DOSAGE AND ADMINISTRATION OF ANTI-C5 ANTIBODIES FOR TREATMENT OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) AND ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS)

Abstract

To provide a dosage and administration of anti-C5 antibodies for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS)SOLUTION: Provided are methods for clinical treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) using an anti-C5 antibody or an antigen binding fragment thereof. Provided herein are compositions and methods for treating PNH or aHUS in a human patient, comprising administering to the patient an anti-C5 antibody or an antigen binding fragment thereof, where the anti-C5 antibody or antigen binding fragment thereof is administered (or is for administration) according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 685,505, filed June 15, 2018, U.S. Provisional Patent Application No. 62 / 685,425, filed June 15, 2018, U.S. Provisional Patent Application No. 62 / 662,503, filed April 25, 2018, U.S. Provisional Patent Application No. 62 / 643,608, filed March 15, 2018, U.S. Provisional Patent Application No. 62 / 643,056, filed March 14, 2018, and U.S. Provisional Patent Application No. 62 / 577,244, filed October 26, 2017. The entire contents of the aforementioned applications are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on October 25, 2018, is named AXJ-224PC_SL.txt, and is 59,066 bytes in size. [Background technology]

[0003] The complement system acts in concert with other immunological systems of the body to defend against invading cellular and viral pathogens. There are at least 25 complement proteins found as a complex collection of plasma proteins and membrane cofactors. Plasma proteins constitute approximately 10% of the globulins in vertebrate serum. Complement components achieve their immune defense function by interacting in a series of complex yet 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 can be found, for example, in The Merck Manual, 16 th It is available in the Edition.

[0004] A properly functioning complement system provides a robust defense against infectious microorganisms, but inappropriate regulation or activation of the complement pathway is involved in the pathogenesis of various disorders, including paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Both PNH and aHUS are extremely rare disorders driven by chronic, uncontrolled complement activation. The resulting inflammation and cellular damage lead to the devastating clinical manifestations of these diseases.

[0005] PNH is a condition in which uncontrolled complement activity leads to systemic complications primarily through intravascular hemolysis and platelet activation (see Socie G, et al., French Society of Haematology. Lancet. 1996;348(9027):573-577 and Brodsky, R., Blood. 2014;124(18):2804-2811). Persistent intravascular hemolysis can be triggered by various stressors, such as infection or physical exertion, which leads to smooth muscle contraction (free hemoglobin), chronic anemia, and an increased risk of severe thromboembolism. Thromboembolism is the most common cause of death in patients with PNH, and pulmonary hypertension and end-organ damage to vital organs such as the liver, kidneys, brain, and intestine are sequelae of such events (Hillmen, P., et al, Am. J. Hematol. 2010;85(8):553-559). Due to these deleterious pathological processes, Patients with PNH have a reduced quality of life (QoL), which can include debilitating fatigue, chronic pain, poor physical function, shortness of breath, abdominal pain, erectile dysfunction, the need for anticoagulation, blood transfusions, and in some cases, the need for dialysis (Weitz, I.C., et al., Thromb Res. 2012;130(3):361-368).

[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 called Shiga toxin-producing E. coli (STEC)-HUS or typical 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 preceding illness with Shiga-like toxin-producing bacteria, such as E. coli O157:H7.

[0007] aHUS can be hereditary, acquired, or idiopathic.Hereditary forms of aHUS can be associated with mutations in several 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 108:1267-1279.A specific mutation in the gene encoding CD55 Mutations in , although not yet associated with aHUS, are associated with the severity of aHUS. See, e.g., Esparza-Gordillo et al. (2005) Hum Mol Genet 14:703-712.

[0008] aHUS is rare and has a mortality rate of up to 25%. Many patients with the disease sustain permanent neurological or renal damage; for example, at least 50% of patients with aHUS progress to end-stage renal failure (ESRF). See, e.g., Kavanagh et al. (2006) British Medical Bulletin 77 and 78:5-22. Until recently, patients with aHUS Treatment options for aHUS have been limited and often include plasma infusion or plasma exchange. In some cases, aHUS patients undergo unilateral or bilateral nephrectomy or kidney transplantation (see Artz et al. (2003) Transplantation 76:821-826). However, disease recurrence in treated patients is common. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Caprioli et al., Blood (2006) 108:1267-1279 [Non-patent document 2] Esparza-Gordillo et al. Hum Mol Genet (2005) 14:703~712 [Non-patent document 3] Kavanagh et al., British Medical Bulletin (2006) 77 and 78:5-22 [Non-patent document 4] Artz et al., Transplantation (2003) 76:821-826 Summary of the Invention [Means for solving the problem]

[0010] Patients with PNH or aHUS are at risk of substantial morbidity and mortality. Accordingly, it is an object of the present invention to provide improved methods for treating patients with PNH or aHUS.

[0011] Provided herein are compositions and methods for treating PNH or aHUS in a human patient, comprising 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 specific clinical dosage regimen (i.e., at a specific dose and according to a specific dosing schedule).

[0012] Any suitable anti-C5 antibody or antigen-binding fragment thereof can be used in the methods described herein. An exemplary anti-C5 antibody is ravulizumab (also known as Ultomiris™, ALXN1210, and antibody BNJ441), or an antigen-binding fragment and variant thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively. In other embodiments, the antibody comprises the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises the heavy chain constant region set forth in SEQ ID NO: 13.

[0013] 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, respectively, in EU numbering, of the native human IgG Fc constant region.

[0014] In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences 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-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of the native human IgG Fc constant region.

[0015] In another embodiment, the antibody has a K D Affinity dissociation constants (K) in the range of ≦1 nM D In another embodiment, the antibody binds to human C5 at a K D In yet another embodiment, the K of the antibody or antigen-binding fragment thereof against human C5 at pH 6.0 and 25°C is ≥ 10 nM. D ) / (K of an antibody or antigen-binding fragment thereof against human C5 at pH 7.4 and 25°C D )] is greater than 25.

[0016] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patent Nos. 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. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having 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 the 7086 antibody having the sequence set forth in SEQ ID NO: 27 and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO: 28.

[0017] Another exemplary anti-C5 antibody is the 8110 antibody, also described in U.S. Patent Nos. 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 heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs:29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs:32, 33, and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO:35 and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO:36.

[0018] 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 CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains 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 forth in SEQ ID NO: 43 and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO: 44.

[0019] Another exemplary anti-C5 antibody is the SKY59 antibody described in Fukuzawa T., et al., Rep. 2017 Apr 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.

[0020] Another exemplary anti-C5 antibody is the REGN3918 antibody (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.

[0021] In another embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as an antibody described above (e.g., eculizumab, ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody). In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% variable region identity) with an antibody described above.

[0022] In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. 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 kg but < 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 kg but < 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, the dosage regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0023] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered in one or more administration cycles. 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 8 weeks thereafter. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every 8 weeks (e.g., at a dose of 3000 mg, 3300 mg, or 3600 mg) for an extension period of up to 2 years after the administration cycle.

[0024] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered in one or more administration cycles. In one embodiment, the administration cycle is 26 weeks. In another embodiment, the treatment includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles. In another embodiment, the treatment continues for the life of the human patient.

[0025] In another embodiment, a method of treating a human patient with PNH or aHUS comprises administering to the patient, during an administration cycle, an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) Once on day 1 of a dosing cycle, at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) On day 15 of the dosing cycle, and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. A method is provided in which the

[0026] In another embodiment, a method of treating a human patient with PNH or aHUS comprises administering to the patient, during an administration cycle, an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, the CDR1, CDR2, and CDR3 light chain sequences 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-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc constant region; and wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) Once on day 1 of a dosing cycle, at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) On day 15 of the dosing cycle, and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. A method is provided in which the

[0027] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg. (a) at a dose of 2400 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3000 mg It is administered.

[0028] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 to < 100 kg. (a) at a dose of 2700 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3300 mg It is administered.

[0029] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧100 kg. (a) at a dose of 3000 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3600 mg It is administered.

[0030] In some embodiments, the patient has not been previously treated with a complement inhibitor (eg, the patient is a complement inhibitor treatment naive patient).

[0031] In other embodiments, the patient has previously been treated with one anti-C5 antibody or its antigen-binding fragment 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 during the treatment period (e.g., 26 weeks), and then treated with another anti-C5 antibody (e.g., ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody), for example, during the extension period. In another embodiment, eculizumab is administered to a patient at a dose of 600 mg on days 1, 8, 15, and 22 of a dosing cycle during an induction phase, followed by a maintenance dose of 900 mg eculizumab on day 19 of the dosing cycle and every two weeks thereafter (e.g., for a total of 26 weeks), followed by treatment with ravulizumab for an extension period of up to two years. In another embodiment, a patient is treated with ravulizumab (e.g., for 26 weeks), and then treated with another anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody), for example, during an extension period.

[0032] Exemplary alternative anti-C5 antibodies include (i) ALXN1210, (ii) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 24, 25, and 26, respectively, (iii) 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, (iv) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 32, 33, and 34, respectively, (v) 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, (vi) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 40, 41, and 42, respectively; (vii) 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; (viii) 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; (ix) 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 (x) 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.

[0033] In some embodiments, the patient has been previously treated with an anti-C5 antibody or antigen-binding fragment thereof (e.g., eculizumab) 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 before switching to another anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab). In certain embodiments, the patient has been previously treated with eculizumab for at least 6 months.

[0034] In another embodiment, when a patient (e.g., a PNH or aHUS patient) is treated with a first anti-C5 antibody and then switched to treatment with a second, different anti-C5 antibody, particularly when the second, different anti-C5 antibody binds to a different epitope on C5 than the first anti-C5 antibody, the administration schedule takes into account the half-life of the first anti-C5 antibody. For example, the half-life of the first anti-C5 antibody is taken into account to ensure that the first anti-C5 antibody is removed (e.g., "washed out") from the patient before the second (different) anti-C5 antibody is administered (e.g., to avoid problems associated with aggregation, immune complex formation, etc.). In one embodiment, the second (different) anti-C5 antibody is not administered until a period of time equivalent to 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, or 7.5 half-lives of the first anti-C5 antibody has elapsed after the final administration of the first anti-C5 antibody.

[0035] In another embodiment, the patient has previously been treated with eculizumab and is then switched to treatment with a second (different) anti-C5 antibody (e.g., ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody). In one embodiment in which eculizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered until, for example, at least 36, 45, 54, 63, 72, 81, 90, 99, 108, 117, or 126 days after the last administration of eculizumab.

[0036] In another embodiment, the patient has previously been treated with ravulizumab and is then switched to treatment with a different anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody). In one embodiment in which ravulizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered until, for example, at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 375, or 400 days have passed since the last administration of ravulizumab.

[0037] Additionally or alternatively, techniques are used to remove or enhance the clearance 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 or transfusion. 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 antibody, or an anti-REGN3918 antibody) is administered to remove or enhance the clearance of the first anti-C5 antibody before the second (different) anti-C5 antibody is administered.

[0038] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof (e.g., ALXN1210) is administered to a patient and the administration cycle begins at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 7 weeks, or at least about 8 weeks after the patient's last dose of eculizumab. In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof (e.g., ALXN1210) is administered to a patient and the administration cycle begins at least 2 weeks after the patient's last dose of eculizumab.

[0039] In some embodiments, patients treated according to the methods described herein have been vaccinated against meningococcal infection within three years prior to or at the time of initiating treatment. In one embodiment, patients treated less than two weeks after receiving a meningococcal vaccine are also treated with appropriate prophylactic antibiotics up to two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serogroups A, C, Y, W135, and / or B.

[0040] In another aspect, the described treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. For example, in one embodiment, the treatment is for a period 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, 275, 280, 285, 290, 300, 305, 310, 315, 320, 325, 330, 340, 345, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 710, 720, 730, 740, 750, 760 The treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 50, 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 higher. In one embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 100 μg / ml or higher. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 150 μg / ml or higher. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 200 μg / ml or higher. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 250 μg / ml or higher. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 300 μg / ml or higher. In another embodiment, the treatment maintains a serum trough 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 serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 175 μg / ml.

[0041] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered at a concentration of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 160 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, 600 μg, 610 μg, 620 μg, 630 μg, In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 50 μg and 250 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 100 μg and 200 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain about 175 μg of antibody per milliliter of blood in the patient.

[0042] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a minimum free C5 concentration. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL, or less. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a free C5 concentration of 0.309-0.5 μg / mL or less. In another embodiment, the treatment described herein reduces free C5 concentrations by greater than 99% throughout the treatment period. In another embodiment, the treatment reduces free C5 concentrations by greater than 99.5% throughout the treatment period.

[0043] The anti-C5 antibody or antigen-binding fragment thereof can be administered to a patient by any suitable means. In one embodiment, the antibody is formulated for intravenous administration.

[0044] The effectiveness of the treatment method provided herein can be evaluated using any suitable means.In one embodiment, for PNH patients, treatment produces at least one therapeutic effect selected from the group consisting of fatigue, abdominal pain, dyspnea, dysphagia, chest pain and erectile dysfunction, which is reduced or stopped.In another embodiment, for aHUS patients, treatment produces at least one therapeutic effect selected from the group consisting of severe hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia and renal dysfunction (e.g., acute renal failure).

[0045] In other embodiments, the treatment results in terminal complement inhibition.

[0046] In other embodiments, treatment results in a shift toward normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone, and D-dimer. In another embodiment, treatment results in an increase in hemoglobin stabilization from the patient's pre-treatment baseline.

[0047] In other embodiments, treatment includes monitoring estimated glomerular filtration rate (eGFR) and spot urine: albumin: creatinine and plasma brain natriuretic peptide (BNP). The method results in a shift towards normal levels of a chronic disease-associated biomarker selected from the group consisting of:

[0048] In other embodiments, treatment results in a reduction in the need for blood transfusions. In another embodiment, treatment results in a greater than 70% increase in transfusion avoidance.

[0049] In other embodiments, treatment results in a reduction in breakthrough hemolysis compared to treatment with eculizumab. In another embodiment, treatment results in the elimination of breakthrough hemolysis during the treatment period. In another embodiment, treatment results in a reduction in breakthrough hemolysis compared to the pre-treatment baseline amount of breakthrough hemolysis.

[0050] In other embodiments, treatment results in a reduction in major adverse vascular events (MAVE).

[0051] In other embodiments, treatment includes Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (FACIT-Fatigue). In another embodiment, treatment results in a change from baseline in quality of life, as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, Version 4, and the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale, of at least 7 points from the patient's untreated baseline score.

[0052] In another embodiment, treatment results in no change in quality of life (QoL) as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4, from baseline to day 183. In another embodiment, treatment results in an increase in quality of life (QoL) as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4, from baseline to day 183. In another embodiment, treatment results in transfusion avoidance from baseline to day 183. In another embodiment, treatment results in the avoidance of a decrease of ≧2 g / dL from baseline in hemoglobin levels without transfusions from baseline to day 183.

[0053] In other embodiments, lactate dehydrogenase (LDH) levels are used to assess responsiveness to treatment (e.g., a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels indicates an improvement in at least one symptom of PNH). For example, in one embodiment, the treatments described herein result in normalization of LDH levels. In another embodiment, patients treated according to the disclosed methods experience a reduction in LDH levels to near normal levels or to within 10% or 20% above levels considered normal (e.g., within 105-333 IU / L (International Units per Liter)). In another embodiment, the patient's LDH levels are normalized throughout the maintenance period of treatment. In another embodiment, the treated patient's LDH levels are normalized at least 95% of the time during the maintenance period of treatment. In another embodiment, 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 embodiment, the patient's LDH level is 1.5 times or more above the upper limit of normal (LDH≧1.5×ULN) before treatment begins. In another embodiment, treatment results in normalization of LDH levels by at least 24 days of treatment. In one embodiment, a patient treated according to the disclosed methods experiences a reduction in LDH levels to within normal levels, or to within 10%, 20%, 30%, 40%, or 50% below what is considered the upper limit of normal (e.g., within 105-333 IU / L (International Units per Liter)). In one embodiment, the patient's LDH level is 1.5 times or more above the upper limit of normal (LDH≧1.5×ULN) before treatment begins. In one embodiment, treatment results in LDH levels below 2× the upper limit of normal (ULN).

[0054] In another embodiment, to a patient with PNH or aHUS: (a) Once on day 1 of a dosing cycle, at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) On day 15 of the dosing cycle, and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. An anti-C5 antibody or antigen-binding fragment thereof for administration is provided, which comprises the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8.

[0055] In one embodiment, the antibody is determined to be safe, tolerated, and sufficiently non-immunogenic after multiple IV doses for use in PNH and aHUS patients.

[0056] Further provided are kits comprising a pharmaceutical composition containing an anti-C5 antibody or antigen-binding fragment thereof, e.g., antibody ravulizumab, in a therapeutically effective amount adapted for use in the methods described herein, and a pharmaceutically acceptable carrier. 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 a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of a light chain variable region 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. Includes.

[0057] In one embodiment, 2400 mg or 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥40 kg but <60 kg. In another embodiment, 2700 mg or 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥60 kg but <100 kg. In another embodiment, 3000 mg or 3600 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥100 kg.

[0058] In another aspect, a method of treating a human patient with a complement-related disorder is provided. In one embodiment, the method includes treating a human patient with a complement-related disorder who is being treated with eculizumab, comprising discontinuing eculizumab treatment and switching the patient to treatment with a different complement inhibitor. In another embodiment, the method includes treating a human patient with a complement-related disorder who is being treated with ravulizumab, comprising discontinuing ravulizumab treatment 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, an 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).

[0059] Exemplary complement-associated conditions that can be treated according to the methods described herein include rheumatoid arthritis, antiphospholipid syndrome, lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense deposit disease, neuromyelitis optica, multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous fetal loss, thrombotic thrombocytopenic purpura, microimmune vasculitis, epidermolysis bullosa, recurrent fetal loss, traumatic brain injury, myocarditis, cerebrovascular disease, peripheral vascular disease, renal vascular disease, mesenteric / intestinal vasculopathy, vasculitis, Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, and immune complex vasculitis. vasculitis), high These conditions include, but are not limited to, Yasu's disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki disease, venous gas embolus, restenosis after stent placement, rotational atherectomy, percutaneous transluminal coronary angioplasty, myasthenia gravis, cold agglutinin disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid syndrome, Graves' disease, atherosclerosis, Alzheimer's disease, systemic inflammatory response, sepsis, septic shock, spinal cord injury, glomerulonephritis, graft rejection, Hashimoto's thyroiditis, type 1 diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture's syndrome, Degos' disease, and catastrophic antiphospholipid syndrome. In one embodiment, the complement-associated condition is PNH. In another embodiment, the complement-associated condition is aHUS. The present invention provides, for example, the following items. (Item 1) 1. A method of treating a human patient with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), comprising administering to the patient during an administration cycle an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) once on day 1 of the administration cycle, at a dose of 2400 mg for patients weighing ≥ 40 kg to < 60 kg, 2700 mg for patients weighing ≥ 60 kg to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; and (b) on day 15 of the administration cycle, and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 kg to < 60 kg, 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg Administered, method. (Item 2) 1. A method of treating a human patient with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), comprising administering to the patient, during an administration cycle, an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, the CDR1, CDR2, and CDR3 light chain sequences 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-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc constant region, and wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) once on day 1 of the administration cycle, at a dose of 2400 mg for patients weighing ≥ 40 kg to < 60 kg, 2700 mg for patients weighing ≥ 60 kg to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; and (b) on day 15 of the administration cycle, and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 kg to < 60 kg, 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg Administered, method. (Item 3) 3. The method of item 1 or 2, wherein the patient has been previously treated with eculizumab. (Item 4) The method of any one of the preceding items, wherein the administration cycle begins at least 2 weeks after the patient's last dose of eculizumab. (Item 5) The method of any one of the preceding items, wherein the patient has been treated with eculizumab for at least 6 months prior to day 1 of the administration cycle. (Item 6) The method of any one of the preceding items, wherein the patient has previously been treated with eculizumab at a dose of 900 mg every two weeks. (Item 7) The method of any one of the preceding items, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 12 and a light chain variable region set forth in SEQ ID NO: 8. The method of any one of the preceding items, wherein the anti-C5 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region set forth in SEQ ID NO: 13. (Item 9) The method of any one of the preceding items, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11. (Item 10) The anti-C5 antibody or antigen-binding fragment thereof has a K D Affinity dissociation constants (K) in the range of ≦1 nM D ) binds to human C5. (Item 11) The anti-C5 antibody or antigen-binding fragment thereof is D The method of any one of the preceding items, wherein the antibody binds to human C5 at ≧10 nM. (Item 12) The anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧40 kg to <60 kg, (a) at a dose of 2400 mg once on day 1 of said administration cycle; and (b) The method of any one of the preceding items, wherein the medicament is administered at a dose of 3000 mg on day 15 of the administration cycle and every 8 weeks thereafter. (Item 13) The anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 kg to < 100 kg, (a) at a dose of 2700 mg once on day 1 of the administration cycle; and (b) The method of any one of items 1 to 11, wherein (b) the medicament is administered at a dose of 3300 mg on day 15 of the administration cycle, and every 8 weeks thereafter. (Item 14) The anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg, (a) at a dose of 3000 mg once on day 1 of said administration cycle; and (b) The method of any one of items 1 to 11, wherein (b) the medicament is administered at a dose of 3600 mg on day 15 of the administration cycle, and every 8 weeks thereafter. (Item 15) The method of any one of the preceding items, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at or above 100 μg / ml during the administration cycle. (Item 16) The method of any one of the preceding items, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at or above 200 μg / ml during the administration cycle. (Item 17) 3. The method of any one of the preceding items, wherein the treatment maintains a free C5 concentration of 0.309 μg / mL to 0.5 μg / mL or less. (Item 18) 3. The method of any one of the preceding items, wherein the treatment reduces free C5 levels by greater than 99% throughout the treatment period. (Item 19) 3. The method of any one of the preceding items, wherein the treatment reduces free C5 levels by greater than 99.5% throughout the treatment period. (Item 20) The method of any one of the preceding items, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg, 3300 mg, or 3600 mg every 8 weeks for up to 2 years following the administration cycle. (Item 21) The method of any one of the preceding items, wherein the anti-C5 antibody or antigen-binding fragment thereof is formulated for intravenous administration. (Item 22) Item 10. The method of any one of the preceding items, wherein the administration cycle is a total of 26 weeks of treatment. (Item 23) The method of any one of the preceding items, wherein the treatment results in terminal complement inhibition. (Item 24) The method of any one of the preceding items, wherein the treatment results in a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels. (Item 25) The method of any one of the preceding items, wherein the treatment results in normalization of LDH levels. (Item 26) The method of any one of the preceding items, wherein the treatment results in normalization of LDH levels by at least 24 days of treatment. (Item 27) The method of any one of the preceding items, wherein the treatment results in a percent change in LDH levels (LDH-PCHG) of less than 15% compared to treatment with eculizumab. (Item 28) The method of any one of the preceding items, wherein the treatment results in a reduction in breakthrough hemolysis compared to treatment with eculizumab. (Item 29) Item 10. The method of any one of the preceding items, wherein the treatment results in the disappearance of breakthrough hemolysis during the treatment period. (Item 30) Item 10. The method of any one of the preceding items, wherein the treatment results in a reduction in breakthrough hemolysis compared to a pre-treatment baseline amount of breakthrough hemolysis. (Item 31) The method of any one of the preceding items, wherein the treatment results in at least one therapeutic effect selected from the group consisting of a reduction or cessation of abdominal pain, dysphagia, dysphagia, chest pain, and erectile dysfunction. (Item 32) The method of any one of the preceding items, wherein the treatment results in a shift toward normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone, and D-dimer. (Item 33) The method according to any one of the preceding items, wherein the treatment produces at least one therapeutic effect selected from the group consisting of severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and reduction or cessation of renal dysfunction. (Item 34) The method of any one of the preceding items, wherein the treatment results in a shift toward normal levels of Ba factor, soluble tumor necrosis factor receptor 1 [sTNFR1], soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin, D-dimer, and cystatin C. (Item 35) The method of any one of the preceding items, wherein the treatment results in an increase in hemoglobin stabilization from a pre-treatment baseline. (Item 36) 20. The method of any one of the preceding items, wherein the treatment results in a reduction in the need for blood transfusions. (Item 37) 20. The method of any one of the preceding items, wherein the treatment results in a greater than 70% increase in transfusion avoidance. (Item 38) The method of any one of the preceding items, wherein the treatment results in a reduction in major adverse vascular events (MAVE). (Item 39) The method of any one of the preceding paragraphs, wherein the treatment results in a shift toward normal levels of a chronic disease-associated biomarker selected from the group consisting of estimated glomerular filtration rate (eGFR) and spot urine:albumin:creatinine and plasma brain natriuretic peptide (BNP). (Item 40) The method of any one of the preceding items, wherein the treatment results in a change from baseline in quality of life as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale. (Item 41) 2. The method of any one of the preceding items, wherein the treatment results in a change from baseline in quality of life, as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale, of at least 7 points from the patient's untreated baseline score. (Item 42) 1. A kit for treating PNH or aHUS in a human patient, comprising: (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of a light chain variable region 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 method of any one of the preceding items. Includes a kit. (Item 43) Item 44. The kit of Item 42, wherein the patient has previously been treated with eculizumab. 44. The kit of item 43, wherein the patient has previously been treated with eculizumab at a dose of 900 mg every two weeks. (Item 45) The anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧40 kg to <60 kg, (a) at a dose of 2400 mg once on day 1 of a dosing cycle; and (b) on the 15th day of the administration 45. The kit of any one of items 42 to 44, wherein the kit is administered intravenously. (Item 46) The anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 kg to < 100 kg, (a) at a dose of 2700 mg once on day 1 of a dosing cycle; and (b) The kit of any one of items 42 to 44, administered at a dose of 3300 mg on day 15 of the administration cycle and every 8 weeks thereafter. (Item 47) The anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg, (a) at a dose of 3000 mg once on day 1 of a dosing cycle; and (b) The kit of any one of items 42 to 44, administered at a dose of 3600 mg on day 15 of the administration cycle and every 8 weeks thereafter. (Item 48) an anti-C5 antibody or antigen-binding fragment thereof, comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8, for administration in cycles; (a) once on day 1 of the administration cycle, at a dose of 2400 mg for patients weighing ≥ 40 kg to < 60 kg, 2700 mg for patients weighing ≥ 60 kg to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; and (b) on day 15 of the administration cycle, and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 kg to < 60 kg, 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg An anti-C5 antibody or antigen-binding fragment thereof is administered. (Item 49) 49. The anti-C5 antibody or antigen-binding fragment thereof of item 48, wherein the patient has been previously treated with eculizumab. (Item 50) 50. The antibody of paragraph 48 or 49, determined to be safe, tolerated, effective and sufficiently non-immunogenic after multiple IV doses for use in PNH patients. (Item 51) 1. A method of treating a human patient having a complement-associated disorder who is being treated with eculizumab, comprising discontinuing treatment with eculizumab and switching the patient to treatment with a different complement inhibitor. (Item 52) 1. A method of treating a human patient having a complement-associated disorder who is being treated with ravulizumab, comprising discontinuing treatment with ravulizumab and switching the patient to treatment with a different complement inhibitor. (Item 53) 1. A method of treating a human patient having a complement-associated disorder who is being treated with eculizumab, comprising discontinuing treatment with eculizumab and switching the patient to treatment with a different anti-C5 antibody. (Item 54) 1. A method of treating a human patient having a complement-associated disorder who is being treated with ravulizumab, comprising discontinuing treatment with ravulizumab and switching the patient to treatment with a different anti-C5 antibody. (Item 55) 53. The method of claim 51 or 52, wherein the different complement inhibitors are selected from the group consisting of small molecules, polypeptides, polypeptide analogs, peptidomimetics, siRNAs, or aptamers. (Item 56) 53. The method of claim 51 or 52, wherein the different complement inhibitors inhibit 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. (Item 57) 54. The method of claim 53, wherein the different anti-C5 antibody is ALXN1210. (Item 58) the different anti-C5 antibodies (i) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 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 heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains 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 heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains 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 55. The method of item 53 or 54, selected from the group consisting of: (Item 59) 59. The method of any one of items 51 to 58, wherein the complement-associated disorder is paroxysmal nocturnal hemoglobinuria (PNH). [Brief explanation of the drawings]

[0060] [Figure 1] FIG. 1 is a schematic diagram showing the design of the Phase III ALXN1210-PNH-301 clinical trial in complement inhibitor treatment-naive PNH patients.

