDH) levels are used to assess responsiveness to a therapy (eg, a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels is indicative of an improvement in at least one PNH signal). For example, in one embodiment, the treatments described herein result in a normalization of LDH levels. In another embodiment, patients treated according to the disclosed methods experience reductions in LDH levels to levels close to normal or to within 10%, or within 20% of what is considered the normal level (e.g., within 105 to 333 IU/l (international units per liter). In another modality, the patient's LDH levels are normalized throughout the maintenance period of treatment. In another modality, the treated patient's LDH levels are normalized by at least 95% of time during the maintenance period of treatment. In another modality, the treated patient's LDH levels are normalized at least 90%, 85%, or 80% of the time during the maintenance period of treatment. In one modality, the levels of The patient's LDH is ≥ 1.5 times the upper limit of normal (LDH ≥ 1.5 X ULN) before starting treatment. In another modality, treatment results in a normalization of LDH levels by at least day 24 of treatment. In a modal In fact, patients treated according to the disclosed methods experience reductions in LDH levels to within normal levels or to within 10%, 20%, 30%, 40% or within 50% below what is considered the upper limit of normal level (for example, within 105 to 333 IU/l (international units per litre). In one embodiment, the patient's LDH levels are ≥ 1.5 times the upper limit of normal (LDH ≥ 1.5 X ULN) before starting treatment. In one modality, treatment results in LDH levels less than 2 x the upper limit of normal (ULN).
[0052] [0052] In another aspect, there is provided an anti-C5 antibody, or antigen-binding fragment thereof, comprising the CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:12 , and light chain variable region CDR1, CDR2 and CDR3 domains having the sequence set forth in SEQ ID NO:8, for administration to a patient who has PNH or aHUS: (a) once on Day 1 of the administration cycle in a dose of: 2400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg, or 3000 mg for a patient weighing ≥ 100 kg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing ≥ 40 to < 60 kg,
[0053] [0053] In one embodiment, the antibody is determined to be safe, tolerable, and sufficiently non-immunogenic after multiple IV doses for use in PNH and aHUS patients.
[0054] [0054] Further provided are kits that include a pharmaceutical composition containing an anti-C5 antibody, or antigen-binding fragment thereof, such as ravulizumab antibody, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the described methods. in this document. In one embodiment, the kit comprises: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence established in the SEQ ID NO:12, and light chain variable region CDR1, CDR2 and CDR3 domains having the sequence set forth in SEQ ID NO:8; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in the methods described herein.
[0055] [0055] In one embodiment, 2400 mg or 3000 mg of the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 to < 60 kg. In another embodiment, 2700 mg or 3300 mg of the anti-
[0056] [0056] In another aspect, methods are provided for treating a human patient who has a complement-associated disorder. In one embodiment, the method comprises treating a human patient who has a complement-associated disorder who is being treated with eculizumab, wherein the method comprises suspending treatment with eculizumab and switching the patient to treatment with a different complement inhibitor. In another embodiment, the method comprises treating a human patient who has a complement-associated disorder who is being treated with ravulizumab, wherein the method comprises suspending treatment with ravulizumab and switching the patient to treatment with a different complement inhibitor. In one embodiment the different complement inhibitor is selected from the group consisting of: a small molecule, a polypeptide, a polypeptide analog, a peptidomimetic, a siRNA, or an aptamer. In another embodiment, the different complement inhibitor inhibits one or more of complement components C1, C2, C3, C4, C5, C6, C7, C8, C9, Factor D, Factor B, properdin, MBL, MASP-1, MASP -2 or biologically active fragments thereof. In another embodiment, the different complement inhibitor is a different anti-C5 antibody (e.g., ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody).
[0057] [0057] Exemplary complement-associated conditions that can be treated according to the methods described herein include, but are not limited to, rheumatoid arthritis, antiphospholipid antibody syndrome, lupus nephritis, ischemia-reperfusion injury, hemolytic-uremic syndrome atypical disease (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense storage disease, neuromyelitis optica, multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous fetal loss, thrombotic thrombocytopenic purpura, pauci- immune, epidermolysis bullosa,
[0058] [0058] Figure 1 is a schematic representation of the design of a Phase III ALXN1210-HPN-301 clinical trial in PNH patients who have never received treatment with a complement inhibitor.
[0059] [0059] Figure 2 is a schematic showing the disposition of patients in ALXN1210-HPN-301 Phase III.
[0060] [0060] Figure 3 is a schematic showing baseline characteristics and demographics of patients in the ALXN1210-HPN-301 Phase III clinical trial.
[0061] [0061] Figure 4 is a graphical schematic showing the main effectiveness results of the two co-primary endpoints.
[0062] [0062] Figure 5 is a graphical display of the major secondary endpoints showing that all endpoints favored ravulizumab (ALXN1210) and exceeded the non-inferiority margins shown by the red triangles in the graph.
[0063] [0063] Figure 6 is a tabulation of the main results of both primary and secondary endpoints.
[0064] [0064] Figure 7 shows the results of multiple sensitivity analyzes of the effectiveness results
[0065] [0065] Figure 8 is a graphical schematic showing subgroup advantage for ravulizumab (ALXN1210) versus eculizumab.
[0066] [0066] Figure 9 is a graphical display of LDH levels over time for patients treated with ravulizumab (ALXN1210) or eculizumab.
[0067] [0067] Figure 10 is a graphical display of time to achieve LDH normalization (LDH-N) for patients treated with ravulizumab (ALXN1210) or eculizumab.
[0068] [0068] Figure 11 is a graphical display of the percentage of patients achieving normalized LDH on ravulizumab (ALXN1210) or eculizumab at various time points from day 8 to day 183.
[0069] [0069] Figure 12 is a graphical display of the percentage of patients with a 10-point improvement from baseline, per consultation (full analysis set), by the Core 30 Global Health Status Subscale Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer.
[0070] [0070] Figure 13 is a graphical display of the percentage of patients with a 10-point baseline improvement, per consultation (full analysis set), by the European Organization for Cancer Research and Treatment.
[0071] [0071] Figure 14 is a graphical display of the percentage of patients with a 10 point improvement from the baseline, per visit (Full Analysis Set), by the European Research Organization Fatigue Subscale Core 30 Quality of Life Questionnaire and Cancer Treatment.
[0072] [0072] Figure 15 is a tabulation of key safety outcomes in the ALXN1210-HPN-301 Phase III clinical trial.
[0073] [0073] Figure 16 is a tabulation of the most common treatment-related adverse events (TEAE) in the ALXN1210-HPN-301 Phase III clinical trial.
[0074] [0074] Figure 17 is a tabulation of treatment-related serious adverse events (TESAE) in the ALXN1210-HPN-301 Phase III clinical trial.
[0075] [0075] Figure 18 is a tabulation of treatment-related adverse events (TEAE) of special interest in the ALXN1210-HPN-301 Phase III clinical trial.
[0076] [0076] Figure 19 is a tabular display of patient-drug compatibility results in the ALXN1210-HPN-301 Phase III clinical trial.
[0077] [0077] Figure 20 is a graphical representation of the pharmacokinetics (PK) of ravulizumab (ALXN1210) and eculizumab showing the serum concentration of each drug over time (linear scale).
[0078] [0078] Figure 21 is a graphical representation of the pharmacokinetics (PK) of ravulizumab (ALXN1210) and eculizumab showing the serum concentration of each drug over time (semi-logarithmic scale).
[0079] [0079] Figure 22 is a graphical representation of the pharmacodynamics (PD) of ravulizumab (ALXN1210) and eculizumab showing the mean concentration of C5 in the presence of each drug over time.
[0080] [0080] Figure 23 is a graphical representation of the pharmacodynamics (PD) of ravulizumab (ALXN1210) and eculizumab showing the mean percent change (± 95% CI) from baseline for total serum C5 concentration in the presence of each drug over time.
[0081] [0081] Figure 24 is a schematic representing the design for clinical protocol ALXN1210-aHUS-311.
[0082] [0082] Figure 25 is a schematic depicting the design of an ALXN1210-HPN-302 Phase III clinical trial in PNH patients who have been treated with eculizumab for at least the last six (6) months, in which an inhibitor of complement plus eculizumab is administered to the patients.
[0083] [0083] Figure 26 is a schematic representation of the dose administration schedule for patients in the ALXN1210-HPN-302 Phase III clinical trial, including actual infusion days.
[0084] [0084] Figure 27 is a schematic showing the disposition of patients enrolled in the ALXN1210-HPN-302 Phase III clinical trial.
[0085] [0085] Figure 28 is a schematic showing baseline characteristics and demographics of patients enrolled in the ALXN1210-HPN-302 Phase III clinical trial.
[0086] [0086] Figure 29 is a schematic showing baseline disease characteristics of patients enrolled in the ALXN1210-HPN-302 Phase III clinical trial.
[0087] [0087] Figure 30 is a graphical schematic showing the primary efficacy outcomes of the primary and secondary endpoints of the ALXN1210-HPN-302 Phase III clinical trial.
[0088] [0088] Figure 31 is a tabulation of key efficacy outcomes of both primary and secondary endpoints from the ALXN1210-HPN-302 Phase III clinical trial.
[0089] [0089] Figure 32 shows the results of multiple sensitivity analyzes of the efficacy results for the primary endpoint of the ALXN1210-HPN-302 Phase III clinical trial.
[0090] [0090] Figure 33 is a graphical display showing efficacy results for subgroups for the primary endpoint of the ALXN1210-HPN-302 Phase III clinical trial.
[0091] [0091] Figure 34 is a graphical display of mean LDH levels over time for patients enrolled in the ALXN1210-HPN-302 Phase III clinical trial.
[0092] [0092] Figure 35 is a graphical display of the percentage of patients achieving normalized LDH during the ALXN1210-HPN-302 Phase III clinical trial.
[0093] [0093] Figure 36 is a graphical display of the mean change compared to baseline in quality of life over time for patients enrolled in the ALXN1210-HPN-302 Phase III clinical trial, as assessed using the fatigue of the Functional Assessment of Chronic Illness Therapy (FACIT).
[0094] [0094] Figure 37 is a graphical display of the mean value for quality of life over time for patients enrolled in the ALXN1210-HPN-302 clinical trial
[0095] [0095] Figure 38 is a tabulation of key safety results from the Phase III clinical trial of ALXN1210-HPN-302.
[0096] [0096] Figure 39 is a tabulation of treatment-related serious adverse events (TESAEs) from the ALXN1210-HPN-302 Phase III clinical trial.
[0097] [0097] Figure 40 is a tabulation of the most common treatment-related adverse events (TEAEs) from the ALXN1210-HPN-302 Phase III clinical trial.
[0098] [0098] Figure 41 is a tabulation of upper respiratory tract infections (URTI) from the ALXN1210-HPN-302 Phase III clinical trial, as determined by standard MedDRA consultation (SMQ).
[0099] [0099] Figure 42 is a tabulation of adverse events arising from Treatment of Special Interest (TEAESI) from the ALXN1210-HPN-302 Phase III clinical trial.
[0100] [0100] Figure 43 is a tabular display of patient drug compatibility results from the ALXN1210-HPN-302 Phase III clinical trial.
[0101] [0101] Figure 44 is a graphical representation of the pharmacokinetics (PK) of ALXN1210 and eculizumab showing the serum concentration of each drug over time.
[0102] [0102] Figure 45 is a graphical representation of the pharmacodynamics (PD) of ALXN1210 and eculizumab showing the mean concentration of C5 in the presence of each drug over time.
[0103] [0103] Figure 46 is a graphical representation of ALXN1210 and eculizumab showing the mean change (± 95% CI) from baseline to total serum C5 concentration in the presence of each drug over time.
[0104] [0104] The anti-C5 antibodies described herein bind to the C5 complement component (e.g., human C5) and inhibit the cleavage of C5 into C5a and C5b fragments. As described above, such antibodies also have, for example, improved pharmacokinetic properties over other anti-C5 antibodies (e.g. eculizumab) used for therapeutic purposes.
[0105] [0105] The term "antibody" describes polypeptides that comprise at least one antibody-derived antigen binding site (eg, VH/VL or Fv region, or CDR). Antibodies include known forms of antibodies. For example, the antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. The antibody can also be a Fab, Fab'2, ScFv, SMIP, Afibody ® , nanobody, or a domain antibody. The antibody may also be of any one of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD and IgE. The antibody may be a naturally occurring antibody, or it may be an antibody that has been altered by a protein engineering technique (e.g., by mutation, deletion, substitution, conjugation to a non-antibody chemical moiety). For example, an antibody may include one or more amino acid variants (compared to a naturally occurring antibody) that alters a property (e.g., a functional property) of the antibody. For example, numerous such changes are known in the art that affect, for example, half-life, effector function, and/or immune responses to antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that comprise at least one antibody-derived antigen binding site.
[0106] [0106] Anti-C5 antibodies (or VH/VL domains derived therefrom) suitable for use in the invention can be generated using methods well known in the art. Alternatively, art-recognized anti-C5 antibodies can be used. Antibodies that compete with any of these art-recognized antibodies for binding to C5 may also be used.
[0107] [0107] Eculizumab (also known as Soliris®) is an anti-C5 antibody comprising the heavy chain domains CDR1, CDR2, and CDR3 that have the sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and domains light chain CDR1, CDR2 and CDR3 having the sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively; Eculizumab comprises a heavy chain variable region having the amino acid sequence set out in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set out in SEQ ID NO: 8. The variable regions of eculizumab are described in PCT/US1995/005688 and in US Patent No. 6,355,245, the teachings of which are incorporated herein by reference. Eculizumab comprises a heavy chain comprising the amino acid sequence set out in SEQ ID NO:10 and a light chain which has the amino acid sequence set out in SEQ ID NO:11. The complete heavy and light chains of eculizumab are described in PCT/US2007/006606, the teachings of which are incorporated herein by reference.
[0108] [0108] An exemplary anti-C5 antibody is ravulizumab which comprises heavy and light chains having the sequences known in SEQ ID NOs: 14 and 11, respectively, or antigen-binding fragments and variants thereof. Ravulizumab (also known as Ultomiris™, BNJ441 and ALXN1210) is described in PCT/US2015/019225 and in U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference. The terms ravulizumab, BNJ441, and ALXN1210 may be used interchangeably throughout this document, but they all refer to the same antibody. Ravulizumab selectively binds to the human complement protein C5, inhibiting its cleavage to C5a and C5b during complement activation. This inhibition prevents the release of the pro-inflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack (MAC) complex C5b-9 while preserving the proximal or early components of complement activation (e.g., C3). and C3b) essential for opsonization of microorganisms and extraction of immune complexes.
[0109] [0109] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. For example, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the ravulizumab VH region which have the sequence set forth in SEQ ID NO:12, and the CDR1, CDR2 and CDR3 domains of the ravulizumab VL region which have the sequence set forth in SEQ ID NO:8. In another embodiment, the antibody comprises CDR1, CDR2, and CDR3 heavy chain domains that have the sequences set forth in SEQ ID Nos: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain domains that have the set forth sequences. in SEQ ID NOs: 4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions that have the amino acid sequences set forth in SEQ ID NO:12 and SEQ ID NO:8, respectively.
[0110] [0110] Another exemplary anti-C5 antibody is the BNJ421 antibody which comprises heavy and light chains having the sequences known in SEQ ID NOs: 20 and 11, respectively, or antigen-binding fragments and variants thereof. BNJ421 (also known as ALXN1211) is described in PCT/US2015/019225 and in U.S. Patent 9,079,949, the teachings of which are incorporated herein by reference.
[0111] [0111] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Therefore, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the BNJ421 VH region which have the sequence set forth in SEQ ID NO:12, and the CDR1, CDR2 and CDR3 domains of the BNJ421 VL region which have the sequence set forth in SEQ ID NO:8. In another embodiment, the antibody comprises CDR1, CDR2, and CDR3 heavy chain domains that have the sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain domains that have the set out sequences. in SEQ ID NOs: 4, 5 and 6, respectively.
[0112] [0112] The exact limits of CDRs have been defined in different ways according to different methods. In some embodiments, the positions of CDRs or framework regions within a light or heavy chain variable domain may be as defined by Kabat et al. [(1991) “Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD]. In such cases, the CDRs may be referred to as “Kabat CDRs” (eg, “LCDR2 Kabat” or “HCDR1 Kabat”). In some embodiments, the positions of the CDRs of a light or heavy chain variable region may be as defined by Chothia et al. (1989) Nature 342:877 to 883 . Accordingly, these regions may be termed "Chothia CDRs" (e.g., "LCDR2 Chothia" or "HCDR3 Chothia"). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions may be as defined by a combined Kabat-Chothia definition. In such embodiments, these regions may be termed “combined Kabat-Chothia CDRs”. Thomas et al. [(1996) Mol Immunol 33(17/18):1389 to 1401] exemplifies the identification of CDR boundaries according to definitions by Kabat and Chothia.
[0113] [0113] In another embodiment, the antibody comprises VH and VL regions that have the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises a heavy chain constant region as set forth in SEQ ID NO:13. In another embodiment, the antibody comprises a heavy chain polypeptide as set forth in SEQ ID NO:14 and a light chain polypeptide as set forth in SEQ ID NO:11. In another embodiment, the antibody comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues that correspond to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering.
[0114] [0114] In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as set out in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set out in SEQ ID NOs : 4, 5 and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions in residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering.
[0115] [0115] In other embodiments, an anti-C5 antibody described herein comprises a CDR1 heavy chain comprising, or consisting of, the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO:19). In another embodiment, an anti-C5 antibody described herein comprises a CDR2 heavy chain comprising, or consisting of, the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO:18).
[0116] [0116] In another embodiment, the antibody binds to human C5 at pH 7.4 and 25 °C with an affinity dissociation constant (KD) that is in the range 0.1 nM ≤ KD ≤ 1 nM. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25 °C with a KD ≥ 10 nM. In yet another embodiment, the [(KD of antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25°C)/(KD of antibody or antigen-binding fragment thereof for human C5 in pH 7.4 and at 25 °C)] of the antibody is greater than 25.
[0117] [0117] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patents 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patents 8,241,628 and 8,883,158). In another embodiment, the antibody, or antigen-binding fragment thereof, comprises the heavy chain domains CDR1, CDR2 and CDR3 having the sequences set forth in SEQ ID NOs: 21, 22 and 23, respectively, and light chain domains CDR1, CDR2 and CDR3 which have the sequences set forth in SEQ ID NOs: 24, 25 and 26, respectively; In another embodiment, the antibody, or antigen-binding fragment thereof, comprises the VH region of antibody 7086 which has the sequence set forth in SEQ ID NO: 27, and the VL region of antibody 7086 which has the sequence set forth in SEQ ID NO: 28.
[0118] [0118] Another exemplary anti-C5 antibody is the 8110 antibody also described in U.S. Patents 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises the heavy chain domains CDR1, CDR2, and CDR3 that have the sequences set out in SEQ ID NOs: 29, 30 and 31, respectively, and CDR1, CDR2 and CDR3 light chain domains having the sequences set out in SEQ ID NOs: 32, 33 and 34, respectively; In another embodiment, the antibody comprises the VH region of the 8110 antibody which has the sequence set forth in SEQ ID NO: 35,
[0119] [0119] Another exemplary anti-C5 antibody is the 305LO5 antibody described in US2016/0176954A1. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises heavy chain domains CDR1, CDR2 and CDR3 having the sequences set forth in SEQ ID NOs: 37, 38 and 39, respectively, and light chain domains CDR1, CDR2 and CDR3 having the sequences set forth in SEQ ID NOs: 40, 41 and 42, respectively; In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence set out in SEQ ID NO: 43, and the VL region of the 305LO5 antibody having the sequence set out in SEQ ID NO: 44.
[0120] [0120] Another exemplary anti-C5 antibody is the SKY59 antibody described in Fukuzawa T., et al., Rep. Apr 24, 2017; 7(1):1080). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.
[0121] [0121] Another exemplary anti-C5 antibody is antibody REGN3918 (also known as H4H12166PP) described in US20170355757. In one embodiment, the antibody comprises a heavy chain variable region comprising SEQ ID NO:47 and a light chain variable region comprising SEQ ID NO:48. In another embodiment, the antibody comprises a heavy chain comprising SEQ ID NO:49 and a light chain comprising SEQ ID NO:50.
[0122] [0122] In another embodiment, the antibody competes for binding with, and/or binds to the same epitope on C5 as, the antibodies mentioned above (e.g., eculizumab, ravulizumab, antibody 7086, antibody 8110, antibody 305LO5, antibody SKY59 or antibody REGN3918). In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity to the antibodies mentioned above (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% variable region identity).
[0123] [0123] An anti-C5 antibody described herein may, in some embodiments, comprise a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with greater affinity than that of the native human Fc constant region from which the variant human Fc constant region was derived. For example, the Fc constant region may comprise one or more (e.g., two, three, four, five, six, seven or eight or more) amino acid substitutions relative to the native human Fc constant region of which the human Fc constant region variant was derived. Substitutions can increase the binding affinity of an IgG antibody containing the variant Fc constant region to FcRn at pH 6.0, while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining pH dependence of the interaction) are known in the art and exemplified in the Examples of work. See, for example, PCT/US2015/019225 and U.S. Patent 9,079,949, the disclosures of which are incorporated in their entirety herein by reference.
[0124] [0124] Substitutions that enhance the binding affinity of an antibody Fc constant region to FcRn are known in the art and include, for example, (1) the M252Y/S254T/T256E triple substitution described by Dall'Acqua et al. (2006) J Biol Chem 281: 23514 to 23524; (2) the M428L or T250Q/M428L substitutions described in Hinton et al. (2004) J Biol Chem 279:6213 to 6216 and Hinton et al. (2006) J Immunol 176:346 to 356; and (3) the N434A or T307/E380A/N434A substitutions described in Petkova et al. (2006) Int Immunol 18(12):1759 to 69 . Additional substitution pairs: P257I/Q311I, P257I/N434H and D376V/N434H are described in, for example, Datta-Mannan et al. (2007) J Biol Chem 282(3):1709 to 1717, the disclosure of which is incorporated in its entirety herein by reference.
[0125] [0125] In some embodiments, the variant constant region has a substitution at the amino acid residue of EU 255 for valine. In some embodiments, the variant constant region has a substitution at the amino acid residue of EU 309 for asparagine. In some embodiments, the variant constant region has a substitution at the amino acid residue of EU 312 for isoleucine. In some embodiments, the variant constant region has a substitution at the amino acid residue of EU 386.
[0126] [0126] In some embodiments, the variant Fc constant region comprises no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, nine, eight, seven, six, five, four, three or two) amino acid substitutions, insertions or deletions with respect to the native constant region from which the itself was derived. In some embodiments, the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of: M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V308F. In some embodiments, the variant human Fc constant region comprises a methionine at position 428 and an asparagine at position 434, each in EU numbering. In some embodiments, the variant Fc constant region comprises a 428L/434S double substitution as described, for example, in U.S. Patent 8,088,376.
[0127] [0127] In some embodiments the precise location of these mutations may be shifted from the native human Fc constant region position due to antibody manipulation. For example, the double substitution 428L/434S when used in a chimeric IgG2/4 Fc can correspond to 429L and 435S as in the M429L and N435S variants found in BNJ441 (ravulizumab) and described in U.S. Patent.
[0128] [0128] In some embodiments, the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, 384, 385, 386, 387, 389, 424, 428, 433, 434 or 436 (EU numbering) relative to native human Fc constant region.
[0129] [0129] Anti-C5 antibodies suitable for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:14 and/or a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:11. Alternatively, anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 20 and/or a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:11.
[0130] [0130] In one embodiment, the antibody binds to C5 at pH 7.4 and 25 °C (and otherwise under physiological conditions) with an affinity dissociation constant (KD) that is at least 0.1 (for example, at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95 or 0.975) nM. In some embodiments, the K D of the anti-C5 antibody, or antigen-binding fragment thereof, is not greater than 1 (e.g., not greater than 0.9, 0.8, 0.7, 0.6 , 0.5, 0.4, 0.3 or 0.2) nM.
[0131] [0131] In other embodiments, the [(C5 antibody K D at pH 6.0 at C)/(C5 antibody K D at pH 7.4 at 25 °C)] is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110 , 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700 , 800, 900, 1000, 1500, 2000,
[0132] [0132] Methods for determining whether an antibody binds to a protein antigen and/or the affinity of an antibody to a protein antigen are known in the art. For example, binding of an antibody to a protein antigen can be detected and/or quantified using various techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) method (for example, for example, BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme-linked immunosorbent assay (ELISA). See, for example, Benny K.C. Lo (2004) "Antibody Engineering: Methods and Protocols," Humana Press (ISBN: 1588290921); Johne et al. (1993) J Immunol Meth 160:191 to 198; Jonsson et al. (1993) Ann Biol Clin 51:19 to 26; and Jonsson et al. (1991) Biotechniques 11:620 a
[0133] [0133] As used herein, the term "ka" refers to the constant rate for association of an antibody with an antigen. The term "k d" refers to the constant rate for dissociation of an antibody from the antibody/antigen complex. The term “KD” refers to the equilibrium dissociation constant of an antibody-antigen interaction. The equilibrium dissociation constant is deduced from the ratio of the kinetic rate constants, KD = ka/kd. Such determinations are preferably measured at 25 °C or 37 °C (see working examples). For example, the kinetics of antibody binding to human C5 can be determined at pH 8.0, 7.4, 7.0, 6.5 and 6.0 using surface plasmon resonance (SPR) on a BIAcore instrument. 3000 using an anti-Fc capture method to immobilize the antibody.
[0134] [0134] In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, blocks the generation or activity of the active C5a and/or C5b fragments of a C5 protein (eg, a human C5 protein). Through this blocking effect, antibodies inhibit, for example, the pro-inflammatory effects of C5a and the generation of the membrane attack complex (MAC) C5b-9 on the surface of a cell.
[0135] [0135] Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of the human C5 complement component can reduce the ability of complement cell lysis in an individual's body fluids. Such reductions in the cell lysis capacity of complement present in the body fluid (or body fluids)
[0136] [0136] Immunological techniques such as, but not limited to, ELISA can be used to measure the concentration of C5 protein and/or its divided products to determine the ability of an anti-C5 antibody, or antigen-binding fragment thereof. , to inhibit the conversion of C5 into biological products. In some embodiments, C5a generation is measured. In some embodiments, antibodies specific for the C5b-9 neoepitope are used to detect terminal complement formation.
[0137] [0137] Hemolytic assays can be used to determine the inhibitory activity of an anti-C5 antibody, or antigen-binding fragment thereof, on complement activation. In order to determine the effect of an anti-C5 antibody, or antigen-binding fragment thereof, on hemolysis mediated by the classical complement pathway in an in vitro serum test solution, e.g., hemolysin-coated sheep erythrocytes or Chicken erythrocytes sensitized with old-line erythrocyte antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis equal to the lysis that occurs in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, for example as used in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, test serum is incubated with an anti-C5 antibody, or antigen-binding fragment thereof, in the presence of a human IgM antibody. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the absorbance at the appropriate wavelength. As a control, test serum is incubated in the absence of anti-C5 antibody, or antigen-binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with a C5 polypeptide.
[0138] [0138] To determine the effect of an anti-C5 antibody, or antigen-binding fragment thereof, on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes can be used as the target cells. In some embodiments, the serum test solution is a C5-deficient serum reconstituted with a C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis equal to the lysis that occurs in the absence of the inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, for example as used in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, test serum is incubated with an anti-C5 antibody, or antigen-binding fragment thereof, in the presence of lipopolysaccharide. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring fluorescence at the appropriate wavelength. As a control, test serum is incubated in the absence of anti-C5 antibody, or antigen-binding fragment thereof.
[0139] [0139] In some embodiments, C5 activity, or inhibition thereof, is quantified using a CH50eq assay. The CH50eq assay is a method for measuring classic serum total complement activity. This test is a lytic assay, which uses erythrocytes sensitized to antibodies such as the classical complement pathway activator and various dilutions of test serum to determine the amount required to achieve 50% lysis (CH50). The percentage of hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measurement of terminal complement complex (TCC) formation, as the TCCs themselves are directly responsible for the hemolysis that is measured.
[0140] [0140] The assay is well known and commonly practiced by those skilled in the art. Briefly, to activate the classical complement pathway, undiluted serum sample (eg, reconstituted human serum sample) is added to microassay wells containing the antibody-sensitized erythrocytes to thereby generate TCC. Then, the activated sera are diluted into microassay wells, which are coated with a capture reagent (eg, an antibody that binds to one or more TCC components). TCC present in activated samples binds to monoclonal antibodies that coat the surface of microassay wells. The wells are washed and a detection reagent is added to each well that is detectably labeled and recognizes bound TCC. The detectable label can be, for example, a fluorescent label or an enzyme label. Assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq/ml).
[0141] [0141] Inhibition, e.g. with respect to terminal complement activity, includes at least a decrease of 5 (e.g. at least one 6, 7, 8, 9, 10, 15, 20, 25, 30 , 35, 40, 45, 50, 55 or 60)% in terminal complement activity in, for example, a hemolytic assay or CH50eq assay compared to the effect of an antibody control (or antigen-binding fragment thereof) on similar conditions and at an equimolar concentration. Substantial inhibition, as used herein, refers to inhibition of a given activity (e.g., terminal complement activity) by at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 or greater)%. In some embodiments, an anti-C5 antibody described herein contains one or more amino acid substitutions relative to the eculizumab CDRs (i.e., SEQ ID Nos: 1 to 6), yet retains at least 30 (e.g., at least 31, 32,
[0142] [0142] An anti-C5 antibody described herein has a serum half-life in humans that is at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29 , 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55) days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is at least 40 days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is approximately 43 days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is between 39 to 48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, an anti-C5 antibody, or antigen-binding fragment thereof, described herein has a serum half-life that is at least 20 (e.g., at least 30, 35, 40, 45, 50 , 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, 500)% greater than the serum half-life of eculizumab, for for example, as measured in one of the mouse model systems described in the working examples (eg, the C5/NOD/scid-deficient mouse model system or the hFcRn transgenic mouse).
[0143] [0143] In one embodiment, the antibody competes for binding with, and/or binds to the same epitope on C5 as the antibodies described herein. The term "binds to the same epitope" with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether antibodies bind to the "same epitope at C5" with the antibodies described herein include, for example, epitope mapping methods such as X-ray analysis of antigen:antibody complex crystals that provide resolution. epitope of the hydrogen/deuterium exchange mass spectrometry (HDX-
[0144] [0144] Antibodies that "compete with another antibody for binding to a target" refers to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, that is, whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition experiments. In certain embodiments, an antibody competes with, and inhibits the binding of, another antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100 %. The level of inhibition or competition may be different depending on which antibody is the “blocking antibody” (ie, the cold antibody that is incubated with the target first). Competing antibodies bind to the same epitope, an overlapping epitope, or epitopes (adjacent, for example, as evidenced by steric hindrance).
[0145] [0145] Anti-C5 antibodies, or antigen-binding fragments thereof described herein, used in the methods described herein can be generated using various art-recognized techniques. Monoclonal antibodies can be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell (see, Kohler & Milstein, Eur. J. Immunol. 6, 511 to 519 (1976)). Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods well known in the art. Colonies arising from single immortalized cells are selected for production of antibodies of the desired antigen specificity and affinity, and the specificity of monoclonal antibodies produced by such cells can be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding a monoclonal antibody or a binding fragment thereof can be isolated by screening a human B cell DNA library according to the general protocol described by Huse, et al., Science 246: 1275 a. 1281 (1989). II. COMPOSITIONS
[0146] [0146] In addition, compositions comprising an anti-C5 antibody, or antigen-binding fragment thereof, are provided herein. In one embodiment, the composition comprises an anti-C5 antibody comprising the CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO:12, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:8. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the known sequences in SEQ ID NOs:14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the known sequences in SEQ ID NOs: 20 and 11, respectively.
