EA043233B1 - DOSING AND ADMINISTRATION OF ANTIBODIES AGAINST C5 FOR THE TREATMENT OF PATIENTS WITH PAROXYSMAL NOCAL HEMOGLOBINURIA (PNH) AND ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS) - Google Patents

Description

The present invention contains a sequence listing, which is filed in electronic form in ASCII format, and the entire content of which is given in the present description by reference. The specified ASCII copy created on October 25, 2018 is named AXJ-224PC_SL.txt and has a size of 59066.

State of the art

The complement system works in conjunction with other immune systems in the body to defend against invading cellular and viral pathogens. There are at least 25 complement proteins that are found as a complex array of plasma proteins and membrane cofactors. Plasma proteins make up approximately 10% of the globulins in vertebrate serum. Complement components perform their immune defense functions through interactions in a series of complex but precise enzymatic cleavage and membrane binding events. The resulting cascade of complement reactions leads to the production of products with opsonic, immunoregulatory and lytic functions. A brief summary of the biological activities associated with complement activation is provided, for example, in The Merck Manual, ^16th Edition.

While a properly functioning complement system provides strong protection against infecting organisms, inadequate regulation or activation of complement pathways has been implicated in the pathogenesis of multiple disorders, including paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). PNH and aHUS are both extremely rare disorders caused by chronic uncontrolled complement activation. The resulting inflammation and cell damage lead to the debilitating clinical manifestations of these diseases.

PNH is a condition in which uncontrolled complement activity leads to systemic complications, principally 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 and results in smooth muscle contraction (due to free hemoglobin), chronic anemia, and an increased risk of severe thromboembolism. Thromboembolism is the most common cause of death in PNH patients, and pulmonary hypertension and end-organ damage to vital organs such as the liver, kidneys, brain, and intestines are consequences of such events (Hillmen, P., et al, Am. J Hematol 2010;85(8):553-559). Due to these adverse pathological processes, patients with PNH have a reduced quality of life (QoL), which may include debilitating fatigue, chronic pain, poor functional status, difficulty breathing, abdominal pain, erectile dysfunction, need for anticoagulant therapy, blood transfusions, and , in some cases, the need for dialysis (Weitz, IC., et al., Thromb Res. 2012;130(3):361-368).

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 referred to as Shiga toxin-producing E. coli (STEC)-HUS or typical HUS) and non-diarrhea or atypical HUS (aHUS). D+ HUS is the most common form, accounting for over 90% of cases, and is caused by a preexisting disease involving a Shiga-like toxin-producing bacterium, such as E. coli O157:H7.

aHUS may be genetic, acquired, or idiopathic. Hereditary forms of aHUS may be associated with mutations in a number of 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. Certain mutations in the gene encoding CD55, although not yet implicated in aHUS, are associated with the severity of aHUS. See, for example, Esparza Gordillo et al. (2005) Hum Mol Genet 14:703-712.

aHUS is rare and has a mortality rate of up to 25%. Many patients with this disease may retain permanent neurological impairment or kidney damage, for example, at least 50% of aHUS patients progress to end stage renal disease (ESRF). See, for example, Kavanagh et al. (2006) British Medical Bulletin 77 and 78:5-1 043233

22. Until recently, treatment options for patients with aHUS were limited and often included plasma infusion or plasma exchange. In some cases, aHUS patients undergo uni- or bilateral nephrectomy or kidney transplant (see Artz et al. (2003) Transplantation 76:821-826). However, disease recurrence in treated patients is common.

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

The essence of the invention

The present invention relates to 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 intended to be administered) in accordance with a particular clinical dosing regimen. (i.e. at a specific dose level and according to a specific dosing schedule).

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

In another embodiment, the antibody comprises a human Fc constant region variant that binds the neonatal human Fc receptor (FcRn), wherein the CH3 human Fc constant region variant contains Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 native human IgG Fc constant regions, each according to EU numbering.

In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 sequences shown in SEQ ID NOs: 4, 5 and 6, respectively, and a human Fc constant region variant that binds the neonatal human Fc receptor (FcRn), wherein the CH3 human Fc constant region variant contains Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 native human IgG Fc constant region, each according to EU numbering.

In another embodiment, the antibody binds human C5 at pH 7.4 and 25° C. with an affinity dissociation constant (KD) in the range 0.1 nM < K _D < 1 nM. In another embodiment, the antibody binds human C5 at pH 6.0 and 25° C. with a KD > 10 nM. In another embodiment, [(KD of the antibody or antigen-binding fragment for human C5 at pH 6.0 and at 25°C)/( _{KD of} the antibody or antigen-binding fragment for human C5 at pH 7.4 and at 25°C)] antibodies is more than 25.

Another illustrative 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 from antibody 7086 (see US Pat. 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 shown in SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NOs: 24, 25 and 26, respectively. In another embodiment, the antibody, or antigen-binding fragment thereof, comprises a VH region from antibody 7086 having the sequence shown in SEQ ID NO: 27 and a VL region from antibody 7086 having the sequence shown in SEQ ID NO: 28.

Another illustrative anti-C5 antibody is the 8110 antibody, also described in U.S. Patent Nos. 8241628 and 8883158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions from the 8110 antibody. : 29, 30 and 31, respectively, and the CDR1 domains,

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Light chain CDR2 and CDR3 having the sequences shown in SEQ ID NOs: 32, 33 and 34, respectively. In another embodiment, the antibody comprises a VH region from antibody 8110 having the sequence shown in SEQ ID NO: 35 and a VL region from antibody 8110 having the sequence shown in SEQ ID NO: 36.