[0061] [Figure 2] Figure 2 is a schematic diagram showing patient disposition in Phase 3 ALXN1210-PNH-301.

[0062] [Figure 3] Figure 3 is a schematic showing the baseline characteristics and demographics of patients in the Phase III ALXN1210-PNH-301 clinical trial.

[0063] [Figure 4] Figure 4 is a graphical overview showing key efficacy results for the two co-primary endpoints.

[0064] [Figure 5] Figure 5 is a graphical representation of key secondary endpoints showing that all endpoints favored ULTOMIRIS (ALXN1210) and exceeded the non-inferiority margin indicated by the red triangles in the graphs.

[0065] [Figure 6] Figure 6 presents a graphical representation of key results from both the primary and secondary endpoints.

[0066] [Figure 7] Figure 7 is a table showing the results from a multiple sensitivity analysis of the efficacy results.

[0067] [Figure 8] FIG. 8 is a graphical overview showing subgroups in which ravulizumab (ALXN1210) has advantage over eculizumab.

[0068] [Figure 9] Figure 9 is a graphical representation of LDH levels over time in patients treated with either ravulizumab (ALXN1210) or eculizumab.

[0069] [Figure 10] FIG. 10 is a graphical representation of the time to reach normalization of LDH (LDH-N) for patients treated with either ravulizumab (ALXN1210) or eculizumab.

[0070] [Figure 11] FIG. 11 is a graphical representation of the percentage of patients achieving normalization of LDH under ravulizumab (ALXN1210) or eculizumab at various time points from day 8 to day 183.

[0071] [Figure 12] Figure 12 is a graphical representation of the percentage of patients with a 10-point improvement from baseline by visit (full analysis set) according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 General Health Subscale.

[0072] [Figure 13] FIG. 13 is a graphical representation of the percentage of patients with a 10-point improvement from baseline per visit (full analysis population) according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Physical Function Subscale.

[0073] [Figure 14] FIG. 14 is a graphical representation of the percentage of patients with a 10-point improvement from baseline per visit (full analysis population) according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Fatigue subscale.

[0074] [Figure 15] Figure 15 is a chart of key safety results from the Phase 3 ALXN1210-PNH-301 clinical trial.

[0075] [Figure 16] Figure 16 is a chart of the most common treatment-emergent adverse events (TEAEs) in the Phase III ALXN1210-PNH-301 clinical trial.

[0076] [Figure 17]FIG. 17 is a chart of treatment-emergent serious adverse events (TESAEs) in the Phase 3 ALXN1210-PNH-301 clinical trial.

[0077] [Figure 18] FIG. 18 is a chart of treatment-emergent adverse events (TEAEs) of particular interest in the Phase III ALXN1210-PNH-301 clinical trial.

[0078] [Figure 19] FIG. 19 is a table of patient compliance results in the Phase III ALXN1210-PNH-301 clinical trial.

[0079] [Figure 20] FIG. 20 is a graphical depiction of the pharmacokinetics (PK) of ravulizumab (ALXN1210) and eculizumab showing serum concentrations of each drug over time (linear scale).

[0080] [Figure 21] FIG. 21 is a graphical depiction of the pharmacokinetics (PK) of ravulizumab (ALXN1210) and eculizumab showing serum concentrations of each drug over time (semi-log scale).

[0081] [Figure 22] FIG. 22 is a graphical depiction of the pharmacodynamics (PD) of ravulizumab (ALXN1210) and eculizumab showing the mean C5 concentrations over time in the presence of each drug.

[0082] [Figure 23] Figure 23 is a graphical depiction of the pharmacodynamics (PD) of ravulizumab (ALXN1210) and eculizumab showing the mean (±95% CI) percent change from baseline in total serum C5 concentrations over time in the presence of each drug.

[0083] [Figure 24] FIG. 24 is a schematic diagram showing the design for clinical protocol ALXN1210-aHUS-311.

[0084] [Figure 25] Figure 25 is a schematic diagram showing the design of the Phase III ALXN1210-PNH-302 clinical trial in patients with PNH who have been treated with eculizumab for at least the past 6 months, administering a complement inhibitor other than eculizumab to patients.

[0085] [Figure 26] FIG. 26 is a schematic diagram showing the dosing schedule, including actual infusion days, for patients in the Phase III ALXN1210-PNH-302 clinical trial.

[0086] [Figure 27] FIG. 27 is a schematic diagram showing the disposition of patients enrolled in the Phase III ALXN1210-PNH-302 clinical trial.

[0087] [Figure 28] FIG. 28 is a schematic showing the baseline characteristics and demographics of patients enrolled in the Phase III ALXN1210-PNH-302 clinical trial.

[0088] [Figure 29] FIG. 29 is a schematic diagram showing baseline disease characteristics of patients enrolled in the Phase III ALXN1210-PNH-302 clinical trial.

[0089] [Figure 30] Figure 30 is a graphical summary showing key efficacy results for the primary and secondary endpoints from the Phase III ALXN1210-PNH-302 clinical trial.

[0090] [Figure 31] Figure 31 is a graphical representation of key efficacy results for both the primary and secondary endpoints from the Phase III ALXN1210-PNH-302 clinical trial.

[0091] [Figure 32] Figure 32 is a table showing the results from a multiple sensitivity analysis of efficacy results for the primary endpoint from the Phase III ALXN1210-PNH-302 clinical trial.

[0092] [Figure 33] Figure 33 is a graphical representation showing efficacy results by subgroup for the primary endpoint from the Phase III ALXN1210-PNH-302 clinical trial.

[0093] [Figure 34] Figure 34 is a graphical representation of mean LDH levels over time for patients enrolled in the Phase III ALXN1210-PNH-302 clinical trial.

[0094] [Figure 35] Figure 35 is a graphical representation of the percentage of patients achieving LDH normalization during the Phase III ALXN1210-PNH-302 clinical trial.

[0095] [Figure 36] Figure 36 is a graphical representation of the mean change compared to baseline in quality of life over time for patients enrolled in the Phase 3 ALXN1210-PNH-302 clinical trial, as assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale.

[0096] [Figure 37] Figure 37 is a graphical representation of mean quality of life over time for patients enrolled in the Phase 3 ALXN1210-PNH-302 clinical trial, as assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale.

[0097] [Figure 38] Figure 38 is a chart of key safety results from the Phase 3 ALXN1210-PNH-302 clinical trial.

[0098] [Figure 39]Figure 39 is a chart of treatment-emergent serious adverse events (TESAEs) from the Phase 3 ALXN1210-PNH-302 clinical trial.

[0099] [Figure 40] Figure 40 is a chart of the most common treatment-emergent adverse events (TEAEs) from the Phase 3 ALXN1210-PNH-302 clinical trial.

[0100] [Figure 41] Figure 41 is a chart of upper respiratory tract infections (URTIs) from the Phase III ALXN1210-PNH-302 clinical trial as determined by standard MedDRA queries (SMQs).

[0101] [Figure 42] Figure 42 is a chart of treatment-emergent adverse events of particular interest (TEAESI) from the Phase III ALXN1210-PNH-302 clinical trial.

[0102] [Figure 43] Figure 43 is a table of patient compliance results from the Phase III ALXN1210-PNH-302 clinical trial.

[0103] [Figure 44] Figure 44 is a graphical depiction of the pharmacokinetics (PK) of ALXN1210 and eculizumab, showing the serum concentrations of each drug over time.

[0104] [Figure 45] Figure 45 is a graphical depiction of the pharmacodynamics (PD) of ALXN1210 and eculizumab showing the mean C5 concentrations over time in the presence of each drug.

[0105] [Figure 46] Figure 46 is a graphical depiction of ALXN1210 and eculizumab showing the mean (±95% CI) change from baseline in total serum C5 concentrations over time in the presence of each drug. DETAILED DESCRIPTION OF THE INVENTION

[0106] I. Anti-C5 antibody The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit cleavage of C5 into fragments C5a and C5b. As noted above, such antibodies also have, for example, improved pharmacokinetic properties compared to other anti-C5 antibodies used for therapeutic purposes (e.g., eculizumab).

[0107] The term "antibody" describes a polypeptide comprising at least one antibody-derived antigen-binding site (e.g., a VH / VL region or Fv, or a CDR). Antibodies include known forms of antibodies. For example, an antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. An antibody can also be a Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or domain antibody. An antibody can also be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, and IgE. An antibody can be a naturally occurring antibody or an antibody altered by protein engineering techniques (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). For example, an antibody can contain one or more variant amino acids that alter the properties (e.g., functional properties) of the antibody (compared to a naturally occurring antibody). Many such modifications are known in the art that affect, for example, the half-life in a patient, effector function, and / or the immune response to the antibody. The term antibody also includes artificial or engineered polypeptide constructs that contain at least one antibody-derived antigen-binding site.

[0108] Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the present 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 can also be used.

[0109] Eculizumab (also known as Soliris®) is an anti-C5 antibody comprising heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains 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 forth in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 8. The variable regions of eculizumab are described in PCT / US1995 / 005688 and U.S. 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 forth in SEQ ID NO: 10 and a light chain having the amino acid sequence set forth 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.

[0110] An exemplary anti-C5 antibody is ravulizumab, or an antigen-binding fragment or variant thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively. Ravulizumab (also known as Ultomiris™, BNJ441, and ALXN1210) is described in PCT / US2015 / 019225 and 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 all refer to the same antibody. Ravulizumab selectively binds to the human complement protein C5 and inhibits its cleavage into C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9, while preserving the proximal or early components of complement activation (e.g., C3 and C3b) that are important for microbial opsonization and immune complex clearance.

[0111] 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 VH region of ravulizumab having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NOs: 12 and 8, respectively.

[0112] Another exemplary anti-C5 antibody is antibody BNJ421, or antigen-binding fragments and variants thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively. BNJ421 (also known as ALXN1211) is described in PCT / US2015 / 019225 and U.S. Patent No. 9,079,949, the teachings of which are incorporated herein by reference.

[0113] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively.

[0114] The exact boundaries of CDRs have been defined differently 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, US Department of Health and Human Services, Bethesda, MD]. In such cases, the CDRs may be referred to as "Kabat CDRs" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In some embodiments, the positions of CDRs within a light or heavy chain variable domain may be as defined by Chothia et al. (1989) Nature 342:877-883. Thus, these regions may be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions may be as defined by the combined Kabat-Chothia definition. In such embodiments, these regions may be referred to as "combined Kabat-Chothia CDRs." Thomas et al. [(1996) Mol Immunol 33(17 / 18):1389-1401] is defined as C according to the definition of Kabat and Chothia Illustrates the identification of the DR boundary.

[0115] In another embodiment, the antibody comprises VH and VL regions having 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 set forth in SEQ ID NO: 13. In another embodiment, the antibody comprises a heavy chain polypeptide set forth in SEQ ID NO: 14 and a light chain polypeptide 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 corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of the native human IgG Fc constant region.

[0116] In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences 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-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of the native human IgG Fc constant region.

[0117] In another embodiment, the anti-C5 antibody described herein has the following amino acid sequence: H In another embodiment, the anti-C5 antibody described herein comprises a heavy chain CDR1 comprising or consisting of the following amino acid sequence: IFSNYWIQ (SEQ ID NO: 19). H It comprises a heavy chain CDR2 comprising or consisting of TEYTENFKD (SEQ ID NO: 18).

[0118] In another embodiment, the antibody has a K D Affinity dissociation constants (K) in the range of ≦1 nM D In another embodiment, the antibody binds to human C5 at a K DIn yet another embodiment, the K of the antibody or antigen-binding fragment thereof against human C5 at pH 6.0 and 25°C is ≥ 10 nM. D ) / (K of an antibody or antigen-binding fragment thereof against human C5 at pH 7.4 and 25°C D )] is greater than 25.

[0119] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patent Nos. 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. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having 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 the 7086 antibody having the sequence set forth in SEQ ID NO: 27 and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO: 28.

[0120] Another exemplary anti-C5 antibody is the 8110 antibody, also described in U.S. Patent Nos. 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 heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs:29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs:32, 33, and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO:35 and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO:36.

[0121] 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 CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains 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 forth in SEQ ID NO: 43 and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO: 44.

[0122] Another exemplary anti-C5 antibody is the SKY59 antibody described in Fukuzawa T., et al., Rep. 2017 Apr 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.

[0123] Another exemplary anti-C5 antibody is the REGN3918 antibody (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.

[0124] In another embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as an antibody described above (e.g., eculizumab, ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody). In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity (e.g., at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% variable region identity) with an antibody described above.

[0125] In some embodiments, the anti-C5 antibodies described herein may comprise a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with higher affinity than the affinity of the native human Fc constant region from which the variant human Fc constant region was derived. For example, the Fc constant region may contain one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions compared to the native human Fc constant region from which the variant human Fc constant region was derived. The substitutions may increase the binding affinity of an IgG antibody containing the variant Fc constant region for FcRn at pH 6.0 while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in an antibody's Fc constant region increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining the pH dependence of the interaction) are known in the art and are exemplified in the Examples. See, e.g., PCT / US2015 / 019225 and U.S. Patent No. 9,079,949. The disclosures of each of these are incorporated herein by reference in their entirety.

[0126] Substitutions that enhance the binding affinity of antibody Fc constant regions 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: 23514-23524; 2) M428L or T250Q / M428 as described in Hinton et al. (2004) J Biol Chem 279:6213-6216 and Hinton et al. (2006) J Immunol 176:346-356 and (3) the N434A or T307 / E380A / N434A substitutions described in Petkova et al. (2006) Int Immunol 18(12):1759-69. Additional substitution pairings include P257I / Q311I, P257I / N434H, and D376V / N434H, for example, as described in Datta-Mannan et al. (2007) J Biol Chem 282(3):1709-1717, the disclosure of which is incorporated herein by reference in its entirety.

[0127] In some embodiments, the variant constant region has a substitution at EU amino acid residue 255 to valine. In some embodiments, the variant constant region has a substitution at EU amino acid residue 309 to asparagine. In some embodiments, the variant constant region has a substitution at EU amino acid residue 312 to isoleucine. In some embodiments, the variant constant region has a substitution at EU amino acid residue 386.

[0128] In some embodiments, the variant Fc constant region comprises 30 or fewer (e.g., 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 or fewer) amino acid substitutions, insertions, or deletions relative to the native constant region from which it is 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 according to EU numbering. In some embodiments, the variant Fc constant region comprises a 428L / 434S double substitution, for example, as described in US Pat. No. 8,088,376.

[0129] In some embodiments, the exact location of these mutations may be shifted from the position of the native human Fc constant region due to antibody engineering. For example, the 428L / 434S double substitution, when used in an IgG2 / 4 chimeric Fc, may correspond to 429L and 435S, such as the M429L and N435S variant found in BNJ441 (ravulizumab), described in U.S. Patent No. 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.

[0130] 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 a native human Fc constant region. In some embodiments, the substitutions are, all in EU numbering, glycine to methionine at position 237; proline to alanine at position 238; serine to lysine at position 239; lysine to isoleucine at position 248; threonine to alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine at position 250; methionine to phenylalanine, tryptophan, or tyrosine at position 252; serine to threonine at position 254; arginine to glutamic acid at position 255; threonine to aspartic acid, glutamic acid, or glutamine at position 256; proline to alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine at position 257; glutamine to threonine at position 258 aspartic acid to histidine at position 265; aspartic acid to alanine at position 270; asparagine to alanine or glutamic acid at position 286; threonine to histidine at position 289; asparagine to alanine at position 297; serine to glycine at position 298; valine to alanine at position 303; valine to alanine at position 305; threonine to alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan or tyrosine at position 307; valine to alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine or threonine at position 308;Leucine or valine to alanine, aspartic acid, glutamic acid, proline, or arginine at position 309; glutamine to alanine, histidine, or isoleucine at position 311; aspartic acid to alanine or histidine at position 312; leucine to lysine or arginine at position 314; asparagine to alanine or histidine at position 315; lysine to alanine at position 317; asparagine to glycine at position 325; isoleucine to valine at position 332; lysine to leucine at position 334; lysine to histidine at position 360; aspartic acid to alanine at position 376; glutamic acid to alanine at position 380; glutamic acid to alanine at position 382; asparagine or serine at position 384 methionine to alanine; glycine to aspartic acid or histidine at position 385; glutamine to proline at position 386; proline to glutamic acid at position 387; asparagine to alanine or serine at position 389; serine to alanine at position 424; methionine to alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan or tyrosine at position 428; histidine to lysine at position 433; asparagine to alanine, phenylalanine, histidine, serine, tryptophan or tyrosine at position 434; and tyrosine or phenylalanine to histidine at position 436.

[0131] Anti-C5 antibodies suitable for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence set forth 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 set forth in SEQ ID NO: 20 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0132] In one embodiment, the antibody has an affinity dissociation constant (K) of at least 0.1 (e.g., 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 at pH 7.4 and 25°C (and otherwise under physiological conditions). D In some embodiments, the K of the anti-C5 antibody or antigen-binding fragment thereof D is 1 or less (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 or less) nM.

[0133] In another embodiment, the K of an antibody against C5 at pH 6.0 and 25°C D ) / (K of antibody against C5 at pH 7.4 and 25°C D )] is greater than 21 (e.g., 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, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910 greater than 0, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

[0134] Methods for determining whether an antibody binds to a protein antigen and / or the affinity of an antibody for a protein antigen are known in the art. For example, the binding of an antibody to a protein antigen can be detected and / or quantified using various techniques, including, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ) or enzyme-linked immunosorbent assay (ELISA). See, for example, Benny KC Lo (2004) "Antibody Engineering: Methods and Protocols," Humana Press (ISBN: 1588290921); Johne et al. (1993) J Immunol Meth 160:191-198; Jonsson et al. (1993) Ann Biol Clin 51:19-26; and Jonsson et al. (1991) Biotechniques 11:620-627. Additionally, methods for measuring affinity (e.g., dissociation and association constants) are provided in the Examples.

[0135] As used herein, the term "k a " refers to the rate constant for the association of an antibody to an antigen. d " refers to the rate constant for dissociation of an antibody from the antibody / antigen complex. And, the term "K D " refers to the equilibrium dissociation constant of the antibody-antigen interaction. The equilibrium dissociation constant is the ratio of the kinetic rate constants, K D =k a / k d Such determinations are preferably measured at 25°C or 37°C (see 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 via surface plasmon resonance (SPR) on a BIAcore 3000 instrument using an anti-Fc capture method to immobilize the antibody.

[0136] In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof blocks the production or activity of C5a and / or C5b active fragments of a C5 protein (e.g., a human C5 protein). Through this blocking effect, the antibody inhibits, for example, the pro-inflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) on the surface of cells.

[0137] Methods for determining whether the specific antibodies described herein inhibit C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cytolytic ability of complement in the subject's body fluid. Such reduction in the cytolytic ability of complement present in body fluid can be measured by methods well known in the art, for example, by conventional hemolysis assays, such as Kabat and Mayer (eds.), "Experimental Immunochemistry, 2 nd Edition," 135-240, Springfield, IL, CC Thomas (1961), pages 135-139. or conventional variations of that assay, such as the chicken erythrocyte hemolysis method described, for example, in Hillman et al. (2004) N Engl J Med 350(6):552. Methods for determining whether a candidate compound inhibits the cleavage of human C5 into the forms C5a and C5b are known in the art and are described in Evans et al. (1995) Mol Immunol 32(16):1183-95. For example, the concentration and / or biological activity of C5a and C5b in body fluids can be measured by methods well known in the art. For C5b, the hemolytic assay discussed herein or an assay for soluble C5b-9 can be used. Other assays known in the art can also be used. These or other suitable types of assays can be used to screen candidate agents capable of inhibiting human complement component C5.

[0138] Immunological techniques, such as, but not limited to, ELISA, can be used to measure the protein concentration of C5 and / or its cleavage products to determine the ability of an anti-C5 antibody or antigen-binding fragment thereof to inhibit the conversion of C5 to biologically active products. In some embodiments, C5a production is measured. In some embodiments, a C5b-9 neoepitope-specific antibody is used to detect the formation of terminal complement.

[0139] Hemolytic assays can be used to determine the inhibitory activity of anti-C5 antibodies or their antigen-binding fragments on complement activation. To determine the effect of anti-C5 antibodies or their antigen-binding fragments on in vitro classical complement pathway-mediated hemolysis in serum test solutions, for example, sheep red blood cells coated with hemolysin or chicken red blood cells sensitized with anti-chicken red blood cell antibodies are used as target cells. The percentage of lysis is normalized by considering lysis equivalent to that occurring in the absence of an inhibitor as 100%. In some embodiments, the classical complement pathway is activated by a human IgM antibody, such as that used in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, test serum is incubated with anti-C5 antibodies or their antigen-binding fragments in the presence of human IgM antibodies. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring absorbance at an appropriate wavelength. As a control, test serum is incubated in the absence of anti-C5 antibody or its antigen-binding fragment. In some embodiments, the test serum is C5-deficient serum reconstituted with C5 polypeptide.

[0140] To determine the effect of an anti-C5 antibody or its antigen-binding fragment on alternative pathway-mediated hemolysis, naive rabbit or guinea pig red blood cells can be used as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with C5 polypeptide. The percentage of lysis is normalized by considering lysis equivalent to that occurring in the absence of an inhibitor as 100%. In some embodiments, the alternative complement pathway is activated by a lipopolysaccharide molecule, such as that utilized in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or its antigen-binding fragment in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring fluorescence at an appropriate wavelength. As a control, test serum is incubated in the absence of anti-C5 antibody or antigen-binding fragment thereof.