[0147] [0147] The compositions can be formulated as a pharmaceutical solution, for example, for administration to a subject for the treatment or prevention of a complement-associated disorder, such as PNH or aHUS. Pharmaceutical compositions will generally include a pharmaceutically acceptable carrier. As used herein, a "pharmaceutically acceptable carrier" refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The compositions may include a pharmaceutically acceptable salt, for example an acid addition salt or a base addition salt, sugars, carbohydrates, polyols and/or tonicity modifiers.
[0148] [0148] The compositions may be formulated according to standard methods. Pharmaceutical formulation is a well-established technique and is further described in, for example, Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) "Pharmaceutical Dosage Forms and Drug Delivery Systems," 7th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) "Handbook of Pharmaceutical Excipients American Pharmaceutical Association," 3rd Edition (ISBN: 091733096X). In some embodiments, a composition may be formulated, for example, as a buffered solution at a suitable concentration and suitable for storage at 2 to 8°C (eg, 4°C). In some embodiments, a composition may be formulated for storage at a temperature below 0°C (eg, -20°C or -80°C). In some embodiments, the composition may be formulated for storage for up to 2 years (e.g., one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 11 months). months, 1 year, 1½ year or 2 years) at 2 to 8 °C (eg 4 °C). Thus, in some embodiments, the compositions described herein are shelf-stable for at least 1 year at 2 to 8°C (eg, 4°C).
[0149] [0149] Pharmaceutical compositions can be in various forms. Such forms include, for example, liquid, semi-solid, and solid dose administration forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. For example, compositions containing a composition intended for systemic or local delivery may be in the form of injectable or infusible solutions. Accordingly, the compositions may be formulated for administration in a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). "Parenteral administration", "parenterally administered" and other grammatically equivalent phrases, as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal injection or infusion. , intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrasternal .
[0150] [0150] In one embodiment, the composition comprises ALXN1210 (also known as Ultomiris™, BNJ441 antibody, or ravulizumab) for injection. In one embodiment, the injection is a sterile, clear to translucent, slightly off-white, preservative-free solution for intravenous use. In another embodiment, each single dose vial contains 300 mg of ALXN1210 for injection at a concentration of 10 mg/ml with a pH of 7.0. In another embodiment, ALXN1210 for injection requires dilution to a final concentration of 5 mg/ml. In another embodiment, each ml additionally comprises polysorbate 80 (0.2 mg) (vegetable source), sodium chloride (8.77 mg), dibasic sodium phosphate (1.78 mg), monobasic sodium phosphate (0.46 mg), and Water for Injection. III. TREATMENT METHODS
[0151] [0151] Provided herein are methods for treating PNH or aHUS in a human patient, which comprise administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or fragment antigen binding thereof, is administered (or is for administration) according to a particular clinical dose administration regimen (i.e., in a particular dose amount and according to a specific dose administration schedule).
[0152] [0152] As used herein, the terms "induction" and "induction phase" are used interchangeably and refer to the first phase of treatment in the clinical trial.
[0153] [0153] As used herein, the terms “maintenance” and “maintenance phase” are used interchangeably and refer to the second phase of treatment in the clinical trial. In certain modalities, treatment is continued as long as clinical benefit is observed or until uncontrollable toxicity or disease progression occurs.
[0154] [0154] As used herein, the term "subject" or "patient" is a human patient (eg, a patient who has a complement-associated condition such as PNH or aHUS).
[0155] [0155] In one embodiment, the complement-associated condition is paroxysmal nocturnal hemoglobinuria (PNH). PNH is an acquired hemolytic disorder that occurs most frequently in adults (Brodsky RA., Blood. 2015;126:2459 to 65). The disease begins with the clonal expansion of a hematopoietic stem cell that has acquired a somatic mutation in the PIGA gene (Brodsky RA., Blood. 2014;124:2804 a 1). Consequently, PNH blood cells lack the glycophosphatidylinositol (GPI) anchor protein and are deficient in the membrane-bound complement inhibitor proteins CD55 and CD59. In the absence of CD55, there is increased deposition of C3 complement protein cleavage products on blood cell membrane surfaces, which in turn lead to the cleavage of C5 into C5a and C5b. The pathology and clinical presentations in PNH patients are triggered by uncontrolled terminal complement activation.
[0156] [0156] C5a is a potent anaphylatoxin, chemotactic factor, and cell-activating molecule that mediates multiple pro-inflammatory and prothrombotic activities (Matis LA, et al., Nat. Med. 1995;1:839 to 42; Prodinger et al. al., Complement. In: Paul WE, editor. Fundamental immunology (4th edition). Philadelphia: Lippincott-Raven Editors; 1999. pp. 967-95). C5b recruits the terminal complement components C6, C7, C8, and C9 to form the pro-inflammatory and prothrombotic cytolytic pore molecule C5b-9, a process that under normal circumstances would be blocked in the erythrocyte membrane (RBC) by CD59. . In PNH patients, however, these final steps proceed unchecked, culminating in hemolysis and the release of free hemoglobin, as well as platelet activation (Hill, et al., Blood 2013; 121:4985 to 96). The signs and symptoms of PNH can be attributed to the chronic, uncontrolled cleavage of C5 from complement and release of C5a and C5b-9 that leads to RBC hemolysis, which together result in (Hill, et al., Blood 2013; 121:4985 -96;
[0157] [0157] In another embodiment, the complement-associated condition is atypical hemolytic uremic syndrome (aHUS). The pathology and clinical presentations of patients with aHUS are also triggered by terminal complement activation. More specifically, C5 activation and dysregulation of complement activation lead to endothelial damage, platelet consumption, and thrombotic microangiopathic events (TMA), characterized by thrombocytopenia, mechanical intravascular hemolysis, and kidney injury. Importantly, approximately 20% of patients also experience extrarenal manifestations of the disease, including central nervous system, cardiac, gastrointestinal, distal extremities, and severe systemic organ involvement (Loirat, et al., Orphanet. J. Rare Dis. 2011;6 :60). Symptoms of aHUS are well known to those skilled in the art of medicine in rare disease or kidney disease and include, for example, severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function (eg. example, acute renal failure).
[0158] [0158] aHUS can be genetic, acquired, or idiopathic. aHUS can be considered genetic when two or more (e.g., three, four, five, or six or more) members of the same family are affected by the disease at least six months apart and exposure to a common triggering agent has been excluded, or when one or more aHUS-associated gene mutations (eg, one or more mutations in CFH, MCP/CD46, CFB, or CFI) are identified in an individual. For example, an individual may have CFH-associated aHUS, CFB-associated aHUS, CFI-associated aHUS, or MCP-associated aHUS. Up to 30% of genetic aHUS is associated with CFH mutations, 12% with MCP mutations, 5 to 10% with CFI mutations, and less than 2% with CFB mutations. Genetic aHUS can be multiplex (ie, familial; two or more family members affected) or simplex (ie, a single occurrence in a family). aHUS can be considered acquired when an underlying environmental factor (eg, a drug, systemic disease, or viral or bacterial agents that do not result in Shiga-like exotoxins) or trigger can be identified. aHUS can be considered idiopathic when there is no obvious trigger (genetic or environmental).
[0159] [0159] Laboratory tests may be performed to determine whether a human subject has thrombocytopenia, microangiopathic hemolytic anemia, or acute renal failure. Thrombocytopenia may be diagnosed by a medical professional as one or more of: (i) a platelet count that is less than
[0160] [0160] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, for example, amelioration of at least one symptom of a disease or disorder. A beneficial effect may take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy in accordance with the method. In the context of PNH, for example, effective treatment may refer to the relief of one or more symptoms selected from the group consisting of fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and/or erectile dysfunction. In the context of aHUS, for example, effective treatment may refer to the relief of one or more symptoms selected from the group consisting of severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and/or impairment of function. renal function (eg, acute renal failure).
[0161] [0161] The term "effective amount" refers to an amount of an agent that provides the desired biological, therapeutic and/or prophylactic result. That result may be reduction, improvement, palliation, lessening, delaying, and/or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In one example, an "effective amount" is the amount of anti-C5 antibody, or antigen-binding fragment thereof, clinically proven to alleviate at least one PNH symptom (e.g., fatigue, abdominal pain, dyspnea, dysphagia, chest pain, or erectile dysfunction) or at least one symptom of aHUS (eg, severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function (eg, acute renal failure) )). An effective amount can be administered in one or more administrations.
[0162] [0162] In one embodiment, the dose of the anti-C5 antibody, or antigen-binding fragment thereof, is based on the weight of the patient. For example, in one embodiment, 2400 mg or 3000 mg of the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 to < 60 kg. In another embodiment, 2700 mg or 3300 mg of the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 60 to < 100 kg. In another embodiment, 3000 mg or 3600 mg of the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 100 kg. In certain embodiments, dose administration regimens are adjusted to provide the optimal desired response (eg, an effective response).
[0163] [0163] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered for one or more cycles of administration. In one embodiment, the administration cycle is 26 weeks. In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered once on Day 1 of the administration cycle, once on Day 15 of the administration cycle, and every eight weeks thereafter. In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered every eight weeks following the administration cycle for an extension period of up to two years (e.g., at a dose of 3000 mg, 3300mg or 3600mg).
[0164] [0164] In another embodiment, there is provided a method of treating a human patient with PNH or aHUS, the method comprising administering to the patient during one cycle of administration an effective amount of an anti-C5 antibody, or anti-C5 antibody-binding fragment. antigen thereof, comprising heavy chain sequences CDR1, CDR2 and CDR3 as set out in SEQ ID NOs: 19, 18 and 3, respectively, and light chain sequences CDR1, CDR2 and CDR3 as set out in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered: (a) once on Day 1 of the administration cycle at a dose of: 2400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg, or 3000 mg for a patient weighing ≥ 100 kg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing ≥ 40 to < 60 kg,
[0165] [0165] In another embodiment, there is provided a method of treating a human patient with PNH or aHUS, the method comprising administering to the patient during one cycle of administration an effective amount of an anti-C5 antibody, or DNA-binding fragment. antigen thereof, comprising heavy chain sequences CDR1, CDR2 and CDR3 as set out in SEQ ID NOs: 19, 18 and 3, respectively, light chain sequences CDR1, CDR2 and CDR3 as set out in SEQ ID NOs: 4, 5 and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues that correspond to the methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered: (a) once on Day 1 of the administration cycle at a dose of: 2,400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg, or 3000 mg for a patient weighing ≥ 100 kg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing ≥ 40 to < 60 kg,
[0166] [0166] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 to < 60 kg: (a) once on Day 1 of the administration cycle in a 2400 mg dose; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg.
[0167] [0167] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 60 to < 100 kg: (a) once on Day 1 of the administration cycle in a 2700 mg dose; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3300 mg.
[0168] [0168] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 100 kg: (a) once on Day 1 of the administration cycle at a dose of 3,000 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3600 mg.
[0169] [0169] In some modalities, the patient has not been previously treated with a complement inhibitor (eg, the patient is a patient who has never received treatment with a complement inhibitor).
[0170] [0170] In other embodiments, the patient has been previously treated with an anti-C5 antibody, or antigen-binding fragment thereof, and is switched to another anti-C5 antibody during the course of treatment. For example, in certain embodiments, different anti-C5 antibodies are administered during the course of treatment. In one embodiment, different anti-C5 antibodies are administered during separate treatment and extension periods. For example, in one embodiment, the patient is treated with eculizumab for a period of treatment (eg, for 26 weeks), followed by treatment with another anti-C5 antibody (eg, ravulizumab, antibody 7086, antibody 8110, antibody 305LO5 ,
[0171] [0171] Exemplary alternative anti-C5 antibodies include, but are not limited to, (i) ALXN1210, (ii) an antibody, or antigen-binding fragment thereof, comprising the heavy chain domains CDR1, CDR2, and CDR3 that comprise SEQ ID NOs: 21, 22 and 23, respectively, and light chain domains CDR1, CDR2 and CDR3 which comprise SEQ ID NOs: 24, 25 and 26, respectively, (iii) an antibody, or DNA-binding fragment antigen thereof, comprising a heavy chain variable region comprising SEQ ID NO: 27 and a light chain variable region comprising SEQ ID NO: 28, (iv) an antibody, or antigen-binding fragment thereof , which comprises the heavy chain domains CDR1, CDR2 and CDR3 which comprise SEQ ID NOs: 29, 30 and 31, respectively, and light chain domains CDR1, CDR2 and CDR3 which comprise SEQ ID NOs: 32, 33 and 34 , respectively, (v) an antibody, or antigen-binding fragment thereof, which comprises a variable region chain comprising SEQ ID NO: 35 and a light chain variable region comprising SEQ ID NO: (vi) an antibody, or antigen-binding fragment thereof, comprising the heavy chain domains CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 37, 38 and 39, respectively, and light chain domains CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 40, 41 and 42, respectively, (vii) an antibody, or fragment binding to the same antigen,
[0172] [0172] In some modalities, the patient has been pretreated for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months with an anti-C5 antibody, or antigen-binding fragment thereof, ( e.g. eculizumab) before switching to another anti-C5 antibody, or antigen-binding fragment thereof (eg, ravulizumab). In one particular modality, the patient was pretreated for at least 6 months with eculizumab.
[0173] [0173] In another embodiment, where a patient (e.g. PNH or aHUS patient) is treated with a first anti-C5 antibody and then switched to treatment with a different second anti-C5 antibody, especially where the second different anti-C5 antibody binds to a different epitope on C5 than the first anti-C5 antibody, administration schedules take into account the half-life of the first anti-C5 antibody. For example, to ensure that the first anti-C5 antibody is extracted (e.g., “cleared”) from the patient before the second (different) anti-C5 antibody is administered (e.g., to avoid issues associated with aggregation, formation of immune complex, etc.), the half-life of the first anti-C5 antibody is taken into account. In one embodiment, the second (different) anti-C5 antibody is not administered until a duration of time corresponding to 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, or 7.5 times the half-life of the first anti-C5 antibody has passed after the final administration of the first anti-C5 antibody.
[0174] [0174] In another embodiment, the patient was pretreated with eculizumab and then switched to treatment with a second (different) anti-C5 antibody (e.g., ravulizumab, antibody 7086, antibody 8110, antibody 305LO5, SKY59 antibody, or antibody REGN3918). In an embodiment where eculizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, for example, until at least 36, 45, 54, 63, 72, 81, 90, 99, 108, 117 or 126 days have passed after the final administration of eculizumab.
[0175] [0175] In another embodiment, the patient was pretreated with ravulizumab and then switched to treatment with a different anti-C5 antibody (e.g. eculizumab, antibody 7086, antibody 8110, antibody 305LO5, antibody SKY59, or antibody REGN3918) . In an embodiment where ravulizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, for example, until at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325 , 375 or 400 days have elapsed after the final administration of ravulizumab.
[0176] [0176] Additionally or alternatively, techniques are used to extract or enhance the extraction of the first anti-C5 antibody before switching to treatment with a second (different) anti-C5 antibody. Exemplary techniques include, but are not limited to, plasma exchange or blood transfusions. In another embodiment, an antibody against the first anti-C5 antibody is administered to extract or enhance the extraction of the first anti-C5 antibody (e.g., an anti-eculizumab antibody, an anti-ravulizumab antibody, an anti-7086 antibody, a anti-8110 antibody, an anti-305LO5 antibody, an anti-SKY59 antibody, or an anti-REGN3918 antibody) before a second (different) anti-C5 antibody is administered.
[0177] [0177] In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ALXN1210), is administered to a patient, wherein the administration cycle begins at least about two weeks, at least about three weeks, at least about four weeks, at least about six weeks, at least about seven weeks, or at least about eight weeks after the patient's last dose of eculizumab. In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ALXN1210), is administered to a patient, wherein the administration cycle begins at least two weeks after the patient's last dose of eculizumab. .
[0178] [0178] In some embodiments, patients treated according to the methods described herein were vaccinated against meningococcal infections within 3 years before or at the time of initiating treatment. In one embodiment, patients who received treatment less than 2 weeks after receiving a meningococcal vaccine are also treated with appropriate prophylactic antibiotics for up to 2 weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135 and/or B.
[0179] [0179] As used herein, the term “minimum serum level” refers to the lowest level at which the agent (e.g., anti-C5 antibody, or antigen-binding fragment thereof,) or drug is present. in the serum. On the other hand, a “peak serum level” refers to the highest level of the agent in the serum. The “mean serum level” refers to the average serum level of the agent over time.
[0180] [0180] In one embodiment, the treatment regimens described are sufficient to maintain particular trough serum concentrations of the anti-C5 antibody, or antigen-binding fragment thereof. For example, in one embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 µg/ml or greater. In one embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 100 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 150 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 200 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 250 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 300 µg/ml or greater. In another embodiment, treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, between 100 µg/ml and 200 µg/ml. In another embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of about 175 µg/ml.
[0181] [0181] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain at least 50 μg, 55μg, 60 μg, 65 μg, 70 μg, 75 μg , 80µg, 85µg, 90µg, 95µg, 100µg, 105µg, 110µg, 115µg, 120µg, 125µg, 130µg, 135µg, 140µg, 145µg, 10µg, 145µg, 1µg μg¸ 165 μg, 170 μg¸ 175 μg, 180 μg, 185 μg, 190 μg¸ 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 240 μg 245 μg, 250 μg, 255 μg, or 260 μg antibody per milliliter of patient blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain between 50 µg and 250 µg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain between 100 µg and 200 µg of antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain about 175 µg of antibody per milliliter of the patient's blood.
[0182] [0182] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain a minimum concentration of free C5. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain a free C5 concentration of 0.2 µg/ml, 0.3 µg/ml, 0.4 µg /ml, 0.5 µg/ml or below. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain a free C5 concentration of 0.309 to 0.5 µg/ml or below. In another embodiment, the treatment described herein reduces the concentration of free C5 by more than 99% over the entire treatment period. In another modality, the treatment reduces the free C5 concentration by more than 99.5% for the entire treatment period.
[0183] [0183] In another aspect, methods are provided for treating a human patient who has a complement-associated disorder. In one embodiment, the method comprises treating a human patient who has a complement-associated disorder who is being treated with eculizumab, wherein the method comprises suspending treatment with eculizumab and switching the patient to treatment with a different complement inhibitor. In another embodiment, the method comprises treating a human patient who has a complement-associated disorder who is being treated with ravulizumab, wherein the method comprises suspending treatment with ravulizumab and switching the patient to treatment with a different complement inhibitor. In one embodiment the different complement inhibitor is selected from the group consisting of: a small molecule, a polypeptide, a polypeptide analog, a peptidomimetic, a siRNA, or an aptamer. In another embodiment, the different complement inhibitor inhibits one or more of complement components C1, C2, C3, C4, C5, C6, C7, C8, C9, Factor D, Factor B, properdin, MBL, MASP-1, MASP -2 or biologically active fragments thereof. In another embodiment, the different complement inhibitor is a different anti-C5 antibody (e.g., ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody).
[0184] [0184] Exemplary complement-associated conditions that can be treated according to the methods described herein include, but are not limited to, rheumatoid arthritis, antiphospholipid antibody syndrome, lupus nephritis, ischemia-reperfusion injury, hemolytic-uremic syndrome atypical (aHUS),
[0185] [0185] Provided herein are methods for treating PNH or aHUS in a patient which comprise administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof.
[0186] [0186] Symptoms of PNH include, but are not limited to, fatigue (e.g. tiredness, difficulty performing daily activities, difficulty concentrating, dizziness, weakness), pain (e.g. stomach pain, leg pain or swelling, chest pain, back pain), dark colored urine, shortness of breath, difficulty swallowing, yellowing of the skin and/or eyes, erectile dysfunction, blood clots, kidney disease, organ damage, stroke or heart attack. Patients treated according to the methods disclosed herein preferably experience improvement in at least one PNH sign. For example, the treatment may produce at least one therapeutic effect selected from the group consisting of a reduction or cessation of fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.
[0187] [0187] Symptoms of aHUS include, but are not limited to, severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function (eg, acute renal failure). Patients treated according to the methods disclosed herein preferably experience improvement in at least one aHUS signal. For example, the treatment may produce at least one therapeutic effect selected from the group consisting of a reduction or cessation of hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function.
[0188] [0188] In other modalities, treatment results in terminal complement inhibition.
[0189] [0189] In other modalities, treatment produces a shift toward normal levels of a hemolysis-related hematologic biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, erythrocyte PNH clone (RBC) and dimer D. In another embodiment, the treatment produces an increase in hemoglobin stabilization from the patient's pretreatment baseline.
[0190] [0190] In other modalities, treatment produces a shift toward normal levels of a biomarker associated with chronic disease selected from the group consisting of estimated glomerular filtration rate (eGFR) and spot urine albumin:creatinine and brain natriuretic peptide in plasma (BNP).
[0191] [0191] In other modalities, treatment produces a reduction in the need for blood transfusions. In another modality, treatment produces a greater than 70% increase in transfusion prevention.
[0192] [0192] In other modalities, treatment results in a reduction in sudden hemolysis relative to eculizumab treatment. In another embodiment, the treatment results in a sudden elimination of hemolysis during the treatment period. In another modality, the treatment results in a reduction in sudden hemolysis compared to the baseline amount of sudden hemolysis pretreatment.
[0193] [0193] In other modalities, treatment produces a reduction in major adverse vascular events (MAVEs).
[0194] [0194] In other modalities, the treatment produces a change from the baseline in quality of life as assessed using the Functional Assessment Fatigue Scale for Chronic Illness Therapy (FACIT), version 4 and the Quality of Life Questionnaire. Life Scale Core 30 of the European Organization for Research and Treatment of Cancer. In another modality, the treatment produces a change from the baseline in quality of life, evaluated using the Functional Assessment Fatigue Scale for Chronic Illness Therapy (FACIT), version 4 and the Quality of Life Questionnaire Core Scale 30 of the European Organization for Research and Treatment of Cancer by at least 7 points from the baseline score of untreated patients.
[0195] [0195] In another modality, the treatment does not result in a change in quality of life (QoL) as assessed using the Chronic Illness Therapy Functional Assessment Fatigue Scale (FACIT), version 4, Baseline-to-Day
[0196] [0196] In other modalities, lactate dehydrogenase (LDH) levels are used to assess responsiveness to a therapy (eg, a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels is indicative of an improvement in at least one PNH signal). LDH is a marker of intravascular hemolysis (Hill, A. et al., Br. J. Haematol., 149:414 to 25, 2010; Hillmen, P. et al., N. Engl. J. Med., 350 :552 to 9, 2004; Parker, C. et al., Blood, 106:3699 to 709, 2005 ). Erythrocytes contain large amounts of LDH, and a correlation between cell-free hemoglobin and LDH concentration has been reported in vitro (Van Lente, F. et al., Clin. Chem., 27:1453 to 5, 1981) and in vivo ( Kato, G. et al., Blood, 107:2279 to 85, 2006 ). The consequences of hemolysis are independent of anemia (Hill, A. et al., Haematologica, 93(s1):359 Abs,0903, 2008; Kanakura, Y. et al., Int. J. Hematol., 93:36 a 46, 2011). The LDH concentration obtained at baseline and then serially over an entire treatment period is an important measure of hemolysis. Baseline plasma cell-free hemoglobin levels are highly elevated in PNH patients with LDH ≥1.5 times the upper limit of normal (LDH ≥ 1.5 × ULN), with a significant correlation between LDH and hemoglobin cell-free plasma ( Hillmen, P. et al., N. Engl. J. Med., 355:1233 to 43, 2006 ). The normal LDH value range is 105 to 333 IU/l (international units per liter).
[0197] [0197] LDH levels can be measured using any suitable test or assay, such as those described by Ferri FF, ed. Ferri's Clinical Advisor
[0198] [0198] In one embodiment, the treatments described herein result in a normalization of LDH levels. In another embodiment, patients treated according to the disclosed methods experience reductions in LDH levels to levels close to normal or to within 10%, or within 20% of what is considered the normal level (e.g., within 105 to 333 IU/l (international units per liter). In another modality, the patient's LDH levels are normalized throughout the maintenance period of treatment. In another modality, the treated patient's LDH levels are normalized by at least 95% of time during the maintenance period of treatment. In another modality, the treated patient's LDH levels are normalized at least 90%, 85%, or 80% of the time during the maintenance period of treatment. In one modality, the levels of The patient's LDH is ≥ 1.5 times the upper limit of normal (LDH ≥ 1.5 X ULN) before starting treatment. In another modality, treatment results in a normalization of LDH levels by at least day 24 of treatment. In a modal In fact, patients treated according to the disclosed methods experience reductions in LDH levels to within normal levels or to within 10%, 20%, 30%, 40% or within 50% below what is considered the upper limit of normal level (for example, within 105 to 333 IU/l (international units per litre). In one embodiment, the patient's LDH levels are ≥ 1.5 times the upper limit of normal (LDH ≥ 1.5 X ULN) before starting treatment. In one modality, treatment results in LDH levels less than 2 x the upper limit of normal (ULN). V. KITS AND UNIT DOSAGE FORMS
[0199] [0199] In addition, kits are provided herein that include a pharmaceutical composition containing an anti-C5 antibody, or antigen-binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted to use in the methods described in this document. The kits optionally may also include instructions, e.g., comprising administration schedules, to allow a professional (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient who has PNH or SHUa. The kit may also include a syringe.
[0200] [0200] Optionally, the kits include multiple packs of single-dose pharmaceutical compositions, each containing an effective amount of the anti-C5 antibody, or antigen-binding fragment thereof, for a single administration in accordance with the methods provided above. Instruments or devices necessary to administer the pharmaceutical composition (or pharmaceutical compositions) may also be included in the kits. For example, a kit may provide one or more pre-filled syringes containing an amount of the anti-C5 antibody, or antigen-binding fragment thereof.
[0201] [0201] In one embodiment, the present invention provides a kit for treating PNH or aHUS in a human patient, the kit comprising: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising the heavy chain variable region domains CDR1, CDR2 and CDR3 having the sequence set out in SEQ ID NO:12, and the light chain variable region CDR1, CDR2 and CDR3 domains having the sequence set out in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in accordance with any of the methods described herein.
[0202] [0202] In one embodiment, the kit comprises a dose of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient. who weigh ≥ 40 to < 60 kg: (a) once on Day 1 of the dosing cycle at a dose of 2400 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg.
[0203] [0203] In another embodiment, the kit comprises a dose of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient who weigh ≥ 60 to < 100 kg: (a) once on Day 1 of the dosing cycle at a dose of 2700 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3300 mg.
[0204] [0204] In another embodiment, the kit comprises a dose of an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 100 kg: (a) once on Day 1 of the dosing cycle at a dose of 3000 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3600 mg.
[0205] [0205] The following examples are illustrative only and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure.
[0206] [0206] The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.
[0207] [0207] In phase 1b/2 studies, treatment with ravulizumab given at prolonged dosing intervals achieved a rapid and sustained reduction in complement-mediated hemolysis in PNH patients. These studies demonstrated drug/exposure versus response relationships, with superior minimal exposure to ravulizumab (1800-mg-q4w cohort) being associated with a greater proportion of patients reaching plasma LDH levels considered to be at low risk for hemolysis (normalization [or below] of 1.5 x ULN]), reductions in free hemoglobin, and absence of sudden hemolysis relative to all other cohorts. Based on these results and subsequent exposure response analyses, a multicenter, randomized, open-label, phase 3, active-control study was conducted to assess the safety and efficacy of ALXN1210 (ravulizumab) versus eculizumab administered by intravenous (IV) infusion for patients adults with PNH who have never received complement inhibitor treatment. In the phase 3 study herein, patients randomized to ravulizumab received a loading dose (2400 mg for patients ≥40 kg to <60 kg, 2700 mg for patients ≥60 kg to <100 kg, 3000 mg for patients ≥100 kg ) on day 1, followed by maintenance doses of ravulizumab (3000 mg for patients ≥40 kg to <60 kg,
[0208] [0208] The primary endpoint of the study was to assess the non-inferiority of ALXN1210 (ravulizumab) compared to eculizumab in adult PNH patients who had never been treated with a complement inhibitor.
[0209] [0209] Non-inferiority was claimed if after 26 weeks of treatment: 1) the lower limit of the 95% confidence interval (CI) for the difference (ALXN1210-eculizumab) in transfusion prevention rate (TA) is greater than -20%, and 2) the lower limit of the 95% CI for the odds index of ALXN1210 compared to eculizumab for lactate dehydrogenase normalization (LDH-N) is greater than 0.39.
[0210] [0210] Secondary objectives included characterizing the safety and tolerability of ALXN1210 in this patient population, evaluating the efficacy of ALXN1210 by additional efficacy measures characterizing pharmacokinetics/pharmacodynamics
[0211] [0211] The overall study design, treatments, and study durations are depicted in Figure 1. Study ALXN1210-HPN-301 is a Phase 3, open-label, randomized, active control multicenter study to evaluate the safety and efficacy of ALXN1210 versus eculizumab administered by intravenous (IV) infusion to adult patients with PNH who have never received complement inhibitor treatment. The study as designed included approximately 214 patients (107 patients per treatment group), but ultimately 246 subjects were enrolled and completed at least 183 days of treatment. Upon completion of the study, 246 subjects enrolled in the extension study and 2 subjects discontinued. The study consisted of a 4-week screening period, a 26-week randomized treatment period, and an extension period of up to 2 years. Patients were stratified into 1 of 6 groups based on their transfusion history (0.1 to 14, or > 14 units of pRBCs in 1 year before the first dose of study drug) and LDH levels (1 .5 to < 3 × ULN or ≥ 3 × ULN). Patients within each of the 6 groups were randomly assigned in a 1:1 ratio to receive either ALXN1210 or eculizumab. Enrollment of patients without a transfusion history in the past year was limited to 20%.
[0212] [0212] Prior to randomization and within 5 days prior to study drug administration on Day 1, each patient's hemoglobin was assessed by a local or central laboratory. If at that time the patient's hemoglobin value meets protocol-specified transfusion guidelines, the patient was transfused with pRBCs to a hemoglobin level above the protocol-specified transfusion threshold to be eligible for randomization. The patient's post-transfusion hemoglobin value was confirmed by the local or central laboratory to be above the transfusion threshold specified in the protocol.
[0213] [0213] Patients randomly assigned to the ALXN1210 group received a loading dose of ALXN1210 (2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, 3000 mg for patients weighing ≥ 60 to < 100 kg weigh ≥ 100 kg) on Day 1, followed by maintenance doses of ALXN1210 (3,000 mg for patients weighing ≥ 40 to < 60 kg, 3,300 mg for patients weighing ≥ 60 to < 100 kg, 3,600 mg for patients weighing ≥ 100 kg) on Day 15 and every 8 weeks (q8w) thereafter for a total of 26 weeks of treatment. Patients randomly assigned to the eculizumab group received induction treatment with 600 mg of eculizumab IV on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter. addition for a total of 26 weeks of treatment. Upon completion of all assessments on Day 183, patients entered an extension period during which patients received ALXN1210 until the product is registered or approved (in accordance with country-specific regulations) or for up to 2 years, whichever occurs. first. From Day 183, patients who were randomized to the ALXN1210 treatment group received a maintenance dose (as described above) of ALXN1210 q8w for up to two years, and patients who were randomized to the eculizumab group received a loading dose. (as described above) of ALXN1210 followed 2 weeks later and q8w thereafter by a weight based maintenance dose of ALXN1210. A pRBC transfusion was administered when a patient had a hemoglobin value of 9 g/dl or less with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of 7 g/dl or less regardless of the presence of signs. or clinical symptoms.
[0214] [0214] The co-primary efficacy endpoints of the study were (1) transfusion prevention, defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through Day 183 (Week 26) and ( 2) hemolysis as directly measured by LDH-N levels from Day 29 (first scheduled assessment situation after initiation of maintenance dose administration) through Day 183 (Week 26).
[0215] [0215] The main secondary efficacy endpoints of the study (tested in a hierarchical manner) were:
[0216] [0216] Other secondary efficacy endpoints of the study were: • Change in Quality of Life Questionnaire Core 30 Scale (QLQ-C30), Version 3.0 of the European Organization for Research and Treatment of Cancer (EORTC), from the Baseline to Day 183 (Week 26); • Time to first occurrence of LDH-N; • Total number of packed red blood cell units (pRBCs) transfused by Day 183 (Week 26); • Change in clinical manifestations of PNH (fatigue, hemoglobinuria, abdominal pain, shortness of breath, anemia, dysphagia, and erectile dysfunction) from Baseline to Day 183 (Week 26); and • Proportion of patients experiencing MAVEs by Day 183 (Week 26).
[0217] [0217] Pharmacokinetic and pharmacodynamic endpoints of the study were: change in serum concentration of ALXN1210 and eculizumab over time,
[0218] [0218] Exploratory endpoints included patient-reported PNH symptoms and healthcare resource utilization. The safety and tolerability of ALXN1210 compared to eculizumab is assessed by physical examinations, vital signs, electrocardiograms (ECGs), laboratory tests, and incidence of adverse events (AEs) and serious adverse events (SAEs). The proportion of patients who developed anti-drug antibodies (ADAs) was also assessed. TABLE 1: SCHEDULE OF CONSULTATIONS AND STUDY ASSESSMENTS:
[0219] [0219] A total of approximately 246 patients with documented PNH were enrolled and randomly assigned to treatment with ALXN1210 or eculizumab at approximately 300 investigational sites globally. Individuals who did not meet the criteria for participation in this study (screening failure) could be resubmitted to screening. Prospective approval of protocol deviations for recruitment and enrollment criteria, also known as protocol exemptions or exceptions, was not permitted.
[0220] [0220] Patients were eligible for study enrollment only if they met all of the following criteria and none of the exclusion criteria:
[0221] [0221] Patients were excluded from study enrollment if they met any of the following criteria:
[0222] [0222] A patient has the right to withdraw from the study at any time. If a patient withdraws consent, the assessments specified for the Early Termination (ET) consultation are performed. Patients who withdrew from the study were not replaced.
[0223] [0223] A patient may be suspended from study drug if it is in the patient's best interest to stop treatment. If a patient is suspended from study drug, the patient is encouraged to return for the remainder of their scheduled protocol visits until initiating a different complement-directed therapy.
[0224] [0224] If a patient is withdrawn from the study with an ongoing adverse event or an unresolved laboratory result that is significantly outside the reference range and clinically significant, the Investigator attempts to provide follow-up until a satisfactory clinical resolution of the laboratory result or event adverse event is reached.
[0225] [0225] The Sponsor or Competent Authority could terminate the study for a reasonable reason. The end of the study is defined as the date of the last visit of the last patient in the Extension Period.
[0226] [0226] Study drugs in this study were ALXN1210 (ravulizumab) and eculizumab (active control). Both ALXN1210 and eculizumab were humanized anti-C5 monoclonal antibodies.
[0227] [0227] Eculizumab is an IgG2 kappa immunoglobulin consisting of human constant regions, and murine complementarity determining regions grafted onto light and heavy chain variable regions of the human framework. To be clear, IgG2/4 is an abbreviated way of describing heavy chain elements that comprise non-naturally occurring protein engineered heavy chain heavy chains both an IgG2 and an IgG4. This unique heavy chain was first described for use in an anti-C5 antibody to eculizumab. Eculizumab is composed of two heavy chains of 448 amino acids and two light chains of 214 amino acids.
[0228] [0228] ALXN1210 was derived through minimal targeted manipulation of eculizumab by introducing 4 unique amino acid substitutions into its heavy chain to extend the half-life of the antibody. ALXN1210 and eculizumab share over 99% primary amino acid sequence identity and have very similar pharmacology.
[0229] [0229] The drug products ALXN1210 and eculizumab were supplied for clinical studies as sterile, preservative-free 10 mg/ml solutions in single-use vials and designed for dilution infusion in commercially available saline (sodium chloride injection at 0.9%; country-specific pharmacopoeia) for administration by IV infusion. Table 4, the current ALXN1210 IB, and the local marker of approved eculizumab or current eculizumab IB provide additional information. TABLE 4: Study Drug Study Drug Product Name ALXN1210 Eculizumab
[0230] [0230] ALXN1210 and eculizumab were packaged in US Pharmacopeia/European Pharmacopeia Type 1 borosilicate glass vials and stoppered with a butyl rubber stopper with an aluminum seal and a flip-off cap. Study drug is provided in kits. Study drug is released to each site upon receipt of all essential documents required based on applicable regulations.
[0231] [0231] Upon arrival of the study drug kits at the study site, the pharmacist or designee promptly removes the study drug kits from the shipping refrigerant and stores them in their original boxes under refrigerated conditions at 2°C to 8°C. °C (35 °F to 47 °F) and protected from light. ALXN1210 and eculizumab must not be frozen. Study drug is stored in a secure area with limited access, and temperature must be monitored daily.
[0232] [0232] The drug product is at room temperature before administration. The material is not heated (eg using a microwave or other heat source) beyond ambient air temperature.
[0233] [0233] Eculizumab or ALXN1210 were not given as a bolus or pulse IV injection. Study drug infusions were prepared using aseptic technique. The required patient dose of ALXN1210 or eculizumab is further diluted in commercially available saline (0.9% sodium chloride; country-specific pharmacopoeia) in the volume specified in the
[0234] [0234] Study drug doses were only prepared and dispensed by a pharmacist or a clinically qualified member of staff. Study drug is dispensed only to enrolled patients who have been confirmed eligible to participate in this study. Once study drug is prepared for a patient, it is administered only to that patient. Study drug vials were for single use only and any drug product remaining in the vial was not used for another patient. Any drug remaining in the infusion tube or infusion bag was not used for another patient.
[0235] [0235] This study involves a direct comparison of ALXN1210 versus the active control, eculizumab. Patients were randomly assigned in a 1:1 ratio to receive either ALXN1210 or eculizumab for 26 weeks. Study drug was administered as a slow IV infusion (see Table 5 and Table 6).
[0236] [0236] The dose regimen for ALXN1210 was a loading dose on Day 1 followed by maintenance doses on Day 15 and q8w thereafter. Dosing of ALXN1210 was based on the patient's body weight at the time of dose administration, as indicated in Table 7. TABLE 7: Weight Based Dosages of ALXN1210 Body Weight of the Loading Dose Group Maintenance Dose Treatment ALXN1210 ≥ 40 to < 60 kg 2,400 mg 3,000 mg ≥ 60 to < 100 kg 2,700 mg 3,300 mg ≥ 100 kg 3,000 mg 3,600 mg
[0237] [0237] Patients randomly assigned to the eculizumab group received eculizumab according to the approved dose administration regimen for the PNH indication, which is 4 weekly induction doses followed by q2w maintenance doses starting at Week 5 (Table 8). TABLE 8: Eculizumab Dosages Induction Dose Treatment Group Maintenance Dose Eculizumab All Patients 600 mg 900 mg
[0238] [0238] After the randomized treatment period, all patients entered the Extension Period and received ALXN1210 until the product is registered or approved (in accordance with country-specific regulations) or for up to 2 years, whichever comes first. From Day 183, patients who were randomized to the ALXN1210 treatment group received their weight-based maintenance dose of ALXN1210 q8w, and patients who were randomized to the eculizumab group received a weight-based loading dose of ALXN1210 followed 2 weeks later and q8w thereafter by a weight-based maintenance dose of ALXN1210 (Table 7).
[0239] [0239] The actual time of all dose administrations was recorded in the patient's eCRF.
[0240] [0240] Patients meeting all criteria for enrollment were randomly assigned to study treatment with ALXN1210 or eculizumab at the Baseline Visit (Day 1). Treatment group assignment was determined by a computer-generated random sequence using an interactive web or voice response system (IxRS). Randomization was a stratified randomization. Patients were stratified into 1 of 6 groups based on their transfusion history (0, 1 to 14, or > 14 units of pRBCs in 1 year before the first dose of study drug) and lactate dehydrogenase (LDH) levels were screened. ) (1.5 to < 3 × ULN or ≥ 3 × ULN). Patients within each of the 6 groups were then randomly assigned in a 1:1 ratio to receive either ALXN1210 or eculizumab during the 26-week randomized treatment period.
[0241] [0241] The weight-based dosages of ALXN1210 in this study (Table 7) were premised on PK/PD data from early developmental studies in healthy adult volunteers, as well as available data from PNH patients in a Phase 1b sequence determination study sequence (ALXN1210-HPN-103) and a Phase 2 proof-of-concept study sequence (ALXN1210-HPN-201). The selection of ALXN1210 dose regimen is based on achieving immediate, complete and sustained inhibition of terminal complement in PNH patients.
[0242] [0242] The eculizumab dosage is the marked dose for the treatment of PNH patients (Soliris® USPI and SmPC).
[0243] [0243] Infusion of other monoclonal antibodies has been associated with infusion reactions, typically appearing during or shortly after completion of the infusion. Past medications (including vitamins and herbal preparations)—including those discussed in the exclusion criteria and procedures (any therapeutic intervention, such as surgery/biopsy or physical therapy) that the patient takes or performs within 28 days (or 3 years for documentation of meningococcal vaccination) prior to initiation of Triage through to the first dose of study drug—were recorded in the patient's eCRF.
[0244] [0244] Transfusions of pRBCs received within 1 year prior to the first administration of study drug were recorded in the patient's eCRF.
[0245] [0245] All drug use and procedures performed during the study are recorded in the patient's source document/medical record and in the eCRF. This registry includes all prescription drugs, herbal products, vitamins, minerals, over-the-counter medications, and current PNH medications. Concomitant medications were recorded from the patient's first infusion of study drug to 56 days after the patient's last dose of study drug. Any changes to concomitant medications were also recorded in the patient's source document/medical record and eCRF. Any concomitant medication deemed necessary for the patient's standard of care during the study, or for the treatment of any AE, along with the permitted medications described below, is provided at the discretion of the Investigator. However, it is the responsibility of the Investigator to ensure that details regarding all medications are fully recorded in the source document/patient's medical record and eCRF.
[0246] [0246] The following concomitant medications were permitted if the following conditions apply, and dose adjustments were not expected during the randomized treatment period: • Erythropoietin, if the patient had been receiving a stable dose for at least 8 weeks prior to Screening. • Immunosuppressants, if the patient had been receiving a stable dose for at least 8 weeks prior to Screening.
[0247] [0247] If considered in the best interest of the patient, the frequency or dose level of any of the above medications could be adjusted.
[0248] [0248] Due to its mechanism of action, the use of eculizumab or ALXN1210 increases the patient's susceptibility to meningococcal infection (N. meningitidis). To reduce the risk of meningococcal infection, all patients were vaccinated against meningococcal infections within 3 years before or at the time of initiating study drug use. Patients who started treatment with study drug less than 2 weeks after receiving a meningococcal vaccine received treatment with appropriate prophylactic antibiotics for up to 2 weeks after vaccination. Vaccines against serotypes A, C, Y, W135 and B, when available, have been recommended to prevent common pathogenic meningococcal serotypes. Patients were vaccinated or revaccinated according to current national vaccination guidelines or local practice for use of complement inhibitor vaccination (eg, eculizumab).
[0249] [0249] Vaccination may not be sufficient to prevent meningococcal infection. Consideration was given to official guidance and local practice on the proper use of antibacterial agents. All patients were monitored for early signs of meningococcal infection, evaluated immediately if infection was suspected, and treated with appropriate antibiotics if necessary.
[0250] [0250] A pRBC transfusion was administered when a patient had a hemoglobin value of 9 g/dl or less with signs or symptoms of sufficient severity to warrant a transfusion, a hemoglobin value of 7 g/dl or less regardless of presence of clinical signs or symptoms.
[0251] [0251] Signs or symptoms typically associated with or precipitating the patient's need for transfusion were documented in the eCRF for each individual patient. Typical anemia-related symptoms warranting transfusions included angina, change in mental status (eg, syncope, mild dizziness, confusion, stroke, transient ischemic attack), severe or worsening shortness of breath, and severe or worsening fatigue.
[0252] [0252] If a patient met any transfusion criteria during the study, the Investigator determined the appropriate number of units of pRBCs to be transfused. It was recommended that the transfusion be performed within 48 hours of determining the hemoglobin responsible for the transfusion. The administration of a transfusion, including the hemoglobin result and symptoms that triggered the transfusion, and the number of units transfused, were documented in the eCRF.
[0253] [0253] Prior to randomization and within 5 days prior to study drug administration on Day 1, each patient's hemoglobin was assessed by a local or central laboratory. If at that time the patient's hemoglobin value met the transfusion guidelines, the patient was transfused with pRBCs to a hemoglobin level above the transfusion threshold in order to be eligible for randomization. The patient's post-transfusion hemoglobin value was confirmed by the local or central laboratory to be above the transfusion threshold. A. LDH AND OTHER LABORATORY PARAMETERS RELATED TO ILLNESSES
[0254] [0254] Blood and urine samples were collected. The following disease-related laboratory parameters were measured during the study: LDH, free hemoglobin, occult blood, urine, total C5, haptoglobin, reticulocyte count, PNH RBC clone size assessed by high-sensitivity flow cytometry, D-dimer, estimated glomerular filtration rate (calculated using the Diet Modification in Kidney Disease formula), spot urine albumin:creatinine ratio, and C-reactive protein. B. PATIENT REPORTED OUTCOME MEASUREMENTS
[0255] [0255] Two validated QoL scales were administered to patients prior to study drug administration. The FACIT-Fatigue Scale, Version 4.0, is a collection of QoL questionnaires relating to the management of fatigue symptoms due to a chronic illness. The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact on daily activities and functions over the previous 7 days. Patients score each item on a 5-point scale: 0 (None) to 4 (Very much). Total scores range from 0 to 52, where higher scores indicate better QoL.
[0256] [0256] The Core 30 Scale Quality of Life Questionnaire (QLQ-C30), Version
[0257] [0257] Two additional questionnaires were completed by patients to assess the burden of disease. These questionnaires were administered to patients before the study drug was infused. The PNH Symptom Questionnaire lists the following symptoms: yellow discoloration of the eyes, discoloration of urine, chest pain, shortness of breath, headache, fatigue, abdominal pain, confusion, erectile dysfunction,
[0258] [0258] The Resource Utilization Questionnaire asks patients to provide the number of times within the past month that they: visited their healthcare provider primarily for treatment of their PNH (excluding study visits specified in the protocol), were to an emergency room primarily for treatment of their PNH, were admitted to a hospital primarily for treatment of their PNH, had dark urine, and/or missed work as a result of PNH symptoms. C. IMPORTANT ADVERSE VASCULAR EVENTS
[0259] [0259] Major adverse vascular events (MAVEs) were assessed as part of the planned assessment for adverse events (AEs). The description of the MAVE, anatomical site, method of diagnosis (e.g., MRI, ultrasound, angiogram), date of diagnosis, and date of resolution (or in progress) were collected in the eCRF as part of the patient's medical history (prior to baseline) and during the study.
[0260] [0260] A MAVE is defined as follows: a) Thrombophlebitis/deep vein thrombosis b) Pulmonary embolism c) Myocardial infarction d) Transient ischemic attack e) Unstable angina f) Renal vein thrombosis g) Acute peripheral vascular occlusion h) Mesenteric/visceral vein thrombosis or infarction i) Mesenteric/visceral arterial thrombosis or infarction j) Hepatic/portal vein thrombosis (Budd-Chiari syndrome)
[0261] [0261] A review of demographic parameters including age, sex, race and ethnicity was performed. A complete medical history was obtained and documented. Weight and height were recorded. Height was measured only at screening.
[0262] [0262] The patient's PNH medical history, including appearance of the first PNH symptom, date of diagnosis, PNH clone size, pRBC transfusions, and history of any MAVEs, was documented at the Screening appointment.
[0263] [0263] The patient's medical history, including prior and concomitant conditions/disorders and transfusion history, was recorded at the Screening Consultation. Medication use (prescription or over-the-counter, including vitamins and/or herbal supplements) during the 28 days (or 3 years for documentation of meningococcal vaccination) prior to initiation of Screening was also recorded in addition to meningococcal vaccination.
[0264] [0264] A physical examination included the following assessments: general appearance; skin; head, ears, eyes, nose and throat; neck; lymph nodes; chest; heart; abdominal cavity; member; central nervous system; and musculoskeletal system. An abbreviated physical examination consisted of a relevant examination of the body system based on the Investigator's judgment and the patient's symptoms.
[0265] [0265] Vital sign measurements were taken after the patient had rested for at least 5 minutes and include systolic and diastolic blood pressure (BP, millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate (breaths/minute). minute), and oral or tympanic temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]).
[0266] [0266] Samples for serum pregnancy testing, hematology, chemistry, clotting and urinalysis were performed. Samples for laboratory evaluations were collected prior to each administration of study drug. If a suspected sudden hemolysis event occurs, an unscheduled visit is performed where a sample is collected for LDH and PK/PD analysis by the central laboratory.
[0267] [0267] It was anticipated that some laboratory values would be outside the normal range due to the underlying disease. The Investigators used their medical judgment in assessing the clinical significance of these values. Clinical significance is defined as any variation in laboratory measurements that has medical relevance and that results in a change in medical care. If clinically significant laboratory changes from baseline were observed, the changes were documented as AEs on the AE eCRF. The Investigator also assessed the study treatment relationship for all clinically significant out-of-range values. The Investigator continued to monitor the patient through further laboratory evaluations until (1) values returned to the normal range or baseline level, or (2) in the judgment of the Investigator, values that were outside the normal range were unrelated to administration. study drug or other protocol-specific procedures.
[0268] [0268] Blood samples were analyzed for serum chemical parameters. Indirect bilirubin is calculated from total and direct bilirubin values; therefore, indirect bilirubin results were not available if direct bilirubin was below the limit of quantification. Serum FSH levels were measured during Screening for postmenopausal female patients to confirm their postmenopausal status. Chemical evaluations were performed. The estimated glomerular filtration rate was calculated using the Diet Modification in Kidney Disease formula for all visits where serum chemistries were collected. Blood samples were analyzed for clotting parameters.
[0269] [0269] Urine samples were analyzed. A microscopic examination of urine samples was performed if the results of the macroscopic analysis were abnormal. Urine samples were also analyzed to measure protein and creatinine in order to calculate the urine protein:creatinine ratio.
[0270] [0270] HIV testing for human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2) is required for all patients prior to enrollment. Known HIV positive patients were not enrolled.
[0271] [0271] For each patient, unique 12-lead digital ECGs were collected. Patients should be supine for approximately 5 to 10 minutes prior to ECG collection and remain in the supine but awake position during ECG collection.
[0272] [0272] Blood samples were collected to test for the presence and titer of ADAs to ALXN1210 or eculizumab in serum prior to administration of study drug. If the test results were positive, the test was repeated every 3 months until the results became negative or stabilized, based on the measured titer and safety assessments. Additional characterization of antibody responses was conducted as appropriate, including binding and neutralizing antibodies, PK/PD, safety, and activity of ALXN1210 or eculizumab.
[0273] [0273] An AE is any medically inappropriate occurrence in a patient who has been administered a pharmaceutical product and which does not necessarily have a causal relationship with that treatment. An AE can therefore be any unfavorable or unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product.
[0274] [0274] Situations in which an improper medical occurrence does not occur (e.g., hospitalization for elective surgery if planned prior to study initiation, hospitalizations for social reasons or for convenience), and predicted daily fluctuations in illness (or illnesses) or condition ( or conditions) pre-existing present or detected at baseline that did not worsen were not AEs.
[0275] [0275] Lack of drug effect is not an AE in clinical studies, due to the fact that the purpose of the clinical study is to establish the effect of the drug.
[0276] [0276] A medication error (including intentional misuse, abuse and overdose of the product) or use beyond what is defined in the protocol is not considered an AE unless there is a medically inappropriate occurrence as a result of a medication error.
[0277] [0277] Pregnancies occurring during maternal or paternal exposure to the investigational product have been reported within 24 hours of knowledge of the Investigator/site. Data on fetal outcomes and breastfeeding are collected for regulatory reporting and safety assessment.
[0278] [0278] Adverse events were recorded from the time of signed consent. An AE reported after informed consent but before administration of study drug is considered a pretreatment AE.
[0279] [0279] C5 inhibition is known to increase susceptibility to infections caused by encapsulated bacteria, particularly N. meningitidis. The following events were major risks identified in this study: Meningococcal Infections, Sepsis, Serious Infections, Aspergillus Infection, and Infusion Reactions. Additional events of interest in this study included the following: Serious skin adverse reactions, cardiac disorders (including ventricular fibrillation), and angioedema.
[0280] [0280] The severity of AEs was rated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or higher. A grading scale (severity) was provided for each AE term. Each CTCAE term is a Lower Level Term (LLT) according to the Medical Dictionary for Regulatory Activities (MedDRA®). Each LLT is coded for a preferred MedDRA term (PT).
[0281] [0281] Grade refers to the severity of the AE. The CTCAE assigns a grade from 1 to 5, with unique clinical descriptions of severity for each AE (Table 9). TABLE 9: Adverse Event Severity Rating Scale Grade Description Mild; asymptomatic or mild symptoms; clinical observations or Grade 1 diagnosis only; intervention not indicated
[0282] [0282] An Investigator must have provided a causality assessment (Unrelated, Unlikely, Possible, Likely, or Definitive) for all AEs (both serious and non-serious) based on the investigator's medical judgment and observed symptoms associated with the event ( Table 10). This assessment has been recorded in the eCRF and in any additional forms as appropriate. TABLE 10: Causality Assessment Descriptions Assessment Description No Suggests that there is no causal association between the product under related/Indepe investigation and the reported event. Suggests that the clinical picture is highly consistent with a cause other than the investigational product, but the Unlikely attribution cannot be made with absolute certainty and a related relationship between the investigational product and the AE cannot be excluded with complete confidence . Suggests that treatment with the investigational drug may have caused or contributed to the AE (i.e. the event Possibly follows a reasonable time sequence from the time of Related drug administration and/or follows a known pattern of response to the drug under investigation investigation, but could also have been produced by other factors).
[0283] [0283] A serious adverse event (SAE) is any medically inappropriate occurrence that: results in death, is life-threatening (i.e. the patient was at risk of death at the time of the event), requires hospital admission or prolonged hospitalization existing, results in persistent or significant disability/disability, and/or is a congenital anomaly/birth defect.
[0284] [0284] Major medical events that may not result in death, be immediately life-threatening, or require hospitalization may be considered a serious adverse event when, based on appropriate medical judgment, they could have compromised the patient or required intervention to prevent a of the results listed above.
[0285] [0285] Suspected Unexpected Serious Adverse Reactions (SUSARs) are serious events that are not listed in the IB and that the Investigator identifies as related to the product or procedure under investigation.
[0286] [0286] All AEs (serious and non-serious) were collected from ICF signing up to 56 days after the last dose of study drug for patients with ET or up to 56 days after the last dose of study drug for patients who completed the study.
[0287] [0287] Blood samples for determination of serum drug concentrations and PD assessments were collected before and after administration of study drug. The actual date and time (24-hour time) of each sampling is recorded. The number of PK sampling time points for any given patient did not exceed the currently planned number of time points; in the case of sudden hemolysis, an additional PK/PD sample was required.
[0288] [0288] Blood samples for evaluation of PK and PD were collected in the arm opposite the arm used for the infusion of the drug.
[0289] [0289] Assessments for PK/PD were as follows: change in serum concentration of ALXN1210 and eculizumab over time, change in cRBC hemolytic activity over time (exploratory), and change in free and total C5 concentrations over time. over time.
[0290] [0290] All data collected is presented in summary tabs. All data, as well as any results derived from the data, are presented in detailed data listings. Graphical displays have also been provided where appropriate. All analyzes were performed using SAS® release, version 9.4 or higher (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. Continuous variables were summarized using descriptive statistics, including number of observations and mean, standard deviation, median, minimum and maximum values. Categorical variables were summarized by frequency counts and percentage of patients. All statistical tests performed were based on a two-sided significance level of 5%, unless otherwise specified. Before finalizing and locking the database, all decisions regarding the inclusion or exclusion of data from the analysis for each patient were determined by appropriate medical and statistical personnel. Any and all exclusions were documented in the patient listings.
[0291] [0291] The details of the statistical analyzes described below were specified in a separate Statistical Analysis Plan (SAP) prior to database locking and analysis. Any change in the data analysis methods described in the protocol requires an amendment only if it changes the primary or secondary primary objectives or the conduct of the study. Any other changes to the data analysis methods described in the protocol or SAP, and the rationale for making the change, are described in the clinical study report (CRS). Additional exploratory analyzes of the data were conducted as appropriate.
[0292] [0292] An RSC was produced based on the efficacy, safety, PK, and PD data collected by the end of the 26-week randomized treatment period (Day 183). A final RSC to summarize parameters of long-term efficacy, safety, PK and PD was produced at the conclusion of the study.
[0293] [0293] Approximately 246 patients were randomly assigned in a 1:1 ratio to receive either ALXN1210 (N = 107) or eculizumab (N = 107) to ensure at least 193 evaluable patients (assuming no more than a dropout rate of no greater than 10%). Sample size estimation was based on a non-inferiority design comparing patients treated with ALXN1210 to those treated with eculizumab. Co-primary endpoints of hemolysis as measured directly by LDH normalization (LDH-N) from Day 29 through Day 183 and the proportion of patients achieving transfusion avoidance (TA) by Day 183 were used to assess non-inferiority. The sample size is based on the evaluation parameter that requires the largest number of patients.
[0294] [0294] For the co-primary endpoint of LDH-N, using a non-inferiority margin (NIM) based on the relative benefit of eculizumab over placebo of 0.39 and a type I error of 2, 5% unilateral, a minimum of 142 patients provides 80% competence to demonstrate non-inferiority of ALXN1210 to eculizumab. The NIM was determined based on a randomized placebo-controlled study (Hillmen P., et al., N. Engl. J. Med., 2006; 355:1233 to 1243), which showed a relative benefit of eculizumab over placebo. , with a probability index of 6.5. This was based on several factors. As baseline LDH is a predictor of the normalization rate, in order to preserve the assumption of constancy, the LDH-N rate was calculated adjusted to the baseline LDH-N observed from the current data from Phase 1b and 2 of the ALXN1210. The estimate of LDH-N for eculizumab was then calculated as a weighted average of the proportions of LDH-N from day 29 to day 183, to be consistent with the proposed analysis plan for this study. As the proportion between patients treated with LDH-N and placebo was 0% at all visits, the upper limit of the 95% CI was used to be able to calculate an odds ratio. The final benefit estimate was based on an LDH-N ratio of 42% for patients treated with eculizumab and 10% for placebo. A traditional NIM choice is one with a loss of benefit ≤ 50%, which results in a NIM with an odds ratio of 0.39. The NIM calculation follows Ng TH (Statist. Med. 2008; 27: 5392 to 5406), where the NIM is given by 1/{OR 0.5}, where OR represents the odds ratio of eculizumab compared to placebo and is given by [0.42/(1-0.42)]/[0.1/(1-0.1)] and 0.5 is the fraction of benefit to be preserved. This approach chooses the NIM on the logarithmic probability scale as described in Section IV of the 2010 Food and Drug Administration (FDA) Industry Guidelines: Clinical Trials of Non-Inferiority. Although more conservative approaches to NIM construction can be used, such as using the lower limit of the 95% CI for eculizumab, the resulting estimated sample size makes this study operationally unfeasible in light of the rarity of PNH and the scarcity of patients. who never received neculizumab.
[0295] [0295] For the other co-primary endpoint of proportion of patients not receiving any transfusions by Day 183, using a NIM of -20% and a one-sided 2.5% Type I error, a minimum of 193 patients provide 80% competence to demonstrate non-inferiority between treatment arms. NIM was determined based on the Global PNH Registry for eculizumab-treated patients who enrolled in the registry in 2012 or later (Soliris Type II Variation Procedure No. EMEA/H/C/000791/II/66). Transfusion history is a predictor of transfusion during treatment To preserve the assumption of constancy, NIM was assessed based on available data from treated and untreated patients, proportionate to expectations of enrollment in the present study. Patients treated with eculizumab (57.1% ED rate) showed a benefit over untreated patients (18.6% ED rate), with a difference of approximately 40% (38.5%) after adjustment. for transfusion history 12 months prior to enrollment. The adjustment comes from an expected proportion of patients with no history of transfusions being no greater than 20%. Patient enrollment for this study is limited to 20% for patients without a transfusion history to ensure consistency is met.
[0296] [0296] A traditional NIM choice is one with ≤ 50% loss of benefit, which results in a NIM of approximately -20%. A more conservative NIM can be used using the lower limit of the 95% CI for the difference in rates, but the estimated resulting sample size makes the study operationally unfeasible in light of the rarity of PNH and the scarcity of patients who never received it. eculizumab with and without a history of transfusions. Furthermore, given the proportion of patients with ED observed in the preliminary results of the program in Phase 1b/2, non-inferiority can be demonstrated with MNIs that are more conservative for the sample size, with limited loss of competence.
[0297] [0297] Due to the sample size estimate based on LDH-N being smaller than that based on TA (Table 11), the final sample size estimate selected for this study was based on the TA evaluation parameter. Adjusting for a possible dropout rate of 10%, approximately 246 patients were enrolled in this study. TABLE 11: SUMMARY OF PARAMETERS USED IN THE ESTIMATION OF
[0298] [0298] Efficacy analyzes were performed on the Full Analysis Set (FAS). Co-primary efficacy endpoint analyses, as well as primary secondary endpoint analyses, were performed on the Per Protocol (PP) set. The FAS is the primary population for all efficacy analyses. The FAS includes all patients who have received at least 1 dose of ALXN1210 or eculizumab and have at least 1 post-first infusion efficacy assessment.
[0299] [0299] The PP pool, which is finalized prior to database locking, consists of FAS patients who meet all of the following criteria: a) No missed doses of ALXN1210 or no more than 1 dose of eculizumab during the period 26-week randomized treatment regimen b) Met inclusion criteria #2, 3, and 4 c) Did not meet exclusion criteria #1, 2, 3, or 4 d) Never received the wrong randomized treatments e) Followed transfusion guidelines specified in the protocol
[0300] [0300] Safety analyzes were performed on the Safety Set, defined as all patients receiving at least 1 dose of study drug. Pharmacokinetic and PD analyzes were performed on all patients who receive at least 1 dose of study drug and who have evaluable PK and PD data.
[0301] [0301] Demographic and baseline characteristics of patients,
[0302] [0302] All patients were included in patient disposition summaries, which describe the frequency and percentage of patients evaluated and treated and who completed or discontinued the study, along with the reason for discontinuation, by treatment group. All patients who withdrew from the study were identified, and the extent of their participation in the study was reported. If known, a reason for its suspension is presented. The numbers of patients who were treated, discontinued treatment (along with reason for discontinuing treatment), entered the Extension Period, and discontinued the Extension Period (along with reason for discontinuing) were tabulated by treatment group and overall.
[0303] [0303] Each patient's prior and concomitant medication use was coded using the World Health Organization Dictionary of Medicines, and the frequency and percentage of concomitant medication are summarized. Drugs were summarized by Anatomical-Therapeutic-Chemical (ATC) class and preferred drug name, using frequency counts and patient percentages in the FAS, Safety, and PP sets.
[0304] [0304] The co-primary efficacy endpoints were 1) the difference between treatment groups in the proportion of patients achieving TA by Day 183, and 2) the relative effect between treatments on LDH-N from Day 29 to Day 183 expressed as a probability index.