[0141] In some embodiments, C5 activity or its inhibition is quantified using a CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. This test is a lytic assay that uses antibody-sensitized red blood cells as an activator of the classical complement pathway and various dilutions of test serum to determine the amount required to obtain 50% lysis (CH50). Percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, because TCC itself is directly responsible for the hemolysis measured.

[0142] The assay is well known and commonly performed by those skilled in the art. Briefly, to activate the classical complement pathway, an undiluted serum sample (e.g., a reconstituted human serum sample) is added to a microassay well containing antibody-sensitized red blood cells, thereby generating TCC. The activated serum is then diluted in a microassay well coated with a capture reagent (e.g., an antibody that binds to one or more components of TCC). TCC present in the activated sample binds to the monoclonal antibody coating the surface of the microassay well. The wells are washed, and a detectably labeled detection reagent that recognizes the bound TCC is added to each well. The detectable label can be, for example, a fluorescent label or an enzyme label. The assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).

[0143] Inhibition, e.g., with respect to terminal complement activity, includes at least a 5 (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60)% decrease in terminal complement activity, e.g., in a hemolytic assay or CH50eq assay, compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at an equimolar concentration. Substantial inhibition, as used herein, refers to at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 or more)% inhibition of a given activity (e.g., terminal complement activity). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions compared to the CDRs of eculizumab (i.e., SEQ ID NOs: 1-6), but still retain at least 30 (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95)% of the complement inhibitory activity of eculizumab in a hemolytic assay or a CH50eq assay.

[0144] The anti-C5 antibodies described herein have 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 antibodies described herein have a serum half-life in humans that is at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans that is approximately 43 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans that is between 39 and 48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibodies or antigen-binding fragments thereof described herein have 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)% longer than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the Examples (e.g., a C5-deficient / NOD / scid mouse or an hFcRn transgenic mouse model system).

[0145] In one embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as an antibody described herein. In reference to two or more antibodies, the term "binds to the same epitope" means that the antibodies bind to the same segment of amino acid residues as determined by a given method. Techniques for determining whether an antibody binds to the "same epitope on C5" as an antibody described herein include, for example, epitope mapping methods, such as x-ray analysis of crystals of antigen:antibody complexes, which provide atomic resolution of the epitope, and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor antibody binding to peptide antigen fragments or mutated variants of the antigen, where loss of binding due to alteration of amino acid residues within the antigen sequence is often considered an indication of epitope components. Furthermore, combinatorial computational methods for epitope mapping can also be used. These methods rely on the ability of an antibody of interest to affinity isolate specific short peptides from a combinatorial phage display peptide library. Antibodies with the same VH and VL or CDR1, 2, and 3 sequences are predicted to bind to the same epitope.

[0146] An antibody that "competes with another antibody for binding to a target" refers to an antibody that inhibits (partially or completely) the binding of the other antibody to a target. Whether two antibodies compete with each other for binding to a target, i.e., 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 another antibody for binding to a target and inhibits the binding of the other antibody to the target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition can vary depending on which antibody is the "blocking antibody" (i.e., the cold antibody that is first incubated with the target). Competing antibodies bind to the same epitope, overlapping epitopes, or adjacent epitopes (e.g., as evidenced by steric hindrance).

[0147] The anti-C5 antibodies or antigen-binding fragments thereof described herein used in the methods described herein can be produced using a variety of art-recognized techniques. Monoclonal antibodies can be obtained by a variety of techniques known to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, typically by fusion with myeloma cells (see Kohler & Milstein, Eur. J. Immunol. 6: 511-519 (1976)). Alternative methods of immortalization include Epstein-Barr virus, oncogenes, and the like. Immortalization techniques include gene or retroviral transformation, or other methods well known in the art. Colonies arising from single immortalized cells are screened for the production of antibodies having the desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by such cells can be enhanced by a variety of techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, the method reviewed by Huse, et al., Science 246: 1275-1281 (1989) DNA sequences encoding monoclonal antibodies or binding fragments thereof can be isolated by screening a DNA library derived from human B cells according to established general protocols.

[0148] II. Composition Also provided herein are compositions comprising an anti-C5 antibody or an antigen-binding fragment thereof. In one embodiment, the composition comprises an anti-C5 antibody comprising CDR1, CDR2, and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and 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 sequences set forth in SEQ ID NOs: 14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively.

[0149] The composition can be formulated as a pharmaceutical solution for administration to a subject for the treatment or prevention of, for example, complement-related disorders, such as PNH or aHUS. Pharmaceutical compositions generally contain a pharmaceutically acceptable carrier. As used herein, " pharmaceutically acceptable carrier " refers to and includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The composition can contain pharmaceutically acceptable salts, such as acid addition salts or base addition salts, sugars, carbohydrates, polyols, and / or tonicity modifiers.

[0150] Compositions may be formulated according to standard methods. Pharmaceutical formulation is a well-established field of art, see, for example, Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20 th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472);Ansel et al. (1999) "Pharmaceutical Dosage Forms and Drug Delivery Systems," 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) "Handbook of Pharmaceutical Excipients American Pharmaceutical Association," 3 rdEdition (ISBN: 091733096X). In some embodiments, the compositions may be formulated, for example, as a buffer solution of appropriate concentration suitable for storage at 2-8°C (e.g., 4°C). In some embodiments, the compositions may be formulated for storage at temperatures below 0°C (e.g., -20°C or -80°C). In some embodiments, the compositions may be formulated for storage at 2-8°C (e.g., 4°C) for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years). Thus, in some embodiments, the compositions described herein are stable upon storage at 2-8°C (e.g., 4°C) for at least 1 year.

[0151] Pharmaceutical compositions can be in various forms. These forms include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. Preferred forms depend in part on the intended mode of administration and therapeutic application. For example, compositions containing compositions intended for systemic or local delivery can be in the form of injectable or infusible solutions. Thus, compositions can be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). The terms "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, including, without limitation, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.

[0152] In one embodiment, the composition comprises ALXN1210 for injection (Ultomiris™, also known as antibody BNJ441 or ravulizumab). In one embodiment, the injection is a sterile, clear to translucent, slightly whitish, 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 at 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 further comprises polysorbate 80 (0.2 mg) (vegetable origin), sodium chloride (8.77 mg), sodium monohydrogen phosphate (1.78 mg), sodium dihydrogen phosphate (0.46 mg), and distilled water for injection.

[0153] III. Treatment Methods Provided herein is a method for treating PNH or aHUS in a human patient, comprising 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 specific clinical dosage regimen (i.e., at a specific dose and according to a specific dosing schedule).

[0154] As used herein, the terms "induction" and "induction phase" are used interchangeably and refer to the first phase of treatment in a clinical trial.

[0155] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to the second phase of treatment in a clinical trial. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

[0156] As used herein, the term "subject" or "patient" refers to a human patient (eg, a patient with a complement-associated condition, such as PNH or aHUS).

[0157] In one embodiment, the complement-associated condition is paroxysmal nocturnal hemoglobinuria (PNH). PNH is the most frequently acquired hemolytic disorder in adults (Brodsky RA., Blood. 2015;126:2459-65). The disease is caused by hematopoietic stem cells that have acquired somatic mutations in the PIGA gene. PNH begins with the clonal expansion of erythropoietin (BPO) (Brodsky RA., Blood. 2014;124:2804-1). Consequently, PNH blood cells lack glycophosphatidylinositol (GPI)-anchored proteins and are deficient in the membrane-bound complement inhibitory proteins CD55 and CD59. In the absence of CD55, there is increased deposition of complement protein C3 cleavage products on the blood cell membrane surface, which in turn leads to cleavage of C5 into C5a and C5b. The pathology and clinical picture in patients with PNH are driven by uncontrolled terminal complement activation.

[0158] C5a is a potent anaphylatoxin, chemotactic factor, and cell activation molecule that mediates multiple proinflammatory and prothrombotic activities (Matis LA, et al., Nat. Med. 1995;1:839-42; Prodinger et al., Complement. In: Paul WE, editor. Fundamental immunology (4th ed). Philadelphia: Lippincott-Raven Publishers; 1999, p. 967-95). C5b recruits terminal complement components C6, C7, C8, and C9. This leads to the formation of the pro-inflammatory, pro-thrombotic cytolytic pore molecule C5b-9, a process that is blocked on the red blood cell (RBC) membrane by CD59 under normal circumstances. However, in patients with PNH, these final steps proceed unchecked, leading to hemolysis and the release of free hemoglobin, as well as platelet activation (Hill, et al., Blood 2013; 121:4985-96). The signs and symptoms of PNH can be attributed to the release of intracellular free hemoglobin and lactate dehydrogenase (LDH) into the circulation as a direct result of hemolysis, the irreversible binding of nitric oxide (NO) by hemoglobin and its inactivation, and the inhibition of NO synthesis, vasoconstriction, and tissue bed ischemia due to the absence of vasodilatory NO, as well as chronic uncontrolled complement C5 cleavage and C5b-9 leading to the release of C5a and RBC hemolysis, which together produce possible microthrombi, platelet activation, and / or a pro-inflammatory and pro-thrombotic state manifested as abdominal pain, dysphagia, and erectile dysfunction (Hill, et al., Blood 2013; 121:4985-96; Brodsky RA., Blood. 2014; 124:2804-1). A substantial proportion of patients with PNH experience renal insufficiency and pulmonary hypertension (Hillmen, et al., Am J Hematol. 2010;85:553-9. [Errata for Am J Hematol. 2010;85:911.]; Hill, et al., Br. J Haematol. 2012;158:409-14.; Hill, et al., Blood 2013;121:4985-96). Patients also experience venous or arterial thrombosis in various sites, including the abdomen or central nervous system (Brodsky RA., Blood. 2014;124:2804-1).

[0159] In another embodiment, the complement-related condition is atypical hemolytic uremic syndrome (aHUS). The pathology and clinical picture of patients with aHUS are also driven by terminal complement activation. More specifically, dysregulation of C5 activation and complement activation leads to endothelial damage, platelet consumption, and thrombotic microangiopathy (TMA) events 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 limb, and severe systemic organ damage (Loirat, et al., Orphanet. J. Rare Dis. 2011;6:60). The effects of aHUS are as follows: Symptoms are well known to those skilled in the art of rare disease or renal disease medicine and include, for example, severe hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction (e.g., acute renal failure).

[0160] aHUS can be hereditary, acquired, or idiopathic. aHUS can be considered hereditary when two or more (e.g., 3, 4, 5, or 6 or more) members of the same family are affected by the disease at least 6 months apart and exposure to a common precipitating agent is excluded, or when one or more aHUS-associated genetic mutations (e.g., one or more mutations in CFH, MCP / CD46, CFB, or CFI) are identified in the subject. For example, a subject may have CFH-associated aHUS, CFB-associated aHUS, CFI-associated aHUS, or MCP-associated aHUS. Up to 30% of hereditary aHUS cases are associated with mutations in CFH, 12% with mutations in MCP, 5-10% with mutations in CFI, and less than 2% with mutations in CFB. Hereditary aHUS can be multiplex (i.e., familial; two or more affected family members). aHUS can be multiple (i.e., multiple members) or simplex (i.e., a single occurrence in a family). aHUS may be considered acquired if an underlying environmental factor (e.g., a drug, systemic illness, or a viral or bacterial agent that does not result in Shiga-like exotoxins) or trigger can be identified. aHUS may be considered idiopathic if no trigger (genetic or environmental) is apparent.

[0161] Laboratory tests can be performed to determine whether a human subject has thrombocytopenia, microangiopathic hemolytic anemia, or acute renal insufficiency. Thrombocytopenia is defined by a medical professional as: (i) a thrombocytopenia of 150,000 / mm 3 Less than (e.g., 60,000 / mm 3(ii) a platelet count of less than 10 mg / dL (e.g., less than 6.5 mg / dL); (ii) a decrease in platelet survival time, reflecting enhanced platelet destruction in the circulation; and (iii) giant platelets observed in a peripheral smear, consistent with secondary activation of thrombopoiesis. Microangiopathic hemolytic anemia can be diagnosed by a medical professional as one or more of the following: (i) a hemoglobin concentration of less than 10 mg / dL (e.g., less than 6.5 mg / dL); (ii) an increased serum lactate dehydrogenase (LDH) concentration (>460 U / L); (iii) hyperbilirubinemia, reticulocytosis, circulating free hemoglobin, and low or undetectable haptoglobin concentration; and (iv) the detection of fragmented red blood cells (schistocytes) with the typical appearance of cuttlefish or helmet cells in a peripheral smear, along with a negative Coombs test. See, for example, Kaplan et al. (1992) "Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura," Informa Health Care (ISBN 0824786637) and Zipfel (2005) "Complement and Kidney Disease," Springer (ISBN 3764371668). The blood levels of C3 and C4 can also be used as a measure of complement activation or dysregulation. In addition, the subject's condition can be further characterized by identifying the subject as having one or more mutations in genes associated with aHUS, such as CFI, CFB, CFH or MCP (see above). Suitable methods for detecting mutations in genes include, for example, DNA sequencing and nucleic acid array technology. For example, see Breslin et al. (2006) Clin Am Soc Nephrol 1:88-99 and Goicoechea de Jorge et al. (2007) Proc Natl Acad Sci USA 104:240-245.

[0162] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement over baseline, i.e., an improvement over measurements or observations made before the start of treatment according to the method. For example, in the context of PNH, effective treatment can refer to a reduction in one or more symptoms selected from the group consisting of fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and / or erectile dysfunction. For example, in the context of aHUS, effective treatment can refer to a reduction in one or more symptoms selected from the group consisting of severe hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and / or renal dysfunction (e.g., acute renal failure).

[0163] The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and / or preventive result. The result can be the reduction, amelioration, alleviation, slowing, delay, 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 an anti-C5 antibody or antigen-binding fragment thereof that has been clinically proven to alleviate at least one symptom of PNH (e.g., fatigue, abdominal pain, dysphagia, dysphagia, chest pain, or erectile dysfunction) or at least one symptom of aHUS (e.g., severe hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction (e.g., acute renal failure)). An effective amount can be administered in one or more doses.

[0164] In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. 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 kg but < 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 kg but < 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, the dosage regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0165] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered in one or more administration cycles. 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 8 weeks thereafter. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every 8 weeks (e.g., at a dose of 3000 mg, 3300 mg, or 3600 mg) for an extension period of up to 2 years after the administration cycle.

[0166] In another embodiment, a method of treating a human patient with PNH or aHUS comprises administering to the patient, during an administration cycle, an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) Once on day 1 of a dosing cycle, at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) On day 15 of the dosing cycle, and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. A method is provided in which the

[0167] In another embodiment, a method of treating a human patient with PNH or aHUS comprises administering to the patient, during an administration cycle, an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, the CDR1, CDR2, and CDR3 light chain sequences 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-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc constant region; and wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) Once on day 1 of a dosing cycle, at a dose of 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) On day 15 of the dosing cycle, and every 8 weeks thereafter, at a dose of 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. A method is provided in which the

[0168] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg. (a) at a dose of 2400 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3000 mg It is administered.

[0169] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 to < 100 kg. (a) at a dose of 2700 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3300 mg It is administered.

[0170] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧100 kg. (a) at a dose of 3000 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3600 mg It is administered.

[0171] In some embodiments, the patient has not been previously treated with a complement inhibitor (eg, the patient is a complement inhibitor treatment naive patient).

[0172] In other embodiments, the patient has previously been treated with one anti-C5 antibody or its antigen-binding fragment 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 during the treatment period (e.g., 26 weeks), and then treated with another anti-C5 antibody (e.g., ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody), for example, during the extension period. In another embodiment, eculizumab is administered to a patient at a dose of 600 mg on days 1, 8, 15, and 22 of a dosing cycle during an induction phase, followed by a maintenance dose of 900 mg eculizumab on day 19 of the dosing cycle and every two weeks thereafter (e.g., for a total of 26 weeks), followed by treatment with ravulizumab for an extension period of up to two years. In another embodiment, a patient is treated with ravulizumab (e.g., for 26 weeks), and then treated with another anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody), for example, during an extension period.

[0173] Exemplary alternative anti-C5 antibodies include (i) ALXN1210, (ii) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 24, 25, and 26, respectively, (iii) 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, (iv) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 32, 33, and 34, respectively, (v) 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, (vi) an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains comprising SEQ ID NOs: 40, 41, and 42, respectively; (vii) 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; (viii) 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; (ix) 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 (x) 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.

[0174] In some embodiments, the patient has been previously treated with an anti-C5 antibody or antigen-binding fragment thereof (e.g., eculizumab) 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 before switching to another anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab). In certain embodiments, the patient has been previously treated with eculizumab for at least 6 months.

[0175] In another embodiment, when a patient (e.g., a PNH or aHUS patient) is treated with a first anti-C5 antibody and then switched to treatment with a second, different anti-C5 antibody, particularly when the second, different anti-C5 antibody binds to a different epitope on C5 than the first anti-C5 antibody, the administration schedule takes into account the half-life of the first anti-C5 antibody. For example, the half-life of the first anti-C5 antibody is taken into account to ensure that the first anti-C5 antibody is removed (e.g., "washed out") from the patient before the second (different) anti-C5 antibody is administered (e.g., to avoid problems associated with aggregation, immune complex formation, etc.). In one embodiment, the second (different) anti-C5 antibody is not administered until a period of time equivalent to 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, or 7.5 half-lives of the first anti-C5 antibody has elapsed after the final administration of the first anti-C5 antibody.

[0176] In another embodiment, the patient has previously been treated with eculizumab and is then switched to treatment with a second (different) anti-C5 antibody (e.g., ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody). In one embodiment in which eculizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered until, for example, at least 36, 45, 54, 63, 72, 81, 90, 99, 108, 117, or 126 days after the last administration of eculizumab.

[0177] In another embodiment, the patient has previously been treated with ravulizumab and is then switched to treatment with a different anti-C5 antibody (e.g., eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody). In one embodiment in which ravulizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered until, for example, at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 375, or 400 days after the last administration of ravulizumab.

[0178] Additionally or alternatively, techniques are used to remove or enhance the clearance 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 or transfusion. In another embodiment, an antibody against the first anti-C5 antibody is administered to remove or enhance the clearance of the first anti-C5 antibody (e.g., anti-eculizumab antibody, anti-ravulizumab antibody, anti-7086 antibody, anti-8110 antibody, anti-305LO5 antibody, anti-SKY59 antibody, or anti-REGN3918 antibody) before the second (different) anti-C5 antibody is administered.

[0179] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof (e.g., ALXN1210) is administered to a patient and the administration cycle begins at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 6 weeks, at least about 7 weeks, or at least about 8 weeks after the patient's last dose of eculizumab. In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof (e.g., ALXN1210) is administered to a patient and the administration cycle begins at least 2 weeks after the patient's last dose of eculizumab.

[0180] In some embodiments, patients treated according to the methods described herein have been vaccinated against meningococcal infection within three years prior to or at the time of initiating treatment. In one embodiment, patients treated less than two weeks after receiving a meningococcal vaccine are also treated with appropriate prophylactic antibiotics up to two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serogroups A, C, Y, W135, and / or B.

[0181] As used herein, the term "serum trough level" refers to the lowest level at which a drug (e.g., an anti-C5 antibody or its antigen-binding fragment) or medicine is present in serum. In contrast, "peak serum level" refers to the highest level of a drug in serum. "Mean serum level" refers to the average level of a drug in serum over time.

[0182] In one embodiment, the described treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. For example, in one embodiment, the treatment is for a period 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, 275, 280, 285, 290, 300, 310, 315, 320, 325, 330, 340, 345, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 710, 720, 730, 740, 750, 760, 770 The treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 50, 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 higher. In one embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 100 μg / ml or higher. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 150 μg / ml or higher. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 200 μg / ml or higher. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 250 μg / ml or higher. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at 300 μg / ml or higher. In another embodiment, the treatment maintains a serum trough 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 serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 175 μg / ml.

[0183] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered at a concentration of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 160 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, 600 μg, 610 μg, 620 μg, 630 μg, In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 50 μg and 250 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 100 μg and 200 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain about 175 μg of antibody per milliliter of blood in the patient.

[0184] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a minimum free C5 concentration. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a free C5 concentration of 0.2 μg / mL, 0.3 μg / mL, 0.4 μg / mL, 0.5 μg / mL, or less. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency sufficient to maintain a free C5 concentration of 0.309-0.5 μg / mL or less. In another embodiment, the treatment described herein reduces free C5 concentrations by greater than 99% throughout the treatment period. In another embodiment, the treatment reduces free C5 concentrations by greater than 99.5% throughout the treatment period.

[0185] In another aspect, a method of treating a human patient with a complement-related disorder is provided. In one embodiment, the method includes treating a human patient with a complement-related disorder who is being treated with eculizumab, comprising discontinuing eculizumab treatment and switching the patient to treatment with a different complement inhibitor. In another embodiment, the method includes treating a human patient with a complement-related disorder who is being treated with ravulizumab, comprising discontinuing ravulizumab treatment 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, an 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).

[0186] Exemplary complement-associated conditions that can be treated according to the methods described herein include rheumatoid arthritis, antiphospholipid syndrome, lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense deposit disease, neuromyelitis optica, multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous abortion, thrombotic thrombocytopenic purpura, microimmune vasculitis, epidermolysis bullosa, recurrent abortion, traumatic brain injury, myocarditis, cerebrovascular disease, peripheral vascular disease, renal vascular disease, mesenteric / intestinal vasculopathy, vasculitis, Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, These conditions include, but are not limited to, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, Takayasu's disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki disease, venous gas embolism, restenosis after stent placement, rotational atherectomy, percutaneous transluminal coronary angioplasty, myasthenia gravis, cold agglutinin disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid syndrome, Graves' disease, atherosclerosis, Alzheimer's disease, systemic inflammatory response, sepsis, septic shock, spinal cord injury, glomerulonephritis, graft rejection, Hashimoto's thyroiditis, type I diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture's syndrome, Degos' disease, and fulminant antiphospholipid syndrome. In one embodiment, the complement-associated condition is PNH. In another embodiment, the complement-associated condition is aHUS.

[0187] IV. Outcome Provided herein are methods for treating PNH or aHUS in a patient, the methods comprising administering to the patient an anti-C5 antibody or antigen-binding fragment thereof.

[0188] Symptoms of PNH include, but are not limited to, fatigue (e.g., tiredness, difficulty performing daily activities, trouble concentrating, dizziness, weakness), pain (e.g., stomach pain, leg pain or swelling, chest pain, back pain), dark 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 an improvement in at least one symptom of PNH. For example, treatment may result in at least one therapeutic effect selected from the group consisting of a reduction or cessation of fatigue, abdominal pain, difficulty breathing, difficulty swallowing, chest pain, and erectile dysfunction.

[0189] Symptoms of aHUS include, but are not limited to, severe hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction (e.g., acute renal failure). Patients treated according to the methods disclosed herein preferably experience improvement in at least one symptom of aHUS. For example, treatment may result in at least one therapeutic effect selected from the group consisting of reduction or cessation of hypertension, proteinuria, uremia, lethargy / fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction.

[0190] In other embodiments, the treatment results in terminal complement inhibition.

[0191] In other embodiments, treatment results in a shift toward normal levels of hemolysis-related hematological biomarkers selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone, and D-dimer. In another embodiment, treatment results in an increase in hemoglobin stabilization from the patient's pre-treatment baseline.

[0192] In other embodiments, treatment results in a shift toward normal levels of chronic disease-associated biomarkers selected from the group consisting of estimated glomerular filtration rate (eGFR) and spot urine: albumin: creatinine and plasma brain natriuretic peptide (BNP).

[0193] In other embodiments, treatment results in a reduction in the need for blood transfusions. In another embodiment, treatment results in a greater than 70% increase in transfusion avoidance.

[0194] In other embodiments, treatment results in a reduction in breakthrough hemolysis compared to treatment with eculizumab. In another embodiment, treatment results in the elimination of breakthrough hemolysis during the treatment period. In another embodiment, treatment results in a reduction in breakthrough hemolysis compared to the pre-treatment baseline amount of breakthrough hemolysis.

[0195] In other embodiments, treatment results in a reduction in major adverse vascular events (MAVE).

[0196] In other embodiments, treatment results in a change from baseline in quality of life as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale. In another embodiment, treatment results in a change from baseline in quality of life as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4 and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale of at least 7 points from the patient's untreated baseline score.

[0197] In another embodiment, treatment results in no change in quality of life (QoL) as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4, from baseline to day 183. In another embodiment, treatment results in an increase in quality of life (QoL) as assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4, from baseline to day 183. In another embodiment, treatment results in transfusion avoidance from baseline to day 183. In another embodiment, treatment results in the avoidance of a decrease of ≧2 g / dL from baseline in hemoglobin levels without transfusions from baseline to day 183.

[0198] In other embodiments, lactate dehydrogenase (LDH) levels are used to assess responsiveness to treatment (e.g., a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels indicates an improvement in at least one symptom of PNH). LDH is a marker of intravascular hemolysis (Hill, A. et al., Br. J. Haematol., 149:414-25, 2010; Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004; Parker, C. et al., Blood, 106:3699-709, 2005). Red blood cells contain large amounts of LDH. The correlation between cell-free hemoglobin and LDH concentrations has been reported in vitro (Van Lente, F. et al., Clin. Chem., 27:1453-5, 1981) and in vivo (Kato, G. et al., Blood, 107:2279-85, 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., 93:36-46, 2011). LDH concentrations obtained at baseline, and then serially throughout the treatment period, are an important measure of hemolysis. Baseline levels of cell-free plasma hemoglobin are highly elevated in patients with PNH, with LDH being 1.5 times or more above the upper limit of normal (LDH ≥ 1.5 × ULN), and there is a significant correlation between LDH and cell-free plasma hemoglobin (Hillmen, P. (E. et al., N. Engl. J. Med., 355:1233-43, 2006). Normal LDH levels range from 105 to 333 IU / L (international units per liter).

[0199] LDH levels can be measured using any suitable test or assay, such as those described by Ferri FF, ed. Ferri's Clinical Advisor 2014. Philadelphia: PA: Elsevier Mosby; 2014: Section IV - Laboratory tests and interpretation of results. LDH concentrations can be measured in various samples obtained from a patient, particularly serum samples. As used herein, the term "sample" refers to biological material from a subject. While serum LDH concentrations are of interest, samples can be derived from other sources, including, for example, single cells, multiple cells, tissues, tumors, biological fluids, biological molecules, or supernatants or extracts of any of the above. Examples include tissue removed for biopsy, tissue removed during resection, blood, urine, lymphatic tissue, lymphatic fluid, cerebrospinal fluid, mucosa, and fecal samples. The sample used will vary based on the assay format, detection method, and the nature of the tumor, tissue, cell, or extract being assayed. Methods for sample preparation are known in the art and can be easily adapted to obtain a sample compatible with the method being utilized.

[0200] In one embodiment, the treatment described herein results in normalization of LDH levels. In another embodiment, a patient treated according to the disclosed methods experiences a reduction in LDH levels to near normal levels or to within 10% or 20% of what is considered normal (e.g., within 105-333 IU / L (International Units per Liter)). In another embodiment, the patient's LDH levels are normalized throughout the maintenance period of treatment. In another embodiment, the treated patient's LDH levels are normalized at least 95% of the time during the maintenance period of treatment. In another embodiment, 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 embodiment, the patient's LDH levels are 1.5 times or more above the upper limit of normal (LDH≧1.5×ULN) before initiating treatment. In another embodiment, the treatment results in normalization of LDH levels by at least 24 days of treatment. In one embodiment, a patient treated according to the disclosed methods experiences a reduction in LDH levels to within normal levels, or to within 10%, 20%, 30%, 40%, or 50% below what is considered the upper limit of normal (e.g., within 10-333 IU / L (International Units per Liter)). In one embodiment, the patient's LDH levels are 1.5 times or more above the upper limit of normal (LDH≧1.5×ULN) before treatment begins. In one embodiment, treatment results in LDH levels below 2× the upper limit of normal (ULN).

[0201] V. Kits and Unit Dosage Forms Also provided herein is a kit comprising a pharmaceutical composition containing an anti-C5 antibody or its antigen-binding fragment, such as ravulizumab, in a therapeutically effective amount adapted for use in the methods described herein, and a pharmaceutically acceptable carrier.The kit can also optionally include instructions, including, for example, an administration schedule, for allowing a practitioner (e.g., a doctor, a nurse, or a patient) to administer the composition contained therein to a patient with PNH or aHUS.The kit can also include a syringe.

[0202] If desired, the kit includes multiple packages of single-dose pharmaceutical compositions, each containing an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, for single administration according to the method provided above. The equipment or device necessary for administering the pharmaceutical composition(s) may also be included in the kit. For example, the kit may provide one or more pre-filled syringes containing a certain amount of an anti-C5 antibody or antigen-binding fragment thereof.

[0203] In one embodiment, the present invention provides a kit for treating PNH or aHUS in a human patient, comprising: (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof according to any of the methods described herein; A kit comprising:

[0204] 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 weighing ≥ 40 to < 60 kg: (a) at a dose of 2400 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3000 mg It is administered.

[0205] 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 ≥ 60 to < 100 kg: (a) at a dose of 2700 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3300 mg It is administered.

[0206] 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) at a dose of 3000 mg once on day 1 of the dosing cycle; (b) on day 15 of the treatment cycle and every 8 weeks thereafter at a dose of 3600 mg It is administered.

[0207] Since numerous variations and equivalents will become apparent to those of skill in the art upon reading this disclosure, the following examples are illustrative only and should not be construed as limiting the scope of the disclosure in any way.

[0208] The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are hereby expressly incorporated by reference. [Example]

[0209] Example 1 A phase III, randomized, open-label, active-controlled trial of ALXN1210 (ravulizumab) versus eculizumab in complement inhibitor-naive adult patients with paroxysmal nocturnal hemoglobinuria (PNH) In phase Ib / II trials, treatment with ULTOMIRIS administered at extended dosing intervals achieved rapid and sustained reductions in complement-mediated hemolysis in patients with PNH. These trials demonstrated a drug / exposure-response relationship, with higher ULTOMIRIS trough exposure (1800 mg q4w cohort) associated with a greater proportion of patients achieving plasma LDH levels considered at low risk for hemolysis (normalization [or below 1.5 × ULN]) compared with all other cohorts, reduced free hemoglobin, and no breakthrough hemolysis. Based on these results and subsequent exposure-response analysis, a phase III, open-label, randomized, active-controlled, multicenter trial was conducted to evaluate the safety and efficacy of ALXN1210 (ULTOMIRIS) versus eculizumab administered by intravenous (IV) infusion in complement inhibitor-naïve adult patients with PNH. In this phase III trial, patients randomized to ULTOMIRIS received a loading dose on day 1 (2400 mg for patients weighing 40 kg to < 60 kg, 2700 mg for patients weighing 60 kg to < 100 kg, and 3000 mg for patients weighing 100 kg or more), followed by maintenance doses of ULTOMIRIS (3000 mg for patients weighing 40 kg to < 60 kg, 3300 mg for patients weighing 60 kg to < 100 kg, and 3600 mg for patients weighing 100 kg or more) on day 15 and thereafter q8w.

[0210] 1. Purpose The primary objective of this study was to evaluate the non-inferiority of ALXN1210 (ravulizumab) compared with eculizumab in adult patients with PNH who had not received treatment with a complement inhibitor.

[0211] After 26 weeks of treatment, non-inferiority was claimed if 1) the lower limit of the 95% confidence interval (CI) for the difference in transfusion avoidance (TA) rate (ALXN1210-eculizumab) was greater than -20% and 2) the lower limit of the 95% CI for the odds ratio comparing ALXN1210 to eculizumab for lactate dehydrogenase normalization (LDH-N) was greater than 0.39.

[0212] Secondary objectives included characterizing the safety and tolerability of ALXN1210 in this patient population, assessing 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.

[0213] 2. Study Design The overall study design, treatment, and study duration are shown in Figure 1. The ALXN1210-PNH-301 study was a Phase III, open-label, randomized, active-controlled, multicenter study to evaluate the safety and efficacy of ALXN1210 versus eculizumab administered by intravenous (IV) infusion in adult patients with PNH who were treatment-naive with complement inhibitors. The study was designed to include approximately 214 patients (107 patients per treatment group), with 246 subjects ultimately enrolled and completing at least 183 days of treatment. Upon study completion, 246 subjects subsequently enrolled in an extension study, and two 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 one of six groups based on transfusion history (0, 1-14, or >14 pRBC units within the year prior to the first dose of study drug) and screening LDH level (<1.5 × ULN to <3 × ULN or >3 × ULN). Patients in each of the six groups were randomly assigned 1:1 to receive either ALXN1210 or eculizumab. Enrollment of patients without a history of transfusion within the past year was capped at 20%.

[0214] Before randomization and within 5 days before administration of study drug on Day 1, each patient's hemoglobin was assessed either at the local laboratory or at a central laboratory. If the patient's hemoglobin level met protocol-defined transfusion guidelines at that time, the patient was transfused with pRBCs to raise the hemoglobin level above the protocol-defined transfusion threshold for randomization eligibility. The patient's post-transfusion hemoglobin level was confirmed by the local or central laboratory to be above the protocol-defined transfusion threshold.

[0215] Patients randomly assigned to the ALXN1210 group received a loading dose of ALXN1210 on Day 1 (2400 mg for patients weighing 40 kg to < 60 kg, 2700 mg for patients weighing 60 kg to < 100 kg, and 3000 mg for patients weighing 100 kg or greater), followed by maintenance doses of ALXN1210 on Day 15 and every 8 weeks (q8w) thereafter (3000 mg for patients weighing 40 kg to < 60 kg, 3300 mg for patients weighing 60 kg to < 100 kg, and 3600 mg for patients weighing 100 kg or greater) for a total of 26 weeks of treatment. Patients randomized to the eculizumab group received induction treatment with eculizumab IV 600 mg on Days 1, 8, 15, and 22, followed by maintenance treatment with eculizumab 900 mg on Day 29 and every 2 weeks thereafter (q2w) for a total of 26 weeks of treatment. After all evaluations were completed on Day 183, patients entered the extension period, during which they received ALXN1210 until the product was registered or approved (according to country-specific regulations) or for up to 2 years, whichever occurred first. Starting on Day 183, patients randomized to the ALXN1210 treatment group received a maintenance dose (as described above) of ALXN1210 q8w for up to 2 years, and patients randomized to the eculizumab group received a loading dose (as described above) of ALXN1210, followed by a weight-based maintenance dose of ALXN1210 q8w 2 weeks later and thereafter. Patients underwent pRBC transfusion if their hemoglobin level was 9 g / dL or less and accompanied by signs or symptoms of sufficient severity to warrant transfusion, or if their hemoglobin level was 7 g / dL or less, regardless of whether clinical signs or symptoms were present.

[0216] 3. Evaluation items The coprimary efficacy endpoints of this study were (1) transfusion avoidance, defined as the proportion of patients who remained transfusion-free according to protocol-defined guidelines and did not require transfusions through Day 183 (Week 26), and (2) hemolysis as measured directly by LDH-N levels from Day 29 (the first scheduled assessment after initiation of maintenance medication) through Day 183 (Week 26).

[0217] The key secondary efficacy endpoints of the study (tested hierarchically) were: 1. Change in percentage of LDH from baseline to day 183 (week 26); 2. Change from baseline to day 183 (week 26) in quality of life (QoL) assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, version 4; 3. The proportion of patients with breakthrough hemolysis, defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g / dL], major adverse vascular events [MAVEs, including thrombosis], dysphagia, or erectile dysfunction) in the setting of an increase in LDH to ≥2 × ULN after a previous decrease in LDH to <1.5 × ULN during treatment; and 4. Percentage of patients with hemoglobin stabilization, defined as being transfusion-free and avoiding a decrease of ≥2 g / dL from baseline in hemoglobin levels by Day 183 (Week 26).

[0218] Other secondary efficacy endpoints of the study included: · Change from baseline to day 183 (week 26) in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 scale (QLQ-C30), version 3.0; · Time to first occurrence of LDH-N; · Total number of packed red blood cell (pRBC) units transfused by day 183 (week 26); Change from baseline to Day 183 (Week 26) in clinical manifestations of PNH (fatigue, hemoglobinuria, abdominal pain, shortness of breath, anemia, dysphagia, and erectile dysfunction); and The proportion of patients who experienced MAVE by Day 183 (Week 26).

[0219] Pharmacokinetic and pharmacodynamic endpoints of the study included: serum ALXN1210 and eculizumab concentrations over time, chicken red blood cell (cRBC) hemolytic activity over time (exploratory), and free complement component 5 (C5) concentrations over time.

[0220] Exploratory endpoints included patient-reported PNH symptoms and healthcare resource utilization. Safety and tolerability of ALXN1210 compared with eculizumab will be assessed by physical examination, vital signs, electrocardiogram (ECG), laboratory assessments, and incidence of adverse events (AEs) and serious adverse events (SAEs). The proportion of patients who developed anti-drug antibodies (ADAs) will also be assessed. [Table 1] Abbreviations: ADA = anti-drug antibodies; ECG = electrocardiogram; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale; ET = early discontinuation; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue scale; LDH = lactate dehydrogenase; N / A = not applicable; PD = pharmacodynamics; PK = pharmacokinetics; PNH = paroxysmal nocturnal hemoglobin (PNH) Vinuria; RBC = red blood cells; WBC = white blood cells a All patients had a meningococcal vaccine against meningococcal infection within 3 years prior to or at the time of study drug initiation. Treatment with the test drug began less than two weeks after receiving the meningococcal vaccine. Patients starting vaccination should be treated with appropriate prophylactic antibiotics for up to 2 weeks after vaccination. It must be. b WBC (granulocyte colony count) was counted by high-sensitivity flow cytometry at screening and day 1. erythrocytes and monocytes) and RBC clone size were measured; on days 71 and 183, only RBC clone size. c Female patients of childbearing potential only. Serum pregnancy test at screening and day 183; urine pregnancy test at all other required time points. A negative urine test result was required before administering ALXN1210 or eculizumab to female patients of childbearing potential at the indicated visit. d Blood transfusions given during and between visits were recorded. e Before randomization and within 5 days before administration of study drug on Day 1, each patient's hemoglobin was assessed either at each site or at a central laboratory. If the patient's hemoglobin level met protocol-defined transfusion guidelines at that time, the patient was transfused with pRBCs to raise the hemoglobin level above the protocol-defined transfusion threshold to be eligible for randomization. Each site or central laboratory confirmed that the patient's post-transfusion hemoglobin level was above the protocol-defined transfusion threshold. f Investigator or designee assessment of the following events: fatigue, abdominal pain, shortness of breath Difficulty swallowing, chest pain, and erectile dysfunction. g Physician-reported and patient-reported assessments were performed before study medication administration. h The abbreviated physical examination consisted of body system-related examinations based on the investigator's (or designee's) judgment and the patient's symptoms. The abbreviated physical examination examined at least one body system. i Vital sign measurements were obtained after the patient had been at rest for at least 5 minutes. These include systolic and diastolic BP (millimeters of mercury [mmHg]), heart rate (beats / min), respiratory rate (breaths / min), and oral or tympanic temperature (Celsius [°C] or Fahrenheit [°F]). On day 1, vital signs were obtained before study drug administration. j A single 12-lead ECG will be obtained at screening and before dosing on days 57 and 183. Patients will be required to remain supine for approximately 5-10 minutes prior to ECG collection. The concentration must remain supine but awake. k Clinical laboratory measurements were collected pre-dose on the day of dosing. Follicle-stimulating hormone levels were measured only during screening to confirm postmenopausal status. l Serum samples for PK / PD analysis were collected pre-dose (within 0.5 hours before the start of the infusion) and at the end of the infusion ( End-of-infusion samples were collected within 0.5 hours of the end of infusion. End-of-infusion samples were drawn from the patient's contralateral, non-infused arm. All collection times were recorded on the eCRF. In the event of breakthrough hemolysis, serum samples for PK / PD analysis will be collected. m Serum samples for PK / PD analysis were collected pre-dose (within 0.5 hours before the start of the infusion) for patients treated with eculizumab and at any time point for patients treated with ALXN1210. All collection times were recorded on the eCRF. In the event of breakthrough hemolysis, serum samples for PK / PD analysis were collected pre-dose (within 0.5 hours before the start of the infusion) for patients treated with ALXN1210. A serum sample is taken. n Samples for ADA were taken before administration. If the test result was positive, Every 3 months until results become negative or stabilize based on potency and safety assessments The test can be repeated at any time. If an event suspected to be breakthrough hemolysis occurs, LDH, PK, and PD parameters If a suspected breakthrough event had not occurred at the scheduled visit, the patient was evaluated and the necessary LDH, PK, and PD parameters were collected. Patients visit the hospital irregularly to receive treatment. LDH results at screening and Patients were randomly assigned to treatment based on transfusion history. ALXN1210 dosing will be based on the patient's last recorded weight at the study visit. The primary efficacy endpoint will be assessed prior to dosing on Day 183. Dosing on Day 183 marks the start of the extension period. See Table 2 and Table 3 for additional post-dose procedures on Day 183. [Table 2] Abbreviations: ADA = anti-drug antibodies; ECG = electrocardiogram; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale; EOS = End of study; ET = Early discontinuation; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue scale; LDH = lactate dehydrogenase; PD = pharmacodynamics; PK = pharmacokinetics; PNH = paroxysmal nocturnal hemoglobin (PNH) Vinuria; RBC = red blood cells a All patients who are carried over into the extension period will receive ALXN1210 after all evaluations are performed on Day 183. b Granulocyte and RBC clonal sizes were measured on days 351 and 743 using a high-sensitivity flow cytometer. at other visits, only RBC clonality was measured. c For female patients of childbearing potential only. Serum pregnancy test at ET only; urine pregnancy test at other times In all cases, a negative urine test is required prior to administration of ALXN1210 to female patients of childbearing potential on the day of dosing. d Blood transfusions given during and between visits were recorded. e Investigator or designee assessment of the following events: fatigue, abdominal pain, shortness of breath Difficulty swallowing, chest pain, and erectile dysfunction. f Physician-reported and patient-reported assessments were performed before study medication administration. gThe abbreviated physical examination consists of body system-related examinations based on the investigator's (or designee's) judgment and the patient's symptoms. At least one body system must be examined during the abbreviated physical examination. It must be. h Vital sign measurements were obtained after the patient had been at rest for at least 5 minutes. These include systolic and diastolic BP (millimeters of mercury [mmHg]), heart rate (beats / min), respiratory rate (breaths / min), and oral or tympanic temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). Patient signs were obtained before each study drug administration. i A single 12-lead ECG will be obtained on Day 911 or at ET. Patients will be monitored for 24 hours prior to ECG collection. The patient must remain supine for 5-10 minutes and remain supine but awake during ECG collection. j Clinical laboratory measurements were collected pre-dose on dosing days. k Serum samples for PK / PD analysis were collected at the end of the infusion on Day 183; pre-dose (within 0.5 hours before the start of the infusion) and end of the infusion (within 0.5 hours after the end of the infusion) on Days 351, 575, and 743; and End-of-infusion samples were collected at any time on Day 911 or at ET. End-of-infusion samples were collected on the opposite side of the patient's infusion. All collection times were recorded on the eCRF. In the event of breakthrough hemolysis, serum samples for PK / PD analysis will be collected. l Samples for ADA were taken before administration. If the test result was positive, Every 3 months until results become negative or stabilize based on potency and safety assessments The test can be repeated at any time. m If a suspected breakthrough hemolysis event occurred, LDH, PK, and PD parameters were analyzed at a central laboratory. If not occurring at the time of visit, patient evaluation and necessary LDH, PK, and PD parameters Patients will visit the hospital irregularly to have their blood samples collected. n ALXN1210 dosing will be based on the patient's last recorded weight at the study visit. [Table 3] Abbreviations: ADA = anti-drug antibodies; ECG = electrocardiogram; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scale; EOS = End of study; ET = Early discontinuation; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue scale; LDH = lactate dehydrogenase; PD = pharmacodynamics; PK = pharmacokinetics; PNH = paroxysmal nocturnal hemoglobin (PNH) Vinuria; RBC = red blood cells a All patients who are carried over into the extension period will receive ALXN1210 after all evaluations have been performed on Day 183. b Granulocytes and RBCs were analyzed by high-sensitivity flow cytometry at days 365 and 757. Clone size was measured; at other visits, only RBC clone size was measured. c For female patients of childbearing potential only. Serum pregnancy test at ET only; urine pregnancy test at other times In all cases, a negative urine test is required prior to administration of ALXN1210 to female patients of childbearing potential on the day of dosing. d Blood transfusions given during and between visits were recorded. e Investigator or designee assessment of the following events: fatigue, abdominal pain, shortness of breath Difficulty swallowing, chest pain, and erectile dysfunction. f Physician-reported and patient-reported assessments will be performed prior to study drug administration. gThe abbreviated physical examination consists of a body system-related examination based on the judgment of the investigator (or designee) and the patient's symptoms. The abbreviated physical examination will examine at least one body system. h Vital sign measurements were obtained after the patient had been at rest for at least 5 minutes. These include systolic and diastolic BP (millimeters of mercury [mmHg]), heart rate (beats / min), respiratory rate (breaths / min), and oral or tympanic temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). Patient signs were obtained before each study drug administration. i A single 12-lead ECG will be obtained on day 925 or at ET. Patients will be monitored for 24 hours prior to ECG collection. The patient must remain supine for 5-10 minutes and remain supine but awake during ECG collection. j Clinical laboratory measurements were collected pre-dose on dosing days. k Serum samples for PK / PD analysis were collected on days 197, 365, 589, and 757 of dosing. Samples were collected before (within 0.5 hours before the start of the infusion) and at the end of the infusion (within 0.5 hours after the end of the infusion); at the end of the infusion on Day 183; and at any time point or ET on Day 925. The end of infusion sample was drawn from the patient's contralateral, non-infused arm. All collection times were recorded on the eCRF. In the event of breakthrough hemolysis, a serum sample for PK / PD analysis will be collected. l Samples for ADA were taken before administration. If the test result was positive, Every 3 months until results become negative or stabilize based on potency and safety assessments The test can be repeated at any time. m If an event suspected to be breakthrough hemolysis occurs, LDH, PK, and PD parameters should be measured. If a suspected breakthrough event had not occurred at the scheduled visit, the patient was evaluated and the necessary LDH, PK, and PD parameters were analyzed. Unscheduled visits should be made for collection. n ALXN1210 dosing will be based on the patient's last recorded weight at the study visit.

[0221] 4. Study population A total of approximately 246 patients with documented PNH were enrolled and randomly assigned to treatment with either ALXN1210 or eculizumab at approximately 300 study sites worldwide. Individuals who did not meet the study entry criteria (screening failures) could be rescreened. No future protocol deviations, also known as protocol waivers or exemptions, from recruitment and enrollment criteria were permitted.

[0222] Patients were eligible for enrollment in the study only if they met all of the following criteria and none of the exclusion criteria: 1. Male or female, 18 years of age or older at the time of consent. 2. Documented diagnosis of PNH, confirmed by sensitive flow cytometric evaluation of RBCs and white blood cells (WBCs) (Borowitz MJ, et al., "Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry", Cytometry Part B. 2010;78B:211-230), with granulocyte or monocyte clone size ≥ 5%. 3. Presence of one or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 g / dL), history of major vascular adverse events (including thrombosis), dysphagia, or erectile dysfunction; or history of pRBC transfusion due to PNH. 4. LDH level at screening is ≥ 1.5 × ULN. 5. To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients must have been vaccinated against meningococcal infection within 3 years prior to or at the time of study drug initiation. Patients who begin study drug treatment less than 2 weeks after receiving meningococcal vaccine must receive appropriate prophylactic antibiotic treatment until 2 weeks after vaccination. 6. Female patients of childbearing potential and male patients with female partners of childbearing potential must follow protocol-specified guidance to avoid pregnancy while undergoing treatment and for 8 months after the last dose of study medication. 7. Patients must provide written informed consent and agree to all study visits and procedures, including the use of any data collection device(s) to directly record patient data.

[0223] Patients were excluded from enrollment in the study if they met any of the following criteria: 1. Current or previous treatment with a complement inhibitor. 2. Platelet count <30,000 / mm at screening 3 (30×10 9 / L). 3. Absolute neutrophil count <500 / μL (0.5 × 10) at screening 9 / L). 4. Having a history of bone marrow transplantation. 5.Weight less than 40 kg at screening. 6. History of N. meningitidis infection. 7. History of recurrent infections of unknown cause. 8. Active systemic bacterial, viral, or fungal infection within 14 days prior to administration of study drug on Day 1. 9. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to administration of study drug on Day 1. 10. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titers). 11. Have been immunized with a live attenuated vaccine within 1 month prior to administration of study drug on Day 1. 12. History of malignancy within 5 years of screening, with the exception of non-melanoma skin cancer or cervical intraepithelial carcinoma that has been treated and has no evidence of recurrence. 13. History or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease (e.g., active hepatitis) that, in the opinion of the investigator or sponsor, would prevent the patient from participating in the clinical trial. 14. Unstable medical conditions that preclude tolerance of protocol (e.g., transfusion guidelines) requirements (e.g., anticipated need for major surgery within 6 months of randomization, coexisting chronic anemia unrelated to PNH, myocardial ischemia, active gastrointestinal bleeding, severe congestive heart failure). 15. Concomitant use of any of the following medications was prohibited unless on a stable regimen for the indicated period prior to screening: a) Erythropoietin or immunosuppressants for at least 8 weeks b) systemic corticosteroids for at least 4 weeks c) Vitamin K antagonists (e.g., warfarin), if the international normalized ratio (INR) is stable, for at least 4 weeks d) iron supplements or folic acid for at least 4 weeks e) Low molecular weight heparin for at least 4 weeks 16. History of hypersensitivity to mouse proteins or any of the test drug excipients (e.g., polysorbate 80). 17. Women who are planning to become pregnant, or are currently pregnant or breastfeeding. 18. Women with a positive pregnancy test result at screening or day 1. 19. Participation in another interventional treatment trial or use of any experimental treatment within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to starting study drug on Day 1 of this study. 20. Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to the start of screening. 21. Known medical or psychological condition(s) or risk factor(s) that, in the opinion of the investigator, may interfere with the patient's full participation in the study, pose any additional risk to the patient, or confound the patient's evaluation or the outcome of the study.