[0305] [0305] Transfusion prevention is achieved only by those patients who have not received a transfusion and have not met the guidelines specified by the protocol for transfusion. The percentage of patients who achieved AT with 95% CIs is calculated at Day 183 for both the ALXN1210 and eculizumab treatment groups and the randomization strata. A difference in the percentage of patients achieving AT in the 2 treatment groups is calculated between the ALXN1210 and eculizumab treatment groups, along with a 95% CI for the difference. The difference between the ALXN1210 and eculizumab treatment groups is calculated as a weighted combination of the differences between the ALXN1210 and eculizumab treatment groups within stratification groups (using Mantel-Haenszel). The 95% CI for the difference between the ALXN1210 and eculizumab treatment groups is calculated using the stratified Newcombe confidence interval method.
[0306] [0306] LDH-N was analyzed using a generalized estimating equation (GEE) approach that accounts for repeated measurements of LDH-N at each visit (Liang KY, et al., Biometrika. 1986;73(1) ):13 to 22). The GHG approach provides probability indices and treatment effect CIs while controlling for the correlation between consultations for a given patient and other baseline factors. LDH-N from Day 29 through Day 183 is used as the dependent variable and an indicator variable for treatment, transfusion history (as a categorical variable based on stratification factor levels), and baseline LDH level ( as a continuous variable) are included in the model as explanatory variables. Intrapatient correlation assumes a first-order autoregressive structure that assumes the highest correlation is between queries that were closer together in time. Day 29 was the first scheduled assessment following initiation of maintenance dose administration, and experience data with eculizumab and Phase 1b/2 of ALXN1210 demonstrate near-maximal suppression of LDH by 4 weeks of treatment. The model results were presented as probability indices with 95% confidence intervals.
[0307] [0307] In order to conclude that ALXN1210 is non-inferior to eculizumab, both co-primary endpoints needed to individually demonstrate non-inferiority. If the lower bound of the 95% CI for the difference (ALXN1210-eculizumab) was greater than the -20% NIM for TA and the lower bound of the 95% CI for the odds index of ALXN1210 compared to eculizumab was greater than the NIM of 0.39 for LDH-N, then treatment with ALXN1210 was considered non-inferior to eculizumab. If non-inferiority was met for both co-primary endpoints and a greater effect for ALXN1210 was observed for either co-primary endpoint, then superiority was assessed using a Hochberg multiple comparison approach.
[0308] [0308] The 4 major secondary efficacy endpoints were summarized by randomization strata and by treatment group at baseline and at study visits where these assessments were collected during the 26-week randomized treatment period. The change in FACIT-Fatigue (and percent change in LDH) from baseline to Week 26 is analyzed using a mixed model for repeated measures (MMRM; see eg Mallinckrodt CH, et al., J. Biopharm Stat. 2001;11:9 to 21 and Mallinckrodt CH, et al., Clinical Trials. 2004;1:477 to 489) with fixed categorical treatment effects, transfusion history stratification randomization indicators (0, 1 to 14, or > 14 units of pRBCs in 1 year before the first dose of study drug) and screening for LDH levels (1.5 to < 3 × ULN or ≥ 3 × ULN), study visit, and consultation study by treatment group interaction, as well as the baseline FACIT-Fatigue (or LDH) continuous fixed covariates and baseline FACIT-Fatigue (or LDH) query interaction as covariates. For percent change in LDH, the baseline level of LDH is included as a continuous variable. The Kenward-Roger approximation is used to estimate denominator degrees of freedom. A difference between the ALXN1210 and eculizumab treatment groups along with a bilateral 95% CI is calculated.
[0309] [0309] For sudden hemolysis and stabilized haemoglobin, the same approach as used for AT was employed. These primary secondary endpoints were tested in a hierarchical manner, provided that non-inferiority was declared for the co-primary endpoints. If non-inferiority was established for a major secondary endpoint and a major effect for ALXN1210 was observed, then superiority was assessed using a two-sided 0.05 test for each endpoint.
[0310] [0310] When performing the analyzes for the main secondary efficacy endpoints, a closed testing procedure was used so that the lack of significance of one test precludes the evaluation of subsequent tests. Estimates and CIs were calculated for all of these major secondary efficacy endpoints, regardless of whether the lack of significance of one test precludes evaluation of subsequent tests. If the upper limit of the 95% CI for the difference between the ALXN1210 and eculizumab treatment groups in percent change from Baseline at Week 26 in LDH was less than the 20% NIM, then ALXN1210 was declared not lower for that parameter and the next parameter was tested. If the lower limit of the 95% CI for the difference between the ALXN1210 and eculizumab treatment groups in change from baseline in FACIT-Fatigue was greater than the NIM of -5, then ALXN1210 was declared non-inferior for this parameter and the next parameter was tested. If the upper limit of the 95% CI for the difference between the ALXN1210 and eculizumab treatment groups in the proportion of patients with sudden hemolysis was less than the 20% NIM, then ALXN1210 was declared non-inferior for that parameter and the next parameter has been tested. If the lower limit of the 95% CI for the difference between the ALXN1210 and eculizumab treatment groups in the proportion of patients with stabilized hemoglobin was greater than the -20% NIM, then ALXN1210 was declared non-inferior for that parameter. . Because the hierarchical test order was pre-specified, no adjustment of the type I error was required.
[0311] [0311] Baseline changes in EORTC-QLQ-C30 were summarized by treatment group at baseline and at study visits where these assessments were collected. Baseline changes in clinical manifestations of PNH were summarized by treatment group and at study visits where these assessments were collected. The number of any treatment-emergent MAVEs (n) and the number of patients with events (n, %) were displayed by treatment group. The total number of units of pRBCs transfused during treatment was summarized by treatment group. Kaplan-Meier curves were produced for both treatment groups and estimates of time to first occurrence of LDH-N since the first study drug. No statistical inference from these parameters is planned.
[0312] [0312] All safety analyzes were performed for the Safety pool, defined as all patients who received at least 1 dose of ALXN1210 or eculizumab. Up to Day 183, safety outcomes were reported by treatment group.
[0313] [0313] The following definitions were used for AEs: a) Pretreatment Adverse Events: Any AE that begins after giving informed consent but before the first infusion of study drug. b) Treatment-emergent adverse event: Any AE that begins during or after the first infusion of study drug. c) Treatment-emergent SAE: A treatment-emergent AE (TEAE) that is serious.
[0314] [0314] The incidence of TEAEs, suspensions due to TEAEs, drug-related TEAEs, TEAEs during study drug administration, severe TEAEs, and SAEs were summarized. All AEs were coded using MedDRA version 18 or higher, and were summarized by system organ class (SOC) and PT. Detailed listings by patient of TEAEs, SAEs, TEAEs, related TEAEs, TEAEs during study drug administration and suspensions due to TEAEs were provided. Adverse Baseline changes in physical examination findings were classified as AEs and analyzed accordingly.
[0315] [0315] Vital signs were descriptively summarized at points in time at Baseline and postbaseline and for Baseline changes by treatment group. Data listings per patient were provided.
[0316] [0316] Changes in clinical chemistry, hematology, and urinalysis results from baseline to post-baseline study time points were descriptively summarized by treatment group. Tables of changes over time have been presented for all core laboratory values, where applicable, using grading criteria from CTCAE v 4.03. Lists of patients with abnormal results were provided.
[0317] [0317] Per patient data listings of ECG parameters have been provided.
[0318] [0318] Abnormal immunogenicity findings, including incidence and titers to ADAs for ALXN1210 or eculizumab, were summarized in tabular format by treatment group. The proportion of always positive patients and the proportion of always negative patients were explored.
[0319] [0319] Individual serum concentration data for all patients who received at least 1 dose of study drug (ie, ALXN1210 or eculizumab) and who had evaluable PK data were used to derive PK parameters for ALXN1210 and eculizumab. Plots of the mean time-concentration profiles in serum were constructed. Serum concentration-time profile graphs were also provided for individual patients. Actual dose administration and sampling times were used for all calculations. Descriptive statistics were calculated for serum concentration data at each sampling time, as appropriate. Population PK assessment was considered using data from this study or in combination with data from other studies.
[0320] [0320] PD analysis was performed for all patients who received at least 1 dose of ALXN1210 or eculizumab and who had evaluable PD data. Descriptive statistics were presented for all PD endpoints of ALXN1210 and eculizumab at each sampling time. The PD effects of IV administered ALXN1210 and eculizumab were assessed by evaluating absolute values and percent changes and changes from baseline in serum total and free C5 concentrations and cRBC hemolysis over time, as appropriate. EXAMPLE 2: RESULTS OF THE RANDOM, OPEN, ACTIVE CONTROL STUDY WITH ALXN1210 (RAVULIZUMABE) VERSUS PHASE 3 ECULIZUMAB IN NEVER RECEIVED ADULT PNH PATIENTS COMPLEMENT INHIBITORS
[0321] [0321] The following is a summary of data obtained from an open-label, sequential phase 3 clinical study performed according to the protocol described above in Example 1. A summary of efficacy and safety results are presented below.
[0322] [0322] This phase III human clinical trial was a randomized open-label active control study comparing the non-inferiority of ALXN1210 versus Soliris® (eculizumab) in adult patients with PNH patients who had never received treatment with a complement inhibitor. The study enrolled 246 patients in total. A total of 244 patients completed the study and were included in this per-protocol analysis. Only 2 subjects suspended the course of the study.
[0323] [0323] This phase III study met its primary endpoint and demonstrated that ALXN1210 (ravulizumab) was non-inferior to Soliris® (eculizumab). Specifically, the study met the pre-designated non-inferiority margins (NIM) for LDH normalization (LDH-N) and transfusion prevention (TA) by margins better than the 10% required by the FDA. Furthermore, the AT endpoint achieved a NIM of less than 5%. In addition, all 4 major secondary endpoints favored ALXN1210 and demonstrated non-inferiority to Soliris® (eculizumab). Sudden hemolysis (BTH) also demonstrated a numerical trend favoring ravulizumab over eculizumab by 4% versus 10.7% respectively, but did not fully achieve the result in this study (p<0.074). The incidence of sudden hemolysis was more than 2-fold higher in the Soliris® group than in the ALXN1210 group and the difference was associated with suboptimal C5 inhibition in the Soliris® group, suggesting that AXLN1210 reduces a risk of sudden hemolysis of the patient through complete and constant inhibition of C5.
[0324] [0324] In summary, Ravulizumab was statistically significantly non-inferior to eculizumab for both co-primaries and all major secondary endpoints: transfusion prevention (73.6% versus 66.1%; difference of 6. 8% [95% CI, -4.7, 18.1]), LDH normalization (53.6% versus 49.4%, odds ratio [1.19 (0.80, 1.77)] ), percentage of LDH reduction
[0325] [0325] The design of the non-inferiority study comparing ALXN1210 and eculizumab is shown in Figure 1. The study compares a weight-based personalized dose administration schedule for ALXN1210 to the existing approved dose administration schedule for eculizumab in PNH in PNH an attempt to show non-inferiority in PNH patients who have never received treatment with a complement inhibitor. The dose chosen for ALXN1210 is based on weight and comprises a loading dose (2400 mg for patients ≥40 kg to <60 kg, 2700 mg for patients ≥60 kg to <100 kg, 3000 mg for patients ≥100 kg) in the day 1, followed by maintenance doses of ALXN1210 (3000 mg for patients ≥40 kg to <60 kg, 3300 mg for patients ≥60 to <100 kg, 3600 mg for patients ≥100 kg) on day 15 and q8w thereafter. See Figure 1. On the other hand, the eculizumab dose comprises four induction doses of 600 mg on days 1, 8, 15 and 22, followed by a maintenance dose of 900 mg administered IV on day 29 and every 2 weeks after that. See Figure 1.
[0326] [0326] The study enrolled more patients than originally planned. Specifically, 246 patients enrolled in the study and were randomized to either the ALXN1210 group or the eculizumab group. See Figure 2. A total of 39 subjects failed screening. Of the 246 patients who entered and completed the 26-week treatment period, 243 continued on the sequence extension study. See Figure 2. The baseline characteristics and demographics of the study population are shown in Figure 3.
[0327] [0327] All 246 treated patients (125 patients in the ALXN1210 group and 121 patients in the eculizumab group) were included in the FAS and Safety Set as set out in Table 12. Two patients were excluded from the PP Set. One patient in the ALXN1210 group and 1 patient in the eculizumab group met protocol-specified criteria for pRBC transfusion (hemoglobin ≤ 7 g/dl) but were not transfused at that time or at any other time during the Primary Assessment Period. Although other patients met the transfusion criteria in a private consultation but did not receive a transfusion, these patients were included in the PP Set due to the fact that they received at least 1 transfusion according to the transfusion criteria. TABLE 12: ANALYSIS DATA SETS (ALL RANDOMIZED PATIENTS) ALXN1210 Eculizumab Total n (%) n (%) n (%) Number of randomized patients 125 (100). 121 (100). 246 (100). Number of patients in FAS 125 (100). 121 (100). 246 (100). Number of patients excluded from the FAS 0 0 0 Number of patients in the PP Set 124 (99.2). 120 (99.2). 244 (99.2). Number of patients excluded from 1 (0.8). 1 (0.8). 2 (0.8). PP Set Number of patients in the Set of 125 (100). 121 (100). 246 (100). Security Number of patients excluded from the 0 0 0 Security Set Number of patients in the Set of 125 (100). 121 (100). 246 (100). PK Analysis Number of patients excluded from the 0 0 0 PK Analysis Set
[0328] [0328] Abbreviations: FAS = Complete Analysis Set; PP = Per Protocol
[0329] [0329] There were no differences in actual stratification at randomization time compared to the observed stratification for the LDH groups (LDH 1.5 to < 3×ULN versus LDH ≥ 3×ULN) (see Table 13). Of the 44 patients stratified to 0 units of pRBCs, 1 patient was observed to receive 1 to 14 units (or units) of pRBCs.
[0330] [0330] Abbreviations: LDH = lactate dehydrogenase; pRBC = erythrocyte concentrate; ULN = upper limit of normal
[0331] [0331] Baseline disease characteristics were similar between the 2 treatment groups (Table 14). In the total population, the mean time from PNH diagnosis to informed consent was 6.6 years (median = 3.9 years).
[0332] [0332] All patients had a diagnosis of PNH confirmed by flow cytometry at Screening. The mean total PNH RBC clone size was 38.57%; mean total PNH granulocyte clone size was 84.74%, and mean total PNH monocyte clone size was 87.99%. TABLE 14: Disease Characteristics (Full Analysis Set) Category ALXN1210 Eculizumab Total Variable (N = 125) (N = 121) (N = 246) Age (years) at diagnosis
[0333] [0333] Abbreviations: max = maximum; min = minimum; SD = standard deviation; PNH = paroxysmal nocturnal hemoglobinuria; RBC = erythrocyte
[0334] [0334] Enrollment in previous 0 units of stratum of erythrocytes was closed once the protocol-specified 20% threshold on enrollment of patients with a history of no transfusion in the previous year was reached. Therefore, the majority of patients (82.5%) had a history of pRBC transfusions in the year prior to the first dose of study drug, as set out in Table 15. In the total population, an average of 6.2 pRBC transfusions/ whole blood were administered and an average of 8.8 units were transfused during the 12 months prior to the first dose. The number of transfusions and the number of units transfused were similar between the 2 treatment groups. TABLE 15: Erythrocyte Transfusions within 12 Months Before First Dose (Full Analysis Set) Category ALXN1210 Eculizumab Total Variable (N = 125) (N = 121) (N = 246) Number of patients with pRBC/whole blood transfusions within 12 months before 103 (82.4). 100 (82.6). 203 (82.5). first dose, n (%) pRBC/whole blood transfusions within 12 months before first dose Total 677 572 1249 Mean (SD) 6.6 (6.04). 5.7 (5.53). 6.2 (5.80). Median 4.0 3.0 4.0 Min, Max 1, 28 1, 28 1, 28 Units of pRBC/whole blood transfused within 12 months before first dose Total 925 861 1786 Mean (SD) 9.0 (7 .74). 8.6 (7.90). 8.8 (7.81). Median 6.0 6.0 6.0 Min, Max 1, 44 1, 32 1, 44 *Abbreviations: max = maximum; min = minimum; pRBC = erythrocyte concentrate; SD = standard deviation
[0335] [0335] As required by the protocol, all patients had at least 1 PNH-associated symptom at baseline. The types of PNH symptoms that patients experienced prior to informed consent were similar between treatment groups, with the most common (>20% of all patients) being fatigue or asthenia (generalized weakness), red or dark urine, lack of breath (dyspnea), jaundice (yellowing of the skin or eyes), abdominal pain, and CNS-related symptoms such as headache, dizziness, or difficulty concentrating.
[0336] [0336] In the total population, 98.0% of patients had documented PNH-associated conditions that were diagnosed prior to informed consent, as shown in Table 16. The majority (84.6%) of patients had a prior diagnosis of anemia; 32.1% of patients had aplastic anemia, 12.2% of patients had a history of renal failure, and 5.3% of patients had myelodysplastic syndrome. TABLE 16: CONDITIONS ASSOCIATED WITH PNH DIAGNOSED TO
[0337] [0337] Abbreviation: PNH = paroxysmal nocturnal hemoglobinuria
[0338] [0338] All 246 patients had a history of prior medication use. All patients received meningococcal vaccine no later than Day 1. The most commonly reported groups (≥10% of patients) of prior medications in addition to meningococcal vaccine were vitamin B12 and folic acid (52.8%), antithrombotic agents (29 .7%), corticosteroids for systemic use (24.8%), drugs for peptic ulcer and gastroesophageal reflux disease (22.8%), iron preparations (15.4%), beta-lactam antibacterials (penicillins) (15, 0%), antihistamines for systemic use (13.0%), selective calcium channel blockers with mainly vascular effects (11.4%) and other analgesics and antipyretics (11.0%).
[0339] [0339] Overall, 95.9% of patients (98.4% in the ALXN1210 group and 93.4% in the eculizumab group) took at least one concomitant medication. The most commonly reported groups (≥10% of patients) of concomitant medications were vitamin B12 and folic acid (54.9%), other analgesics and antipyretics (38.6%), beta-lactam antibacterials (penicillins) (38.6%) , antithrombotic agents (31.3%), drugs for peptic ulcer and gastroesophageal reflux disease (29.3%), quinolone antibacterials (26.0%), antihistamines for systemic use (24.8%), corticosteroids for systemic use (24.4%), anti-inflammatory and antirheumatic products (21.1%), iron preparations (17.1%), other beta-lactam antibacterials (13.0%), expectorants excluding combinations with cough suppressants (11.4%), selective calcium channel blockers with mainly vascular events (12.6%) and immunosuppressants (10.2%). During the study, a total of 30.9% patients underwent a non-pharmacological medical procedure.
[0340] [0340] The two co-primary efficacy endpoints of transfusion prevention (TA) and LDH normalization (LDH-N) were very clearly met and exceeded as shown in Figure 4. The red triangle in Figure 4 indicates the margin of no inferiority required by the FDA. For the evaluation parameters of
[0341] [0341] Percentage change in major secondary endpoints of LDH (LDH-PCHG), change in FACIT scores fatigue, sudden hemolysis (BTH) and hemoglobin stabilization (HGB-S) were also positive and favored ALXN1210 over eculizumab. See Figure 5. Furthermore, not only did all secondary endpoints favor ALXN1210, but they all substantially exceeded the non-inferiority margins shown by the red triangles in the graph. See Figure 5.
[0342] [0342] The primary and secondary endpoints are tabulated in Figure 6. The treatment effect for each endpoint in favor of ALXN1210 over that of eculizumab is also shown. For example, the first row shows that the transfusion prevention treatment effect for ALXN120 versus eculizumab was 6.8%, much greater than the required -20% non-inferior margin and provides a finding of non-inferiority. Likewise, all primary and secondary endpoints lead to the same conclusion of non-inferior for ALXN1210 versus eculizumab. Presented another way, ALXN1210 was found to be better than eculizumab, but the sample size was insufficient to reach a statistical conclusion of superiority. See Figure 6.
[0343] [0343] Efficacy data from this study underwent multiple different sensitivity analyses. The results are shown in Figure 7. For example, the treatment effect (point estimate) for ALXN1210 was 6.8% better than for eculizumab, with a 95% confidence interval (CI) of -4.7 % to 18.1%. The -4.7% number is substantially better than the default non-inferiority margin of -20%. This table shows several sensitivity analyses, all of which support the robust finding of the primary analysis. It is noteworthy that this consistency is unusual for a clinical trial of this type and supports the idea that this study was conducted with very high quality.
[0344] [0344] Efficacy results for the primary endpoint of LDH-N were analyzed as subgroups of the patient population and are shown in Figure 8. LDH-N (Lactate Dehydrogenase Normalization) refers to LDH levels less than or equal to at 1xULN, from Day 29 to Day 183. Subgroup analyzes for LDH-N revealed that the preponderance of evidence favored ALXN1210. Gray lines have 95% confidence intervals and blue squares are point estimates. The estimation was based on a generalized estimating equation (GHG) approach. The model included the following terms: treatment group, transfusion history, and baseline LDH levels. Estimates to the right of 1 favor ALXN1210 and estimates to the left favor eculizumab. All point estimates were to the right of the non-predefined inferiority margin (red triangle) (-20%). There were only 3 endpoints that favored eculizumab that did not, and 2 of them had small sample sizes. In conclusion, most subgroups clearly favored ALXN1210 over eculizumab. Consult the Figure
[0345] [0345] As shown in Figure 9, the mean values for LDH were normalized in the patient population to the upper limit of normal (1X ULN LDH) around day 22 to day 24 and remained at that level throughout the study. The dotted line in Figure 9 shows the upper limit value of normal for LDH or 1X ULN LDH. The box below the graph shows the number of patients in each group that contributed to the average for that day. In conclusion, it is clear that the mean value of LDH in patients on ALXN1210 remained below the critical level of 1.5X ULN. See Figure 9.
[0346] [0346] The time to reach LDH normalization is shown in Figure 10 for groups treated with both ALXN1210 and eculizumab. Patients on ALXN1210 achieved normalization about 5 days earlier than patients on eculizumab. See Figure 10. Mean ALXN120 patients reached normalization on day 24 versus day 29 for patients treated with eculizumab. The numbered box under the graph shows the number of patients in each group used to calculate the average for that day. See Figure 10.
[0347] [0347] The percentage of patients achieving LDH normalization at various time points during the course of the study is shown in Figure 11. Overall, more than 50% of ALXN1210 patients remained in the normal range throughout the study, while less than 50% of eculizumab-treated patients remained in the normal range during the study and through day 183. See Figure
[0348] [0348] In addition, at baseline, the mean Global Health Status QLQ-C30 EORTC subscale scores were 56.13 for the ALXN1210 group and 57.51 for the eculizumab group. An improvement of ≥ 10 points on 3 subscales of the Global Health Status QLQ-C30 EORTC, Physical Functioning and EORTC Fatigue is considered to indicate a clinically significant improvement (King, 1996; Osoba, 1998). A higher percentage of patients in the ALXN1210 group had at least a 10-point improvement in the EORTC QLQ-C30, Overall Health Status, Physical Functioning, and Fatigue scores on Day 29 and throughout the Primary Assessment Period compared with eculizumab group, as shown in Figures 12, 13 and 14.
[0349] [0349] There were no notable safety differences in adverse events (AEs) or serious adverse events (SAEs) observed between ALXN1210 and eculizumab-treated patients. See Figures 15 and 16. In addition, there were no meningococcal infections, suspensions due to AEs, and deaths observed during the primary assessment period. See Figures 17 and 18. The most frequent AE was headache in 35%. See Figure 16.
[0350] [0350] A history of one or more MAVEs was reported for 17.1% of patients overall, as set out in Table 17.
[0351] [0351] Abbreviation: MAVE = Major Adverse Vascular Event
[0352] [0352] There was an emerging case of anti-drug antibody (ADA) treatment observed for each of ALXN1210 and eculizumab. Neither produced neutralizing antibodies and there was no effect on PK, PD, efficacy or safety by these apparently transient ADAs.
[0353] [0353] Figure 15 is a tabulation of key safety outcomes in the Phase III clinical trial of ALXN1210-HPN-301.
[0354] [0354] Drug non-compliance was nearly perfect for this clinical trial, as shown in Figure 19. There was only a single incidence of drug non-compliance in the eculizumab arm, as shown in Figure 19.
[0355] [0355] The mean serum concentration (± SD) of ALXN1210 and eculizumab versus time profile for the respective treatment groups (linear scale) is shown in Figure 20. The mean serum concentration (± SD) of ALXN1210 and eculizumab versus profile of time for the respective treatment groups (semi-logarithmic scale) is shown in Figure 21.
[0356] [0356] The pharmacokinetic parameters for ALXN1210 are summarized in Table 18 and Table 19 for the first (induction) and last (maintenance) doses, respectively. The geometric mean (geometric CV%) Cmax and Cmin of ALXN1210 following the first dose in all patients was 753.7 (22.45) and 376.44 (26.17) μg/ml, respectively. After the last dose of ALXN1210, the geometric mean (%CV) of Cmax and Cmin in all patients was 1350.5 (20.8) and 446.1 (36.2) μg/ml, respectively. TABLE 18: PHARMACOKINETIC PARAMETERS OF ALXN1210 (Cmax and Cmin) AFTER THE FIRST DOSE (LOAD) OF ALXN1210 (PHARMACOKINETIC ANALYSIS SET) All ≥ 60 to < 100 ≥ 40 to < 60 kg ≥ 100 kg Statistical Parameter Patients kg (N= 41) (N=5) (N=125) (N=79) Medium 771.4 846.7 740.3 645.0 SD 165.89 174.34 146.62 181.25 CV% 21.51 20, 59 19.80 28.10 Median 761.0 846.0 736.0 656.0 Cmax (μg/ml) Minimum 403 470 414 403 Maximum 1,310 1,160 1,310 905 Mean 753.7 828.6 726.2 623.9 Geometric
[0357] [0357] Abbreviations: Cmax = maximum serum concentration; Cmin = minimum serum concentration; CV = coefficient of variation; SD = standard deviation TABLE 19: ALXN1210 Pharmacokinetic Parameters (Cmax and Cmin) After Final Maintenance Dose of ALXN1210 (pharmacokinetic analysis set) All ≥ 60 to < 100 ≥ 40 to < 60 kg ≥ 100 kg Parameter Patients kg ( N=41) (N=6) (N=124) (N=77) Medium 1378.5 1528.8 1292.9 1450.0 SD 275.94 279.47 242.83 219.00 CV% 20.02 18.28 18.78 15.10 Median 1365.0 1520.0 1280.0 1365.0 Minimum 780 909 780 1260 Cmax (μg/ml) Maximum 2100 2100 1790 1790 Mean 1350.5 1502.8 1269.6 1436 9 Geometric
[0358] [0358] Abbreviations: Cmax = maximum serum concentration; Cmin = minimum serum concentration; CV = coefficient of variation; SD = standard deviation
[0359] [0359] Non-compartmental PK parameters were measured for the ALXN1210 group only. Results after the last maintenance dose of ALXN1210 are shown in Table 20. Steady PK status of ALXN1210 was achieved after multiple dose administration for all maintenance doses on a weight basis (Table 21). TABLE 20: SUMMARY OF ALXN1210 PHARMACOKINETIC PARAMETERS
[0360] [0360] Note: Mean half-life could not be estimated reliably due to continuous therapeutic maintenance dose administration, a Tmax values are presented as median (minimum, maximum).
[0361] [0361] Abbreviations: AUCτ = area under the curve of serum concentration versus time during the dose administration interval; Cmax = maximum observed serum concentration; Cmin = concentrations at the end of the dose administration interval; CL = total extraction; CV = coefficient of variation; SD = standard deviation; tmax = time to maximum observed serum concentration; Vz = volume of distribution at steady state TABLE 21: ASSESSMENT OF ACHIEVEMENT OF PHARMACOKINETIC STABLE STATE OF ALXN1210 (PHARMACOKINETIC ANALYSIS SET) Maintenance Dose Attainment in State Lower IC Upper CI mg Status Slope Stable at 95% to 95% Stable (Group Weight Reached Body) Days 15, 71, 3,000 (≥ 40 to < 60 0.0002512 0.00007432 -0.00010259 Yes 127, 183 kg) 3 Days 15, 71, 3,300 (≥ 60 to < 100 0.0001025 0.00000884 -0.00008491 Yes 127, 183 kg) 9 Days 15, 71, 0.0002959
[0362] [0362] Treatment with ALXN1210 resulted in immediate, complete and sustained inhibition of complement C5 throughout the 8 week dose range. See Figure 19. Dosing based on weight every 8 weeks resulted in maximum steady state and minimum exposures as shown in Figure 19.
[0363] [0363] Table 22 summarizes mean percent change from baseline in serum free C5 concentrations following treatment with ALXN1210 (dose based on q8w body weight) or eculizumab (900 mg q2w). Some free C5 samples were excluded as they were considered biologically implausible. The exclusions were supported by the paired PK data, as the PK and free C5 samples were collected from the same blood draw. These exclusions are as follows: ALXN1210 group: For 3 patients (2.4%), Day 1 free C5 samples at the end of infusion had similar values to pretreatment values. Eculizumab Group: For 3 patients (2.5%), Day 1 free C5 samples were below the pretreatment limit of quantification (BLQ); for 5 patients (4.1%), Day 1 free C5 samples on EOI had similar values to pretreatment values.
[0364] [0364] The mean serum concentration of free C5 at the very first end of infusion and at all subsequent troughs was < 0.5 µg/ml in the ALXN1210 group. This threshold was not consistently met in the eculizumab group. In addition, more individual free C5 values greater than the target free C5 threshold of 0.5 µg/ml were observed in the eculizumab group than in the ALXN1210 group. The imbalance in free C5 control appears to explain the observed difference in sudden hemolysis events between treatment groups (ALXN1210: n = 5, eculizumab: n = 15). TABLE 22: MEAN SERUM FREE C5 CONCENTRATION AND NUMBER (PERCENTAGE) OF PATIENTS WITH SERUM FREE C5 CONCENTRATION > 0.05 µg/ml OVER TIME (FULL ANALYSIS SET) ALXN1210 Eculizumab n (%) of n (%) de Consult Concentration Patients Concentration Patients aa Mean Serum With Mean Serum With nn Free C5, Free C5 Concentration, µg/ml Concentration o Serum µg/ml Serum C5 Free C5 > 0.5 Free > 0.5 µg/ml µg/ml Day 1 122 0.01 0 114 0.01 10 (8.62). Day 8 120 0.04 0 116 3.60 1 (0.85). Day 15 125 0.05 0 117 0.28 0 Day 22 124 0.03 0 117 0.05 0 Day 29 125 0.03 0 116 0.05 0 Day 43 125 0.04 0 116 0.05 1 (0 .87). Day 57 124 0.05 0 115 0.26 2 (1.74). Day 71 125 0.06 0 115 0.76 1 (0.88). Day 85 124 0.03 0 114 0.18 3 (2.61). Day 99 124 0.04 0 115 0.70 2 (1.74). Day 113 124 0.05 0 115 0.22 2 (1.72). Day 127 124 0.06 0 116 0.29 1 (0.86). Day 141 125 0.04 0 116 0.15 4 (3.45). Day 155 125 0.05 0 116 0.53 4 (3.48). Day 169 123 0.06 0 115 0.94 5 (4.31). Day 183 125 0.07 0 116 3.00 10 (8.62).
[0365] [0365] Mean free C5 levels were inhibited by more than 99% by the end of the first infusion with ALXN1210 and remained inhibited by more than 99% for the duration of the study treatment period. On the other hand, free C5 did not remain inhibited by more than 99% at all times in the eculizumab group (see Figure 22).