[0224] Patients had the right to withdraw from the study at any time. If a patient withdrew consent, a scheduled evaluation for an early termination (ET) visit was performed. Patients who withdrew from the study were not replaced.

[0225] Patients could discontinue study drug if it was in their best interest to stop treatment. If patients discontinued study drug, they were encouraged to return for the remainder of their scheduled protocol visits until a different complement-targeted therapy was initiated.

[0226] If a patient discontinued the study with an ongoing adverse event or an unresolved laboratory result that was significantly outside the reference range and clinically significant, the investigator attempted to provide follow-up until satisfactory clinical resolution of the laboratory result or adverse event was achieved.

[0227] The sponsor or regulatory authority may terminate the study for any reasonable reason, which will be defined as the date of the last patient's final visit during the extension period.

[0228] 5. Test Procedures The study drugs were ALXN1210 (ravulizumab) and eculizumab (active control). Both ALXN1210 and eculizumab are humanized anti-C5 monoclonal antibodies.

[0229] Eculizumab is an IgG2 / 4 kappa immunoglobulin consisting of mouse complementarity-determining regions grafted onto human constant regions and human framework light and heavy chain variable regions. For clarity, IgG2 / 4 is shorthand to describe a non-naturally occurring, protein-engineered heavy chain that contains elements derived from both the IgG2 heavy chain and the IgG4 heavy chain. This unique heavy chain was first described for use in anti-C5 antibodies in eculizumab. Eculizumab is composed of two 448-amino acid heavy chains and two 214-amino acid light chains.

[0230] ALXN1210 was derived from minimal targeted engineering of eculizumab by introducing four unique amino acid substitutions in the heavy chain of eculizumab to extend antibody half-life. ALXN1210 and eculizumab share over 99% primary amino acid sequence identity and have highly similar pharmacology.

[0231] The ALXN1210 and eculizumab formulations were supplied to clinical trials as sterile, preservative-free 10 mg / mL solutions in single-use vials and were designed for infusion by dilution in commercially available saline (0.9% sodium chloride injection; country-specific pharmacopoeia) for administration by IV infusion. Additional information is provided by Table 4, current ALXN1210 IB, and local labeling of approved eculizumab or current eculizumab IB. [Table 4]

[0232] ALXN1210 and eculizumab were packaged in USP / EP Type 1 borosilicate glass vials and stoppered with butyl rubber stoppers with aluminum overseals and flip-off caps. Study drug will be supplied as a kit. Upon receipt of required documentation as required by applicable regulations, study drug will be released to each site.

[0233] Upon arrival of the study drug kits at the study site, a pharmacist or designee will immediately remove the study drug kits from the shipping cooler and store them in their original boxes under refrigerated conditions at 2°C to 8°C (35°F to 47°F), protected from light. ALXN1210 and eculizumab were not frozen. Study drug must be stored in a secure, restricted-access storage area, and the temperature must be monitored daily.

[0234] The formulation is allowed to come to room temperature before administration. Materials are not heated other than by ambient air temperature (e.g., by using a microwave or other heat source).

[0235] Eculizumab or ALXN1210 was not administered as an IV push or bolus injection. Study drug infusions were prepared using aseptic technique. The patient's required dose of ALXN1210 or eculizumab was further diluted in commercially available normal saline (0.9% sodium chloride; country-specific pharmacopoeia) to the volume specified in Table 5 for ALXN1210 or Table 6 for eculizumab (see also approved local labeling or current IB for eculizumab). The ALXN1210 or eculizumab solution in diluent was administered to patients via an infusion pump using an IV tubing administration set. The use of an in-line filter for infusion was required. [Table 5] Note: See Pharmacy Manual for additional dose preparation instructions. aBody weight recorded at the last study visit. [Table 6]

[0236] Study drug doses were prepared and administered only by pharmacists or medically qualified staff members. Study drug was administered only to enrolled patients who were confirmed to be eligible to participate in the study. Once study drug was prepared for a patient, it was administered only to that patient. Study drug vials were for single use only, and any remaining formulation in the vial was not used by another patient. Any drug remaining in the infusion tubing or infusion bag was not used by another patient.

[0237] This study involved a head-to-head comparison of ALXN1210 with the active comparator eculizumab. Patients were randomly assigned in a 1:1 ratio to receive either ALXN1210 or eculizumab for 26 weeks. The study drug was administered as a slow IV infusion (see Tables 5 and 6).

[0238] The dosing regimen for ALXN1210 was a loading dose on day 1, followed by a maintenance dose q8w on day 15 and thereafter. ALXN1210 dosing was based on patient weight at the time of dose administration, as shown in Table 7. [Table 7]

[0239] Patients randomly assigned to the eculizumab group received eculizumab according to the approved dosing regimen for PNH indications: four weekly induction doses followed by maintenance doses q2w starting at week 5 (Table 8). [Table 8]

[0240] After the randomized treatment period, all patients entered an extension period in which they received ALXN1210 until the product was registered or approved (according to country-specific regulations) or for up to 2 years, whichever occurred first. Starting on day 183, patients randomized to the ALXN1210 treatment group received a weight-based maintenance dose of ALXN1210 q8w, and patients randomized to the eculizumab group received a weight-based loading dose of ALXN1210, followed by a weight-based maintenance dose of ALXN1210 q8w 2 weeks later and thereafter (Table 7).

[0241] Actual times for all dose administration were recorded on the patient's eCRF. Patients who met all enrollment criteria 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 voice or web-based response system (IxRS). Randomization was stratified. Patients were stratified into one of six groups based on transfusion history (0, 1–14, or >14 pRBC units within the year prior to the first dose of study drug) and screening lactate dehydrogenase (LDH) level (<1.5 × ULN–3 × ULN or ≥3 × ULN). Patients in each of the six groups were then randomly assigned 1:1 to receive ALXN1210 or eculizumab for the 26-week randomized treatment period.

[0242] The weight-based dosing of ALXN1210 in this study (Table 7) was based on PK / PD data from early development studies in healthy adult volunteers, as well as available data from patients with PNH in an ongoing Phase 1b dose-finding study (ALXN1210-PNH-103) and an ongoing Phase 2 proof-of-concept study (ALXN1210-PNH-201). The selection of the ALXN1210 dose regimen was based on targeting immediate, complete, and sustained inhibition of terminal complement in patients with PNH.

[0243] Eculizumab dosage is the labeled dose for treatment of patients with PNH (Soliris® USPI and SmPC).

[0244] Infusions of other monoclonal antibodies are associated with infusion reactions that commonly occur during the infusion or shortly after completion of the infusion. Previous medications (including vitamins and herbal preparations) that patients took or received within 28 days prior to the start of screening (or within 3 years for documented meningococcal vaccination) up to the first dose of study medication, including those discussed in the exclusion criteria and procedures (any interventions such as surgery / biopsy or physical therapy), were recorded on the patient's eCRF.

[0245] Any pRBC transfusions received within 1 year prior to the first study drug administration were recorded on the patient's eCRF.

[0246] All medication use and procedures performed during the study will be recorded on the patient's source document / chart and eCRF. This record will include all prescription medications, herbal products, vitamins, minerals, over-the-counter medications, and current medications for PNH. Concomitant medications will be recorded from the first infusion of study medication until 56 days after the patient's last dose of study medication. Any changes in concomitant medications will be recorded on the patient's source document / chart and eCRF. Any concomitant medications deemed necessary for the patient's standard of care during the study or to treat any AEs will be provided, at the investigator's discretion, along with the allowed medications listed below. However, the investigator is responsible for ensuring that all medication details are completely recorded on the patient's source document / chart and eCRF.

[0247] The following concomitant medications were allowed if the following conditions were met, and no dose adjustments were anticipated during the randomized treatment period: Erythropoietin, if the patient has been receiving a stable dose for at least 8 weeks prior to screening. Immunosuppressants, if the patient has been receiving a stable dose for at least 8 weeks prior to screening. Corticosteroids, if the patient has been receiving a stable dose for at least 4 weeks prior to screening. Vitamin K antagonists (e.g., warfarin), if the INR has been stable for at least 4 weeks prior to screening. Iron supplements or folic acid, if the patient has been receiving a stable dose for at least 4 weeks prior to screening. Low molecular weight heparin, if the patient has been receiving a stable dose for at least 4 weeks prior to screening.

[0248] The frequency or dose level of any of the above medications could be adjusted if deemed to be in the patient's best interest.

[0249] Due to their mechanism of action, the use of eculizumab or ALXN1210 increases patients' susceptibility to meningococcal infection (N. meningitidis). To reduce the risk of meningococcal infection, all patients were vaccinated against meningococcal infection within 3 years prior to or at the time of study drug initiation. Patients who initiated study drug treatment less than 2 weeks after receiving a meningococcal vaccine received appropriate prophylactic antibiotic treatment until 2 weeks after vaccination. To protect against common pathogenic meningococcal serotypes, vaccines against serotypes A, C, Y, W135, and B were recommended, if available. Patients were vaccinated or revaccinated according to current national vaccination guidelines or local practice regarding the use of vaccinations with complement inhibitors (e.g., eculizumab).

[0250] Vaccination may not be sufficient to prevent meningococcal infection. Appropriate use of antibacterial agents was considered in accordance with official guidance and local practice. All patients were monitored for early signs of meningococcal infection and, if infection was suspected, were immediately evaluated and treated with appropriate antibiotics if necessary.

[0251] 6.Efficacy evaluation pRBC transfusions were administered if the patient had a hemoglobin level of 9 g / dL or less and signs or symptoms of sufficient severity to warrant transfusion, or if the hemoglobin level was 7 g / dL or less, regardless of whether clinical signs or symptoms were present.

[0252] Signs or symptoms generally associated with or contributing to a patient's need for a blood transfusion were recorded on the eCRF for each patient. Typical anemia-related symptoms warranting a transfusion include angina, altered mental status (e.g., syncope, lightheadedness, confusion, stroke), and These included severe or worsening shortness of breath, severe or worsening fatigue, severe or worsening shortness of breath ...

[0253] If a patient met any transfusion criteria during the study, the investigator determined the appropriate number of pRBC units to transfuse. Transfusions were recommended to occur within 48 hours of determining the transfusion-inducing hemoglobin. The hemoglobin result and transfusion-inducing symptoms, as well as transfusion administration, including the number of units to be transfused, were recorded on the eCRF.

[0254] Before randomization and within 5 days before administration of study drug on Day 1, each patient's hemoglobin was assessed either at each site or at a central laboratory. If the patient's hemoglobin level met these transfusion guidelines at that time, the patient was transfused with pRBCs to bring the hemoglobin level above the transfusion threshold to be eligible for randomization. Each site or central laboratory confirmed that the patient's post-transfusion hemoglobin level was above the transfusion threshold.

[0255] A. LDH and other disease-related test parameters Blood and urine samples were collected, and the following disease-related laboratory parameters were measured during the study: LDH, free hemoglobin, urinary occult blood, total C5, haptoglobin, reticulocyte count, PNH RBC clone size assessed by high-sensitivity flow cytometry, D-dimer concentration, estimated glomerular filtration rate (calculated using the Modification of Diet in Renal Disease formula), spot urine albumin:creatinine ratio, and C-reactive protein.

[0256] B. Patient-Reported Outcome Measures Two validated QoL scales were administered to patients before study medication administration. The FACIT-Fatigue scale, version 4.0, is a collection of QoL questionnaires regarding the management of fatigue symptoms due to chronic illness. The FACIT-Fatigue is a 13-item questionnaire assessing self-reported fatigue over the previous 7 days and its impact on daily activities and function. Patients score each item on a 5-point scale: 0 (not at all) to 4 (very much). Total scores range from 0 to 52, with higher scores indicating better QoL.

[0257] The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Scale (QLQ-C30), version 3.0, is a questionnaire developed to assess the QoL of cancer patients. This questionnaire includes the following subscales: overall health, functional scales (physical functioning, role functioning, emotional functioning). The questionnaire includes three subscales: functional, cognitive, and social activities; symptom scales (fatigue, nausea and vomiting, and pain); and single-item items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulties). Thirty questions relate to QoL; the first 28 questions are scored on a 4-point scale (1 = not at all to 4 = very much); the final two questions, exploring the patient's overall health and QoL, are scored on a scale of 1 (very poor) to 7 (excellent). Each subscale ranges from 0 to 100%, with higher scores representing a greater level of response. Thus, a high score on the functioning scale represents a higher level of function, whereas a high score on the symptom scale represents a higher level of overall symptoms / problems.

[0258] To assess disease burden, patients completed two additional questionnaires. These questionnaires were administered to patients before infusion of study medication. The PNH Symptom Questionnaire listed the following symptoms: yellowing of the eyes, discoloration of the urine, chest pain, shortness of breath, headache, fatigue, abdominal pain, confusion, erectile dysfunction, difficulty swallowing, and other. Patients indicated whether they had experienced each symptom in the past week and, if so, rated its frequency (on a 4-point scale ranging from rarely to almost constantly), severity (on a 4-point scale ranging from mild to very severe), and the degree of distress / embarrassment associated with it (on a 5-point scale ranging from not at all to very much).

[0259] The resource utilization questionnaire asks patients to indicate the number of visits they have made to a healthcare provider within the past month primarily for treatment of PNH (excluding protocol-defined study visits), the number of emergency room visits primarily for treatment of PNH, the number of hospital admissions primarily for treatment of PNH, the number of times they had dark urine, and / or the number of times they missed work as a result of PNH symptoms.

[0260] C. Major vascular adverse events Major adverse vascular events (MAVEs) were assessed as part of the planned assessment of adverse events (AEs). Description of MAVEs, anatomical site, diagnostic method (e.g., magnetic resonance imaging, ultrasound, angiogram), date of diagnosis, and date of resolution (or ongoing) were collected in the eCRF as part of the patient's medical history (before baseline) and during the study. 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 artery thrombosis or infarction j) Liver / portal vein thrombosis (Budd-Chiari syndrome) k) Cerebral artery occlusion / cerebrovascular accident l) Cerebral venous occlusion m) Renal artery thrombosis n) Gangrene (non-traumatic; non-diabetic) o) Amputation (non-traumatic; non-diabetic) p) Skin thrombosis q) Other, please specify

[0261] D. Major vascular adverse events Demographic parameters including age, sex, race, and ethnicity were reviewed. A complete medical history was obtained and recorded. Weight and height were recorded. Height was measured only at screening.

[0262] Patients' PNH history, including onset of first PNH symptoms, date of diagnosis, PNH clone size, pRBC transfusions, and any history of MAVE, was recorded at the screening visit.

[0263] Patient medical history, including previous and concurrent conditions / disorders and blood transfusion history, was recorded at the screening visit. Medication use (prescription or over-the-counter, including vitamin and / or herbal supplements) over the 28 days (or 3 years for meningococcal vaccination records) prior to the start of screening was also recorded, in addition to meningococcal vaccination.

[0264] The physical examination included evaluation of the following: general appearance; skin; head, ears, eyes, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous system; and musculoskeletal system. The abbreviated physical examination consisted of relevant body system examinations based on the investigator's judgment and the patient's symptoms.

[0265] Vital sign measurements were obtained after the patient had rested for at least 5 minutes and included systolic and diastolic blood pressure (BP; millimeters of mercury [mmHg]), heart rate (beats / min), respiratory rate (breaths / min), and oral or tympanic temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]).

[0266] Samples for serum pregnancy, hematology, chemistry, coagulation, and urinalysis were performed. Samples for laboratory evaluation were collected before each study drug administration. If an event suspected of breakthrough hemolysis occurred, an unscheduled visit was conducted to collect samples for LDH and PK / PD analysis at a central laboratory.

[0267] It was expected that some laboratory values ​​would be outside the normal range due to underlying disease. The investigators used medical judgment in assessing the clinical significance of these values. Clinical significance is defined as any variation in a laboratory measurement that has medical relevance and results in a change in practice. If a clinically significant laboratory change from baseline was observed, the change was recorded as an AE in the AE eCRF. The investigators also assessed the relationship of all clinically significant out-of-range values ​​to study treatment. The investigators continued to monitor patients with additional laboratory evaluations until (1) the values ​​returned to the normal range or baseline levels, or (2) in the investigator's judgment, the out-of-normal range values ​​were no longer related to study drug administration or other protocol-specific procedures.

[0268] Blood samples were analyzed for serum chemistry parameters. Indirect bilirubin was calculated from total and direct bilirubin values; therefore, if direct bilirubin was below the limit of quantitation, an indirect bilirubin result was unavailable. For postmenopausal female patients, serum FSH levels were measured during screening to confirm postmenopausal status. Chemistry assessments were performed. Estimated glomerular filtration rates were calculated using the Modification of Diet in Renal Disease formula at all visits where serum chemistry was collected. Blood samples were analyzed for coagulation parameters.

[0269] Urine samples were analyzed. 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 urinary protein:creatinine ratio.

[0270] HIV testing for human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2) was required for all patients before enrollment. Known HIV-positive patients were not enrolled.

[0271] A single 12-lead digital ECG was obtained for each patient. Patients were required to be supine for approximately 5-10 minutes before ECG collection and to remain supine but awake during ECG collection.

[0272] Blood samples were collected to test for the presence and titer of ADAs to ALXN1210 or eculizumab in serum before study drug administration. If the test results were positive, they were repeated every three months until the results became negative or stabilized, based on the measured titers and safety assessments. Further characterization of the antibody response, including binding and neutralizing antibodies, PK / PD, safety, and ALXN1210 or eculizumab activity, was performed as needed.

[0273] An AE is any untoward medical occurrence in a patient administered a medicinal product, which does not necessarily have a causal relationship to that treatment. Thus, an AE can be any untoward or unintended sign (e.g., abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not it is considered medicinal product-related.

[0274] The absence of an unfavorable medical event (e.g., hospitalization for elective surgery if planned before the start of the study, hospitalization for social or convenience reasons), and expected day-to-day fluctuations in pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen are not AEs.

[0275] The lack of efficacy of a drug is not an AE in a clinical trial because the purpose of the clinical trial is to establish the efficacy of the drug.

[0276] Medication errors (including intentional misuse, abuse, and overdose of the product) or use other than that defined in the protocol will not be considered an AE unless there is an adverse medical event as a result of the medication error.

[0277] Pregnancy occurring during maternal or paternal exposure to the investigational product was reported within 24 hours of the investigator / site's knowledge. Data regarding fetal outcome and lactation will be collected for regulatory reporting and safety evaluation.

[0278] Adverse events were recorded from the time of consent signing. AEs reported after informed consent but before study drug administration were considered pretreatment AEs.

[0279] C5 inhibition has been shown to increase susceptibility to infections caused by encapsulated bacteria, particularly N. meningitidis. The following events were important identified risks in this study: meningococcal infection, sepsis, serious infection, Aspergillus infection, and infusion reactions. Additional events of interest in this study included: serious skin adverse reactions, cardiac disorders (including ventricular fibrillation), and angioedema.

[0280] AEs were graded for severity using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or later. A grading (severity) scale was provided for each AE term. Each CTCAE term is a Lowest Level Term (LLT) according to the Medical Dictionary for Regulatory Affairs (MedDRA®). Each LLT is coded to a MedDRA Preferred Term (PT).

[0281] Grade refers to the severity of the AE. In the CTCAE, grades 1 to 5 are assigned to each AE, along with a unique clinical description of severity (Table 9). [Table 9] Abbreviations: ADL = activities of daily living; AE = adverse events a Instrumental ADLs include preparing meals, shopping for groceries and clothing, using the telephone, and managing money. It refers to the following: bDaily ADLs include bathing, dressing and undressing, eating, using the toilet, and administering medicine. This refers to oral medication and not being bedridden.

[0282] For all AEs (both serious and non-serious), the investigator must provide a causality assessment (absent, probably not, possible, probably, definitely) based on the investigator's medical judgment and the symptoms associated with the observed event (Table 10). This assessment was recorded on the eCRF and any additional forms as needed. [Table 10-1] [Table 10-2]

[0283] A serious adverse event (SAE) is any untoward medical occurrence that results in death, is life-threatening (i.e., the patient was at risk of death at the time the event occurred), requires inpatient hospitalization or an extension of an existing hospitalization, leads to persistent or significant disability / incapacity, and / or is a congenital anomaly / birth defect.

[0284] A significant medical event that may not result in death, may not be immediately life-threatening, or may not require hospitalization may be considered a serious adverse event if, based on sound medical judgment, intervention may be required to put the patient at risk or prevent one of the outcomes listed above.

[0285] Suspected unexpected serious adverse reactions (SUSARs) were serious events not listed in the IB and identified by the investigator as related to the investigational product or procedure.

[0286] All AEs (serious and non-serious) were collected from ICF signs 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] 7. Pharmacokinetics and Pharmacodynamics Blood samples for serum drug concentration determination and PD assessment were collected before and after administration of study drug. The actual date and time (time in a 24-hour period) of each sample collection is recorded. The number of PK sampling time points for any given patient did not exceed the number of currently planned time points; in the event of breakthrough hemolysis, additional PK / PD samples were required.

[0288] Blood samples for PK and PD evaluation were drawn from the arm opposite the arm used for drug infusion.

[0289] PK / PD assessments included: changes in serum ALXN1210 and eculizumab concentrations over time, changes in cRBC hemolytic activity over time (exploratory), and changes in free and total C5 concentrations over time.

[0290] 8. Statistical methods and planned analyses All collected data are presented in schematic diagrams and tables. All data, as well as any outcomes derived from the data, are presented in detailed data listings. Graphical displays are also provided where appropriate. All analyses were performed using SAS® release, version 9.4 or later (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. Continuous variables were summarized using descriptive statistics, including the number of observations and the mean, standard deviation, median, minimum, and maximum. Categorical variables were summarized by frequency counts and percentages of patients. Unless otherwise specified, all statistical tests were performed based on a two-sided 5% level of significance. All decisions regarding the inclusion or exclusion of data from analyses for each patient were made by appropriate medical and statistical personnel before the database was finalized and locked. Any and all exclusions were recorded in the patient listing.

[0291] The following statistical analysis details will be specified in a separate Statistical Analysis Plan (SAP) prior to database lock and analysis. Any changes to the data analysis methods described in the protocol will only require modification if they result in a change to the primary or important secondary objectives or study controls. Any other changes to the data analysis methods described in the protocol or SAP, and justification for making the changes, will be described in the clinical study report (CSR). Additional exploratory analyses of the data were performed where deemed appropriate.

[0292] CSRs were generated based on efficacy, safety, PK, and PD data collected through the end of the 26-week randomized treatment period (Day 183). A final CSR was generated at study completion to summarize long-term efficacy, safety, PK, and PD parameters.

[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 patients would be evaluable (assuming a dropout rate of 10% or less). Sample size estimation was based on a non-inferiority design comparing patients treated with ALXN1210 with those treated with eculizumab. Non-inferiority was assessed using the coprimary endpoints of hemolysis, measured directly by the proportion of patients achieving LDH normalization (LDH-N) from days 29 to 183 and transfusion freedom (TA) by day 183. Sample size was based on endpoints requiring a larger number of patients.