[0366] [0366] Total C5 levels were similar for both the ALXN1210 and eculizumab groups. The mean percent change (± 95% CI) from baseline for total serum C5 concentration versus time profile is shown in Figure 23. The rate and magnitude of change in total serum C5 was similar between treatments. Baseline was defined as the last non-missing endpoint before the first dose of study drug. ^ indicates that the Day 1 data is from end of infusion, while on Days 8, 22, 29, 43, 57, 85, 99, 113, 141, 155, and 169, the data are from any time to the ALXN1210 group and pre-dose for eculizumab group; on Days 15, 71 and 127 data are pre-dose for both treatment groups; and at Day 183 data are from the end of the Randomized Treatment Period for both treatment groups. EXAMPLE 3: A SINGLE ARM MULTI-CENTRIC STUDY OF PHASE 3 ALXN1210 IN ADULT PATIENTS NEVER RECEIVED COMPLEMENT INHIBITOR WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME (AHUA)
[0367] [0367] A single-arm study of ALXN1210 (ALXN1210-aSHU-311) is conducted in complement-naïve adult and adolescent patients with atypical hemolytic uremic syndrome (aHUS).
[0368] [0368] aHUS is a thrombotic microangiopathy (TMA), most often caused by mutations in genes encoding proteins involved in the alternative complement pathway (APC) or by autoantibodies against APC regulatory proteins (Noris, et al., Clin. J. Am. Soc. Nephrol. 2010;5:1844 to 59). Patients with aHUS are at risk for life-threatening manifestations of disease that result from endothelial damage, including thrombocytopenia, intravascular hemolysis, acute renal failure, and extrarenal tissue damage. Importantly, approximately 20% of patients experience extrarenal manifestations of the disease, including central nervous system, cardiac, GI, distal extremity, and severe systemic organ involvement (Loirat, et al., Orphanet J. Rare Dis. 2011;6:60 and Brodsky, Blood. 2015;126:2459 to 65). Prior to the availability of eculizumab, mortality rates among aHUS patients were up to 15% during the acute phase of disease progression (Noris, et al., Clin. J. Am. Soc. Nephrol. 2010;5:1844 at 59) and Sellier-Leclerc, J. Am. Soc. Nephrol. 2007;18:2392 to 2400). Up to 50% of patients progressed to end-stage renal disease (ESKD), often within a year of disease onset, and required dialysis or kidney transplantation to sustain life. Chronic and uncontrolled activation of terminal complement, specifically the activation of complement component 5 (C5) and dysregulation of complement activity, is central to the pathogenesis of aHUS and the devastating manifestations of this disease. As a result, targeted blockade of C5, with selective inhibition of C5a and C5b-9 generation, represents an important therapeutic mechanism of treatment.
[0369] [0369] The primary objective of the study is to assess the efficacy of ALXN1210 in complement-naïve adolescent and adult patients with aHUS to inhibit complement-mediated TMA as characterized by thrombocytopenia, hemolysis, and renal failure.
[0370] [0370] The secondary objectives of the study are (1) to characterize the safety and tolerability of ALXN1210 in this patient population, (2) to assess the efficacy of ALXN1210 by additional measures (eg, dialysis requirement situation, time to complete response of TMA, TMA Complete Response status over time, observed value, and baseline change in estimated glomerular filtration rate (eGFR), chronic kidney disease (CKD) stage (assessed on selected target days and rated as improved , stable (no change) or worsened compared to baseline), observed value and baseline change in hematologic parameters (platelets, LDH, hemoglobin), increase in hemoglobin of ≥ 20 g/l from baseline (supported by at least 2 consecutive measurements taken at least 4 weeks apart), baseline change in quality of life (QoL) (as measured by EuroQol 5 level 3 dimensions (EQ-5D-3L; all patients tes), Functional Assessment of Chronic Therapy (FACIT), version 4 of Fatigue (patients < 18 years of age) and Pediatric FACIT Fatigue Questionnaires (patients <18 years)), (3) to characterize the PK/pharmacodynamics (PD) of ALXN1210 by changes in serious concentration of ALXN1210 over time and changes in free C5 concentrations over time and (4) to assess the long-term safety and efficacy of ALXN1210.
[0371] [0371] The primary efficacy endpoint of the study is Complete TMA Response during the 26-week Initial Assessment Period, as evidenced by normalization of hematologic parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine baseline, and confirmed by 2 consecutive measurements taken at least 4 weeks apart.
[0372] [0372] The secondary efficacy endpoints of the study are as follows: A. Dialysis requirement status; B. Time to Complete TMA Response; C. Full TMA Response Status over time; D. Observed value and change in eGFR baseline; E. Stage of CKD, as assessed by the Investigator on selected target days and classified as improved, stable (no change), or worsened compared to baseline; F. Observed value and change in baseline in hematological parameters (platelets, LDH, hemoglobin); G. Increase in hemoglobin of ≥ 20 g/L from baseline, supported by at least 2 consecutive measurements taken at least 4 weeks apart; H. Change from baseline in QoL, as measured by EQ-5D-3L questionnaires (all patients), FACIT Fatigue version 4 (patients ≥ 18 years of age), and FACIT Pediatric Fatigue (patients < 18 years of age).
[0373] [0373] The Pharmacokinetic (PK) and Pharmacodynamic (PD) endpoints of this study are changes in serum ALXN1210 concentration over time and changes in free C5 concentrations over time.
[0374] [0374] The safety and tolerability of ALXN1210 is assessed by physical examinations, vital signs, electrocardiograms (ECGs), laboratory assessments, and incidence of AEs and SAEs. The proportion of patients who developed anti-drug antibodies (ADA) is also assessed.
[0375] [0375] Exploratory biomarkers of PD effect include, but are not limited to, change from baseline in levels of complement dysregulation markers (e.g., Factor Ba), vascular inflammation (e.g., soluble tumor necrosis 1 [sTNFR1]), endothelial activation/damage (eg, soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin), coagulation (eg, D-dimer), and kidney injury (eg, cystatin C). Additional assessments may include measurements of urinary ALXN1210 excretion, chicken erythrocyte hemolysis (cRBC), total C5, autoantibodies to complement proteins (eg, anti-factor H), and APC activity (eg, modified Ham test, complement deposition).
[0376] [0376] Exploratory genetics can be performed to investigate genetic variants in genes known to be associated with aHUS, as well as identify original genetic variants associated with aHUS, dysregulation of complement or metabolism or efficacy of ALXN1210. Patients can choose to provide a sample for exploratory genetics and still participate in the study.
[0377] [0377] The ALXN1210-SHUa-311 study is an active-controlled, single-arm, open-label Phase 3, multicenter study to evaluate the safety and efficacy of ALXN1210 administered by intravenous (IV) infusion for adolescents (12 to < 18 years of age). ) and adult patients (≥ 18 years of age) with aHUS. The study involves approximately 55 patients to receive ALXN1210. Figure 24 illustrates the study design. All patients have never received complement inhibitor treatment and include at least 6 and up to 10 adolescent patients (12 to < 18 years of age at Screening) and at least 10 and up to 25 prior kidney transplant patients.
[0378] [0378] The study consists of a Screening Period of up to 7 days, an Initial Evaluation Period of 26 weeks and an Extension Period of up to 2 years. Dosages are based on the patient's last recorded visit body weight of the study (Table 27). Patients receive a loading dose of ALXN1210 IV (2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, 3000 mg for patients weighing ≥ 100 kg) on Day 1 , followed by maintenance doses of IV ALXN1210 (3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 60 kg).
[0379] [0379] This single-arm, open-label Phase 3 study evaluates the safety and efficacy of treatment with ALXN1210. Although no formal comparison analysis is planned for this study, the results of patients treated with ALXN1210 are evaluated in the context of results observed in a historical control group of patients treated with eculizumab. The historical control group is comprised of aHUS patients who were treated with eculizumab in prospective registry studies C08-002A/B, C10-003, and C10-004, for which the study design and conduct characteristics of interest that may influencing the effect were similar to the current study. In addition, the control group is restricted to patients ≥ 12 years of age and 4 weeks or less on PE/PI prior to eculizumab treatment to further align with eligibility criteria for the current study.
[0380] [0380] The Screening Assessment Schedule and Initial Assessment Period is shown in Table 23. The Assessment Schedule for the Extension Period is shown in Table 24. Additional (unscheduled) appointments outside of the specified appointments are permitted at discretion of the Investigator. Procedures, tests and evaluations are performed at the discretion of the Investigator. Any tests, procedures, or assessments performed on Unscheduled Consultations are recorded in Electronic Case Report Forms (eCRFs). Local lab or central lab analyzes are used for Unscheduled Consultation tests. However, if local laboratory tests are used, duplicate samples will be collected at the Unscheduled Consultation for testing at the central laboratory.
[0381] [0381] Abbreviations: ADA = anti-drug antibody; ADAMTS13 = a disintegrin and metalloproteinase with a type 1 thrombospondin motif, member 13; aHUS = atypical hemolytic uremic syndrome; APC = alternative complement pathway; ECG = electrocardiogram; EQ-5D-3L = EuroQol5 level 3 dimensions; ET = early termination; FACIT = functional assessment of chronic disease therapy; HUS = hemolytic uremic syndrome; LDH = lactate dehydrogenase; N/A = not applicable; PD = pharmacodynamics; PK = pharmacokinetics; QoL = quality of life; ST-HUS = Shiga toxin-related hemolytic uremic syndrome. a All patients are vaccinated against meningococcal infections within 3 years before or at the time of initiating study drug use.
[0382] [0382] Serum sampling is performed pre-dose on dosed days and on non-dose days at any time of day. All collection times are recorded in the eCRF. p Serum, plasma, and urine collection for exploratory biomarker analysis is collected at Baseline and at post-treatment time points immediately prior to dose administration of ALXN1210.
[0383] [0383] A total of approximately 55 patients with documented aHUS are enrolled and assigned to treatment with ALXN1210 at approximately 200 investigational sites globally. The study involves at least 6 and up to 10 adolescent patients (12 to < 18 years of age at Triage) and at least 10 and up to 25 patients with a previous kidney transplant.
[0384] [0384] Individuals who did not meet the criteria for participation in this study (screening failure) may be re-screened. Patients can be rescreened a maximum of 2 times. Prospective approval of protocol deviations for recruitment and enrollment criteria, also known as protocol exemptions or exceptions, is not permitted.
[0385] [0385] Patients are eligible for study enrollment only if they meet all of the following criteria and none of the exclusion criteria:
[0386] [0386] Male or female patients aged ≥ 12 years and weighing ≥ 40 kg at the time of consent. · Evidence of TMA, including thrombocytopenia, evidence of hemolysis, and renal dysfunction, based on the following Screening Visit laboratory findings: Platelet count < 150,000 per microliter (µl), and LDH ≥ 1.5 × upper limit of normal (ULN) ), and hemoglobin ≤ lower limit of normal (LLN) for age and sex, and serum creatinine level ≥ ULN in adults (≥ 18 years of age), or ≥ 97.5th percentile for age in Adolescent Screening (12 to < 18 years of age) (patients requiring dialysis for acute kidney injury are also eligible). · Among kidney transplant patients: known history of aHUS prior to current kidney transplantation, or no known history of aHUS, and persistent evidence of TMA after calcineurin inhibitor ([CNI] dose discontinuation; e.g. cyclosporine, tacrolimus ) or rapamycin inhibitor target mammal ([mTORi] ; e.g. sirolimus, everolimus) for a minimum of 4 days and a maximum of 7 days. · Among patients with onset of postpartum TMA, persistent evidence of TMA for > 3 days after the day of delivery. · To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients must be vaccinated against meningococcal infections within 3 years before or at the time of initiating study drug use. Patients who receive a meningococcal vaccine less than 2 weeks before starting treatment with ALXN1210 receive treatment with appropriate prophylactic antibiotics for up to 2 weeks after vaccination. Patients who were not vaccinated before starting treatment with ALXN1210 receive prophylactic antibiotics before and for at least 2 weeks after meningococcal vaccination. · Patients < 18 years of age must have been vaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae according to national and local vaccination schedule guidelines. · Female patients of childbearing potential and male patients with female partners of childbearing potential should follow guidelines specified in the protocol to avoid pregnancy during treatment and for 8 months after the last dose of study drug. · Willing and able to give written informed consent and adhere to the study's appointment schedule. For patients < 18 years of age, the patient's legal guardian must be willing and able to give written informed consent and the patient must be willing to give written informed consent.
[0387] [0387] Samples collected in Screening can be tested at a local or central laboratory. If onsite laboratory testing is used for LDH, platelet count, hemoglobin and serum creatinine, duplicate samples are collected for testing at the central laboratory to ensure that measurements for baseline and postbaseline analyzes are a result of the central laboratory . While results from local laboratories can be used to expedite the eligibility assessment, the final determination of these Inclusion Criteria should be based on the results of the central laboratory.
[0388] [0388] Patients are excluded from study enrollment if they meet any of the following criteria: a) A known disintegrin and metalloproteinase deficiency with a thrombospondin type 1, limb 13 motif (ADAMTS13) (activity < 5%) . b) Shiga toxin-related hemolytic uremic syndrome (ST-SHU). c) Streptococcal pneumoniae-related hemolytic uremic syndrome (HUS), as evidenced by a positive direct Coombs test and Streptococcal pneumoniae infection (eg, culture, antigen test). d) Known Human Immunodeficiency Virus (HIV) infection. e) Unresolved systemic meningococcal disease. f) Patients with a confirmed diagnosis of ongoing sepsis defined as positive blood cultures within 7 days prior to initiation of Screening and no antibiotic treatment. g) Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator, confuses an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease. h) Pregnancy or lactation. i) Transplantation of heart, lung, small intestine or liver. j) Among kidney transplant patients, any of the following: a) Acute renal dysfunction within 4 weeks after transplantation, consistent with a diagnosis of antibody-mediated acute rejection (ADR), according to the 2013 Banff criteria , or b) Acute renal dysfunction within 4 weeks after transplantation and an increase in donor-specific antibody (DSA), consistent with a clinical diagnosis of acute ADR. c) History of polycystic kidney disease. k) Among patients aged ≥ 18 years who have a systolic blood pressure (SBP) ≥ 170 mmHg or patients aged 12 to < 18 years who have a clinical diagnosis of hypertension, any of the following:
[0389] [0389] Laboratory results for Exclusion Criterion #1 may not be available prior to the first dose. Subsequent results for Exclusion Criterion Index A may lead to discontinuation and patient replacement.
[0390] [0390] A patient has the right to withdraw from the study at any time. If a patient withdraws consent, the assessments specified for the Early Termination (ET) consultation are performed. Patients who withdrew from the study are not replaced. A patient may be suspended from study drug if the Investigator or Sponsor has reason to believe that it is in the patient's best interest to stop treatment.
[0391] [0391] Prior kidney transplant patients who develop AMR (C4d positive renal biopsy) and for whom rituximab is considered an appropriate treatment should be withdrawn from the study and given standard care therapy. The main reason and any other reason (or reasons) for suspension are recorded in the eCRF.
[0392] [0392] If a patient is suspended from the study with an ongoing AE or an unresolved laboratory result that is significantly outside the reference range and clinically significant, the Investigator attempts to provide follow-up until a satisfactory clinical resolution of the laboratory result or adverse event be achieved.
[0393] [0393] The Sponsor or Competent Authority may terminate the study for a reasonable reason. Conditions that warrant study termination include, but are not limited to: (1) discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the study, (2) sponsor's decision to suspend or discontinue the trial, evaluation, or development of the study. study drug, (3) failure of the
[0394] [0394] If it is determined at any point that the patient's Screening data does not meet one or more of the following inclusion/exclusion criteria (Inclusion Criterion number 2 or Exclusion Criterion number 1), after receiving at least 1 dose of investigational product (eg, it is later determined by a central laboratory that the patient's local laboratory data used to confirm eligibility criteria does not meet the eligibility criteria), the patient is suspended from the study and may be replaced. Early termination procedures are performed on patients who terminate early, and all AEs are collected within 60 days after the patient's last study drug dose.
[0395] [0395] End of study is defined as the date of the last visit of the last patient in the Extension Period.
[0396] [0396] ALXN1210, a humanized anti-C5 monoclonal antibody composed of two 448 amino acid heavy chains and two 214 amino acid light chains, is an IgG2/4 kappa immunoglobulin consisting of human constant regions and murine complementarity determining regions grafted onto and light and heavy chain variable regions of the human framework. ALXN1210 and eculizumab share over 99% primary amino acid sequence identity and have very similar pharmacology.
[0397] [0397] Drug product ALXN1210 is supplied for clinical studies as a sterile, preservative-free 10 mg/ml solution in single-use vials designed for dilution infusion into commercially available saline (sodium chloride injection at 0 .9%; country-specific pharmacopoeia) for administration by IV infusion. Table 25 and the current IB provide additional information.
[0398] [0398] ALXN1210 is packaged in United States Pharmacopeia (USP)/European Union Pharmacopeia (EP) Type 1 borosilicate glass vials and stoppered with a butyl rubber stopper with an aluminum seal and a cap. flip-off type. Study drug is provided in kits. ALXN1210 is released to each location upon receipt of all essential documents required based on applicable regulations.
[0399] [0399] Upon arrival of the study drug kits at the study site, the pharmacist or designee promptly removes the study drug kits from the shipping refrigerant and stores them in their original boxes under refrigerated conditions at 2°C to 8°C. °C (35 °F to 47 °F) and protected from light. The ALXN1210 is not frozen. Study drug is stored in a secure area with limited access, and temperature was monitored daily.
[0400] [0400] Drug product is at room temperature prior to administration. The material is not heated (eg using a microwave or other heat source) beyond ambient air temperature.
[0401] [0401] ALXN1210 is not administered as a pulse or bolus IV injection. Study drug infusions are prepared using aseptic technique. The patient's required dose of ALXN1210 is further diluted in commercially available saline (0.9% sodium chloride; country-specific pharmacopoeia) in the volume specified in Table 26. The ALXN1210 diluent solution is administered to the patient using a an administration set of IV tubes via an infusion pump. The use of an in-line infusion filter is required. TABLE 26: DOSE ADMINISTRATION REFERENCE CHART FOR PREPARING THE DOSE OF ALXN1210 Dose Type Body Weight Dose ALXN Solution Vol. Min. Max. (kg)a (mg) 1210 Saline Total Minutes Rate Vol. (ml) Vol (ml) (ml) Duration of infusion Infusion (ml/hour) (hours) Loading ≥ 40 to < 60 2,400 240 240 480 114 (1.9). 253 ≥ 60 to < 100 2,700 270 270 540 102 (1.7). 333 ≥ 100 3,000 300 300 600 108 (1.8). 333 Maintenance ≥ 40 to < 60 3,000 300 300 600 138 (2.3). 267 ≥ 60 to < 100 3,300 330 330 660 120 (2.0). 333 ≥ 100 3,600 360 360 720 132 (2.2). 333 Consult the Pharmacy Manual for additional instructions on dose preparation. a Body weight as recorded at the last study visit.
[0402] [0402] Study drug doses are only prepared and dispensed by a pharmacist or a clinically qualified member of staff. Study drug is dispensed only to enrolled patients who are confirmed eligible to participate in this study. Once study drug is prepared for a patient, it is administered only to that patient. Study drug vials are for single use only and any drug product remaining in the vial is not used for another patient. Any drug remaining in the infusion tube or infusion bag is not used for another patient.
[0403] [0403] All clinical study material is stored in a secure location and allocated and dispensed by suitably trained personnel. Detailed records of quantities of product under investigation received, dispensed and destroyed are maintained. Unless otherwise noted, empty vials and vials with residual materials are held for inspection and accountability by the study monitor before being destroyed or handled in accordance with local pharmacy standard operating procedures (SOPs) for clinical trial drugs . To meet regulatory requirements related to drug liability, at the end of the study, all remaining inventory of ALXN1210 is reconciled and destroyed or returned to Alexion in accordance with applicable regulations.
[0404] [0404] Patients receive ALXN1210 for 26 weeks. ALXN1210 is given as a slow IV infusion over approximately 2 hours. ALXN1210 is not given as a bolus or pulse IV injection.
[0405] [0405] The dose regimen for ALXN1210 during the Initial Assessment Period is based on the patient's last recorded study visit body weight (Table 27). Patients receive a loading dose of ALXN1210 IV on Day 1, followed by administration of a maintenance dose of ALXN1210 IV on Day 15 and q8w (every eight weeks) thereafter. TABLE 27: LOADING TREATMENT SCHEMES AND
[0406] [0406] After the Initial Assessment Period, all patients move into an Extension Period of up to 2 years during which all patients receive ALXN1210 q8w (every eight weeks). The actual time of all dose administrations is recorded in the patient's eCRF.
[0407] [0407] This is an open study. Patients who meet all criteria for enrollment are assigned to study treatment with ALXN1210 at the Baseline Visit (Day 1). The interactive web or voice response system (IxRS) is used to assign vials containing ALXN1210 to each patient.
[0408] [0408] The weight-based dosages of ALXN1210 in this study (Table 27) were premised on PK/PD data from early developmental studies in healthy adult volunteers, as well as available data from patients with PNH in an ongoing Phase 1b dose determination study (ALXN1210-
[0409] [0409] Infusion of other monoclonal antibodies has been associated with infusion reactions, typically appearing during or shortly after completion of the infusion.
[0410] [0410] Past medications (including vitamins and herbal preparations)—including those discussed in the exclusion criteria and procedures (any therapeutic intervention, such as surgery/biopsy or physical therapy) that the patient takes or performs within 28 days (or 3 years for documentation of meningococcal vaccination) prior to initiation of Screening up to the first dose of ALXN1210 — are recorded in the patient's eCRF.
[0411] [0411] For analytical purposes, any dialysis within the 14 day period immediately following the first dose of ALXN1210 is not considered "re-dialysis".
[0412] [0412] All drug use and procedures performed during the study are recorded in the patient's source document/medical record and eCRF. This record includes all prescription drugs, herbal products, vitamins, minerals, over-the-counter drugs, and current medications. Concomitant medications were recorded from the patient's first infusion of study drug to 56 days after the patient's last dose of study drug. Any changes to concomitant medications are also recorded in the patient's source document/medical record and eCRF. Any concomitant medication deemed necessary for the patient's standard of care during the study, or for the treatment of any AE, along with the permitted medications described below are provided at the discretion of the Investigator. However, it is the responsibility of the Investigator to ensure that details regarding all medications are fully recorded in the source document/patient's medical record and eCRF.
[0413] [0413] Patients are prohibited from receiving any of the following drugs and procedures at any time after the first dose of study drug: eculizumab or other complement inhibitors, use of any other investigational drug or device as part of a trial clinical trial, IVIg (unless for an unrelated medical need, e.g., hypogammaglobinemia), Rituximab, PE/PI after first dose, and re-dialysis with the first period 48 hours after the first dose of ALXN1210, unless there is a compelling medical need as assessed by (1) hypervolemia unresponsive to diuretics, (2) refractory electrolyte imbalance, or (3) recent-onset uremic encephalopathy. Exceptions must be approved prior to administration of dialysis on a case-by-case basis by Sponsor.
[0414] [0414] The following concomitant medications and procedures are permitted under certain circumstances and with the following restrictions: use of other immunosuppressive therapies (such as steroids, mTORi [eg sirolimus, everolimus], CNI [eg cyclosporine or tacrolimus]) prior to screening or during the study are not permitted unless: a) part of an established post-transplant anti-rejection regimen, or b) patient has confirmed anti-complement factor antibodies, antibody requiring immunosuppressive therapy, or c) steroids are being used for a condition other than aHUS (eg, asthma).
[0415] [0415] Any patients receiving other complement inhibitors (including eculizumab) or who are on PE/PI after the first dose of study drug are withdrawn from the study.
[0416] [0416] Due to its mechanism of action, the use of ALXN1210 increases the patient's susceptibility to infection. To reduce the risk of infection, all patients are vaccinated against N. meningitidis, Hib, and Streptococcus pneumoniae.
[0417] [0417] Patients are vaccinated against N. meningitidis within 3 years prior to, or at the time of receiving the first dose of ALXN1210. Patients who are drug-treated less than 2 weeks after receiving a meningococcal vaccine receive treatment with appropriate prophylactic antibiotics for up to 2 weeks after vaccination. Vaccines against serotypes A, C, Y, W135 and B, when available, are recommended to prevent common pathogenic meningococcal serotypes. Patients are vaccinated or revaccinated according to current national vaccination guidelines or local practice for use of vaccination with complement inhibitors (eg, eculizumab).
[0418] [0418] It is recognized that some patients who have not been vaccinated against N. meningiditis within 3 years prior to receiving the first dose of ALXN1210 may not be able to receive a vaccination at the time of the first dose. Patients who were not vaccinated before starting treatment with ALXN1210 receive prophylactic antibiotics before and for at least 2 weeks after meningococcal vaccination.
[0419] [0419] Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance and local practice on the proper use of antibacterial agents. All patients are monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics if necessary.
[0420] [0420] In order to raise awareness of the risks and promote rapid disclosure of any potential signs or symptoms of infection experienced by patients during the course of the study, a safety card is provided which patients must carry at all times. Further discussion and explanation of potential risks, signs, and symptoms occurs at specific time points, as part of the patient safety card review and throughout the study, as outlined in the Schedule of Assessments (Table 23 and Table 24).
[0421] [0421] Patients are vaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae according to national and local vaccination schedule guidelines, before or at the time of receiving the first dose of ALXN1210. Vaccination status for N. meningitidis, Hib, and S. pnemoniae is recorded in the patient's eCRF.
[0422] [0422] Patients receive study drug in a controlled environment under the supervision of the Investigator or designee, thereby ensuring compliance with the administration of study drug. The investigator or designee ensures that all patients are adequately informed of the specific dose administration regimen required to comply with the study protocol, ensure that the patient receives the appropriate dose at the designated time points during the study, and that monitoring of adequate safety during infusion.
[0423] [0423] Prior to receiving study drug, female patients who consider themselves postmenopausal should provide evidence of menopause based on a combination of amenorrhea for at least 1 year and an increased level of serum follicle stimulating hormone (FSH) (> 30 IU/l) (eg, in the absence of hormone replacement therapy, dietary phytoestrogens).
[0424] [0424] Female patients of childbearing potential use a highly effective method of contraception (as defined below), which begins at Triage and continues for at least 8 months after the last dose of study drug. Highly effective contraceptive methods* include: hormonal contraception associated with ovulation inhibition, intrauterine device, intrauterine hormone delivery system, bilateral tubal occlusion, vasectomized partner (provided the partner is the patient's only sexual partner), sexual abstinence (defined as abstaining from heterosexual intercourse throughout the period of risk associated with study drug treatment; reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the patient's preferred and habitual lifestyle), male condom combination with cover, diaphragm or sponge with spermicide (double barrier methods). Male patients with a wife/partner of childbearing potential or a pregnant or breastfeeding wife or partner agree to use dual-barrier contraception (male condom plus partner-appropriate barrier method) during treatment and for at least 8 months thereafter. the last dose of study drug. Dual barrier contraception is required even with documented medical assessment of the surgical success of a vasectomy.
[0425] [0425] Male patients do not donate sperm during treatment and for at least 8 months after the last dose of study drug.
[0426] [0426] The primary efficacy assessment is Complete TMA Response during the 26-week Initial Assessment Period. Criteria for Complete TMA Response are (1) platelet count normalization, (2) LDH normalization, and (3) ≥ 25% improvement in baseline serum creatinine.
[0427] [0427] Patients who meet all criteria for a Complete TMA Response, confirmed by 2 consecutive measurements taken at least 4 weeks apart, are classified as having met the primary efficacy endpoint.
[0428] [0428] The following secondary efficacy assessments are measured during the study: A. Dialysis requirement status; B. Time to Full TMA Response C. Full TMA Response Status over time; D. Observed value and change in eGFR baseline; E. Stage of CKD, as assessed by the Investigator on selected target days and classified as improved, stable (no change), or worsened compared to baseline; F. Observed value and change in baseline in hematological parameters (platelets, LDH, hemoglobin); G. Increase in hemoglobin of ≥ 20 g/L from baseline, supported by at least 2 consecutive measurements taken at least 4 weeks apart; H. Change from baseline in QoL, as measured by EQ-5D-3L questionnaires (all patients), FACIT Fatigue version 4 (patients ≥ 18 years of age), and FACIT Pediatric Fatigue (patients < 18 years of age).
[0429] [0429] The Investigator or his/her designee meets with patients to discuss the potential safety risks of ALXN1210 and to give the Investigator the opportunity to address any of the patient's safety concerns regarding the study.
[0430] [0430] The collection of AEs is monitored from the time informed consent is obtained until the conclusion of the study. Investigators follow any AEs to completion (resolution or stabilization). In the case of a patient withdrawn from the study, monitoring of the AE continues until the last visit of the last patient in the study, if possible. The timing of clinical assessments and laboratory assessments is performed by the Assessment Schedule (Tables 23 and 24). Any clinically significant abnormal results are followed until resolution or stabilization.
[0431] [0431] A review of demographic parameters including age, sex, race and ethnicity is performed. A complete medical history is obtained and documented. Weight and height are recorded. Height is measured in Triage only.
[0432] [0432] The patient's aHUS medical history, including the onset of the first aHUS symptom and the date of diagnosis, is documented at the screening appointment.
[0433] [0433] The patient's medical history, including prior and concomitant conditions/disorders, is recorded at the Triage Consultation. Medication use (prescription or over-the-counter, including vitamins and/or herbal supplements) during the 28 days (or 3 years for documentation of meningococcal vaccination) prior to initiation of Screening is also recorded in addition to meningococcal vaccination.
[0434] [0434] A physical examination includes the following assessments: general appearance; skin; head, ears, eyes, nose and throat; neck; lymph nodes; chest; heart; abdominal cavity; member; central nervous system; and musculoskeletal system. An abbreviated physical examination is a relevant examination of the body system based on the Investigator's judgment and the patient's symptoms. Vital sign measurements are taken after the patient has rested for at least
[0435] [0435] Serum pregnancy, hematology, chemistry, clotting, and urinalysis samples are taken at the times specified in the Assessment Schedule (Tables 23 and 24). Samples for laboratory evaluations are collected prior to each administration of study drug.
[0436] [0436] Samples collected in Screening can be tested at a local or central laboratory. If onsite laboratory testing is used for LDH, platelet count, hemoglobin and serum creatinine, duplicate samples are collected for testing at the central laboratory to ensure that measurements for baseline and postbaseline analyzes are a result of the central laboratory . In the case of duplicate samples from local and central laboratories, the results from the central laboratory are used for analysis.
[0437] [0437] It is anticipated that some laboratory values may be outside the normal range due to the underlying disease. Investigators should use their medical judgment in assessing the clinical significance of these values. Clinical significance is defined as any variation in laboratory measurements that has medical relevance and that results in a change in medical care. If clinically significant laboratory changes from baseline are observed, the changes are documented as AEs in the AE eCRF. The Investigator assesses the study treatment ratio for all clinically significant out-of-range values. The Investigator continues to monitor the patient through further laboratory evaluations until (1) values have returned to the normal range or baseline level, or (2) in the judgment of the Investigator, values that are outside the normal range are unrelated to the administration of study drug or other protocol-specific procedures.
[0438] [0438] For females of childbearing potential, a serum or urine pregnancy test (i.e., human chorionic gonadotropin [β-hCG]) is performed according to the Schedule of Assessments (Tables 23 and 24) , Blood samples are analyzed for hematology parameters.
[0439] [0439] Blood samples are analyzed for serum chemical parameters. Indirect bilirubin is calculated from total and direct bilirubin values; therefore, indirect bilirubin results are not available if direct bilirubin is below the limit of quantification. The serum FSH level is measured during Screening for postmenopausal female patients to confirm their postmenopausal status.
[0440] [0440] Chemical assessments are performed at the time points specified in the Assessment Schedule (Tables 23 and 24). The eGFR is calculated for all visits where serum chemistries are collected using the Diet Modification in Kidney Disease formula in patients ≥18 years of age and Diet Modification in Kidney Disease in the Schwartz formula in patients < 18 years of age .
[0441] [0441] Blood samples are analyzed for clotting parameters.
[0442] [0442] Urine samples are analyzed. A microscopic examination of urine samples is performed if the results of the macroscopic analysis are abnormal. Urine samples are also analyzed to measure protein and creatinine in order to calculate the total urine protein:creatinine ratio.
[0443] [0443] For each patient, single 12-lead digital ECGs are collected according to the Schedule of Assessments (Tables 23 and 24). Patients should be supine for approximately 5 to 10 minutes prior to ECG collection and remain in the supine but awake position during ECG collection. The Investigator or designee is responsible for reviewing the ECG to assess whether the ECG is within normal limits and to determine the clinical significance of the results. These assessments are indicated in the CRF.
[0444] [0444] Blood samples are collected for testing for the presence and titer of ADAs to ALXN1210 in serum prior to administration of study drug as indicated in the Schedule of Assessments (see Tables 23 and 24). If the test results are positive, the test can be repeated every 3 months until the results become negative or stabilize, based on the measured titer and safety assessments. Additional characterization of antibody responses can be conducted as appropriate, including binding and neutralizing antibodies, PK/PD, safety, and ALXN1210 activity.
[0445] [0445] An AE is any medically inappropriate occurrence in a patient who has been administered a pharmaceutical product and which does not necessarily have a causal relationship with that treatment. An AE can therefore be any unfavorable or unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product.
[0446] [0446] Situations in which an inappropriate medical occurrence does not occur (e.g., hospitalization for elective surgery if planned prior to study initiation, hospitalizations for social or convenience reasons), and predicted daily fluctuations in illness (or illnesses) or condition (or pre-existing conditions) present or detected at baseline that do not worsen are not AEs.
[0447] [0447] Lack of drug effect is not an AE in clinical studies, due to the fact that the purpose of the clinical study is to establish the effect of the drug.
[0448] [0448] A medication error (including intentional misuse, abuse and overdose of the product) or use beyond what is defined in the protocol is not considered an AE unless there is a medically inappropriate occurrence as a result of a medication error.
[0449] [0449] Pregnancies occurring during maternal or paternal exposure to the investigational product must be reported within 24 hours of knowledge of the Investigator/site. Data on fetal outcomes and breastfeeding are collected for regulatory reporting and safety assessment.
[0450] [0450] Adverse events are recorded from the moment of signed consent. An AE reported after informed consent but before administration of study drug is considered a pretreatment AE.
[0451] [0451] The following events are important risks identified in this study: Meningococcal infections.
[0452] [0452] Severity of AEs is rated using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or higher. A grading scale (severity) is provided for each EA term. Each CTCAE term is a Lower Level Term (LLT) according to the Medical Dictionary for Regulatory Activities (MedDRA®). Each LLT is coded for a preferred MedDRA term (PT). Grade refers to the severity of the AE. The CTCAE assigns a grade from 1 to 5, with unique clinical descriptions of severity for each AE (Table 28). TABLE 28: Adverse Event Severity Rating Scale Grade Description Mild; asymptomatic or mild symptoms; Grade 1 clinical or diagnostic observations only; intervention not indicated Moderate; minimal, local or non-invasive intervention indicated; that limits Grade 2 age-appropriate instrumental activities of daily living (ADL) to Severe or clinically significant, but not immediately life threatening Grade 3; indicated hospitalization or prolongation of hospitalization; disabling; limiting self-care ADL b Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 AE-related death. Abbreviations: ADL = activities of daily living; AE = adverse event instrumental ADL refers to preparing meals, shopping for groceries or clothing, using the telephone, managing money, etc. b Self-care ADL refers to bathing, dressing and undressing, eating, using the bathroom, taking medication and not being bedridden.
[0453] [0453] Any change in the severity of an EA is documented based on specific guidelines in the eCRF Completion Guidelines. Severity and severity are distinguished: severity describes the intensity of an AE, while the term seriousness refers to an AE that has met specific criteria for a serious adverse event (SAE).
[0454] [0454] An Investigator must provide a causality assessment (Unrelated, Unlikely, Possible, Likely, or Definitive) for all AEs (both serious and non-serious) based on the investigator's medical judgment and observed symptoms associated with the event (Table 29). This assessment is recorded in the eCRF and in any additional forms, as appropriate. TABLE 29: CAUSALITY ASSESSMENT DESCRIPTIONS Assessment Description No Suggests that there is no causal association between the product under related/Independent investigation and the reported event. It suggests that the clinical picture is highly consistent with a cause other than the investigational product, but the Unlikely Related attribution cannot be made with absolute certainty and a relationship between the investigational product and the AE cannot be excluded with complete confidence. Suggests that treatment with the investigational drug may have caused or contributed to the AE (i.e. the event Possibly follows a reasonable time sequence from the time of Related drug administration and/or follows a known pattern of response to the drug under investigation investigation, but could also have been produced by other factors). It suggests that there is a reasonable temporal sequence of the event with the administration of the investigational product and the probable causal association of the event with the investigational product. This will likely be based on the known pharmacological action of the investigational Related product, known or previously reported adverse reactions of the investigational product, or drug class or judgment based on the Investigator's clinical experience. Temporal relationship to investigational product, other conditions (concurrent illness, simultaneous reaction to medication Definitely or progression/expression of disease state) unrelated appear to explain the event, match known pharmaceutical profile, improvement on discontinuation, reappearance on new challenge.
[0455] [0455] A serious adverse event (SAE) is any medically inappropriate occurrence that: · Results in death · Is life-threatening (i.e. the patient was at risk of death at the time of the event) · Requires hospital admission or prolonged hospitalization Existing · Results in persistent or significant disability/disability · Is a congenital anomaly/birth defect
[0456] [0456] Major medical events that may not result in death, be immediately life-threatening, or require hospitalization may be considered a serious adverse event when, based on appropriate medical judgment, they may compromise the patient or may require intervention to prevent a of the results listed above.
[0457] [0457] Suspected Unexpected Serious Adverse Reactions (SUSARs) are serious events that are not listed in the IB and that the Investigator identifies as related to the product or procedure under investigation. The United States Code of Federal Regulations (CFR) 312.32 Title 21 and the European Union Clinical Trials Directive 2001/20/EC and associated detailed guidance or national regulatory requirements of participating countries require notification of SUSARs.
[0458] [0458] All AEs (serious and non-serious) are collected from ICF signing up to 60 days after the last dose of study drug for patients with ET or up to 56 days after the last dose of study drug for patients who have completed the study. All AEs are recorded in the eCRF when the investigator or his/her team becomes aware of their occurrence.
[0459] [0459] All SAEs are recorded regardless of the Investigator's causality assessment. There is no time limit for reporting SAEs that are considered causally related to the study drug. Investigators are free to report SAEs regardless of causality at any time.
[0460] [0460] For all SAEs, the Investigator must provide the following: appropriate and requested follow-up information, causality of the SAE (or SAEs), treatment/intervention for the SAE (or SAEs), outcome of the SAE (or SAEs), and records supporting physicians and laboratory/diagnostic information.
[0461] [0461] Pregnancy data is collected during this study for all patients and spouse/partner of male patients. Exposure during pregnancy (also called exposure in utero) can be the result of maternal exposure or transmission of the drug through semen after paternal exposure. Pregnancy itself is not considered an AE unless there is a suspicion that the investigational product may have interfered with the effectiveness of a contraceptive drug. However, pregnancy complications and abnormal pregnancy outcomes are AEs and may meet criteria for an SAE (eg, ectopic pregnancy, miscarriage, intrauterine fetal death, neonatal death, or congenital anomaly). Uncomplicated elective abortions should not be reported as AEs.
[0462] [0462] Blood samples for determination of serum drug concentrations and PD assessments are collected before and after administration of study drug at the time points indicated in the Assessment Schedule (see Tables 23 and 24). The actual date and time (24-hour time) of each sampling is recorded. The number of PK sampling time points for any given patient does not exceed the number of currently planned time points.
[0463] [0463] Blood samples for evaluation of PK and PD are collected in the arm opposite the arm used for the infusion of the drug. Assessments for PK/PD are as follows: (1) changes in serum ALXN1210 concentration over time and (2) changes in free C5 concentrations.
[0464] [0464] For exploratory analyzes of biomarkers, actual statistical summaries, change and percentage change from baseline are presented.
[0465] [0465] The relationship between ALXN1210 concentration and exploratory biomarkers or the correlation between clinical benefit and key exploratory biomarkers can be assessed by graphical display. Exploratory analyzes and potential relationships between clinical outcomes, PK/PD, genetic profile and biomarker levels can also be performed. APC activity and autoantibody results are summarized if evaluated.
[0466] [0466] Exploratory genetics can be performed to investigate genetic variants in genes known to be associated with aHUS, as well as identify original genetic variants associated with aHUS, dysregulation of complement or metabolism or efficacy of ALXN1210.
[0467] [0467] Known clinically relevant genetic mutations in aHUS are communicated to the patient or guardian by the Investigator along with appropriate genetic counseling. Genetic variants of unknown clinical significance should not be communicated to patients or their investigators.
[0468] [0468] Additional signs or symptoms of aHUS are assessed using the Resource Utilization Patient Questionnaire and the Patient-Reported aHUS Symptoms Questionnaire.
[0469] [0469] The components of aHUS extrarenal signs or symptoms, including vital signs and clinical laboratories, can be descriptively summarized at baseline and post-baseline time points and for changes from baseline. Listings per patient can be provided.
[0470] [0470] Analysis of signs, symptomatology and resource utilization may include standard approaches to categorical results with or without repeated measures.
[0471] [0471] If a Day 1 assessment is absent, the Screening assessment is used as the baseline assessment.
[0472] [0472] For assessment of Complete TMA Response during the 26-week Initial Assessment Period (primary endpoint), patients who do not have an efficacy assessment that is part of the definition of Complete TMA Response while still on study have their last observation carried forward (LOCF). For patients who discontinued the study prior to Week 26, their data up to the time of discontinuation are used to assess the Complete TMA Response.
[0473] [0473] Missing data for QoL instruments is handled as specified in the instructions for each instrument.
[0474] [0474] A preliminary review is planned for this study at the end of the 26 week Initial Assessment Period after all patients have completed or withdrawn from the 26 week Initial Assessment Period. In addition, a second analysis to summarize the parameters of efficacy, safety, and long-term PK is performed at the end of the 2-year Extension Period. EXAMPLE 4: A PHASE 3, RANDOM, OPEN, ACTIVE CONTROL STUDY OF ALXN1210 VERSUS ECULIZUMAB IN ADULT PATIENTS WITH PAROXYSTIC NOCTURNAL HEMOGLOBINURIA (PNH) PREVIOUSLY TREATED WITH ECULIZUMAB.
[0475] [0475] A multicentre, randomized, open-label, Phase 3, active-control study was conducted to assess the safety and efficacy of ALXN1210 (also known as Ultomiris™, BNJ441 antibody, or ravulizumab) versus eculizumab administered by intravenous (IV) infusion for adult patients with PNH who were treated with eculizumab for at least 6 months.
[0476] [0476] The primary endpoint was to assess the non-inferiority of ALXN1210 (ravulizumab) compared to eculizumab in adult PNH patients who were treated with eculizumab for at least 6 months.
[0477] [0477] Non-inferiority was claimed if after 26 weeks of treatment the upper limit of the 95% confidence interval (CI) for the difference (ALXN1210-eculizumab) in percent change in LDH level (LDH-PCHG) was less than 15%.
[0478] [0478] Secondary objectives included characterizing the safety and tolerability of ALXN1210 in patients who switched from eculizumab to ALXN1210, evaluating the efficacy of ALXN1210 by additional efficacy measures, characterizing the pharmacokinetics/pharmacodynamics (PK/PD) and immunogenicity of ALXN1210, and evaluating the long-term safety and efficacy of ALXN1210.
[0479] [0479] The study's primary efficacy endpoint was hemolysis as measured directly by the percent change in lactate dehydrogenase (LDH-PCHG) level from Baseline to Day 183. The primary study's secondary efficacy endpoints (the to be tested in a hierarchical manner) were:
[0480] [0480] Other secondary efficacy endpoints of the study included assessment of: (1) total number of packed red cell units (pRBCs) transfused from Baseline to Day 183, (2) proportion of patients with LDH in the normal range on Day 183, (3) change in the Quality of Life Questionnaire Core 30 Scale (QLQ-C30), Version 3.0 of the European Organization for Research and Treatment of Cancer (EORTC), from Baseline to Day 183, (4) change in clinical manifestations of PNH (fatigue, hemoglobinuria, abdominal pain, shortness of breath, anemia, dysphagia, and erectile dysfunction) from Baseline to Day 183 and (5) proportion of patients experiencing MAVEs from Baseline to Day 183.
[0481] [0481] Pharmacokinetic and pharmacodynamic endpoints included assessment of: (1) change in serum concentration of ALXN1210 and eculizumab over time, (2) change in hen erythrocyte hemolytic activity (cRBC)
[0482] [0482] Exploratory endpoints included assessment of patient-reported PNH symptoms and healthcare resource utilization.
[0483] [0483] The safety and tolerability of ALXN1210 compared to eculizumab is assessed by physical examinations, vital signs, electrocardiograms (ECGs), laboratory assessments, and incidence of adverse events (AEs) and serious adverse events (SAEs). The proportion of patients who developed anti-drug antibodies (ADAs) was also assessed by the end of the study.
[0484] [0484] This study was to evaluate the safety and efficacy of ALXN1210 (ravulizumab) versus eculizumab given by intravenous (IV) infusion for adult PNH patients who have been treated with eculizumab for at least the last 6 months. The study as designed was expected to include approximately 192 patients (96 patients per treatment group), but ultimately 195 subjects were enrolled in the study and 186 subjects were analyzed as part of the per-protocol analysis. The study comprised a 4-week screening period, a 26-week randomized treatment period, and an extension period of up to 2 years. Patients were stratified into 1 of 2 groups based on their transfusion history (received a transfusion of packed red blood cells (pRBCs) within 12 months prior to Day 1, yes or no). Patients within each of the 2 groups were randomly assigned in a 1:1 ratio to continue eculizumab or switch to ALXN1210. 97 patients were assigned to the ALXN1210 group and 98 patients were assigned to the eculizumab group. Upon completion of the study, 191 subjects enrolled in the extension study, while 4 subjects (1 in the ALXN1210 group and 3 in the eculizumab group) discontinued treatment.
[0485] [0485] Prior to randomization and within 5 days prior to study drug administration on Day 1, each patient's hemoglobin was assessed by a local or central laboratory. If at that time the patient's hemoglobin value met protocol-specified transfusion guidelines, the patient was transfused with pRBCs to a hemoglobin level above the protocol-specified transfusion threshold in order to be eligible for randomization. The patient's post-transfusion hemoglobin value was confirmed by a local or central laboratory to be above the transfusion threshold specified in the protocol.
[0486] [0486] Day 1 of study treatment occurred 2 weeks from the patient's last dose of eculizumab. Patients randomly assigned to the ALXN1210 group received a loading dose (see Table 7) of ALXN1210 on Day 1, followed by maintenance doses of ALXN1210 on Day 15 and every 8 weeks (q8w) thereafter for a total of 26 weeks of treatment. Patients randomly assigned to the eculizumab group continued to receive the approved dose of eculizumab for the treatment of PNH (900 mg every 2 weeks [q2w]) for a total of 26 weeks of study treatment.
[0487] [0487] Upon completion of all assessments on Day 183, patients entered an extension period and received and will continue to receive ALXN1210 until the product is registered or approved (as per country-specific regulations) or for up to 2 years , what happens first. From Day 183, patients who were randomized to the ALXN1210 treatment group received a maintenance dose (as described above) of ALXN1210 every 8 weeks (q8w), and patients who were randomized to the eculizumab group received a loading dose (as described above) of ALXN1210 followed 2 weeks later and every 8 weeks (q8w) thereafter by a weight-based maintenance dose of ALXN1210. Figures 25 and 26 illustrate the study design.
[0488] [0488] A pRBC transfusion was administered when a patient had a hemoglobin value of 9 g/dl or less with signs or symptoms of sufficient severity to warrant a transfusion or a hemoglobin value of 7 g/dl or less regardless of presence of clinical signs or symptoms.
[0489] [0489] The Schedule of Assessments is provided in Table 30 for the Randomized Screening and Treatment Period and in Table 31 (patients entering the screening group).
[0490] [0490] Additional (unscheduled) queries outside of specified queries are permitted at the discretion of the Investigator. Procedures, tests and evaluations are performed at the discretion of the Investigator. Any tests, procedures, or assessments performed at the Unscheduled Appointments were recorded on electronic case report forms (eCRFs).
[0491] [0491] In addition, if a suspected event of sudden hemolysis occurred, LDH, PK and PD parameters were analyzed in the central laboratory. If the suspected sudden-onset event did not occur at a scheduled appointment, an unscheduled appointment took place for patient assessment and collection of required LDH, PK, and PD parameters. For the purpose of defining sudden hemolysis, the LDH assessment was based on a central laboratory value. TABLE 30: SCHEDULE OF CONSULTATIONS AND STUDY ASSESSMENTS:
[0492] [0492] A total of 195 patients with documented PNH were enrolled and randomly assigned to treatment with ALXN1210 or eculizumab at approximately 50 investigational sites globally. Individuals who did not meet the criteria for participation in this study (screening failure) could be resubmitted to screening. Prospective approval of protocol deviations for recruitment and enrollment criteria, also known as protocol exemptions or exceptions, was not permitted.
[0493] [0493] Patients were eligible for study enrollment only if they met all of the following criteria and none of the exclusion criteria:
[0494] [0494] Patients were excluded from study enrollment if they met any of the following criteria:
[0495] [0495] A patient had the right to withdraw from the study at any time. If a patient withdrew consent, the assessments specified for the Early Termination (ET) consultation were performed. Patients who withdrew from the study were not replaced.
[0496] [0496] Patients were permanently discontinued from ALXN1210 treatment if any of the following occurred during the study:
[0497] [0497] If a patient is suspended from study drug, the patient is encouraged to return for the remainder of their scheduled protocol visits until initiating a different complement-targeted therapy.
[0498] [0498] If a patient was discontinued from the study with an ongoing adverse event or an unresolved laboratory result that, in the opinion of the Investigator, was significantly outside the reference range and clinically significant, the Investigator attempted to provide follow-up until a clinical resolution satisfactory outcome of the laboratory result or adverse event was achieved. If a female patient were permanently discontinued from ALXN1210 treatment due to pregnancy, the Investigator would attempt to follow up on pregnancy outcome.
[0499] [0499] The sponsor or health authority may have terminated the study for a reasonable reason. The end of the study was defined as the date of the last visit of the last patient in the Extension Period.
[0500] [0500] Study drugs in this study were ALXN1210 (ravulizumab) and eculizumab (active control). Both ALXN1210 and eculizumab are humanized anti-C5 monoclonal antibodies.
[0501] [0501] The drug products ALXN1210 and eculizumab were supplied for clinical studies as sterile, preservative-free 10 mg/ml solutions in single-use vials and designed for dilution infusion in commercially available saline (sodium chloride injection at 0.9%; country-specific pharmacopoeia) for administration by IV infusion (see Table 33).
[0502] [0502] ALXN1210 and eculizumab were packaged in US Pharmacopeia/European Pharmacopeia Type 1 borosilicate glass vials and stoppered with a butyl rubber stopper with an aluminum seal and a flip-off cap. Study drug was provided in kits. Study drug orders were released for each site upon receipt of all required documents based on applicable regulations.
[0503] [0503] Upon arrival of the study drug kits at the study site, the pharmacist or designee promptly removed the study drug kits from the shipping refrigerant and stored them in their original boxes under refrigerated conditions at 2°C to 8°C. °C (35 °F to 47 °F) and protected from light. ALXN1210 and eculizumab must not be frozen. Study drug was stored in a secure area with limited access, and temperature was monitored daily.
[0504] [0504] Eculizumab or ALXN1210 was not administered as a bolus or pulse IV injection. Study drug infusions were prepared using aseptic technique. The required patient dose of ALXN1210 or eculizumab was further diluted in commercially available saline (0.9% sodium chloride; country-specific pharmacopeia) in the volume specified in Table 34 for ALXN1210 or Table 35 for eculizumab (see also local marker approved or current IB for eculizumab). The mixture of ALXN1210 or eculizumab was administered to the patient using an IV tube administration set via an infusion pump. The use of a 0.2 micron filter was required during the infusion of ALXN1210. TABLE 34: DOSE ADMINISTRATION REFERENCE TABLE FOR ALXN1210 DOSE PREPARATION Volume Duration Rate Minimum Body Weight Volume Dose Maximum Dose Type Volume ALXN1210 Solution Infusion in (kg) to (mg) Total (ml) Infusion ( ml) Saline Minutes (ml/hour) (ml) (hours) ≥ 40 to < 60 2,400 240 240 480 114 (1.9). 253 Loading ≥ 60 to < 100 2,700 270 270 540 102 (1.7). 318 ≥ 100 3,000 300 300 600 108 (1.8). 333 ≥ 40 to < 60 3,000 300 300 600 140 (2.4). 250 Maintenance ≥ 60 to < 100 3,300 330 330 660 120 (2.0). 330 ≥ 100 3,600 360 360 720 132 (2.2). 328 Note: Please refer to the Pharmacy Manual for additional instructions on dose preparation. a Body weight as recorded at the last study visit. TABLE 35: DOSE ADMINISTRATION REFERENCE TABLE FOR
[0505] [0505] Study drug doses were only prepared and dispensed by a pharmacist or a clinically qualified member of staff. Study drug was dispensed only to enrolled patients who were confirmed eligible to participate in this study. Once study drug was prepared for one patient, it was administered to that patient only. Study drug vials are for single use only and any drug product remaining in the vial has not been used for another patient. Any drug remaining in the infusion tube or infusion bag was not used for another patient.
[0506] [0506] Patients were randomly assigned on a 1:1 ratio to continue on eculizumab or switch to ALXN1210 for 26 weeks. Study drug was administered as a slow IV infusion (see Table 34 and Table 35). Day 1 of study treatment occurred 2 weeks from the patient's last dose of eculizumab.
[0507] [0507] The dosing regimen for ALXN1210 was a loading dose on Day 1 followed by maintenance doses on Day 15 and every 8 weeks (q8w) thereafter. Dosage of ALXN1210 was based on body weight at the last recorded visit of the patient's study, as indicated in Table 36. TABLE 36: Weight-Based Dosages of ALXN1210 Treatment Group Body Weight ALXN1210 Loading Dose Maintenance Dose ≥ 40 to < 60 kg 2,400 mg 3,000 mg ≥ 60 to < 100 kg 2,700 mg 3,300 mg ≥ 100 kg 3,000 mg 3,600 mg
[0508] [0508] Patients randomly assigned to continue on eculizumab continued to receive maintenance dose administration of eculizumab according to the approved dose administration regimen for the PNH indication, which was 900 mg q2w.
[0509] [0509] After the randomized treatment period all patients entered the Extension Period and received and will continue to receive ALXN1210 until the product is registered or approved (in accordance with country-specific regulations) or for up to 2 years, whichever occurs first. From Day 183, patients who were randomized to the ALXN1210 treatment group received their weight-based maintenance dose of ALXN1210 every 8 weeks (q8w), and patients randomized to the eculizumab group received a dose with weight-based loading of ALXN1210 followed 2 weeks later and every 8 weeks (q8w) thereafter by a weight-based maintenance dose of
[0510] [0510] Patients who met all criteria for enrollment were randomly assigned to study treatment with ALXN1210 or eculizumab at the Baseline Visit (Day 1). Treatment group assignment was determined by a computer-generated random sequence using an interactive web or voice response system (IxRS). Randomization was a stratified randomization. Patients were stratified into 1 of 2 groups based on their transfusion history (received a transfusion of pRBCs within 12 months prior to Day 1, yes or no). Patients within both groups were then randomly assigned in a 1:1 ratio to continue on eculizumab or switch to ALXN1210 during the 26-week randomized treatment period.
[0511] [0511] The weight-based dosages of ALXN1210 in this study (Table 36) were premised on PK/PD data from early developmental studies in healthy adult volunteers, as well as available data from PNH patients in a Phase 1b sequence determination study sequence (ALXN1210-HPN-103) and a Phase 2 proof-of-concept study sequence (ALXN1210-HPN-201). The selection of ALXN1210 dose regimen was based on achieving immediate, complete and sustained inhibition of terminal complement in PNH patients.
[0512] [0512] The eculizumab dosage was the approved dose for the treatment of PNH patients (Soliris® United States Prescribing Information [USPI] and Summary of Product Characteristics [SmPC]).
[0513] [0513] Infusion of other monoclonal antibodies has been associated with infusion reactions, typically appearing during or shortly after completion of the infusion. Past medications (including vitamins and herbal preparations)—including those discussed in the exclusion criteria and procedures (any therapeutic intervention, such as surgery/biopsy or physical therapy) that the patient takes or performs within 28 days (or 3 years for documentation of meningococcal vaccination) prior to the initiation of Screening through to the first dose of study drug—were recorded on the electronic patient case report form (eCRF).
[0514] [0514] Transfusions of pRBCs received within 1 year prior to the first administration of study drug were recorded in the patient's eCRF.
[0515] [0515] All drug use and procedures performed during the study were recorded in the patient's source document/medical record and eCRF. This registry included all prescription drugs, herbal products, vitamins, minerals, over-the-counter medications, and current PNH medications. Concomitant medications were recorded from the patient's first infusion of study drug to 56 days after the patient's last dose of study drug. Any changes to concomitant medications were also recorded in the patient's source document/medical record and eCRF. Any concomitant medication deemed necessary for the patient's standard of care during the study, or for the treatment of any adverse event (AE), along with the permitted medications described below were provided at the discretion of the Investigator.
[0516] [0516] Concomitant use of anticoagulants was prohibited if not on a stable dose regimen for at least 2 weeks prior to Day 1. Use of complement inhibitors in addition to the study treatment assigned to the patient was prohibited.
[0517] [0517] Due to its mechanism of action, the use of eculizumab or ALXN1210 increases the patient's susceptibility to meningococcal infection (N. meningitidis). To reduce the risk of meningococcal infection, all patients were vaccinated against meningococcal infections within 3 years before or at the time of initiating study drug use. Patients who started treatment with study drug less than 2 weeks after receiving a meningococcal vaccine received treatment with appropriate prophylactic antibiotics for up to 2 weeks after vaccination. Vaccines against serotypes A, C, Y, W135 and B, when available, have been recommended to prevent common pathogenic meningococcal serotypes. Patients were vaccinated or revaccinated according to current national vaccination guidelines or local practice for use of complement inhibitor vaccination (eg, eculizumab).
[0518] [0518] Vaccination may not be sufficient to prevent meningococcal infection. It could have been considered by official guidance and local practice on the proper use of antibacterial agents. All patients could have been monitored for early signs of meningococcal infection, evaluated immediately if infection was suspected, and treated with appropriate antibiotics if necessary.
[0519] [0519] A packed red blood cell (pRBC) transfusion was given when a patient had a • hemoglobin value of 9 g/dl or less with signs or symptoms of sufficient severity to warrant a transfusion • hemoglobin value of 7 g/dl or lower regardless of the presence of clinical signs or symptoms
[0520] [0520] Signs or symptoms typically associated with or precipitating the patient's need for transfusion have been documented in the eCRF for each individual patient. Typical anemia-related symptoms warranting transfusions included angina, change in mental status (eg, syncope, mild dizziness, confusion, stroke, transient ischemic attack), severe or worsening shortness of breath, and severe or worsening fatigue. Other symptoms precipitating a potential need for transfusion could have been discussed with the Medical Monitor before the transfusion was administered.
[0521] [0521] If a patient met any transfusion criteria during the study, the Investigator determined the appropriate number of units of pRBCs to be transfused. It was recommended that the transfusion be performed within 48 hours of determining the hemoglobin responsible for the transfusion. The administration of a transfusion, including the hemoglobin result and symptoms that triggered the transfusion, and the number of units transfused, were documented in the eCRF.
[0522] [0522] Prior to randomization and within 5 days prior to study drug administration on Day 1, each patient's hemoglobin was assessed by a local or central laboratory. If at that time the patient's hemoglobin value met the transfusion guidelines, the patient was transfused with pRBCs to a hemoglobin level above the transfusion threshold in order to be eligible for randomization. The patient's post-transfusion hemoglobin value was confirmed by the local or central laboratory to be above the transfusion threshold. E. LDH and Other Disease-Related Laboratory Parameters
[0523] [0523] Blood and urine samples were collected. The following disease-related laboratory parameters were measured during the study: LDH, free hemoglobin, occult blood, urine, total C5, haptoglobin, reticulocyte count, PNH RBC clone size assessed by high-sensitivity flow cytometry, D-dimer, estimated glomerular filtration rate (calculated using the Diet Modification in Kidney Disease formula), spot urine albumin:creatinine ratio, and C-reactive protein. F. PNH Quality of Life, Additional Signs and Symptoms, and Resource Utilization Questionnaires.
[0524] [0524] Two validated QoL scales were administered to patients prior to administration of study drug. The FACIT-Fatigue Scale, Version 4.0, is a collection of QoL questionnaires relating to the management of fatigue symptoms due to a chronic illness. The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact on daily activities and functions over the previous 7 days. Patients scored each item on a 5-point scale: 0 (None) to 4 (Very). Total scores ranged from 0 to 52, where higher scores indicate better QoL.
[0525] [0525] The Core 30 Scale Quality of Life Questionnaire (QLQ-C30), Version
[0526] [0526] Two additional questionnaires were completed by patients to assess the burden of disease. These questionnaires were administered to patients before the study drug was infused. The PNH Symptom Questionnaire listed the following symptoms: yellow discoloration of the eyes, discoloration of urine, chest pain, shortness of breath, headache, fatigue, abdominal pain, confusion, erectile dysfunction, difficulty swallowing, and others. Patients indicated whether they had experienced each of the symptoms in the past week and, if so, rated frequency (4-point scale ranging from rarely to almost constantly), severity (4-point scale ranging from mild to very severe), and extent of suffering/discomfort associated with it (5-point scale ranging from none to a lot).
[0527] [0527] The Resource Utilization Questionnaire asked patients to provide the number of times within the past month that they had: visited their healthcare provider primarily for treatment of their PNH (excluding study visits specified in the protocol), been to an emergency room primarily for treatment of their PNH, been admitted to a hospital primarily for treatment of their PNH, had dark urine and/or missed work as a result of symptoms of PNH. a) Important Adverse Vascular Events
[0528] [0528] Major adverse vascular events (MAVEs) were assessed as part of the planned assessment for adverse events (AEs). The description of the MAVE, including the method of diagnosis and the date resolved (or in progress) were collected in the eCRF as part of the patient's medical history (prior to baseline).
[0529] [0529] A MAVE was defined as follows: Thrombophlebitis/deep vein thrombosis, Pulmonary embolism, Myocardial infarction, Transient ischemic attack, Unstable angina, Renal vein thrombosis, Acute peripheral vascular occlusion, Mesenteric/visceral vein thrombosis or infarction, Mesenteric/visceral arterial thrombosis or infarction, Hepatic/portal vein thrombosis (Budd-Chiari syndrome), Cerebral arterial occlusion/stroke, Cerebral venous occlusion, Renal arterial thrombosis, Gangrene (non-traumatic; non-diabetic), Amputation (non-diabetic), traumatic; non-diabetic) and Other Dermal Thrombosis. G. Security Assessments
[0530] [0530] The Investigator or his/her designee met with the patients to discuss the potential safety risks of ALXN1210 (ravulizumab) and eculizumab and gave the Investigator the opportunity to address any of the patient's safety concerns in relation to the study. Investigators followed any AEs to completion (resolution or stabilization). The timing of clinical and laboratory assessments is specified in the Assessment Schedule. Any clinically significant abnormal results were followed until resolution or stabilization.
[0531] [0531] A review of demographic parameters including age, sex, race and ethnicity was performed. A complete medical history was obtained and documented. Weight and height were recorded. Height was measured only at screening.
[0532] [0532] The patient's PNH medical history, including appearance of the first PNH symptom, date of diagnosis, PNH clone size, pRBC transfusions, and history of any MAVEs, was documented at the Screening appointment.