[0294] For the coprimary endpoint of LDH-N, a noninferiority margin (NIM) based on a relative benefit of eculizumab versus placebo of 0.39 and a one-sided type I error of 2.5% was used, and a minimum of 142 patients would provide 80% power to demonstrate noninferiority of ALXN1210 to eculizumab. The NIM was determined based on a randomized, placebo-controlled trial in which the relative benefit of eculizumab versus placebo was demonstrated with an odds ratio of 6.5 (Hillmen P., et al., N. Engl. J. Med., 2006; 355: 1233-1243). This was based on several factors. Because baseline LDH is a predictor of rate of normalization, to preserve the assumption of stationarity, rates of LDH-N were calculated and adjusted for the observed baseline LDH-N from the current ALXN1210 Phase 1b and Phase 2 data. An estimate of LDH-N for eculizumab was then calculated to be the weighted average of the LDH-N rates from days 29 to 183, consistent with the proposed analysis plan for this study. Because the LDH-N rate for placebo-treated patients was 0% at all visits, the upper bound of the 95% CI was used to allow for the calculation of odds ratios. The final benefit estimate was based on LDH-N rates of 42% for eculizumab-treated patients and 10% for placebo. The traditional NIM selection is one with a ≤50% loss of benefit, resulting in an odds ratio of NIM of 0.39. NIM calculation follows Ng TH (Statist. Med. 2008; 27: 5392-5406), where NIM is calculated as 1 / {OR 0.5}, where: The OR represents the odds ratio of eculizumab compared with placebo and is given by [0.42 / (1-0.42)] / [0.1 / (1-0.1)], where 0.5 is the fraction of benefit protected. This approach selects the NIM on a log-odds scale, as described in Section IV of the 2010 Food and Drug Administration (FDA) Guidance for Industry: Non-Inferiority Clinical Trials. A more conservative approach to constructing the NIM, such as using the lower limit of the 95% CI for eculizumab, could be used, but the resulting estimated sample size would make the study operationally infeasible given the rarity of PNH and the paucity of eculizumab-naive patients.

[0295] For the other coprimary endpoint, the proportion of patients free of any transfusions by day 183, a NIM of -20% and a one-sided type I error of 2.5% required a minimum of 193 patients to provide 80% power to demonstrate noninferiority between treatment arms. The NIM was determined based on the International PNH Registry (Soliris Type II Variation Procedure No. EMEA / H / C / 000791 / II / 66), in which eculizumab-treated patients were enrolled in 2012 or later. Transfusion history is a predictor of transfusion under treatment; therefore, to preserve the assumption of stationarity, the NIM was estimated based on available data from treated and untreated patients in proportion to expected enrollment in this study. Patients treated with eculizumab (TA rate 57.1%) demonstrated benefit compared with untreated patients (TA rate 18.6%), with a difference of approximately 40% (38.5%) after adjusting for transfusion history in the 12 months prior to enrollment. The adjustment was made by limiting the expected proportion of transfusion-naive patients to 20% or less. To ensure constancy was achieved, enrollment in the study was capped at 20% transfusion-naive patients.

[0296] The traditional choice of NIM is one with a ≤50% loss of benefit, resulting in an NIM of approximately -20%. Using the lower bound of the 95% CI for the difference in rates, a more conservative NIM could be used; however, the resulting estimated sample size would make the study operationally impractical given the rarity of PNH and the paucity of eculizumab-naive patients with and without a history of transfusion. Furthermore, given the proportion of patients in whom TA was observed in preliminary results from the Phase Ib / II program, it is possible to limit the loss of power and demonstrate noninferiority with a more conservative NIM for a given sample size.

[0297] Because the sample size estimate based on LDH-N was smaller than that based on TA (Table 11), the final sample size estimate selected for this study was based on the TA endpoint. Adjusting for a possible 10% dropout rate, approximately 246 patients were enrolled in the study. [Table 11] Note: Software package: Hintze, J. (2011). PASS 11. NCSS, LLC. Kaysville, Utah, US. www.ncss.com a. TRIUMPH response rate adjusted for baseline LDH. b. Response rate in the Global PNH Registry, adjusted for transfusion history.

[0298] Efficacy analyses were performed on the Full Analysis Set (FAS). Co-primary efficacy endpoint analyses, as well as key 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 received at least one dose of ALXN1210 or eculizumab and had at least one efficacy assessment after the first infusion. The PP analysis population, established before database lock, consists of FAS patients who meet all of the following criteria: a) Did not miss any dose of ALXN1210 or missed ≤1 dose of eculizumab during the 26-week randomized treatment period b) Met inclusion criteria #2, 3, and 4 c) Did not meet exclusion criteria #1, #2, #3, or #4 d) Not receiving the wrong randomization treatment e) The transfusion guidelines specified in the protocol were followed.

[0299] Safety analyses were performed on the Safety Set, defined as all patients who received at least one dose of study drug. Pharmacokinetic and PD analyses were performed on all patients who received at least one dose of study drug and had evaluable PK and PD data.

[0300] Patient demographics and baseline characteristics, including medical and transfusion history, were summarized by treatment group and across the FAS, safety population, and PP population. No formal statistical comparisons were performed.

[0301] All patients were included in a patient disposition summary that described, by treatment group, the frequency and percentage of patients who were screened and received treatment, and who completed or discontinued the study, along with the reason for discontinuation. All patients who discontinued the study were identified, and their extent of study participation was reported. Reasons for discontinuation, if known, were provided. The number of patients who received treatment, the number of patients who discontinued treatment (with reasons for discontinuation), the number of patients who entered the extension period, and the number of patients who discontinued the extension period (with reasons for discontinuation) were tabulated by treatment group and overall.

[0302] Previous and concomitant medication use for each patient will be coded using the World Health Organization Drug Dictionary, and the frequency and percentage of concomitant medications will be summarized. Medications were summarized by Anatomical Therapeutic Chemical (ATC) class and preferred drug name using frequency counts and percentages of patients in the FAS, safety population, and PP population.

[0303] 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 odds ratios. Transfusion avoidance was achieved only by patients who were transfusion-free and did not meet protocol-defined guidelines for transfusion. The percentage of patients achieving TA with 95% CIs was computed for both the ALXN1210 and eculizumab treatment groups and randomization strata at Day 183. The difference in the percentage of patients achieving TA in the two treatment groups was calculated between the ALXN1210 and eculizumab treatment groups, along with the 95% CI for the difference. The difference between the ALXN1210 and eculizumab treatment groups was computed 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 will be calculated using the stratified Newcombe confidence interval method.

[0304] LDH-N was analyzed using generalized estimating equation (GEE) techniques, accounting for repeated measurements of LDH-N at each visit (Liang KY, et al., Biometrika. 1986; 73 (1): 13-22). The GEE technique yields odds ratios and CIs for treatment effects while controlling for correlations between a given patient's visit and other baseline factors. LDH-N from days 29 to 183 was used as the dependent and indicator variables for treatment, with transfusion history (as a categorical variable based on stratification factor levels) and baseline LDH level (as a continuous variable) included as explanatory variables in the model. Within-patient correlations assumed a first-order autoregressive structure, assuming the highest correlation between visits closest in time. Day 29 was the first scheduled assessment after initiation of maintenance dosing, and experience with eculizumab and phase Ib / II ALXN1210 data demonstrates near-maximal suppression of LDH with 4 weeks of treatment. Results from this model were presented as odds ratios with 95% confidence intervals.

[0305] To conclude that ALXN1210 is non-inferior to eculizumab, non-inferiority must be demonstrated for both co-primary endpoints separately. If the lower limit of the 95% CI for the difference (ALXN1210 minus eculizumab) was greater than the NIM of -20% for TA and the lower limit of the 95% CI for the odds ratio comparing ALXN1210 to eculizumab was greater than the NIM of 0.39 for LDH-N, treatment with ALXN1210 was concluded to be non-inferior to eculizumab. If non-inferiority was met for both co-primary endpoints and a greater effect was observed for ALXN1210 on either of the co-primary endpoints, superiority was assessed using the Hochberg multiple comparison procedure.

[0306] Four key secondary efficacy endpoints were summarized by randomization stratum and treatment group at study visits where these assessments were collected at baseline and during the 26-week randomized treatment period. Changes in FACIT-Fatigue (and percent change in LDH) from baseline to week 26 were analyzed using mixed models for repeated measures (MMRM; e.g., Mallinckrodt CH, et al., J. Biopharm. Stat. 2001;11:9-21 and Mallinckrodt CH, et al., Analyses will be performed using the ANOVA (see Clinical Trials. 2004;1:477-489) with a fixed categorical effect of treatment, stratified randomization criteria for transfusion history (0, 1-14, or >14 pRBC units within 1 year prior to first dose of study drug) and screening LDH level (<1.5 × ULN to <3 × ULN or ≥3 × ULN), study visit and its interaction with treatment group, and fixed continuous covariates for baseline FACIT-Fatigue (or LDH) and the interaction of baseline FACIT-Fatigue (or LDH) with visit as covariates. For percent change in LDH, baseline LDH level will be included as a continuous variable. The Kenward-Roger approximation will be used to estimate the degrees of freedom in the denominator. Differences between the ALXN1210 and eculizumab treatment groups will be calculated with two-sided 95% CIs.

[0307] For breakthrough hemolysis and hemoglobin stabilization, the same approach was used as for TA. Provided non-inferiority was asserted for the coprimary endpoints, these key secondary endpoints were tested hierarchically. Once non-inferiority for the key secondary endpoints was established, if a greater effect was observed for ALXN1210, superiority was assessed using a two-sided 0.05 test for each parameter.

[0308] When analyzing key secondary efficacy endpoints, closed testing procedures were used; therefore, lack of test significance prevented subsequent evaluation of the test. For all of these key secondary efficacy endpoints, estimates and CIs were computed regardless of whether lack of test significance prevented subsequent evaluation of the test. If the upper limit of the 95% CI for the difference between the ALXN1210 and eculizumab treatment groups in the percentage change in LDH from baseline to week 26 was below the NIM of 20%, ALXN1210 was declared non-inferior for this 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 the change from baseline in FACIT-Fatigue was greater than the NIM of -5, 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 breakthrough hemolysis was below the NIM of 20%, ALXN1210 was declared non-inferior for this 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 the proportion of patients with hemoglobin stabilization was above the NIM of -20%, ALXN1210 was declared non-inferior for this parameter. Because the order of hierarchical testing was prespecified, no adjustment for type I error was required.

[0309] Changes from baseline in EORTC-QLQ-C30 were summarized by treatment group at baseline and at study visits where these assessments were collected. Shifts from baseline in clinical manifestations of PNH were summarized by treatment group at study visits where these assessments were collected. The number of any treatment-emergent MAVEs (n) and the number of patients with an event (n, %) were presented by treatment group. The total number of pRBC units transfused during treatment was summarized by treatment group. Kaplan-Meier curves and estimates of the time from first study drug to first occurrence of LDH-N were generated for both treatment groups. Statistical inference of these parameters is not planned.

[0310] All safety analyses were performed on the safety population, defined as all patients who received at least one dose of ALXN1210 or eculizumab. Safety outcomes were reported by treatment group up to Day 183.

[0311] The following definitions were used for AEs: a) Pre-treatment Adverse Event: Any AE that begins after providing 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 SAEs: serious treatment-emergent AEs (TEAEs). Incidence of TEAEs, discontinuations due to TEAEs, drug-related TEAEs, on-treatment TEAEs, severe TEAEs, and SAEs were summarized. All AEs were coded using MedDRA version 18 or later and summarized by system organ class (SOC) and PT. Detailed patient-specific listings of TEAEs, SAEs, TEAEs, drug-related TEAEs, on-treatment TEAEs, and discontinuations due to TEAEs were provided. Adverse changes from baseline in physical examination findings were classified as AEs and analyzed accordingly.

[0312] Vital signs were summarized narratively by treatment group at baseline and post-baseline time points and for change from baseline. Data tabulations were provided for each patient. Clinical chemistry, hematology, and urinalysis results changes from baseline to post-baseline testing time points were summarized narratively by treatment group. Shift tables were provided over time for all applicable central laboratory values ​​using CTCAE v4.03 classification criteria. Tables of patients with abnormal results were provided.

[0313] Patient-specific data tables of ECG parameters were presented. Changes from baseline in electrocardiogram intervals (PR, RR, QT, and QTcF) were presented by treatment group. QT intervals were corrected for heart rate using the Fridericia formula (QTcF).

[0314] Abnormal immunogenicity findings, including incidence and titers of ADAs to ALXN1210 or eculizumab, were summarized in a tabular format by treatment group. The proportion of patients who were consistently positive and consistently negative was explored.

[0315] Individual serum concentration data for all patients who received at least one dose of study drug (i.e., ALXN1210 or eculizumab) and had evaluable PK data were used to derive PK parameters for ALXN1210 and eculizumab. Mean serum concentration-time profile graphs were constructed. Serum concentration-time profile graphs for individual patients are also presented. Actual dose administration and sample collection times were used for all calculations. Descriptive statistics were calculated for serum concentration data at each sample collection time, as appropriate. Population-PK assessments were considered using data from this study or in combination with data from other studies.

[0316] PD analyses were performed on all patients who received at least one dose of ALXN1210 or eculizumab and had evaluable PD data. Descriptive statistics are presented for all ALXN1210 and eculizumab PD endpoints at each sample collection time. PD efficacy of IV-administered ALXN1210 and eculizumab was assessed by assessing absolute and percentage changes from baseline in total and free C5 serum concentrations and cRBC hemolysis over time, as appropriate.

[0317] Example 2 ALXN1210 (ravulizumab) vs. ALXN1210 in complement inhibitor-naive adult patients with PNH Results of a Phase III, randomized, open-label, active-controlled trial of eculizumab The following is a summary of data obtained from an ongoing, open-label, Phase III clinical trial conducted according to the protocol described above in Example 1. A summary of efficacy and safety results is provided below.

[0318] 1. Study Summary This Phase III human clinical trial was a randomized, open-label, active-controlled study comparing the non-inferiority of ALXN1210 versus Soliris® (eculizumab) in complement inhibitor-naive adult patients with PNH. A total of 246 patients were enrolled in the study. A total of 244 patients completed the study and were included in this per-protocol analysis. Only two subjects discontinued during the course of the study.

[0319] This Phase 3 study achieved its primary objective, demonstrating non-inferiority of ALXN1210 (ravulizumab) to Soliris® (eculizumab). Specifically, the study achieved pre-specified non-inferiority margins (NIMs) for LDH normalization (LDH-N) and transfusion avoidance (TA) that were better than the 10% margin required by the FDA. Additionally, a NIM of less than 5% was achieved for the TA endpoint. Furthermore, all four key secondary endpoints favored ALXN1210, demonstrating non-inferiority to Soliris® (eculizumab). Breakthrough hemolysis (BTH) also demonstrated a numerical trend in favor of ravulizumab versus eculizumab, at 4% vs. 10.7%, respectively, although the study did not achieve a tab ( p<0.074). The incidence of breakthrough hemolysis was more than twice as high in the Soliris® group as in the ALXN1210 group, and this difference was associated with suboptimal C5 inhibition in the Soliris® group, suggesting that ALXN1210 reduces patients' risk of breakthrough hemolysis through consistent, complete C5 inhibition.

[0320] In summary, ULTOMIRIS was statistically significantly noninferior to eculizumab for both the coprimary endpoint and all key secondary endpoints: transfusion avoidance (73.6% vs. 66.1%; difference 6.8% [95% CI, -4.7, 18.1]), LDH normalization (53.6% vs. 49.4%; odds ratio [1.19 (0.80, 1.77)]), and percent reduction in LDH (76.8% vs. 76.0%; difference Difference [95% CI], -0.83% [-5.2, 3.6]), change in FACIT-Fatigue score (7.1 vs. 6.4; difference [95% CI], 0.67 [-1.2, 2.6]), breakthrough hemolysis (4.0% vs. 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and hemoglobin stabilization (68.0% vs. 64.5%; difference [95% CI], 2.9 [-8.8, 14.6]). Importantly, sensitivity analyses demonstrated robust results for all efficacy endpoints. The data are presented in the accompanying figures and tables and discussed in more detail below.

[0321] The design of the non-inferiority trial comparing ALXN1210 to eculizumab is shown in Figure 1. This study compares an individualized, weight-based dosing scheme for ALXN1210 with the existing approved dosing scheme for eculizumab in PNH to demonstrate non-inferiority in complement inhibitor treatment-naive patients with PNH. The dose selected for ALXN1210 is weight-based and includes a loading dose on Day 1 (2400 mg for patients weighing 40 kg to < 60 kg, 2700 mg for patients weighing 60 kg to < 100 kg, and 3000 mg for patients weighing 100 kg or more), followed by maintenance doses of ALXN1210 on Day 15 and thereafter q8w (3000 mg for patients weighing 40 kg to < 60 kg, 3300 mg for patients weighing 60 kg to < 100 kg, and 3600 mg for patients weighing 100 kg or more). See Figure 1. In contrast, eculizumab dosing includes four 600 mg induction doses on days 1, 8, 15, and 22, followed by a 900 mg maintenance dose administered IV on day 29 and every two weeks thereafter. See Figure 1.

[0322] The study enrolled more patients than originally planned. Specifically, 246 patients were enrolled in the study and randomized to either the ALXN1210 or eculizumab group. See Figure 2. A total of 39 subjects did not pass screening. Of the 246 patients who entered and completed the 26-week treatment period, 243 progressed to the ongoing extension study. See Figure 2. Baseline characteristics and demographics of the study population are shown in Figure 3.

[0323] All 246 treated patients (125 patients in the ALXN1210 group and 121 patients in the eculizumab group) were included in the FAS and safety analysis set, as described in Table 12. Two patients were excluded from the PP analysis set. One patient in the ALXN1210 group and one patient in the eculizumab group met protocol-specified criteria for pRBC transfusion (hemoglobin ≤ 7 g / dL) but did not receive a transfusion at that time or at any other time during the primary evaluation period. There were other patients who met transfusion criteria at specific visits but did not receive a transfusion; these patients were included in the PP analysis set because they received at least one transfusion according to the transfusion criteria. [Table 12] Abbreviations: FAS = Full Analysis Set; PP = Per Protocol

[0324] There was no difference in actual stratification at randomization compared to the stratification observed for the LDH group (LDH <1.5 x ULN to 3 x ULN vs. LDH ≥ 3 x ULN) (see Table 13). Of 44 patients stratified to 0 units of pRBC, 1 patient was observed to receive 1 to 14 units of pRBC. Of 157 patients stratified to 1 to 14 units of pRBC, 3 patients were observed to receive > 14 units of pRBC. Of 45 patients stratified to > 14 units of pRBC, 1 patient was observed to receive 1 to 14 units of pRBC. [Table 13] Note: Baseline was defined as the last non-missing value before the first dose of study medication. The ULN for LDH is 246 U / L. Abbreviations: LDH = lactate dehydrogenase; pRBC = packed red blood cells; ULN = upper limit of normal

[0325] Baseline disease characteristics were similar between the two 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).

[0326] All patients had a PNH diagnosis confirmed by flow cytometry at screening. The mean total PNH RBC clone size was 38.57%, the mean total PNH granulocyte clone size was 84.74%, and the mean total PNH monocyte clone size was 87.99%. [Table 14-1] [Table 14-2] NOTE: Total RBC, granulocyte, and monocyte clone sizes = total RBC, granulocyte, and monocyte clone sizes of type II and III, respectively. Spherical clonality size. Baseline was defined as the last non-missing value before the first dose of study medication. a The "Other" category includes Coombs test, Flaer test, clinical signs / symptoms (all i.e., clinical data, clinical picture, or clinical diagnosis), immunophenotyping, methods used for diagnosis Combined methods, osmotic fragility test, diagnosis at another hospital, and unknown were included. Abbreviations: max = maximum value; min = minimum value; SD = standard deviation; PNH = paroxysmal nocturnal hemoglobinuria; RBC = red blood cells

[0327] Enrollment in the 0-unit prior RBC stratum was censored once the protocol-specified 20% limit for enrolling patients without a transfusion history in the previous year was reached. Thus, as shown in Table 15, the majority of patients (82.5%) had a pRBC transfusion in the year prior to their first dose of study drug. In the total population, a mean of 6.2 pRBCs / whole blood transfusion was administered, and a mean of 8.8 units were transfused in the 12 months prior to first dose. The number of transfusions and units transfused were similar between the two treatment groups. [Table 15-1] [Table 15-2] Abbreviations: max = maximum value; min = minimum value; pRBC = packed red blood cells; SD = standard deviation

[0328] As required by protocol, all patients had at least one PNH-related symptom at baseline. The types of PNH symptoms experienced by patients before informed consent were similar across treatment groups, with the most common (>20% of all patients) being fatigue or asthenia (general weakness), red or dark urine, shortness of breath (difficulty breathing), jaundice (yellowing of the skin or eyes), abdominal pain, and CNS-related symptoms such as headache, dizziness, or difficulty concentrating.

[0329] In the total population, 98.0% of patients had a documented PNH-related condition diagnosed before informed consent, as shown in Table 16. The majority of patients (84.6%) had a previous 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] Note: Patients may be counted in more than one category. aThe "other" category included the most commonly (n ≥ 2) reported conditions. The "other" category also included a history of at least one other PNH-associated condition, including thrombocytopenia (n = 5), chronic kidney disease (n = 4), pancytopenia (n = 3), elevated AST (n = 2), renal parenchymal disease (n = 2), leukopenia / thrombocytopenia (n = 2), gallstones (n = 2), hepatosplenomegaly, myeloid, and megakaryocytic disorders. aplasia, hemolytic events, bone marrow cytopenia, pancytopenia, bone marrow hypoplasia, signs of hemolysis, chronic hemolysis, bilateral renal parenchymal disease / hypokalemia, suspected aplastic anemia, miscarriage, ischemic stroke / chronic kidney disease, bone marrow hyperplasia, thrombocytopenia / epistaxis, increased bilirubin, bone marrow hypoplasia, or Leukopenia / thrombocytopenia / history of splenectomy were reported in one patient each. Abbreviations: PNH = paroxysmal nocturnal hemoglobinuria

[0330] All 246 patients had a history of prior medication use. All patients had received meningococcal vaccine by day 1. The most commonly reported (≥10% of patients) prior medication groups other than meningococcal vaccine were vitamin B12 and folic acid (52.8%), antithrombotic agents (29.7%), systemic corticosteroids (24.8%), medications for peptic ulcer and gastroesophageal reflux disease (22.8%), iron supplements (15.4%), beta-lactam antibacterials (penicillin) (15.0%), systemic antihistamines (13.0%), selective calcium channel blockers with primarily vascular effects (11.4%), and other analgesics and antipyretics (11.0%).

[0331] Overall, 95.9% of patients (98.4% in the ALXN1210 group and 93.4% in the eculizumab group) were taking at least one concomitant medication. The most commonly reported (≥10% of patients) concomitant medication groups were vitamin B12 and folic acid (54.9%), other analgesics and antipyretics (38.6%), beta-lactam antibacterials (penicillins) (38.6%), antithrombotic agents (31.3%), medications for peptic ulcer and gastroesophageal reflux disease (29.3%), quinolone antibacterials (26.0%), systemic antihistamines (24.8%), systemic corticosteroids (24.4%), anti-inflammatory and antirheumatic products (21.1%), iron preparations (17.1%), other beta-lactam antibacterials (13.0%), expectorants excluding those in combination with antitussives (11.4%), selective calcium channel blockers primarily associated with vascular events (12.6%), and immunosuppressants (10.2%). A total of 30.9% of patients underwent non-pharmacological medical procedures during the study.

[0332] 2. Primary / secondary endpoints and disease-related parameters The two co-primary efficacy endpoints, transfusion avoidance (TA) and LDH normalization (LDH-N), were very clearly met and exceeded, as shown in Figure 4. The red triangles in Figure 4 indicate the non-inferiority margins required by the FDA. For both the TA and LDH-N endpoints, the 20% non-inferiority margin was substantially exceeded. In fact, the TA endpoint simply did not achieve a 20% margin, but a 5% margin. Similarly, LDH-N exceeded the 20% margin and achieved the equivalent of an additional 10% margin. See Figure 4.

[0333] The key secondary endpoints of LDH percent change (LDH-PCHG), change in FACIT fatigue score, breakthrough hemolysis (BTH), and hemoglobin stabilization (HGB-S) were also positive, favoring ALXN1210 over eculizumab. See Figure 5. Furthermore, not only were all secondary endpoints favoring ALXN1210, but all were substantially above the non-inferiority margin, indicated by the red triangle in the graph. See Figure 5.

[0334] The key primary and secondary endpoints are tabulated in Figure 6. The treatment effect for each endpoint, where ALXN1210 is favored over eculizumab, is also shown. For example, the first row shows that the treatment effect for ALXN1210 on transfusion avoidance was 6.8% compared to eculizumab, which is much larger than the required non-inferiority margin of -20%, leading to a finding of non-inferiority. Similarly, the same conclusion was reached that ALXN1210 is non-inferior to eculizumab for all primary and secondary endpoints. In other words, ALXN1210 was found to be better than eculizumab, but the sample size was insufficient to reach a statistical conclusion of superiority. See Figure 6.

[0335] The efficacy data from this study were subjected to a number of different sensitivity analyses. The results are shown in Figure 7. For example, the treatment effect (point estimate) for 1210 was 6.8%, better than eculizumab, with a 95% confidence interval (CI) of -4.7% to 18.1%. The -4.7% figure is substantially better than the predefined non-inferiority margin of -20%. The table shows various sensitivity analyses, all of which support the robust findings of the primary analysis. It is noteworthy that this consistency is unusual for clinical trials of this type and supports the notion that this study was conducted with very high quality.

[0336] Efficacy results for the primary endpoint of LDH-N were analyzed by subgroup of the patient population and are shown in Figure 8. LDH-N (lactate dehydrogenase normalization) refers to LDH levels less than or equal to 1 × ULN from Day 29 to Day 183. Subgroup analysis for LDH-N revealed preponderance of evidence favoring ALXN1210. Gray lines are 95% confidence intervals, and blue boxes are point estimates. Estimates were based on generalized estimating equation (GEE) techniques. The model included the following terms: treatment group, transfusion history, and baseline LDH level. Estimates to the right of 1 favor ALXN1210, and estimates to the left favor eculizumab. All point estimates fell to the right of the predefined non-inferiority margin (red triangle) (-20%). Only three endpoints favored eculizumab, two of which had small sample sizes. In conclusion, ALXN1210 showed a clear advantage over eculizumab in the majority of subgroups. See Figure 8.

[0337] As shown in Figure 9, mean LDH values ​​normalized to the upper limit of normal (LDH 1 x ULN) in the patient population by approximately days 22-24 and remained at that level throughout the study. The dotted line in Figure 9 indicates the upper limit of normal for LDH or LDH 1 x ULN. The box below the graph indicates the number of patients in each group who contributed to the average for that day. In conclusion, it is clear that mean LDH values ​​in patients on ALXN1210 remained below the dangerous level of 1.5 x ULN. See Figure 9.

[0338] The time to reach LDH normalization for both the ALXN1210 and eculizumab treatment groups is shown in Figure 10. Patients under ALXN1210 reached normalization approximately 5 days earlier than patients under eculizumab. See Figure 10. On average, ALXN1210 patients reached normalization by day 24, whereas patients treated with eculizumab reached normalization by day 29. The boxes with numbers below the graph indicate the number of patients in each group used to calculate the average for that day. See Figure 10.

[0339] The percentage of patients who achieved LDH normalization at various time points during the course of the study is shown in Figure 11. In general, greater than 50% of ALXN1210 patients remained within the normal range throughout the study, while less than 50% of patients treated with eculizumab remained within the normal range throughout the study and through Day 183. See Figure 11.

[0340] Furthermore, at baseline, the mean EORTC QLQ-C30 general health subscale score was 56.13 for the ALXN1210 group and 57.51 for the eculizumab group. A 10-point or greater improvement in the three EORTC QLQ-C30 subscales, general health, physical function, and EORTC-Fatigue, is considered to indicate a clinically meaningful improvement (King, 1996; Osoba, 1998). As shown in Figures 12, 13, and 14, a higher percentage of patients in the ALXN1210 group had at least a 10-point improvement in the EORTC QLQ-C30 general health, physical function, and fatigue subscale scores at Day 29 and throughout the primary evaluation period compared with the eculizumab group.

[0341] 3.Safety No notable safety differences in adverse events (AEs) or serious adverse events (SAEs) were observed between patients treated with ALXN1210 and those treated with eculizumab. See Figures 15 and 16. Additionally, no meningococcal infections, discontinuations due to AEs, or deaths were observed during the primary evaluation period. See Figures 17 and 18. The most common AE was headache, at 35%. See Figure 16.

[0342] Overall, 17.1% of patients reported one or more prior MAVEs, as described in Table 17. [Table 17] Note: Patients may be counted in more than one category. Abbreviations: MAVE = major adverse vascular event

[0343] One case of treatment-emergent anti-drug antibody (ADA) was observed for each of ALXN1210 and eculizumab. Neutralizing antibodies were not produced, and these apparently transient ADAs did not impact PK, PD, efficacy, or safety. Figure 15 graphically depicts key safety results from the Phase 3 ALXN1210-PNH-301 clinical trial.

[0344] Compliance was nearly perfect for this clinical trial, as shown in Figure 19. As shown in Figure 19, there was only one non-compliance in the eculizumab arm.

[0345] 4.Pharmacokinetic results The mean (±SD) ALXN1210 and eculizumab serum concentration versus time profiles (linear scale) for each treatment group are shown in Figure 20. The mean (±SD) ALXN1210 and eculizumab serum concentration versus time profiles (semi-log scale) for each treatment group are shown in Figure 21.

[0346] Pharmacokinetic parameters for ALXN1210 are summarized in Tables 18 and 19 for the first (induction) dose and last (maintenance) dose, respectively. Geometric mean (geometric CV%) C of ALXN1210 after first dose in all patients max and C trough The geometric mean (%CV) C values ​​for all patients after the last ALXN1210 dose were 753.7 μg / mL (22.45) and 376.44 μg / mL (26.17), respectively. max and C trough were 1350.5 μg / mL (20.8) and 446.1 μg / mL (36.2), respectively. [Table 18-1] [Table 18-2] Abbreviation:C max = maximum serum concentration; C trough = trough serum concentration; CV = coefficient of variation; SD = standard deviation [Table 19] Abbreviation:C max = maximum serum concentration; C trough = trough serum concentration; CV = coefficient of variation; SD = standard deviation

[0347] Non-compartmental PK parameters were measured only for the ALXN1210 group. Results after the last maintenance dose of ALXN1210 are shown in Table 20. ALXN1210 PK steady state was achieved after multiple dose administration for all weight-based maintenance doses (Table 21). [Table 20]

[0348] [Table 21] Abbreviations: CI = confidence interval

[0349] 5. Pharmacodynamic results Treatment with ALXN1210 resulted in immediate, complete, and sustained complement C5 inhibition throughout the 8-week dosing interval. See Figure 19. As shown in Figure 19, weight-based dosing every 8 weeks resulted in the greatest steady-state and trough exposure.

[0350] Table 22 summarizes the mean percent change from baseline in serum free C5 concentrations after treatment with ALXN1210 (weight-based dosing, q8w) or eculizumab (900 mg q2w). Some free C5 samples were deemed biologically implausible and excluded. Because PK and free C5 samples were collected from the same blood draw, paired PK data were used to confirm this exclusion. These exclusions were as follows: ALXN1210 group: For 3 (2.4%) patients, the free C5 sample value at end of infusion on Day 1 was similar to the pretreatment value. Eculizumab group: For 3 (2.5%) patients, the free C5 sample at pretreatment on Day 1 was below the limit of quantitation (BLQ); for 5 (4.1%) patients, the free C5 sample value at EOI on Day 1 was similar to the pretreatment value.

[0351] In the ALXN1210 group, mean serum free C5 concentrations were <0.5 μg / mL as early as the end of the first infusion and at all subsequent trough time points. This threshold was not consistently achieved in the eculizumab group. Furthermore, more individual free C5 values ​​above the target free C5 threshold of 0.5 μg / mL were observed in the eculizumab group than in the ALXN1210 group. This imbalance in free C5 control is likely due to differences in breakthrough hemolysis events observed between the treatment groups (ALXN1210: n=5, eculizumab: n=15). [Table 22-1] [Table 22-2]

[0352] Mean free C5 levels were inhibited by greater than 99% by the end of the first infusion of ALXN1210 and remained inhibited by greater than 99% for the duration of the study treatment period. In contrast, in the eculizumab group, free C5 was not consistently inhibited by greater than 99% (see Figure 22).

[0353] Total C5 levels were similar for both the ALXN1210 and eculizumab groups. The mean (±95% CI) percent change from baseline for the total serum C5 concentration versus time profiles is shown in Figure 23. The rate and magnitude of change in serum total C5 were similar between treatments. Baseline was defined as the last non-missing assessment before the first dose of study drug. ^ indicates data for Day 1 are from the end of infusion, while data for Days 8, 22, 29, 43, 57, 85, 99, 113, 141, 155, and 169 are from any time point for the ALXN1210 group and pre-dose for the eculizumab group; data for Days 15, 71, and 127 are pre-dose for both treatment groups, and data for Day 183 are from the end of the randomized treatment period for both treatment groups.

[0354] Example 3 A Phase III, Single-Arm, Multicenter Study of ALXN1210 in Complement Inhibitor-Naive Adult Patients with Atypical Hemolytic Uremic Syndrome (aHUS) A single-arm study (ALXN1210-aHUS-311) of ALXN1210 was conducted in complement inhibitor treatment-naive adult and adolescent patients with atypical hemolytic uremic syndrome (aHUS).

[0355] aHUS is often caused by mutations in genes encoding proteins involved in the alternative complement pathway (APC), thrombotic microangiopathy (TMA), or autoantibodies against APC regulatory proteins (Noris, et al., Clin. J. Am. Soc. Nephrol. 2010;5:1844-59). Patients with aHUS are at risk for life-threatening manifestations of the disease due to endothelial injury, including thrombocytopenia, intravascular hemolysis, acute renal failure, and extrarenal tissue damage. Importantly, approximately 20% of patients develop extrarenal manifestations of the disease, including central nervous system, cardiac, GI, distal limb, and severe systemic organ damage (Loirat, et al., Orphanet J. Rare Dis. 2011;6:60 and Brodsky, Blood. 2015;126:2459-65). Before the availability of eculizumab, the mortality rate for patients with aHUS was as high as 15% during the acute, progressive phase of the disease (Noris, et al., Clin. J. Am. Soc. Nephrol. 2010; 5: 1844-59) and Sellier-Leclerc, J. Am. Soc. Nephrol. 2007; 18: 2392-2400). Up to 50% of patients progress to end-stage kidney disease (ESKD), often within one year of disease onset, requiring dialysis or kidney transplantation to sustain life. Chronic uncontrolled terminal complement activation, specifically activation of complement component 5 (C5) and dysregulation of complement activity, are central to the pathogenesis of aHUS and the devastating manifestations of this disease. Consequently, targeted blockade of C5 using selective inhibition of C5a and C5b-9 generation represents an important therapeutic mechanism of treatment.

[0356] 1. Purpose The primary objective of this study is to evaluate the efficacy of ALXN1210 to inhibit complement-mediated TMA, characterized by thrombocytopenia, hemolysis, and nephropathy, in adolescent and adult patients with aHUS who are treatment-naive with complement inhibitors.

[0357] Secondary objectives of the study are: (1) to characterize the safety and tolerability of ALXN1210 in this patient population; (2) to evaluate the efficacy of ALXN1210 on additional outcome measures (e.g., dialysis status, time to complete TMA response, status of complete TMA response over time, observed and change from baseline in estimated glomerular filtration rate (eGFR); chronic kidney disease (CKD) stage (assessed at the selected target date and categorized as improved, stable (no change), or worsening compared to baseline); observed and change from baseline in blood parameters (platelets, LDH, hemoglobin); an increase of 20 g / L or more from baseline in hemoglobin (sustained over at least two consecutive measurements taken at least 4 weeks apart); and change from baseline in quality of life (QoL) (EuroQol 5 dimensions 3). (3) to characterize the PK / pharmacodynamics (PD) of ALXN1210 by changes in serum ALXN1210 concentrations over time and changes in free C5 concentrations over time; and (4) to evaluate the long-term safety and efficacy of ALXN1210.

[0358] 2. Evaluation items The primary efficacy endpoint of the study was complete TMA response during the 26-week initial evaluation period, evidenced by normalization of hematological parameters (platelet count and LDH) and a 25% or greater improvement from baseline in serum creatinine, confirmed by two consecutive measurements taken at least four weeks apart.

[0359] Secondary efficacy endpoints of the study include: A. Whether or not your condition requires dialysis; B. Time to complete TMA response; C. Status of complete TMA response over time; D. Observed eGFR and change from baseline; E. CKD stage assessed by the investigator on the selection target date and classified as improved, stable (no change), or worsening compared to baseline; F. Observed values ​​and changes from baseline of blood parameters (platelets, LDH, hemoglobin); G. An increase of 20 g / L or more from baseline in hemoglobin sustained over at least two consecutive measurements taken at least 4 weeks apart; H. Change from baseline in QoL as measured by the EQ-5D-3L questionnaire (all patients), the FACIT Fatigue version 4 questionnaire (patients aged 18 years and older), and the Pediatric FACIT Fatigue questionnaire (patients under 18 years).

[0360] The pharmacokinetic (PK) and pharmacodynamic (PD) endpoints of this study are the change in serum ALXN1210 concentration over time and the change in free C5 concentration over time.

[0361] The safety and tolerability of ALXN1210 will be assessed by physical examination, vital signs, electrocardiogram (ECG), laboratory evaluations, and the incidence of AEs and SAEs. The proportion of patients who develop anti-drug antibodies (ADAs) will also be assessed.

[0362] Exploratory biomarkers of PD efficacy include, but are not limited to, changes from baseline in levels of markers of complement dysregulation (e.g., Ba factor), markers of vascular inflammation (e.g., soluble tumor necrosis factor receptor 1 [sTNFR1]), markers of endothelial activation / damage (e.g., soluble vascular adhesion molecule 1 [sVCAM1], thrombomodulin), markers of coagulation (e.g., D-dimer), and markers of renal injury (e.g., cystatin C). Additional assessments may include measurement of urinary ALXN1210 excretion, chicken red blood cell (cRBC) hemolysis, total C5, autoantibodies to complement proteins (e.g., anti-factor H), and APC activity (e.g., modified Ham's test, complement deposition assay).

[0363] Exploratory genetics may be performed to investigate genetic variants in genes known to be associated with aHUS, as well as to identify novel genetic variants associated with aHUS, complement dysregulation, or the metabolism or efficacy of ALXN1210. Patients may opt out of providing samples for exploratory genetics and still participate in the study.

[0364] 3. Summary of study design The ALXN1210-aHUS-311 study is a Phase 3, open-label, single-arm, multicenter study to evaluate the safety and efficacy of ALXN1210 administered by intravenous (IV) infusion to adolescent (ages 12 to <18 years) and adult (ages 18 years or older) patients with aHUS. The study will enroll approximately 55 patients who will receive ALXN1210. The study design is illustrated in Figure 24. All patients will be complement inhibitor treatment-naïve and will include at least 6 and up to 10 adolescent (ages 12 to <18 years at screening) patients and at least 10 and up to 25 patients who have received a previous kidney transplant.

[0365] 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. Dosing is based on the patient's weight at their last recorded study visit (Table 27). Patients will receive a loading dose of ALXN1210 IV on Day 1 (2400 mg for patients weighing 40 kg to < 60 kg, 2700 mg for patients weighing 60 kg to < 100 kg, and 3000 mg for patients weighing 100 kg or greater), followed by maintenance doses of ALXN1210 IV on Day 15 and every 8 weeks thereafter (3000 mg for patients weighing 40 kg to < 60 kg, 3300 mg for patients weighing 60 kg to < 100 kg, and 3600 mg for patients weighing 100 kg or greater) for a total of 26 weeks of treatment. After the initial evaluation period, patients will enter an extension period in which they will receive ALXN1210 until the product is registered or approved (according to country-specific regulations) or for up to two years, whichever occurs first. The end of the study will be defined as the last patient's final visit.

[0366] This Phase 3, open-label, single-arm study will evaluate the safety and efficacy of treatment with ALXN1210. While no formal comparative analyses are planned for this study, results from patients treated with ALXN1210 will be evaluated against those observed in patients treated with eculizumab, a historical control group. The historical control group consists of patients with aHUS who were treated with eculizumab in the C08-002A / B, C10-003, and C10-004 prospective registrational trials, which had similar study design and objective implementation characteristics that may affect effect sizes. Furthermore, to further align with the eligibility criteria for this study, the control group is limited to patients aged 12 years or older who had PE / PI for 4 weeks or less prior to treatment with eculizumab.

[0367] The schedule of assessments for the screening and initial evaluation period is shown in Table 23. The schedule of assessments for the extension period is shown in Table 24. Additional (unscheduled) visits beyond the scheduled visits were permitted at the discretion of the investigator. Procedures, tests, and assessments would be performed at the discretion of the investigator. Any tests, procedures, or assessments performed at unscheduled visits would be recorded on the electronic case report form (eCRF). Testing at unscheduled visits would use local laboratory or central laboratory analysis. However, local laboratory testing should be used, and duplicate samples would be collected for central laboratory testing at unscheduled visits. [Table 23-1] [Table 23-2] Abbreviations: ADA = anti-drug antibody; ADAMTS13 = a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; aHUS = atypical hemolytic uremic syndrome; APC = complement Systemic accessory pathway; ECG = electrocardiogram; EQ-5D-3L = EuroQol 5 dimensions 3 level; ET = early discontinuation; FACIT = functional assessment of chronic illness treatment; HUS = hemolytic uremic syndrome; LDH = lactate dehydrogenase; N / A = not applicable; PD = pharmacodynamics; PK = pharmacokinetics; QoL = quality of life; ST-HUS = Shiga toxin-associated hemolytic uremic syndrome. a All patients had received vaccination against meningococcal infection within 3 years prior to starting the study drug or Patients who start treatment with the study drug less than 2 weeks after receiving the meningococcal vaccine should receive appropriate prophylactic antibiotic treatment until 2 weeks after vaccination. Patients who have not received vaccinations prior to initiating treatment with ALXN1210 should receive prophylactic antibiotics before and for at least 2 weeks after receiving meningococcal vaccination. do. b Human immunodeficiency virus type 1 and human immunodeficiency virus type 2 screening. c Stool samples for Shiga toxin enzyme immunoassay. d Female patients of childbearing potential only. Serum pregnancy test at screening and day 183; urine pregnancy test at all other required time points. A negative urine test result is required before administering study drug to female patients of childbearing potential at any potential study visit. e For patients 18 years of age and older, use the FACIT-Fatigue version 4 at screening. For patients under 18 years of age, use the Pediatric FACIT-Fatigue at screening. f On dosing days, a patient-reported assessment will be performed prior to dosing. g The abbreviated physical examination consists of a body system-related examination based on the investigator's (or designee's) judgment and the patient's symptoms. The abbreviated physical examination will examine at least one body system. hVital sign measurements were obtained after the patient had rested for at least 5 minutes, including systolic and diastolic BP (millimeters of mercury [mmHg]), pulse oximetry, and heart rate (beats / min). , respiratory rate (breaths / min), and oral or tympanic temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On dosing days, vital signs will be obtained before dosing. i A single 12-lead ECG will be obtained at screening, on Day 57, and before dosing on Day 183. Patients will be in a supine position for approximately 5-10 minutes before ECG collection and will remain in a supine position during ECG collection. But he is awakened. j Clinical safety laboratory measurements will be taken pre-dose on the day of dosing. LDH for eligibility is determined from a chemical evaluation. Follicle-stimulating hormone levels are measured during screening only to confirm postmenopausal status. k Serum samples for LDH isoenzyme testing were selected depending on the availability of the sample test. The data will be collected at any / all time points prior to ALXN1210 dosing only at designated facilities. l Assessment of safety, as well as primary and secondary endpoints. m Serum samples for PK / PD analysis will be collected pre-dose (within 0.5 hours before the start of the infusion) and at the end of infusion (EOI) (within 0.5 hours after the EOI) on Days 1, 15, 71, and 127; and at any time on Days 29, 43, 57, 85, 99, 113, 141, 155, and 169; and pre-dose on Day 183 (with an additional PK / PD sample collected on Day 183 as part of the extension period). (Note that the end-of-infusion sample should be taken from the patient's contralateral side where the infusion was not initiated.) All sampling times will be recorded on the eCRF. nUrine samples for drug determination will be collected at the end of infusion (EOI) on days 1, 15, and 71 (within 0.5 hours after EOI); and at any time on day 29. o Serum samples will be collected pre-dose on dosing days and at random times on non-dose days. All collection times will be recorded on the eCRF. p Serum, plasma, and urine collections for exploratory biomarker analysis will be performed at baseline and at post-treatment time points immediately prior to ALXN1210 dosing. q A single whole blood draw from patients who consent to genetic testing can be performed at any time during the study. r ADA serum samples will be collected pre-dose on Days 1, 71, and 127. The Day 183 collection will occur prior to the first dose of the extension period. All collection times will be recorded on the eCRF. If the test result is positive, the test will be repeated every 3 months until the result becomes negative or stabilizes based on measured potency and safety assessments. s Concomitant medications must be collected at all study visits and checked against a list of prohibited medications. stomach. t ALXN1210 dosing will be based on the patient's last recorded weight at the study visit. u Local or central laboratory analysis may be used to determine eligibility at screening. However, if local laboratory testing is used, duplicate samples for LDH, platelet count, hemoglobin, and serum creatinine will be collected at that visit for central laboratory testing. v The primary efficacy endpoint will be assessed prior to dosing on Day 183, which marks the start of the extension period. [Table 24-1] [Table 24-2] Abbreviations: ADA = anti-drug antibodies; aHUS = atypical hemolytic uremic syndrome; ECG = electrocardiogram; EOS = end of study; EQ-5D = EuroQol 5 dimensions; ET = early discontinuation; FACIT = Functional Assessment of Chronic Illness Therapy; PD = pharmacodynamics; PK = Pharmacokinetics; QoL = quality of life a For female patients of childbearing potential only. Serum pregnancy test at ET only; urine at all other required times Pregnancy Testing. A negative urine test result is required prior to administration of ALXN1210 to female patients of childbearing potential at the indicated study visit. b For patients 18 years of age and older, use the FACIT-Fatigue version 4 at screening. For patients under 18 years of age, use the Pediatric FACIT-Fatigue at screening. c On dosing days, a patient-reported assessment will be performed prior to dosing. d The brief physical examination will consist of a body system-related examination based on the investigator's judgment and the patient's symptoms. e Vital sign measurements were obtained after the patient had rested for at least 5 minutes, including systolic and diastolic BP (millimeters of mercury [mmHg]), pulse oximetry, and heart rate (beats / min). , respiratory rate (breaths / min), and oral or tympanic temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On dosing days, vital signs will be obtained before dosing. f A single 12-lead ECG will be obtained on day 911 or at ET. Patients will be monitored for approximately 5-10 minutes before ECG collection. The patient must remain supine throughout the entire procedure and must remain supine but awake during ECG collection. It must be. g Assessment of safety, as well as primary and secondary endpoints. h Serum samples for PK / PD analysis were collected pre-dose (at the start of infusion) on Days 351, 575, and 743. EOI (within 0.5 hours before the start of treatment) and EOI (within 0.5 hours after the EOI); EOI on the 183rd day (within 0.5 hours after the EOI); and at any time on days 911 or ET. End-of-infusion samples were collected from the patient's contralateral Collect from the uninjected arm. Record all collection times on the eCRF. i Serum, plasma, and urine for exploratory biomarker analysis will be collected immediately prior to ALXN1210 dosing at the indicated time points; and at any time point or ET on Day 911. All collection times will be recorded on the eCRF. j Pre-dose serum samples will be collected on days 351, 575, and 743. Serum samples will be collected on day 911. or ET. All collection times will be recorded on the eCRF. If the test result is positive, the test will be repeated every 3 months until the result becomes negative or stabilizes based on the measured potency and safety assessments. k Concomitant medications will be collected at all study visits and checked against a list of prohibited medications. l The extension period begins at the start of dosing on Day 183. ALXN1210 dosing is based on the patient's weight at their last recorded study visit.

[0368] 4. Study population A total of approximately 55 patients with documented aHUS will be enrolled and assigned to treatment with ALXN1210 at approximately 200 research sites worldwide. The study will enroll at least six and up to 10 adolescent (ages 12 to less than 18 years at screening) patients and at least 10 and up to 25 patients who have undergone a previous kidney transplant.

[0369] Individuals who do not meet the study entry criteria (screening failures) may be rescreened. Patients may be rescreened a maximum of two times. Future approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, will not be permitted.

[0370] Patients are eligible for enrollment in the study if they meet all of the following criteria and none of the exclusion criteria:

[0371] Male or female patients aged 12 years or older and weighing 40 kg or more at the time of consent. Thrombocytopenia, evidence of hemolysis, and evidence of TMA, including renal insufficiency, based on the following screening visit laboratory findings: platelet count less than 150,000 / microliter (μL), LDH ≥ 1.5 × upper limit of normal (ULN), and hemoglobin ≤ age- and sex-specific lower limit of normal (LLN), and serum creatinine level ≥ ULN for adults (18 years and older) or ≥ 97.5th percentile for age at screening for adolescents (12 to < 18 years). (Patients requiring dialysis for acute kidney injury are also eligible.) Among patients undergoing kidney transplantation: known history of aHUS before current kidney transplant, or no known history of aHUS, and persistent evidence of TMA for a minimum of 4 days and a maximum of 7 days after temporary discontinuation of calcineurin inhibitors (CNIs; e.g., cyclosporine, tacrolimus) or mammalian target of rapamycin inhibitors (mTORi; e.g., sirolimus, everolimus). Among patients who developed postpartum TMA, evidence of persistent TMA for >3 days from the day of delivery. To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients will be vaccinated against meningococcal infection within 3 years prior to or at the time of study drug initiation. Patients who begin treatment with ALXN1210 less than two weeks after receiving a meningococcal vaccine will receive appropriate prophylactic antibiotic treatment until two weeks after vaccination. Patients who have not been vaccinated before initiating ALXN1210 treatment will receive prophylactic antibiotic treatment before and for at least two weeks after receiving a meningococcal vaccine. Patients under 18 years of age must be 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 must follow protocol-specified guidance to avoid pregnancy while undergoing treatment and for 8 months after the last dose of study medication. Be willing and able to provide written informed consent and comply with the study visit schedule. For patients under 18 years of age, the patient's legal guardian must be willing and able to provide written informed consent, and the patient must be willing to provide written informed consent.