[0533] [0533] The patient's medical history, including prior and concomitant conditions/disorders and transfusion history, was recorded at the Screening Consultation. Drug use (prescription or over-the-counter, including vitamins and/or herbal supplements) within 28 days prior to initiation of Screening and meningococcal vaccination within 3 years prior to the first dose of study drug were also recorded.
[0534] [0534] A physical examination included the following assessments: general appearance; skin; head, ears, eyes, nose and throat; neck; lymph nodes; chest; heart; abdominal cavity; member; central nervous system; and musculoskeletal system. An abbreviated physical examination consisted of a relevant examination of the body system based on the Investigator's judgment and the patient's symptoms.
[0535] [0535] Vital sign measurements were taken after the patient had been rested for at least 5 minutes and included systolic and diastolic blood pressure (BP, millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate (breaths /minute), and oral or tympanic temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]).
[0536] [0536] Samples for serum pregnancy testing, hematology, chemistry, clotting and urinalysis were performed. Samples for laboratory evaluations were collected prior to each administration of study drug. If a suspected sudden hemolysis event occurred, an unscheduled visit was performed where a sample was collected for LDH and PK/PD analysis by the central laboratory.
[0537] [0537] It was anticipated that some laboratory values may be outside the normal range due to underlying disease. The Investigators used their medical judgment in assessing the clinical significance of these values. Clinical significance was defined as any variation in laboratory measurements that had medical relevance and that resulted in a change in medical care. If clinically significant laboratory changes from baseline were observed, the changes were documented as AEs on the AE eCRF. The Investigator also assessed the study treatment relationship for all clinically significant out-of-range values. The Investigator continued to monitor the patient through further laboratory evaluations until (1) values had returned to the normal range or baseline level, or (2) in the judgment of the Investigator, values that were outside the normal range were unrelated to the administration of study drug or other protocol-specific procedures.
[0538] [0538] For women of childbearing potential, a serum or urine pregnancy test (ie, beta-human chorionic gonadotropin [β-hCG]) was performed.
[0539] [0539] Blood samples were analyzed for serum chemical parameters. Indirect bilirubin was calculated from total and direct bilirubin values; therefore, indirect bilirubin results were not available if direct bilirubin was below the limit of quantification. Serum FSH levels were measured during Screening for postmenopausal female patients to confirm their postmenopausal status. Chemical evaluations were performed. The estimated glomerular filtration rate was calculated using the Diet Modification in Kidney Disease formula for all visits where serum chemistries were collected. Blood samples were analyzed for clotting parameters.
[0540] [0540] Urine samples were analyzed. A microscopic examination of urine samples was performed if the results of the macroscopic analysis were abnormal. Urine samples were also analyzed to measure protein and creatinine in order to calculate the urine protein:creatinine ratio.
[0541] [0541] HIV testing for human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2) was required for all patients prior to enrollment. Known HIV positive patients were not enrolled.
[0542] [0542] For each patient, unique 12-lead digital ECGs were collected. Patients were in the supine position for approximately 5 to 10 minutes prior to the ECG collection and remained in the supine but awake position during the ECG collection.
[0543] [0543] Blood samples were collected to test for the presence and titer of ADAs to ALXN1210 or eculizumab in serum prior to administration of study drug. Additional characterization of antibody responses was conducted as appropriate, including binding and neutralizing antibodies, PK/PD, safety, and activity of ALXN1210 or eculizumab.
[0544] [0544] An adverse event (AE) was any medically inappropriate occurrence in a patient who was administered a pharmaceutical product and which did not necessarily have a causal relationship with that treatment. An AE can therefore be any unfavorable or unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product.
[0545] [0545] Situations in which an improper medical occurrence does not occur (e.g., hospitalization for elective surgery if planned prior to the start of the study, hospitalizations for social reasons or for convenience), and predicted daily fluctuations in illness (or illnesses) or condition ( or conditions) pre-existing present or detected at baseline that did not worsen were not AEs.
[0546] [0546] Lack of drug effect was not an AE in clinical studies, due to the fact that the purpose of the clinical study was to establish drug effect.
[0547] [0547] A medication error (including intentional misuse, abuse and overdose of the product) or use beyond what was defined in the protocol was not considered an AE unless there was a medically inappropriate occurrence as a result of a medication error.
[0548] [0548] Pregnancies that occurred during maternal or paternal exposure to the investigational product have been reported within 24 hours of knowledge of the Investigator/site. Data on fetal outcomes and breastfeeding were collected for regulatory reporting and safety assessment.
[0549] [0549] Adverse events were recorded from the time of signed consent. An AE reported after informed consent but before administration of study drug was considered a pretreatment AE.
[0550] [0550] C5 inhibition is known to increase susceptibility to infections caused by encapsulated bacteria, particularly N. meningitidis. The following events were major risks identified in this study: meningococcal infections, sepsis, serious infections, aspergillus infection, infusion reactions. Additional events of interest in this study included the following: serious skin adverse reactions, cardiac disorders (including ventricular fibrillation), and angioedema.
[0551] [0551] The severity of adverse events (AEs) was classified using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or higher. A grading scale (severity) was provided for each AE term. Each CTCAE term was a Lower Level Term (LLT) according to the Medical Dictionary for Regulatory Activities (MedDRA®). Each LLT was coded for a preferred MedDRA term (PT).
[0552] [0552] Grade referred to the severity of the AE. The CTCAE assigns a grade from 1 to 5, with unique clinical descriptions of severity for each AE (Table 37). TABLE 37: Adverse Event Severity Rating Scale Grade Description Mild; asymptomatic or mild symptoms; clinical or diagnostic Grade 1 observations only; intervention not indicated Moderate; minimal, local or non-invasive intervention indicated; that Grade 2 limits age-appropriate instrumental activities of daily living (ADL) to Severe or clinically significant, but not immediately life threatening Grade 3; indicated hospitalization or prolongation of hospitalization; disabling; limiting self-care ADL b Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 AE-related death. Abbreviations: ADL = activities of daily living; AE = adverse event instrumental ADL referred to preparing meals, shopping for groceries or clothing, using the telephone, administering money, etc. b Self-care ADL referred to bathing, dressing and undressing, eating, using the bathroom, taking medication and not being bedridden.
[0553] [0553] Any change in the severity of an AE has been documented based on specific guidelines in the eCRF Completion Guidelines. Severity and seriousness were differentiated: severity described the intensity of an AE, while the term seriousness referred to an AE that met specific criteria for an SAE.
[0554] [0554] An Investigator must have provided a causality assessment (Unrelated, Unlikely, Possible, Likely, or Definitive) for all AEs (both serious and non-serious) based on the investigator's medical judgment and the observed symptoms associated with the event ( Table 38). This assessment has been recorded in the eCRF and in any additional forms as appropriate. TABLE 38: CAUSALITY ASSESSMENT DESCRIPTIONS Assessment Description No Suggests that there is no causal association between the investigational related/undesired product and the reported event. pending Suggests that the clinical picture is highly consistent with a cause other than the investigational product, but the attribution Unlikely cannot be made with absolute certainty and a relationship between the Related investigational product and the AE cannot be excluded with complete confidence . Suggests that treatment with the investigational product may have caused or contributed to the AE (i.e., the event follows a reasonable time sequence Possibly from the time of Related drug administration and/or follows a known pattern of response to the investigational product investigation, but could also have been produced by other factors). It suggests that there is a reasonable temporal sequence of the event with the administration of the investigational product and the probable causal association of the event with the investigational product. This is likely based on the known pharmacological action of the investigational product, known or previously reported adverse reactions of the investigational product, or drug class or judgment based on the Investigator's clinical experience. Temporal relationship to investigational product, other conditions (concurrent illness, simultaneous reaction to medication Definitely or progression/expression of disease state) unrelated appear to explain the event, match known pharmaceutical profile, improvement on discontinuation, reappearance on new challenge.
[0555] [0555] A serious adverse event (SAE) was any medically inappropriate occurrence that:
[0556] [0556] Major medical events that may not have resulted in death, immediate life-threatening or necessary hospitalization may have been considered a serious adverse event when, based on appropriate medical judgment, they compromised the patient or required intervention to avoid one of the results listed above.
[0557] [0557] Suspected Unexpected Serious Adverse Reactions (SUSARs) were serious events that were not listed in the IB and that the Investigator identified as related to the product or procedure under investigation.
[0558] [0558] All AEs (serious and non-serious) were collected from ICF signing up to 56 days after the last dose of study drug for patients with ET or up to 56 days after the last dose of study drug for patients who completed the study. (i) Pharmacokinetics and pharmacodynamics
[0559] [0559] Blood samples for determination of serum drug concentrations and PD assessments were collected before and after administration of study drug. The actual date and time (24-hour time) of each sampling was recorded. The number of PK sampling timepoints for any given patient did not exceed the currently planned timepoints. In the case of sudden hemolysis, an additional PK/PD sample was required.
[0560] [0560] End-of-infusion blood samples for PK and PD assessment were collected from the arm opposite the arm used for drug infusion.
[0561] [0561] Assessments for PK/PD were as follows: change in serum concentration of ALXN1210 and eculizumab over time, change in cRBC hemolytic activity over time (exploratory), and change in free and total C5 concentrations over time. over time. (ii) Statistical Methods and Planned Analyzes
[0562] [0562] All data collected were presented in summary tabulations. All data, as well as any results derived from the data, were presented in detailed data listings. Graphical displays have also been provided where appropriate. All analyzes were performed using SAS® release, version 9.4 or higher (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. Continuous variables were summarized using descriptive statistics, including number of observations and mean, standard deviation, median, minimum and maximum values. Categorical variables were summarized by frequency counts and percentage of patients. All statistical tests performed were based on a two-sided significance level of 5%, unless otherwise specified. Any and all exclusions were documented in the patient listings.
[0563] [0563] The details of the statistical analyzes described below were specified in a separate Statistical Analysis Plan (SAP) prior to database locking and analysis. Any change in the data analysis methods described in the protocol required an amendment only if it changed the primary or secondary primary objectives or the conduct of the study. Any other changes to the data analysis methods described in the protocol or SAP, and the rationale for making the change, were described in the clinical study report (CRS). Additional exploratory analyzes of the data were conducted as appropriate.
[0564] [0564] An RSC is produced based on efficacy, safety, PK, and PD, and immunogenicity data when all patients remaining in the study have completed the 26-week randomized treatment period. A final RSC to summarize efficacy, safety, PK and PD, and long-term immunogenicity data is produced upon completion of the study.
[0565] [0565] 195 patients were randomly assigned in a 1:1 ratio to continue on eculizumab (N = 98) or switch to ALXN1210 (N = 97) to ensure at least 172 evaluable patients (assuming no more than a 10% dropout rate). Sample size estimation was based on a non-inferiority design comparing patients treated with ALXN1210 to those treated with eculizumab. The primary endpoint of hemolysis as measured directly by LDH-PCHG from Baseline through Day 183 was used to assess non-inferiority. TABLE 39: SUMMARY OF PARAMETERS USED IN ESTIMATING THE
[0566] [0566] Efficacy analyzes were performed on the Full Analysis Set (FAS). Primary efficacy endpoint analysis, as well as primary secondary endpoint analyses, were also performed on the Per Protocol (PP) set. FAS was the primary population for all efficacy analyses. The FAS included all patients who received at least 1 dose of ALXN1210 or eculizumab.
[0567] [0567] The PP pool, which was finalized prior to the database lock, consisted of FAS patients who met all of the following criteria: • No missed doses of ALXN1210 or no more than 1 dose of eculizumab during the period of 26-week randomized treatment • Met inclusion criteria #2, 3, and 4
[0568] [0568] Safety analyzes were performed on the Safety pool, defined as all patients who received at least 1 dose of ALXN1210 or eculizumab. Pharmacokinetic and PD analyzes were performed on all patients who received at least 1 dose of study drug and who had evaluable PK and PD data. Demographic and baseline characteristics of patients, including medical history and transfusion history, were summarized by treatment group and overall for the FAS and Safety sets. The number of infusions received per patient was tabulated by treatment group for the SAF and Safety sets.
[0569] [0569] The primary efficacy endpoint was the difference between treatment arms in LDH-PCHG from Baseline to Day 183. Baseline was defined as the mean of all assessments analyzed by the central laboratory prior to the first administration of study drug.
[0570] [0570] Percent change in LDH was analyzed using a mixed model for repeated measures (MMRM) with fixed categorical treatment effects, study query, and study query by treatment group interaction as well as the continuous covariate and fixed baseline LDH and pRBC transfusion history randomization indicator stratification (yes/no within 12 months prior to Day 1). The Kenward-Roger approximation was used to estimate denominator degrees of freedom. A difference in LDH-PCHG between the ALXN1210 and eculizumab treatment groups along with a bilateral 95% CI were calculated.
[0571] [0571] If the upper limit of the 95% CI for difference (ALXN1210-eculizumab) was less than the 15% NIM, then treatment with ALXN1210 was considered non-inferior to eculizumab. If non-inferiority was established and a greater effect for ALXN1210 was observed, then superiority was assessed using a 5% two-sided test.
[0572] [0572] Major secondary efficacy endpoints of proportion of patients with sudden hemolysis, change from baseline in FACIT-Fatigue, proportion of patients not requiring a transfusion, and proportion of patients with stabilized hemoglobin were summarized by treatment group . The percentage of patients with sudden hemolysis was calculated for both the ALXN1210 and eculizumab treatment groups. A difference in the percentage of patients with sudden hemolysis in the 2 treatment groups was calculated, along with a 95% CI for the difference. The 95% CI for the difference between the ALXN1210 and eculizumab treatment groups was calculated using the Newcombe confidence interval method. The same approach was used for transfusion prevention and stabilized hemoglobin. Transfusion prevention was achieved only by those patients who did not receive a transfusion and did not meet the guidelines specified by the protocol for transfusion. To change the baseline in FACIT-Fatigue, the same approach used for the primary endpoint was employed.
[0573] [0573] These primary secondary endpoints were tested in a hierarchical manner provided that non-inferiority was declared for the primary endpoint. If non-inferiority was established for a major secondary endpoint and a major effect for ALXN1210 was observed, then superiority was assessed using a two-sided 0.05 test for each endpoint.
[0574] [0574] When performing the analyzes for the major secondary efficacy endpoints, a closed testing procedure was used; lack of significance of one test excluded evaluation of subsequent tests. Estimates and CIs were calculated for all major secondary efficacy endpoints, regardless of whether the lack of significance of one test precluded the assessment of subsequent tests.
[0575] [0575] The total number of units of pRBCs transfused during treatment and the number (%) of patients with LDH within the normal range at each study visit were calculated for both the ALXN1210 and eculizumab treatment groups. Baseline changes in EORTC-QLQ-C30 were summarized by treatment group at baseline and at study visits where these assessments were collected. Baseline changes in clinical manifestations of PNH were summarized by treatment group and at study visits where these assessments were collected. The number of any treatment-emergent MAVEs (n) and the number of patients with events (n, %) were displayed by treatment group.
[0576] [0576] All safety analyzes were performed for the Safety pool, defined as all patients receiving at least 1 dose of ALXN1210 or eculizumab. Safety results were reported by the treatment group.
[0577] [0577] The following definitions were used for AEs:
[0578] [0578] The incidence of TEAEs, TEAEs leading to study withdrawal, TEAEs leading to discontinuation of study treatment, drug-related TEAEs, TEAEs during study drug administration, severe TEAEs, and SAEs was summarized. All AEs were coded using MedDRA version 18 or higher, and were summarized by system organ class (SOC) and PT.
[0579] [0579] Adverse Baseline changes in physical examination findings were classified as AEs and analyzed accordingly. Vital signs were descriptively summarized at time points at Baseline and postbaseline and for Baseline changes by treatment group.
[0580] [0580] Observed baseline values and changes in clinical chemistry, hematology, and urinalysis were descriptively summarized at baseline and at each post-baseline time point. For lab results that can be classified as normal, low, or high based on normal range values, baseline changes in classification have been summarized for all study queries.
[0581] [0581] Per patient data listings of ECG parameters have been provided. Changes from baseline in electrocardiogram intervals (PR, RR, QT, and QTcF) were provided by treatment group. The QT interval was corrected for heart rate using Fridericia's formula (QTcF).
[0582] [0582] Abnormal immunogenicity findings, including incidence and titers to ADAs for ALXN1210 or eculizumab, were summarized in tabular format by treatment group. The proportion of always positive patients and the proportion of always negative patients could have been explored.
[0583] [0583] Individual serum concentration data for all patients who received at least 1 dose of study drug (ie, ALXN1210 or eculizumab) and who had evaluable PK data were used to derive PK parameters for ALXN1210 and eculizumab.
[0584] [0584] Plots were constructed of the mean time-concentration profiles in serum. Serum concentration-time profile plots for individual patients could also have been provided. Actual dose administration and sampling times were used for all calculations. Descriptive statistics were calculated for serum concentration data at each sampling time, as appropriate. Population PK assessment could have been considered using data from this study or in combination with data from other studies.
[0585] [0585] Descriptive statistics were presented for all PD endpoints of ALXN1210 and eculizumab at each sampling time. The PD effects of IV administered ALXN1210 and eculizumab were assessed by evaluating absolute values and percent changes and changes from baseline in serum total and free C5 concentrations and cRBC hemolysis over time, as appropriate. Assessments of PK/PD ratios of ALXN1210 could have been explored using data from this study or in combination with data from other studies.
[0586] [0586] If a Day 1 assessment was absent, the Screening assessment was used as the Baseline Assessment. Missing data for QoL instruments were handled as specified in the instructions for each instrument. EXAMPLE 5: RESULTS OF A PHASE 3 OPEN, RANDOM, ACTIVE CONTROL STUDY OF ALXN1210 VERSUS ECULIZUMAB IN ADULT PATIENTS WITH PAROXYSTIC NOCTURNAL HEMOGLOBINURIA (PNH) PREVIOUSLY TREATED WITH ECULIZUMAB.
[0587] [0587] The following is a summary of data obtained from an open-label, sequential phase 3 clinical study performed according to the protocol described above in Example 4. A summary of efficacy and safety results are presented below.
[0588] [0588] This Phase 3 Human Clinical Trial was an open-label, randomized, active-control study conducted to assess the safety and efficacy of ALXN1210 (also known as Ultomiris™, BNJ441 antibody, or ravulizumab) versus eculizumab (Soliris®) administered by intravenous (IV) infusion for adult PNH patients who have been treated with eculizumab for at least 6 months. The study enrolled 195 patients in total. A total of 191 patients completed the study and 186 of these patients were included in this per-protocol analysis. Only 4 subjects discontinued during the course of the study (1 from the ALXN1210 group and 3 from the eculizumab group).
[0589] [0589] This phase 3 study met its primary endpoint and demonstrated that ALXN1210 (ravulizumab) was non-inferior to eculizumab. Specifically, the study met pre-designated baseline non-inferiority margins (NIM) for percent change in LDH (LDH-PCHG) by margins better than the 15% required by the FDA and as specified in the protocol, but did not achieve completely superior in this study (p<0.0583). In addition, all 4 major secondary endpoints favored ALXN1210 and demonstrated non-inferiority to eculizumab. Sudden hemolysis (BTH) also demonstrated a numerical trend favoring ALXN1210 over eculizumab by 0% versus 5.1% respectively. In fact, no patient on ALXN1210 experienced BTH compared to 5 for eculizumab (1 patient on eculizumab had 3 events of 3 BTH). Importantly, the sensitivity analysis showed robust results in all parameters of efficacy assessment. The data are presented in the attached Figures and Tables and discussed in more detail below.
[0590] [0590] The design of the non-inferiority study comparing ALXN1210 and eculizumab is shown in Figure 25. The study compared a weight-based personalized dose administration schedule for ALXN1210 to the existing approved dose administration schedule for eculizumab in PNH in an attempt to show non-inferiority in PNH patients who had received eculizumab for at least 6 months prior to starting this study. The dose chosen for ALXN1210 was based on weight and comprised a loading dose (2400 mg for patients ≥40 kg to <60 kg, 2700 mg for patients ≥60 kg to <100 kg, 3000 mg for patients ≥100 kg) at day 1, followed by maintenance doses of ALXN1210 (3,000 mg for patients ≥40 kg to <60 kg, 3,300 mg for patients ≥60 to <100 kg, 3,600 mg for patients ≥100 kg) on day 15 and every 8 weeks after that. See Figure 25. On the other hand, the eculizumab dose comprises a maintenance dose of 900 mg administered IV on day 1 and every 2 weeks thereafter. See Figure 25. Upon completion of the study, both subjects in both the ALXN1210 and eculizumab groups entered an extension period as described in Example 4. During the extension period, the ALXN1210 group continued to receive ALXN1210 at every 8 weeks. The eculizumab group received a loading dose of ALXN1210 (2400 mg for patients ≥40 kg to <60 kg, 2700 mg for patients ≥60 kg to <100 kg, 3000 mg for patients ≥100 kg) on day 183, followed by maintenance doses of ALXN1210 (3000 mg for patients ≥40 kg to <60 kg, 3300 mg for patients ≥60 to <100 kg, 3600 mg for patients ≥100 kg) on day 197 and every 8 weeks thereafter. The complete dosing schedule for both the ALXN1210 and eculizumab groups is shown in Figure 26.
[0591] [0591] The study enrolled more patients than originally planned. Specifically, 195 patients enrolled in the study and were randomized to either the ALXN1210 group or the eculizumab group (see Figure 27). A total of 13 subjects failed the screening. Of the 195 patients who entered and completed the 26-week treatment period, 191 continued on the sequence extension study (see Figure 27). The baseline characteristics and demographics of the study population are shown in Figure 28. The baseline characteristics of the disease are shown in Figure 29.
[0592] [0592] Of the 197 randomized patients, 195 treated patients (97 patients in the ALXN1210 group and 98 patients in the eculizumab group) were included in the FAS and Safety Set as set out below in Table 40.
[0593] [0593] Eleven patients were excluded from the PP Set (ALXN1210: n=5, eculizumab, n=6). The reasons for exclusion were as follows. Two patients were randomized but untreated due to patient withdrawal before the first dose (see Table 41). It was determined that two patients in the ALXN1210 group did not meet the criteria to be treated with eculizumab as per the PNH scheduled dose administration recommendation (eculizumab every 14 ± 2 days) within 6 months prior to Day 1, as some of the eculizumab doses were administered outside the ± 2 day window. Two patients in the eculizumab group were determined to have an LDH value > 2 × ULN within 6 months prior to Day 1. Five patients (ALXN1210: n = 2, eculizumab: n = 3) met protocol-specified criteria for pRBC transfusion (hemoglobin ≤ 7 g/dl), but not transfused at that time or at any other time during the Primary Assessment Period. Although other patients met the transfusion criteria in a private consultation but did not receive a transfusion, these patients were included in the PP Set due to the fact that they received at least 1 transfusion according to the transfusion criteria.
[0594] [0594] Three differences in the actual stratification at randomization time compared to the observed stratification for transfusion history occurred in this study, as set out in Table 41. Of the 24 patients stratified for transfusion history “Yes”, 1 patient was determined not to have transfusion history. Of the 173 patients stratified as a “No” transfusion history, 2 patients had a previous transfusion history. TABLE 41: RANDOMIZED AND OBSERVED STRATIFICATION GROUPS (ALL RANDOMIZED PATIENTS) ALXN1210 Eculizumab Group Groups Total Stratification Stratification (N = 98) (N = 99) (N = 197) in Randomization Observed Transfusion history, n (% ) Yes Yes 12 (12.2). 11 (11.1). 23 (11.7). Yes No 0 1 (1.0). 1 (0.5). No Yes 1 (1.0). 1 (1.0). 2 (1.0). No No 85 (86.7). 86 (86.9). 171 (86.8). Note: Baseline was defined as the last non-missing value before the first dose of study drug. The ULN for LDH is 246 U/L.
[0595] [0595] In the study population of patients with stable disease, only 12.8% had a history of pRBC transfusions in the year prior to the first dose of study drug, as shown in Table 42. The mean number of transfusions within 1 year of first dose was higher in the ALXN1210 group than in the eculizumab group, as was the mean number of units transfused. This difference is attributable to 2 ALXN1210 patients heavily transfusion dependent.
[0596] [0596] The types of PNH symptoms that patients experienced prior to informed consent were similar between treatment groups, with the most common (>20% of all patients) fatigue or asthenia (generalized weakness), red or dark urine , abdominal pain and shortness of breath (dyspnea), CNS-related symptoms such as headache, dizziness or difficulty concentrating, jaundice (yellowing of the skin or eyes), and dysphagia.
[0597] [0597] In the total population, 95.4% of patients had documented PNH-associated conditions that were diagnosed prior to informed consent, as shown in Table 43. Note that 37.4% of patients had a history of aplastic anemia, 9 .2% of patients had a history of renal failure and 4.6% of patients had myelodysplastic syndrome.
[0598] [0598] Abbreviation: PNH = paroxysmal nocturnal hemoglobinuria
[0599] [0599] A history of one or more MAVEs was reported for 25.6% of patients overall, as set out below in Table 44.
[0600] [0600] Abbreviation: MAVE = Major Adverse Vascular Event
[0601] [0601] As required, all 195 patients had a history of eculizumab use. Two patients in the ALXN1210 group were not vaccinated for meningococcal infection within 3 years before or at the time of study drug initiation. All other patients received meningococcal vaccine no later than Day 1.
[0602] [0602] The most commonly reported groups (≥10% of patients) of prior medications other than meningococcal vaccine were vitamin B12 and folic acid (59.5%), beta-lactam antibacterials (penicillins) (43.1%), antithrombotic agents (19.0%), drugs for peptic ulcer and gastroesophageal reflux disease (15.4%) and other analgesics and antipyretics (12.8%).
[0603] [0603] Overall, 97.9% of patients (97.9% in the ALXN1210 group and 98.0% in the eculizumab group) took at least one concomitant medication. The most commonly reported groups (≥ 10% of patients) of concomitant medications were vitamin B12 and folic acid (62.1%), beta-lactam antibacterials (penicillins) (52.8%), other analgesics and antipyretics (36.9%) , bacterial vaccines (29.2%), antithrombotics (22.6%), viral vaccines (19.5%), drugs for peptic ulcer and gastroesophageal reflux disease (19.0%), quinolone antibacterials (16.4 %), anti-inflammatory and antirheumatic products, non-steroids (13.3%) and opioids (10.3%). During the study, a total of 30.3% patients underwent a non-pharmacological medical procedure.
[0604] [0604] ALXN1210 achieved statistically significant non-inferiority compared to eculizumab for the primary endpoint, percent change in LDH (LDH-PCHG) from baseline to Day 183, for FAS. Specifically, the LDH percent change primary efficacy endpoint (LDH-PCHG) was very clearly met and exceeded as shown in Figure 30. The red triangle in Figure 30 indicates the non-inferiority margin required by the FDA and as specified in the protocol. For the LDH-PCHG endpoint, the non-inferiority margins of 15% were substantially exceeded and achieved a non-inferiority margin of better than 1%. See Figure 30.
[0605] [0605] Major secondary endpoints: sudden hemolysis (BTH), change in FACIT fatigue score, transfusion prevention (TA), and hemoglobin stabilization (HGB-S) were also positive and favored ALXN1210 over eculizumab ( see Figure 30). Furthermore, not only did all secondary endpoints favor ALXN1210, but they all substantially exceeded the non-inferiority margins shown by the red triangles in the graph (see Figure 30).
[0606] [0606] The primary and secondary endpoints are tabulated in Figure 31. Also shown is the treatment effect for each endpoint in favor of ALXN1210 over that of eculizumab. For example, the first row shows that the treatment effect for percent change in LDH (LDH-PCHG) for ALXN1210 versus eculizumab was -9.2%, much greater than the required non-inferiority margin of 15% and makes clear the finding of non-inferior. Likewise, all primary and secondary endpoints lead to the same conclusion of non-inferior for ALXN1210 versus eculizumab. Presented another way, ALXN1210 was found to be better than eculizumab; conclusions of statistical superiority could not be reached, probably due to the sample size (see Figure 31).
[0607] [0607] Efficacy data from this study for LDH-PCHG underwent multiple different sensitivity analyses. The results are shown in Figure
[0608] [0608] Efficacy results for the primary endpoint of LDH-PCHG were analyzed as subgroups of the patient population and are shown in Figure 33. LDH-PCHG (lactate dehydrogenase percent change) refers to the percent change in LDH from baseline baseline at day 183. Subgroup analyzes for LDH-PCHG revealed that the preponderance of evidence favored ALXN1210. Gray lines have 95% confidence intervals and blue squares are point estimates. The estimation was based on a generalized estimating equation (GHG) approach. The model included the following terms: treatment group, transfusion history, and baseline LDH levels. Estimates to the right of 1 favor ALXN1210 and estimates to the left favor eculizumab. All point estimates were to the right of the non-predefined inferiority margin (red triangle) (15%). No endpoint clearly favored eculizumab. In conclusion, all subgroups favored ALXN1210 over eculizumab (see Figure 33).
[0609] [0609] Figure 34 shows the mean values for percentage change in both baseline (top panel) and total level (bottom panel) of LDH over time. As shown in Figure 34, the mean values for the LDH level were within the normal range of the patient population at baseline and remained below the upper limit of normal (1X LSN LDH) throughout the study for the ALXN1210-treated group. . On the other hand, the mean LDH level exceeded this upper limit of normal in the eculizumab-treated group on days 29, 113, and 127. The dotted line in Figure 34 shows the upper limit of normal value for LDH or 1X ULN LDH. The box below the graph shows the number of patients in each group that contributed to the average for that day. In conclusion, it is clear that the mean LDH value in patients on the ALXN1210 remained below the critical level of 1.5X ULN (see Figure 34). The percentage of patients who maintain LDH normalization at various time points during the course of the study is shown in Figure 35. More than 50% of patients on both ALXN1210 and eculizumab remained in the normal range throughout the study (see Figure 35). Figure 36 shows the mean change in the baseline quality of life assessed using the Chronic Illness Therapy Functional Assessment Fatigue Scale (FACIT), version 4, over time. Figure 37 shows the average value assessed for FACIT fatigue over time. As shown in Figure 36, the mean change from baseline showed improvement for the ALXN1210-treated group throughout the study and at most time points trended higher than the improvement seen in the eculizumab-treated group. However, despite the improvement in FACIT fatigue scores from baseline, no group demonstrated a mean increase greater than 3 points (>3 points) as indicated by the dashed line. The box below the graph shows the number of patients in each group that contributed to the average for that day. As shown in Figure 37, which shows the average scores assessed on the FACIT fatigue scale (0 to 52 where a higher score indicates less fatigue), the ALXN1210-treated group showed higher average FACIT fatigue scores than the eculizumab-treated group on all counts. points in time.
[0610] [0610] In addition, for the primary and secondary endpoints, the following disease-related laboratory endpoints were measured during the study: free hemoglobin, urine occult blood, total C5, haptoglobin, reticulocyte count, RBC clone size of PNH, D-dimer concentration, eGFR, urine albumin:creatinine ratio and C-reactive protein. Total PNH RBC clone size was similar between treatment groups at baseline, with no notable changes in either group during the study. No apparent trend in mean free hemoglobin change from baseline over time was observed in either treatment group. Mean D-dimer levels decreased from baseline at most post-baseline study visits in both treatment groups. Mean haptoglobin was low (reference range: 0.4-2.4 g/l) at baseline and throughout the 26-week treatment period in both treatment groups (ALXN1210: 0.283 g/l to 0.298 g/l). l; eculizumab: 0.255 g/l to 0.257 g/l of baseline on Day 183). Urinary occult blood was negative in most patients in the ALXN1210 and eculizumab treatment groups, and remained negative throughout the treatment period. The reticulocyte/erythrocyte ratio was stable and consistent in both groups throughout the 26-week treatment period (ALXN1210: 5.70% to 6.54%; eculizumab: 5.54% to 5.87% of baseline to Day 183). No notable change from baseline was observed in the mean urine microalbumin:creatinine ratio over time in both treatment groups. Mean C-reactive protein levels were similar between treatment groups at baseline, with little change seen over time in both treatment groups.
[0611] [0611] Figure 38 is a tabulation of key safety outcomes in the Phase III clinical trial of ALXN1210-HPN-301. Overall safety differences in adverse events (AEs) were observed at generally similar rates between ALXN1210 and eculizumab and there were no interruptions due to AEs or deaths observed during the primary assessment period (see Figure 38). Serious adverse events (SAEs) were less frequent for ALXN1210 compared to eculizumab (4% vs. 8%), as shown in Figure 39. The most frequent AEs were headache (27% vs. 17%) and nasopharyngitis. (22% vs. 20%), as shown in Figures 40 and 41. In addition, there were no meningococcal infections during the primary assessment period (see Figure 42).
[0612] [0612] There were no observed anti-drug antibody (ADA) treatment emerging cases observed for ALXN1210 and there was 1 case observed for eculizumab. No neutralizing antibodies were produced and there was no apparent effect on PK/PD, efficacy or safety.
[0613] [0613] Drug suitability was perfect for this clinical trial, demonstrating 100% drug suitability over the 6 month treatment period (see Figure 43).
[0614] [0614] The pharmacokinetic parameters for ALXN1210 are summarized below in Tables 45 and 46 for the first (induction) and last (maintenance) doses, respectively. The geometric mean (geometric CV%) Cmax and Cmin of ALXN1210 following the first dose in all patients was 822.3 (22.03) and 390.9 (26.78) μg/ml, respectively. After the last dose of ALXN1210, the geometric mean (%CV) of Cmax and Cmin in all patients was 1359.3 (19.50) and 479.8 (30.68) μg/ml, respectively. TABLE 45: PHARMACOKINETIC PARAMETERS OF ALXN1210 (Cmax and Cmin) AFTER FIRST DOSE (LOAD) OF ALXN1210 (PHARMACOKINETIC ANALYSIS SET) All ≥ 40 to < 60 ≥ 60 to < 100 ≥ 100 kg Statistical Parameter Patients kg kg (N= 7) (N=96) (N=26) (N=63) n 95 26 62 7 Medium 842.9 903.2 823.1 794.7 SD 203.47 150.42 216.00 239.70 CV% 24.14 16.65 26.24 30.16 Median 811.0 893.0 779.5 802.0 Cmax Minimum 511 656 536 511 (μg/ml) Maximum 1750 1450 1750 1240 Mean 822.3 892.6 801, 0 765.1 geometric
[0615] [0615] Abbreviations: Cmax = maximum serum concentration; Cmin = minimum serum concentration; CV = coefficient of variation; SD = standard deviation TABLE 46: ALXN1210 Pharmacokinetic Parameters (Cmax and Cmin) After Final Maintenance Dose of ALXN1210 (pharmacokinetic analysis set) All ≥ 60 to < 100 ≥ 40 to < 60 kg ≥ 100 kg Parameter Patients kg ( N=27) (N=8) (N=96) (N=61) n 96 27 61 8 Medium 1,384.5 1,561.1 1,347.4 1,071.1 SD 267.61 261.30 231.75 115.87 CV% 19.33 16.74 17.20 10.82 Median 1,395.0 1,520.0 1,360.0 1,040.0 Cmax (μg/ml) Minimum 902 1040 902 924 Maximum 2,320 2,320 1,850 1,240 Average
[0616] [0616] Non-behavioral PK parameters after the last maintenance dose of ALXN1210 are shown in Table 47. Steady PK status of ALXN1210 was achieved after multiple dose administration for all weight-based maintenance doses (Table 48). TABLE 47: SUMMARY OF ALXN1210 PHARMACOKINETIC PARAMETERS
[0617] [0617] Abbreviations: AUCτ = area under the curve of serum concentration versus time during the dose administration interval; Cmax = maximum observed serum concentration; Cmin = concentrations at the end of the dose administration interval; CL = total extraction; CV = coefficient of variation; SD = standard deviation; t max = time to maximum observed serum concentration; V z = volume of distribution in steady state
[0618] [0618] Figure 44 shows the mean serum concentration of each study drug, ALXN1210 and eculizumab, across the study. Administration of a weight-based dose every 8 weeks resulted in maximal steady state and minimal exposures as shown in Figure 44. In addition, serum concentrations of ALXN1210 were consistently higher than the corresponding concentrations of eculizumab at each time point (see Figure 44).
[0619] [0619] Treatment with ALXN1210 resulted in sustained and complete inhibition of C5 complement throughout the trial and each dose administration interval, compared to the larger fluctuations observed for the eculizumab treatment group, as shown in Figure 45.
[0620] [0620] Table 49 summarizes the mean serum free C5 concentration and the number (%) of patients with serum free C5 concentration ≥ 0.5 µg/ml over time after treatment with ALXN1210 (dose based on weight). q8w) or eculizumab (900 mg q2w). Mean free C5 levels were inhibited by more than 99% by the end of the first infusion with ALXN1210 and remained inhibited by more than 99% for the duration of the study treatment period (see Figure 45, Upper Panel). On the other hand, free C5 did not remain inhibited by more than 99% at all times in the eculizumab group (see Figure 45, bottom panel). TABLE 49: MEAN SERUM FREE C5 CONCENTRATION AND NUMBER (PERCENTAGE) OF PATIENTS WITH SERUM FREE C5 CONCENTRATION > 0.5 µg/ml OVER TIME (FULL ANALYSIS SET)
[0621] [0621] Note: One Day 1 baseline free C5 sample from each treatment group was excluded as the data were considered biologically implausible. The exclusion was supported by the paired PK data, as the PK and free C5 samples were collected from the same collection.
[0622] [0622] Note: Days 29, 43, 57, 85, 99, 113, 141, 155 and 169 represent any time for ALXN1210 and pre-dose for eculizumab. For free C5, BLOQ/2=0.00915 μg/ml was used for results that were BLOQ. The percentages were calculated using n as the denominator.
[0623] [0623] ALXN1210 and eculizumab free C5 data are generated from different bioanalytical assays.
[0624] [0624] Abbreviations: BLOQ = below the limit of quantification; C5 = 5's complement component; EOI = end of infusion
[0625] [0625] The mean change (± 95% CI %) from baseline for total serum C5 concentration versus time profile is shown in Figure 46. Total serum C5 values were similar at baseline across treatments and remained unchanged. relatively stable throughout the treatment period, with transient reductions in total C5 concentrations observed for ALXN1210 in the EOI after all infusions. EXAMPLE 6:
[0626] [0626] Descriptive statistics of ravulizumab pharmacokinetic parameters of ALXN-HPN -301 and ALXN-HPN -302 Phase 3 described above are shown below in Table 50.
[0627] [0627] The mean extraction estimate (CL) for ravulizumab was 0.00332 l/h (standard deviation (SD), 0.00094). The mean extraction SD was 0.00266 l/h (0.00054) for patients with body weight ≥ 40 to < 60 kg, 0.00354 l/h (0.00090) for patients with body weight ≥ 60 to < 100 kg, and 0.00441 l/h (0.00096) for patients with a body weight of ≥ 100 kg. The mean terminal elimination half-life (SD) of ravulizumab in 222 Phase 3 PNH patients was 1193 hours or 49.7 (8.94) days. The mean Vss (SD) of ravulizumab was 5.35 (0.916) l.
[0628] [0628] Summaries of individual Bayesian estimates for a Phase 3 study using eculizumab (ECU-MG-301) are presented below in Table 51. TABLE 51: SUMMARY OF INDIVIDUAL BAYESIAN ESTIMATES OF THE FINAL POPULATION OF THE PHARMACOKINETIC MODEL (RUN 72 ) FOR THE STUDY ECU-MG-301 Cmax AUC SS SS ½ life CL V1 V2 Q Observe SS Cmax Cmin Term (l/h) (l) (l) (l/h) of (μg*h/ (μg/ml ) (μg/ml) (h) (μg/ml) ml)
[0629] [0629] For eculizumab, the mean terminal elimination half-life for the ECU-MG-301 Phase 3 study was 436 hours or 18.1 days.
[0630] [0630] A patient who has a complement-associated disorder (eg PNH or aHUS) is treated with a first anti-C5 antibody and then switched to treatment with a different second anti-C5 antibody. In a preferred embodiment, the second anti-C5 antibody binds to a different epitope than the first anti-C5 antibody. To ensure that the first anti-C5 antibody is extracted (e.g., “cleared”) from the patient before the second (different) anti-C5 antibody is administered (e.g., to avoid issues associated with aggregation,
[0631] [0631] In one case, the patient was pretreated with eculizumab and then switched to treatment with a different anti-C5 antibody (e.g. ravulizumab, antibody 7086, antibody 8110, antibody 305LO5, SKY59 antibody, or REGN3918 antibody) . When eculizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, for example, until at least 36, 45, 54, 63, 72, 81, 90, 99, 108, 117, or 126 days have passed after the final administration of eculizumab.
[0632] [0632] In another case, the patient was pretreated with ravulizumab and then switched to treatment with a different anti-C5 antibody (e.g. eculizumab, antibody 7086, antibody 8110, antibody 305LO5, SKY59 antibody, or REGN3918 antibody) . When ravulizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, for example, until at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, or 400 days have passed after the final administration of ravulizumab.
[0633] [0633] In addition or alternatively, techniques are used to extract or enhance the extraction of the first anti-C5 antibody before switching to treatment with a second (different) anti-C5 antibody. Exemplary techniques include, but are not limited to, plasmapheresis, blood transfusions, or administering an antibody against the first anti-C5 antibody (e.g., an anti-eculizumab antibody, an anti-ravulizumab antibody, an anti-7086 antibody, an anti-C5 antibody, an -8110, an anti-305LO5 antibody, an anti-SKY59 antibody, or an anti-REGN3918 antibody) to extract or boost the extraction of the first anti-C5 antibody before a second (different) anti-C5 antibody is administered.
SEQUENCE SUMMARY SEQ ID NO:1
GYIFSNYWIQ SEQ ID NO: 2
EILPGSGSTEYTENFKD SEQ ID NO:3
YFFGSSPNWYFDV SEQ ID NO:4
GASENIYGALN SEQ ID NO:5
GATNLAD SEQ ID NO:6
QNVLNTPLT SEQ ID NO:7 QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWM GEILPGSGSTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARY
FFGSSPNWYFDVWGQGTLVTVSS SEQ ID NO:8 DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGA TNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTK
VEIK SEQ ID NO:9 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKC CVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQF NWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCS
VMHEALHNHYTQKSLSSLGK SEQ ID NO:10 QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWM GEILPGSGSTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR YFFGSSPNWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYT CNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV
DKSRWQEGNVFSCSVMHEALHNHYTQKSLSSLGK SEQ ID NO:11 DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYG ATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQ GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV
TKSFNRGEC SEQ ID NO:12 QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEW MGEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYC
ARYFFGSSPNWYFDVWGQGTLVTVSS SEQ ID NO:13 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVER KCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN
VFSCSVLHEALHSHYTQKSLSLSLGK SEQ ID NO:14 QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWM GEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR YFFGSSPNWYFDVWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYT CNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV
DKSRWQEGNVFSCSVLHEALHSHYTQKSLSSLGK SEQ ID NO:15 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKC CVECPPCPAPPVAGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVQF NWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKV SNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVF
SCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:16 QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWM GEILPGSGSTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR YFFGSSPNWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNF GTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKP KDTLYITREPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQ FNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS
PGK SEQ ID NO:17
GASENIYHALN SEQ ID NO:18
EILPGSGHTEYTENFKD SEQ ID NO:19
GHIFSNYWIQ SEQ ID NO: 20 QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEW MGEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYC ARYFFGSSPNWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQT YTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV
DKSRWQEGNVFSCSVMHEALHNHYTQKSLSSLGK SEQ ID NO: 21
SYAIS SEQ ID NO: 22
GIGPFFGTANYAQKFQG SEQ ID NO: 23
DTPYFDY SEQ ID NO: 24
SGDSIPNYYVY SEQ ID NO: 25
DDSNRPS SEQ ID NO: 26
QSFDSSLNAEV SEQ ID NO: 27 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISVWRQAPGQGLEWMGGIGPF FGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDTPYFD
YWGQGTLVTVSS SEQ ID NO: 28 DIELTQPPSVSVAPGQTARISCSGDSIPNYYVYWYQQKPGQAPVLVIYDDSNRPSGI PERFSGSNSGNTATLTISGTQAEDEADYYCQSFDSSLNAEVFGGGTK LTVL
SEQ ID NO: 29
NYIS SEQ ID NO:30
IIPDDSYTEYSPSFQG SEQ ID NO:31
YEYGGFDI SEQ ID NO:32
SGDNIGNSYVH SEQ ID NO:33
KDNDRPS SEQ ID NO:34
GTYDIESYV SEQ ID NO:35 EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYISWVRQMPGKGLEWMGIIDPDDS YTEYSPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARYEYGGFDI
WGQGTLVTVSS SEQ ID NO:36
SYELTQPPSVSVAPGQTARISCSGDNIGNSYVHWYQQKPGQAPVLVIYKDNDRPS GIPERFSGSNSGNT ATLTISGTQAEDEADYYCGTYDIESYVFGGGTKLTV l SEQ ID NO:37
SSYYVA SEQ ID NO:38
AIYTGSGATYKASWAKG SEQ ID NO:39
DGGYDYPTHAMHY SEQ ID NO:40
QASQNIGSSLA SEQ ID NO:41
GASKTHS SEQ ID NO:42
QSTKVGSSYGNH SEQ ID NO:43 QVQLVESGGGLVQPGGSLRLSCAASGFTSHSSYYVAWVRQAPGKGLEWVGAIYT GSGATYKASWAKGRFTISKDTSKNQVVLTTMNMDPVDTATYYCASDGGYDYPTHA
MHYWGQGTLVTVSS SEQ ID NO:44 DVVMTQSPSSLSASVGDRVTITCQASQNIGSSLAWYQQKPGQAPRLLIYGASKTH SGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQSTKVGSSYGNHFGGGTKVEIK
SEQ ID NO:45 QVQLVESGGGLVQPGRSLRLSCAASGFTVHSSYYMAWVRQAPGKGLEWVGAIFT GSGAEYKAEWAKGRVTISKDTSKNQVVLTTMNMDPVDTATYYCASDAGYDYPTHA MHYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPERRRGPKVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHA
HYTRKELSLSP SEQ ID NO:46 DIQMTQSPSSLSASVGDRVTITCRASQGISSSLAWYQQKPGKAPKLLIYGASETES GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNTKVGSSYGNTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT
EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:47 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSG SSNYNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWG
QGTLVTVSS SEQ ID NO:48 AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQS
GVPSRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK SEQ ID NO:49 QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSG SSNYNPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWG QGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL
SLGK SEQ ID NO:50 AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQS GVPSRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

权利要求:
Claims (59)
[1]
1. Method for treating a human patient with Paroxysmal Nocturnal Hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), the method being characterized in that it comprises administering to the patient during an administration cycle an effective amount of an antibody anti-C5, or antigen binding fragment thereof, comprising heavy chain sequences CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and light chain sequences CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered: (a) once on Day 1 of the administration cycle in a dose of : 2400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg, or 3000 mg for a patient weighing ≥ 100 kg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing ≥ 40 to < 60 kg, 3300 mg for a patient weighing ≥ 60 to < 100 kg, or 3600 mg for a patient weighing ≥ 100 kg.
[2]
2. A method for treating a human patient with Paroxysmal Nocturnal Hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), the method being characterized in that it comprises administering to the patient during an administration cycle an effective amount of an antibody anti-C5, or antigen-binding fragment thereof, comprising heavy chain sequences CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs: 19, 18 and 3, respectively, light chain sequences CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs: 4, 5 and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn substitutions. - 435-Ser at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering, into which the anti-C5 antibody, or antigen-binding fragment thereof, is administered:
(a) once on Day 1 of the dosing cycle at a dose of: 2400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg or 3000 mg for a patient that weighs ≥ 100 kg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing ≥ 40 to < 60 kg, 3300 mg for a patient weighing ≥ 60 to < 100 kg, or 3600 mg for a patient weighing ≥ 100 kg.
[3]
3. Method according to claim 1 or 2, characterized in that the patient was previously treated with eculizumab.
[4]
4. Method according to any one of the preceding claims, characterized in that the administration cycle starts at least two weeks after the patient's last dose of eculizumab.
[5]
A method according to any one of the preceding claims, characterized in that the patient has been treated with eculizumab for at least 6 months prior to Day 1 of the administration cycle.
[6]
6. Method according to any one of the preceding claims, characterized in that the patient was previously treated with eculizumab at a dose of 900 mg every 2 weeks.
[7]
7. Method according to any one of the preceding claims, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region represented in SEQ ID NO:12 and a region light chain variable depicted in SEQ ID NO:8.
[8]
A method according to any one of the preceding claims, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, further comprises a heavy chain constant region represented in SEQ ID NO:13.
[9]
Method according to any one of the preceding claims, characterized in that the antibody, or antigen-binding fragment thereof, comprises a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO:14 and a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:11.
[10]
10. Method according to any one of the preceding claims, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5 at pH 7.4 and 25 °C with a constant dissociation affinity (KD) which is in the range 0.1 nM ≤ KD ≤ 1 nM.
[11]
11. Method according to any one of the preceding claims, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5 at pH 6.0 and 25 °C with a KD ≥ 10 nM.
[12]
12. Method according to any one of the preceding claims, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 to < 60 kg: (a) once on Day 1 of the dosing cycle at a dose of 2400 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg.
[13]
13. Method according to any one of claims 1 to 11, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 60 to < 100 kg: ( a) once on Day 1 of the administration cycle at a dose of 2700 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3300 mg.
[14]
14. Method according to any one of claims 1 to 11, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 100 kg: (a) a once on Day 1 of the dosing cycle at a dose of 3000 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3600 mg.
[15]
A method according to any one of the preceding claims,
characterized by the fact that the treatment maintains a minimum serum concentration of anti-C5 antibody, or antigen-binding fragment thereof, of 100 µg/ml or greater during the administration cycle.
[16]
16. Method according to any one of the preceding claims, characterized in that the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 200 µg/ml or greater during the cycle administration.
[17]
17. Method according to any one of the preceding claims, characterized in that the treatment maintains a free C5 concentration of 0.309 to 0.5 µg/ml or below.
[18]
18. Method according to any one of the preceding claims, characterized in that the treatment reduces the concentration of free C5 by more than 99% throughout the treatment period.
[19]
19. Method according to any one of the preceding claims, characterized in that the treatment reduces the concentration of free C5 by more than 99.5% throughout the treatment period.
[20]
20. Method according to any one of the preceding claims, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, is administered at a dose of 3,000 mg, 3,300 mg or 3,600 mg every eight weeks after the dosing cycle for up to two years.
[21]
21. Method according to any one of the preceding claims, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, is formulated for intravenous administration.
[22]
22. Method according to any one of the preceding claims, characterized in that the administration cycle is a total of 26 weeks of treatment.
[23]
23. Method according to any one of the preceding claims, characterized in that the treatment results in terminal complement inhibition.
[24]
A method according to any one of the preceding claims,
characterized by the fact that treatment results in a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels.
[25]
25. Method according to any one of the preceding claims, characterized in that the treatment results in a normalization of LDH levels.
[26]
26. Method according to any one of the preceding claims, characterized in that the treatment results in a normalization of LDH levels at least on day 24 of treatment.
[27]
27. Method according to any one of the preceding claims, characterized in that the treatment results in a percentage change in LDH levels (LDH-PCHG) of less than 15% compared to treatment with eculizumab.
[28]
28. Method according to any one of the preceding claims, characterized in that the treatment results in a reduction in sudden hemolysis compared to treatment with eculizumab.
[29]
29. Method according to any one of the preceding claims, characterized in that the treatment results in an elimination of sudden hemolysis during the treatment period.
[30]
30. Method according to any one of the preceding claims, characterized in that the treatment results in a reduction of sudden hemolysis compared to the baseline amount of sudden hemolysis pre-treatment.
[31]
31. Method according to any one of the preceding claims, characterized in that the treatment produces at least one therapeutic effect selected from the group consisting of a reduction or cessation of abdominal pain, dyspnea, dysphagia, chest pain, dysfunction erectile.
[32]
32. Method according to any one of the preceding claims, characterized in that the treatment produces a shift towards normal levels of a hemolysis-related hematological biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count ,
Erythrocyte PNH clone (RBC) and D-dimer.
[33]
33. Method according to any one of the preceding claims, characterized in that the treatment produces at least one therapeutic effect selected from the group consisting of a reduction or cessation of severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability , thrombocytopenia, microangiopathic hemolytic anemia and impaired renal function.
[34]
34. Method according to any one of the preceding claims, characterized in that the treatment produces a shift towards normal levels of Factor Ba, soluble tumor necrosis factor 1 receptor [sTNFR1]), soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin, D-dimer, and cystatin C.
[35]
35. Method according to any one of the preceding claims, characterized in that the treatment produces an increase in hemoglobin stabilization from the pre-treatment baseline.
[36]
36. Method according to any one of the preceding claims, characterized in that the treatment produces a reduction in the need for blood transfusions.
[37]
37. Method according to any one of the preceding claims, characterized in that the treatment produces a greater than 70% increase in transfusion prevention.
[38]
38. Method according to any one of the preceding claims, characterized in that the treatment produces a reduction in major adverse vascular events (MAVEs).
[39]
39. Method according to any one of the preceding claims, characterized in that the treatment produces a shift towards normal levels of a biomarker associated with chronic disease selected from the group consisting of glomerular filtration rate (eGFR) and albumin:creatinine in spot urine and plasma brain natriuretic peptide (BNP).
[40]
40. Method, according to any of the previous claims, characterized by the fact that the treatment produces a change from the baseline in quality of life, evaluated through the Chronic Disease Therapy Functional Assessment Fatigue Scale ( FACIT), version 4 and the Quality of Life Questionnaire Core 30 Scale of the European Organization for Research and Treatment of Cancer.
[41]
41. Method, according to any of the previous claims, characterized by the fact that the treatment produces a change from the baseline in quality of life, evaluated through the Functional Assessment Fatigue Scale of Chronic Illness Therapy ( FACIT), version 4 and the European Organization for Research and Treatment of Cancer Quality of Life Scale Core 30 Questionnaire by at least 7 points from the baseline score of the untreated patient.
[42]
42. Kit for treating PNH or aHUS in a human patient, the kit being characterized in that it comprises: (a) a dose of an anti-C5 antibody, or antigen-binding fragment thereof, comprising the domains heavy chain variable region CDR1, CDR2 and CDR3 having the sequence set out in SEQ ID NO:12, and light chain variable region CDR1, CDR2 and CDR3 domains having the sequence set out in SEQ ID NO:8; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in the method of any preceding claim.
[43]
43. Kit, according to claim 42, characterized by the fact that the patient was previously treated with eculizumab.
[44]
44. Kit according to claim 43, characterized in that the patient was previously treated with eculizumab at a dose of 900 mg every 2 weeks.
[45]
45. Kit according to any one of claims 42 to 44, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 40 to < 60 kg: ( a) once on Day 1 of the administration cycle at a dose of 2400 mg; and
(b) on the 15th of the administration.
[46]
46. Kit according to any one of claims 42 to 44, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 60 to < 100 kg: ( a) once on Day 1 of the administration cycle at a dose of 2700 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3300 mg.
[47]
47. Kit according to any one of claims 42 to 44, characterized in that the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing ≥ 100 kg: (a) a once on Day 1 of the dosing cycle at a dose of 3000 mg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3600 mg.
[48]
48. Anti-C5 antibody, or antigen-binding fragment thereof, characterized in that it comprises the CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:12, and CDR1 domains , CDR2 and light chain variable region CDR3 having the sequence set forth in SEQ ID NO:8, for administration in one cycle, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered: (a ) once on Day 1 of the dosing cycle at a dose of: 2400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg, or 3000 mg for a patient weighing ≥ 60 to < 100 kg ≥ 100 kg; and (b) on Day 15 of the dosing cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing ≥ 40 to < 60 kg, 3300 mg for a patient weighing ≥ 60 to < 100 kg, or 3600 mg for a patient weighing ≥ 100 kg.
[49]
49. Anti-C5 antibody, or antigen-binding fragment thereof, according to claim 48, characterized by the fact that the patient was previously treated with eculizumab.
[50]
50. Antibody according to claim 48 or 49, characterized in that the antibody is determined to be safe, tolerable, effective and sufficiently non-immunogenic after multiple IV doses for use in PNH patients.
[51]
51. A method for treating a human patient who has a complement-associated disorder who is being treated with eculizumab, the method being characterized in that it comprises withholding eculizumab treatment and switching the patient to treatment with a different complement inhibitor .
[52]
52. A method for treating a human patient who has a complement-associated disorder who is being treated with ravulizumab, the method being characterized in that it comprises withholding ravulizumab treatment and switching the patient to treatment with a different complement inhibitor .
[53]
53. A method for treating a human patient who has a complement-associated disorder who is being treated with eculizumab, the method being characterized in that it comprises withholding treatment with eculizumab and switching the patient to treatment with an anti-C5 antibody different.
[54]
54. A method for treating a human patient who has a complement-associated disorder who is being treated with ravulizumab, the method being characterized in that it comprises withholding ravulizumab treatment and switching the patient to treatment with an anti-C5 antibody different.
[55]
55. Method according to claim 51 or 52, characterized in that the different complement inhibitor is selected from the group consisting of: a small molecule, a polypeptide, a polypeptide analog, a peptidomimetic, a siRNA or an aptamer.
[56]
56. Method according to claim 51 or 52, characterized in that the different complement inhibitor inhibits one or more of the complement components C1, C2, C3, C4, C5, C6, C7, C8, C9, Factor D, Factor B,
properdin, MBL, MASP-1, MASP-2, or biologically active fragments thereof.
[57]
57. Method according to claim 53, characterized in that the different anti-C5 antibody is ALXN1210.
[58]
58. Method according to claim 53 or 54, characterized in that the different anti-C5 antibody is selected from the group consisting of: (i) an antibody, or antigen-binding fragment thereof, which comprises CDR1, CDR2 and CDR3 heavy chain domains comprising SEQ ID NOs: 21, 22 and 23, respectively, and CDR1, CDR2 and CDR3 light chain domains comprising SEQ ID NOs: 24, 25 and 26, respectively; (ii) an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO: 27 and a light chain variable region comprising SEQ ID NO: 28; (iii) an antibody, or antigen-binding fragment thereof, comprising the heavy chain domains CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 29, 30 and 31, respectively, and light chain domains CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 32, 33 and 34, respectively; (iv) an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO: 35 and a light chain variable region comprising SEQ ID NO: 36; (v) an antibody, or antigen-binding fragment thereof, comprising the heavy chain domains CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 37, 38 and 39, respectively, and light chain domains CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 40, 41 and 42, respectively; (vi) an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO: 43 and a light chain variable region comprising SEQ ID NO: 44; (vii) an antibody, or antigen-binding fragment thereof, comprising a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46; (viii) an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region comprising SEQ ID NO: 47 and a light chain variable region comprising SEQ ID NO: 48; and (ix) an antibody, or antigen-binding fragment thereof, comprising a heavy chain comprising SEQ ID NO: 49 and a light chain comprising SEQ ID NO: 50.
[59]
59. Method according to any one of claims 51 to 58, characterized in that the complement-associated disorder is paroxysmal nocturnal hemoglobinuria (PNH).
Schematic Study Project for Clinical Protocol ALXN1210-PNH-301
Screening up to 4 Random Treatment Period 26 Extension period 2 weeks weeks years
Petition 870200051058, of 04/24/2020, page 278/325 *Loading dose of *Maintenance dose of *ALXN1210 maintenance dose ALXN1210 ALXN1210 continuous Day 1 Day 15 and every 8 weeks every 8 weeks
Patients who have never received complement inhibitors *Dose of *Maintenance dose of 1/46 loading of ALXN1210 ALXN1210 Day 197 and every 8 Day 183 weeks
**Eculizumab induction dose **eculizumab maintenance dose eculizumab Days 1, 8, 15 and 22 Day 29 and every 2 weeks
*Dosage of ALXN1210: loading dose=2400 mg for patients weighing •40 kg to <60 kg, 2700 mg for patients weighing •60 kg to <100 kg, 3000 mg for patients weighing •100 kg, maintenance dose =3000mg for patients weighing •40 kg to <60 kg, 3300mg for patients weighing •60 kg to <100 kg, 3600 mg for patients weighing •100 kg. **Dosage of eculizumab: induction dose = 600 mg; maintenance dose = 900 mg.
patient disposition
screened
Petition 870200051058, of 04/24/2020, page 279/325 Not randomized (a) Randomized (b) 2/46
Completed Week 26 Suspended Treat.
Completed Treat Suspended Treat. (ç)
Extension (d) Extension
*244/246 were included in per-protocol analysis (a) 39 subjects were not screened, but 46 were not screened because several subjects failed to screen more than once (b) Randomized=Treated.(c)=Decision of the doctor (N=1). Individual decision (N=1). (d) Individual's decision not to continue in the extension
Baseline characteristics and demographics
Statistical Variable
Sex
Petition 870200051058, of 04/24/2020, page 280/325 Male Female Female
Age at infusion (years) Mean (SD) Ethnicity (Not Hisp./Lat.)
Race Asian Non-Japanese 3/46
Japanese White Other
Body weight (kg) Mean (SD)
height (cm) Mean (SD)
0 Units 1-14 Units > 14 Units
Core Efficacy Results of Co-Primary Endpoints Dif (95% CI)
Petition 870200051058, of 04/24/2020, page 281/325 Favors Eculizumab Favors ALXN1210 Diff (95% CI) 4/46
Favors Eculizumab Favors ALXN1210
Note: CI=Confidence Interval.
Diff=difference.
TA=Prevention of transfusions.
LDH-N=LDH Normalization Note: Black triangle indicates non-inferiority margin Note: For TA assessment parameters, Dif (95% CI) are based on estimated percentage differences with 95% CI.
For LDH-N, Dif (95% CI) are based on probability index.
Treatment difference is estimated for ALXN1210-eculizumab
Major Efficacy Results of Secondary Endpoints Diff (95% CI) [1] Petition 870200051058, 24/04/2020, pg. 282/325 Change in FACIT Fatigue 5/46 Favors Eculizumab Favors ALXN1210 Note:CI=Confidence Interval. Diff=difference.LDH-PCHG=Percentage change in LDH. BTH=Sudden hemolysis. HGB-S=stabilized hemoglobin. Note: The black triangle indicates the margin of non-inferiority.
[1] For evaluation parameters of LDH-PCHG, BTH and HGB-S, Dif (95% CI) are based on estimated percentage differences with 95% CI
[2] Treatment difference is estimated for ALXN1210-eculizumab except for LDH-PCHG and BTH where the treatment difference is based on eculizumab-ALXN1210
Key effectiveness results of primary and secondary endpoints
Est.(atistic) Parameter for Treatment Effect Conclusion(1) Comparison of Treat. evaluation (feeding)
Petition 870200051058, of 04/24/2020, page 283/325 Co-primary
Difference in Not lesser rate
Non-Inferior Odds Index
Main secondary 6/46
Difference in change % of base Non-inferior reference
Difference in base change Non-inferior reference
Difference in Not lesser rate
Difference in Not lesser rate
Sensitivity analysis for AT
Petition 870200051058, of 04/24/2020, page 284/325 Analysis Treatment Effect
full analysis
By Protocol
pRBC categories: 7/46 and units
Regardless of guidelines specified in the protocol
Regardless of randomization factors

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法律状态:
2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762577244P| true| 2017-10-26|2017-10-26|

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PCT/US2018/057760|WO2019084438A1|2017-10-26|2018-10-26|Dosage and administration of anti-c5 antibodies for treatment of paroxysmal nocturnal hemoglobinuriaand atypical hemolytic uremic syndrome |

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