[0372] Samples collected at screening can be tested either at each site or at a central laboratory. If local testing is used for LDH, platelet count, hemoglobin, and serum creatinine, duplicate samples will be collected for central laboratory testing to ensure that the baseline and post-baseline measurements for analysis are from the central laboratory. While local laboratory test results can be used to expedite the assessment of eligibility, the final determination of these inclusion criteria will be based on the central laboratory results.

[0373] Patients were excluded from study enrollment if they met any of the following criteria: A. Known "A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13" (ADAMTS13) deficiency (activity <5%). B. Shiga toxin-associated hemolytic uremic syndrome (ST-HUS). C. Streptococcus as evidenced by a positive direct Coombs test and infection with Streptococcus pneumoniae (e.g., culture, antigen test) pneumoniae-associated hemolytic uremic syndrome (HUS). D. Known human immunodeficiency virus (HIV) infection. E. Unresolved systemic meningococcal disease. F. Patients with an ongoing confirmed diagnosis of sepsis, defined as a positive blood culture within 7 days prior to the start of screening and not treated with antibiotics. G. Presence or suspicion of an active, untreated systemic bacterial infection that, in the opinion of the investigator, may confound the accurate diagnosis of aHUS or interfere with the ability to manage aHUS disease. H. Pregnancy or breastfeeding. I. Heart, lung, small intestine, or liver transplant. J. In patients undergoing kidney transplantation, any of the following: Acute renal insufficiency within 4 weeks of transplantation consistent with a diagnosis of acute antibody-mediated rejection (AMR) according to the Banff 2013 criteria, or b. Acute renal dysfunction and rising donor-specific antibodies (DSA) within 4 weeks of transplantation consistent with a clinical diagnosis of acute AMR. c. History of polycystic kidney disease. K. In patients aged 18 years or older with a systolic blood pressure (SBP) of ≥ 170 mmHg or in patients aged 12 to < 18 years with a clinical diagnosis of hypertension, any of the following: a. Evidence of sustained TMA (inclusion criterion #2) for less than 4 days after blood pressure (BP) reduction to ≤140 mmHg. b. Known left ventricular hypertrophy. c. Known small hyperechoic kidneys on ultrasound. L. Identified drug exposure-associated HUS. M. For the current TMA, have received PE / PI for 28 days or longer prior to the start of screening. N. History of malignant disease within 5 years of screening, with the exception of non-melanoma skin cancer or cervical intraepithelial carcinoma that has been treated and has no evidence of recurrence. O. Bone marrow transplant (BMT) / hematopoietic stem cell transplant (HSCT) within 90 days prior to the start of screening. P. HUS associated with vitamin B12 deficiency. Q. Known systemic sclerosis (scleroderma), systemic lupus erythematosus (SLE), or antiphospholipid antibody positivity or syndrome. R. Chronic dialysis (defined as regular dialysis as renal replacement therapy for ESKD). S. Patients receiving chronic intravenous immunoglobulin (IVIg), except for an unrelated medical condition (e.g., hypogammaglobulinemia), within 8 weeks prior to the start of screening; or patients receiving chronic rituximab treatment within 12 weeks prior to the start of screening. T. Patients receiving other immunosuppressive therapy, such as steroids, mTORi (e.g., sirolimus, everolimus), or CNI (e.g., cyclosporine or tacrolimus), will be excluded, except in the following cases: a) as part of an established post-transplant anti-rejection regimen, or b) the patient has confirmed anti-complement factor antibodies that necessitate immunosuppressive therapy, or c) steroids are being used for a condition other than aHUS (e.g., asthma). U. Participation in another interventional treatment trial or use of any experimental treatment within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to starting study drug on Day 1 of this study. V. Previous use of eculizumab or other complement inhibitors. W. Hypersensitivity to mouse protein or to one of the excipients. X. Any medical or psychological condition that, in the opinion of the investigator, may increase the patient's risk from participation in the study or may confound the outcome of the study. Y. Known or suspected history of drug or alcohol abuse or dependence within one year prior to the start of screening.

[0374] Test results for exclusion criterion number 1 may not be available before first dose. Later results for exclusion criterion number A may lead to discontinuation and patient recruitment.

[0375] Patients have the right to withdraw from the study at any time. If a patient withdraws consent, a defined evaluation will be conducted for the Early Discontinuation (ET) visit. Patients who withdraw from the study will not be replaced. Patients may discontinue study medication if the investigator or sponsor has reason to believe that stopping treatment is in the patient's best interest.

[0376] Patients who develop AMR (C4d-positive kidney biopsy), have had a previous kidney transplant, and for whom rituximab is deemed appropriate treatment must be withdrawn from the study and treated with standard of care. The primary reason for discontinuation and any other reason(s) will be recorded on the eCRF.

[0377] If a patient discontinues the study with an ongoing AE or an unresolved laboratory result that is significantly out of reference range and clinically significant, the investigator will attempt to provide follow-up until satisfactory clinical resolution of the laboratory result or adverse event is achieved.

[0378] A sponsor or regulatory authority may terminate a trial for reasonable cause, including, but not limited to, (1) the discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the trial, (2) a decision by the sponsor to temporarily halt or discontinue the testing, evaluation, or development of the investigational drug, (3) the investigator's failure to comply with the approved protocol, relevant guidelines, and / or regulations, and (4) the investigator's willful submission of false information to the sponsor and / or regulatory authority.

[0379] If at any time after receiving at least one dose of investigational product, a patient's screening data are determined to no longer meet one or more of the following inclusion / exclusion criteria (Inclusion Criterion #2 or Exclusion Criterion #1) (e.g., if the patient's local laboratory data used to confirm the eligibility criteria are subsequently determined by a central laboratory to no longer meet the eligibility criteria), the patient may be discontinued from the study and refilled. Early discontinuation procedures will be implemented for patients who terminate early, and all AEs will be collected up to 60 days after the patient's last dose of study drug.

[0380] The end of the study will be defined as the date of the last patient's final visit during the extension period.

[0381] 5. Test Procedures 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 mouse complementarity-determining regions grafted onto human constant regions and human framework light and heavy chain variable regions. ALXN1210 and eculizumab share greater than 99% primary amino acid sequence identity and have highly similar pharmacology.

[0382] For clinical trials, the ALXN1210 formulation will be supplied as a sterile, preservative-free 10 mg / mL solution in single-use vials and designed for infusion by dilution in commercially available saline (0.9% sodium chloride injection; country-specific pharmacopoeia) for administration by IV infusion. Table 25 and the current IB provide additional information. [Table 25-1] [Table 25-2]

[0383] ALXN1210 will be packaged in United States Pharmacopoeia (USP) / European Pharmacopoeia (EP) Type 1 borosilicate glass vials and stoppered with butyl rubber stoppers with aluminum overseals and flip-off caps. The study drug will be supplied as a kit. ALXN1210 will be released to each study site upon receipt of all required documentation required under applicable regulations.

[0384] Upon arrival at the study site, a pharmacist (or trained designee) will immediately remove the study medication kits from the shipping cooler and store them in their original boxes under refrigerated conditions at 2°C to 8°C (35°F to 47°F), protected from light. Do not freeze ALXN1210. Store the study medication in a secure, restricted-access storage area, with the temperature monitored daily.

[0385] The formulation is allowed to come to room temperature before administration. Materials are not heated other than by ambient air temperature (e.g., by using a microwave or other heat source).

[0386] ALXN1210 was not administered as an IV push or bolus injection. Study drug infusions are prepared using aseptic technique. The patient's required dose of ALXN1210 is further diluted in commercially available normal saline (0.9% sodium chloride; country-specific pharmacopoeia) at the volumes specified in Table 26. The ALXN1210 solution in diluent is administered to patients via an infusion pump using an IV tubing administration set. The use of an in-line filter for infusion is required. [Table 26] Please refer to the Pharmacy Manual for additional dosage preparation instructions. a Body weight recorded at the last study visit.

[0387] Study drug doses will be prepared and administered only by pharmacists or medically qualified staff members. Study drug will be administered only to enrolled patients who are confirmed to be eligible to participate in the study. Once study drug is prepared for a patient, it will be administered only to that patient. Study drug vials are for single use only, and any remaining formulation in the vial will not be used by another patient. Any drug remaining in the infusion tubing or infusion bag will not be used by another patient.

[0388] Store all clinical trial materials in a secure location and allocate and dispense them by appropriately trained personnel. Maintain detailed records of the amounts of investigational product received, dispensed, and discarded. Unless otherwise notified, retain empty vials and vials with residual material for inspection and accountability by study monitoring, after which they will be destroyed or handled in accordance with each site's investigational drug standard operating procedure (SOP). To meet regulatory requirements for drug accountability, reconcile all remaining inventory of ALXN1210 at the end of the study and destroy or return to Alexion in accordance with applicable regulations.

[0389] Patients will receive ALXN1210 for 26 weeks. ALXN1210 will be administered as a slow IV infusion over approximately 2 hours. ALXN1210 was not administered as an IV push or bolus injection.

[0390] The ALXN1210 dosing regimen during the initial evaluation period is based on the patient's weight at their last recorded study visit (Table 27). Patients will receive a loading dose of ALXN1210 IV on Day 1, followed by maintenance doses of ALXN1210 IV q8w (every 8 weeks) on Day 15 and thereafter. [Table 27] a Body weight recorded at the last study visit.

[0391] After the initial evaluation period, all patients will roll over into a maximum 2-year extension period, during which they will receive ALXN1210 q8w (every 8 weeks). The actual times of all dose administration will be recorded on the patient's eCRF.

[0392] This is an open-label study. Patients who meet all enrollment criteria will be assigned to study treatment with ALXN1210 at the baseline visit (Day 1). An interactive voice or web response system (IxRS) will be used to assign each patient a vial containing ALXN1210.

[0393] The weight-based dosing of ALXN1210 in this study (Table 27) is premised on PK / PD data from early development studies in healthy adult volunteers, as well as available data from patients with PNH in an ongoing Phase 1b dose-finding study (ALXN1210-PNH-103) and an ongoing Phase 2 proof-of-concept study (ALXN1210-PNH-201). The selection of the ALXN1210 dose regimen for patients with aHUS is based on targeting immediate, complete, and sustained inhibition of terminal complement in patients with PNH, which is expected to correspond to the immediate, complete, and sustained inhibition of terminal complement in patients with aHUS shown in clinical trial data for eculizumab in patients with PNH and aHUS.

[0394] Infusions of other monoclonal antibodies have been associated with infusion reactions that generally occur during or shortly after completion of the infusion.

[0395] Previous medications (including vitamins and herbal preparations) that patients had taken or received within 28 days prior to the start of screening (or within 3 years for documented meningococcal vaccination) up to the first dose of ALXN1210, including those discussed in the exclusion criteria and procedures (any interventions such as surgery / biopsy or physical therapy), were recorded on the patient's eCRF.

[0396] For analytical purposes, any dialysis within the 14-day period immediately following the first ALXN1210 dose will not be considered a "new dialysis."

[0397] All medication use and procedures performed during the study will be recorded on the patient's source document / chart and eCRF. This record will include all prescription medications, herbal products, vitamins, minerals, over-the-counter medications, and current medications. Concomitant medications will be recorded from the first infusion of study medication until 56 days after the patient's last dose of study medication. Any changes in concomitant medications will also be recorded on the patient's source document / chart and eCRF. Any concomitant medications deemed necessary for the patient's standard of care during the study or to treat any AEs will be provided, at the investigator's discretion, along with the allowed medications listed below. However, the investigator is responsible for ensuring that all medication details are completely recorded on the patient's source document / chart and eCRF.

[0398] Patients are prohibited from receiving any of the following medications 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 the clinical trial, IVIg (except for unrelated medical need, e.g., for hypogammaglobulinemia), rituximab, PE / PI after the first dose, and new dialysis in the first 48 hours after the first dose of ALXN1210 unless there is compelling medical need as assessed by (1) hypervolemia unresponsive to diuretics, (2) refractory electrolyte imbalance, or (3) new onset of uremic encephalopathy. Exceptions must be approved by the sponsor on a case-by-case basis before dialysis is administered.

[0399] The following concomitant medications and procedures are permitted under certain circumstances and with the following restrictions: Use of other immunosuppressive therapies (e.g., steroids, mTORi [e.g., sirolimus, everolimus], CNIs [e.g., cyclosporine or tacrolimus], etc.) prior to screening or during the study is not permitted unless a) they are part of an established post-transplant anti-rejection regimen, or b) the patient has confirmed anti-complement factor antibodies requiring immunosuppressive therapy, or c) steroids are being used for a condition other than aHUS (e.g., asthma).

[0400] Any patient receiving other complement inhibitors (including eculizumab) or progressing to PE / PI after the first dose of study drug will be withdrawn from the study.

[0401] Use of ALXN1210 increases patient susceptibility to infection due to its mechanism of action. To reduce the risk of infection, all patients will be vaccinated against N. meningitidis, Hib, and Streptococcus pneumoniae.

[0402] Patients will be vaccinated against N. meningitidis within 3 years prior to or at the time of the first dose of ALXN1210. Patients treated with the drug less than 2 weeks after receiving a meningococcal vaccine will receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. To protect against common pathogenic meningococcal serotypes, vaccines against serotypes A, C, Y, W135, and B are recommended, if available. Patients will be vaccinated or revaccinated according to current national vaccination guidelines or local practice regarding the use of vaccinations with complement inhibitors (e.g., eculizumab).

[0403] It is understood that some patients who have not been vaccinated against N. meningiditis within three years prior to receiving their first dose of ALXN1210 may not be able to be vaccinated at the time of their first dose. Patients who have not been vaccinated prior to initiating treatment with ALXN1210 will receive prophylactic antibiotics before and for at least two weeks after receiving meningococcal vaccination.

[0404] Vaccination may not be sufficient to prevent meningococcal infection. Appropriate use of antibacterial agents should be considered in accordance with official guidance and local practice. All patients will be monitored for early signs of meningococcal infection, and any suspected infection will be evaluated promptly and treated with appropriate antibiotics if necessary. To increase risk awareness and facilitate prompt disclosure of any potential signs or symptoms of infection experienced by patients during the course of the study, patients will be provided with a safety card to carry with them at all times. Additional discussion and explanation of potential risks, signs, and symptoms will occur at specific times as part of the patient safety card review and throughout the study as described in the schedule of assessments (Tables 23 and 24).

[0405] Patients will be vaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae according to national and local vaccination schedule guidelines before or at the time of their first dose of ALXN1210. Vaccination status against N. meningitidis, Hib, and S. pneumoniae will be recorded on the patient's eCRF.

[0406] Patients will receive the study drug in a controlled environment under the supervision of the Investigator or designee, thereby ensuring compliance with study drug administration. The Investigator or designee will ensure that all patients are adequately informed of the specific dosing regimen required to comply with the study protocol, ensure that patients receive the correct dose at the specified time points during the study, and ensure that appropriate safety monitoring occurs during the infusion.

[0407] Female patients who considered themselves postmenopausal before receiving study drug must provide evidence of menopause based on amenorrhea for at least 1 year in combination with elevated serum follicle-stimulating hormone (FSH) levels (>30 IU / L) (e.g., in the absence of hormone replacement therapy, dietary phytoestrogens).

[0408] Female patients of childbearing potential will use highly effective contraceptive methods (as defined below) beginning at screening and continuing for at least 8 months after the last dose of study drug. * These include hormonal contraception with ovulation inhibition, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, partner vasectomy (provided the partner is the patient's only sexual partner), abstinence (defined as abstinence from heterosexual intercourse for the entire period of risk associated with treatment with the study drug; the reliability of abstinence must be assessed in relation to the duration of the clinical trial and the patient's preferred usual lifestyle), and a combination of male condoms and either spermicide-containing caps, contraceptive diaphragms, or sponges (double-barrier methods). Male patients with a female spouse / partner of childbearing potential or a pregnant or lactating spouse or partner agree to double-barrier contraception (male condoms plus an appropriate barrier method for the female partner) while undergoing treatment and for at least 8 months after the last dose of study drug. Double-barrier contraception is required even if there is a medical evaluation documenting the surgical success of the vasectomy.

[0409] Male patients will not donate sperm while undergoing treatment and for at least 8 months after their last dose of study drug.

[0410] 6.Efficacy evaluation The primary efficacy outcome was a complete TMA response during the 26-week initial evaluation period. Criteria for a complete TMA response were: (1) normalization of platelet count, (2) normalization of LDH, and (3) a 25% or greater improvement from baseline in serum creatinine.

[0411] Patients who meet all of the complete TMA response criteria, confirmed by two consecutive measurements taken at least four weeks apart, will be classified as meeting the primary efficacy endpoint.

[0412] The following secondary efficacy endpoints will be measured during the study: A. Whether dialysis is necessary B. Time to complete TMA response C. Complete TMA response over time D. Observed eGFR and change from baseline E. CKD stage assessed by the investigator on the selected target date and classified as improved, stable (no change), or worsening compared to baseline F. Observed values ​​and changes from baseline of blood parameters (platelets, LDH, hemoglobin) G. A sustained increase in hemoglobin from baseline of 20 g / L or more over at least two consecutive measurements taken at least 4 weeks apart H. Change from baseline in QoL as measured by the EQ-5D-3L questionnaire (all patients), the FACIT Fatigue version 4 questionnaire (patients aged 18 years and older), and the Pediatric FACIT Fatigue questionnaire (patients under 18 years).

[0413] 7. Safety Assessment The investigator or the patient's designee will meet with the patient to discuss potential safety risks of ALXN1210 and to provide the investigator an opportunity to address any safety concerns the patient may have regarding the study.

[0414] Collection of AEs will be monitored from the time informed consent is obtained until study completion. The investigator will follow any AEs until their outcome (resolution or stabilization). If a patient withdraws from the study, AE monitoring will continue until the last patient's final study visit, if possible. The timing of clinical and laboratory evaluations will be performed according to the schedule of evaluations (Tables 23 and 24). Any clinically significant abnormal results will be followed until resolution or stabilization.

[0415] A survey of demographic parameters including age, sex, race, and ethnicity will be conducted. A complete medical history will be obtained and recorded. Weight and height will be recorded. Height will be measured only at screening.

[0416] The patient's aHUS history, including the onset of the first aHUS symptom and the date of diagnosis, will be recorded at the screening visit.

[0417] Patient medical history, including previous and concurrent conditions / disorders, will be recorded at the screening visit. In addition to meningococcal vaccination, medication (prescription or over-the-counter, including vitamin and / or herbal supplements) use over the 28 days (or 3 years for documented meningococcal vaccination) prior to the start of screening will also be recorded.

[0418] The physical examination will include an evaluation of the following: general appearance; skin; head, ears, eyes, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous system; and musculoskeletal system. The abbreviated physical examination will consist of relevant body system tests based on the investigator's judgment and the patient's symptoms. Vital sign measurements will be obtained after the patient has rested for at least 5 minutes and will include systolic and diastolic BP (millimeters of mercury [mmHg]), pulse oximetry, heart rate (beats / min), respiratory rate (breaths / min), and oral or tympanic temperature (in degrees Celsius [°C] or degrees Fahrenheit [°F]).

[0419] Samples for serum pregnancy, hematology, chemistry, coagulation, and urinalysis will be taken at the specified time points in the Schedule of Evaluations (Tables 23 and 24). Samples for laboratory evaluations will be taken prior to each study drug administration.

[0420] Samples collected at screening can be tested either at each site or at a central laboratory. If local testing is used for LDH, platelet count, hemoglobin, and serum creatinine, duplicate samples will be collected for central laboratory testing to ensure that the baseline and post-baseline measurements for analysis are from the central laboratory. If duplicate samples are from each site and the central laboratory, the central laboratory results will be used for analysis.

[0421] It is expected that some laboratory values ​​will be outside the normal range due to underlying disease. Investigators should use medical judgment in assessing the clinical significance of these values. Clinical significance is defined as any variation in a laboratory measurement that has medical relevance and results in a change in practice. If a clinically significant laboratory change from baseline is observed, the change will be recorded as an AE on the AE eCRF. Investigators will assess the relationship of all clinically significant out-of-range values ​​to study treatment. Investigators will continue to monitor patients with additional laboratory evaluations until (1) values ​​return to normal range or baseline levels, or (2) in the investigator's judgment, the out-of-normal values ​​are no longer related to study drug administration or other protocol-specific procedures.

[0422] For women of childbearing potential, a serum or urine pregnancy test (i.e., beta-human chorionic gonadotropin [β-hCG]) will be performed according to the schedule of evaluations (Tables 23 and 24). Blood samples will be analyzed for hematological parameters.

[0423] Blood samples are analyzed for serum chemistry parameters. Indirect bilirubin is calculated from total and direct bilirubin values; therefore, if direct bilirubin is below the limit of quantitation, an indirect bilirubin result is unavailable. For postmenopausal female patients, serum FSH levels are measured during screening to confirm postmenopausal status.

[0424] Chemistry assessments will be performed at the time points specified in the Schedule of Assessments (Tables 23 and 24). At all visits where serum chemistry is collected, eGFR will be calculated using the Modification of Diet in Renal Disease formula in patients 18 years of age and older and the Schwartz formula in patients under 18 years of age.

[0425] Blood samples are analyzed for coagulation parameters.

[0426] Analyze a urine sample. If the macroscopic analysis is abnormal, perform a microscopic examination of the urine sample. Also analyze the urine sample for protein and creatinine to calculate the urinary total protein:creatinine ratio.

[0427] For each patient, a single 12-lead digital ECG will be collected according to the schedule of assessments (Tables 23 and 24). Patients should be supine for approximately 5-10 minutes before ECG collection and should remain supine but awake during ECG collection. The investigator or designee is responsible for reviewing the ECG to assess whether it is within normal limits and to determine the clinical significance of the results. These assessments should be indicated on the CRF.

[0428] As indicated in the evaluation schedule, blood samples were collected to test for the presence and titer of ADAs to ALXN1210 in serum prior to study drug administration (see Tables 23 and 24). If the test results are positive, the test can be repeated every three months until the results become negative or stabilize, based on the measured titer and safety assessments. Further characterization of the antibody response, including binding and neutralizing antibodies, PK / PD, safety, and activity of ALXN1210, can be performed as needed.

[0429] An AE is any untoward medical occurrence in a patient administered a medicinal product, which does not necessarily have a causal relationship to that treatment. Thus, an AE can be any untoward or unintended sign (e.g., abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not it is considered medicinal product-related.

[0430] The absence of an unfavorable medical event (e.g., hospitalization for elective surgery if planned before the start of the study, hospitalization for social or convenience reasons), and expected day-to-day fluctuations in pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen are not AEs.

[0431] The lack of efficacy of a drug is not an AE in a clinical trial because the purpose of the clinical trial is to establish the efficacy of the drug.

[0432] Medication errors (including intentional misuse, abuse, and overdose of the product) or use other than that defined in the protocol will not be considered an AE unless there is an adverse medical event as a result of the medication error.

[0433] If pregnancy occurs during maternal or paternal exposure to the investigational product, it should be reported within 24 hours of the investigator / institution's knowledge. Data regarding fetal outcome and lactation will be collected for regulatory reporting and safety evaluation.

[0434] Adverse events will be recorded from the time of consent signing. AEs reported after informed consent but before study drug administration will be considered pre-treatment AEs.

[0435] The following events are important identified risks in this study: meningococcal infection.

[0436] AEs are graded for severity using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or later. A grading (severity) scale is provided for each AE term. Each CTCAE term is a Lowest Level Term (LLT) according to the Dictionary of Regulatory Terms for Drugs and Medical Devices (MedDRA®). Each LLT is coded to a MedDRA Preferred Term. Grade refers to the severity of the AE. In the CTCAE, grades 1 to 5 are assigned for each AE, along with a unique clinical description of severity (Table 28). [Table 28] Abbreviations: ADL = activities of daily living; AE = adverse events a Instrumental ADLs include preparing meals, shopping for groceries and clothing, using the telephone, and managing money. It refers to b Daily ADLs include bathing, dressing and undressing, eating, using the toilet, and administering medicine. This refers to oral medication and not being bedridden.

[0437] Any changes in the severity of an AE will be recorded based on specific guidelines within the eCRF completion guidelines. A distinction is made between severity and seriousness: severity describes the intensity of an AE, whereas the term seriousness refers to an AE that meets specific criteria for a serious adverse event (SAE).

[0438] For all AEs (both serious and non-serious), the investigator must provide a causality assessment (absent, probably not, possible, probably, definitely) based on the investigator's medical judgment and the symptoms associated with the observed event (Table 29). This assessment will be recorded on the eCRF and any additional forms as needed. [Ta...

Claims

[Claim 1] The invention as described in the drawings.

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