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 from the 305LO5 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NOs: 40, 41 and 42, respectively. In another embodiment, the antibody comprises a VH region from a 305LO5 antibody having the sequence shown in SEQ ID NO: 43 and a VL region from a 305LO5 antibody having the sequence shown in SEQ ID NO: 44.

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 from 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.

Another exemplary 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 contains a heavy chain containing SEQ ID NO: 49 and a light chain containing SEQ ID NO: 50.

In another embodiment, the antibody competes for binding and/or binds to the same epitope on C5 as the aforementioned antibodies (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 with the aforementioned antibodies (e.g., at least about 90%, 91, 92, 93, 94, 95, 96, 97, 98, or 99% variable region identity ).

In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the weight of the patient. For example, in one embodiment, 2400 mg or 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >40-<60 kg. In another embodiment, 2700 or 3300 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >60-<100 kg. In another embodiment, 3000 or 3600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >100 kg. In specific embodiments, dosing regimens are adjusted to provide the optimal desired response (eg, effective response).

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered over 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 eight weeks thereafter. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every eight weeks after the administration cycle for an extension period of up to two years (eg, at a dose of 3000, 3300 or 3600 mg).

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered over one or more administration cycles. In one embodiment, the administration cycle is 26 weeks. In another embodiment, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 cycles. In another embodiment, treatment is continued for the lifetime of the human patient.

In another embodiment, the present invention relates to a method of treating a human patient with PNH or aHUS comprising administering to the patient, during an administration cycle, an effective amount of an anti-C5 antibody, or an antigen-binding fragment thereof, comprising the heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 19 , 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered:

(a) once a day for 1 cycle of administration at a dose of: 2400 mg for a patient weighing >40-<60 kg, 2700 mg for a patient weighing >60-<100 kg, or 3000 mg for a patient weighing >100 kg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing >40-<60 kg, 3300 mg for a patient weighing >60-<100 kg, or 3600 mg for a patient weighing >100 kg.

In another embodiment, the present invention relates to a method of treating a human patient with PNH or aHUS comprising administering to the patient during an administration cycle of an effective

- 3 043233 amounts of an anti-C5 antibody or antigen-binding fragment thereof, containing the heavy chain CDR1, CDR2 and CDR3 sequences shown in SEQ ID NOs: 19, 18 and 3, respectively, the light chain CDR1, CDR2 and CDR3 sequences shown in SEQ ID NO: 4, 5, and 6, respectively, and a human Fc constant region variant that binds the neonatal human Fc receptor (FcRn), wherein the CH3 human Fc constant region variant contains the Met-429-Leu and Asn-435-Ser substitutions at methionine 428 residues. and asparagine 434 of a native human IgG Fc constant region, each according to EU numbering, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered:

(a) once a day for 1 cycle of administration at a dose of: 2400 mg for a patient weighing >40-<60 kg, 2700 mg for a patient weighing >60-<100 kg, or 3000 mg for a patient weighing >100 kg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing >40-<60 kg, 3300 mg for a patient weighing >60-<100 kg, or 3600 mg for a patient weighing >100 kg.

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing >40-<60 kg:

(a) once a day 1 cycle of administration at a dose of 2400 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg.

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing >60-<100 kg:

(a) once a day 1 cycle of administration at a dose of 2700 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3300 mg.

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing >100 kg:

(a) once a day 1 cycle of administration at a dose of 3000 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3600 mg.

In some embodiments, the patient has not previously been treated with a complement inhibitor (eg, the patient is a patient naïve to treatment with a complement inhibitor).

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

Exemplary alternative anti-C5 antibodies include, but are not limited to, (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 CDR1 domains , CDR2 and CDR3 light chain containing SEQ ID NO: 24, 25 and 26, respectively, (iii) an antibody or antigennegative fragment containing a heavy chain variable region containing SEQ ID NO: 27, and a light chain variable region containing SEQ ID NO: 28, (iv) an antibody or antigen-binding fragment thereof containing heavy chain CDR1, CDR2 and CDR3 domains containing SEQ ID NOs: 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains containing SEQ ID NO: 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 containing heavy chain CDR1, CDR2 and CDR3 domains containing SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains containing SEQ ID NOs: 40, 41 and 42, respectively, (vii) an antibody or its antigen-binding fragment containing a heavy chain variable region containing SEQ ID NO: 43, and a light chain variable region containing SEQ ID NO: 44, (viii) an antibody or antigen-binding fragment containing a heavy chain containing SEQ ID NO: 45, and a light chain containing SEQ ID NO: 46, (ix) an antibody or antigen-binding fragment containing a heavy chain variable region containing SEQ ID NO: 47, and a light chain variable region containing

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SEQ ID NO: 48, and (x) an antibody or antigen-binding fragment thereof containing a heavy chain containing SEQ ID NO: 49 and a light chain containing SEQ ID NO: 50.

In some embodiments, the patient has previously been treated 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 using an anti-C5 antibody, or its antigen-binding fragment (eg, eculizumab) before switching to another anti-C5 antibody or antigen-binding fragment (eg, ravulizumab). In a specific embodiment, the patient has previously been treated for at least 6 months with eculizumab.

In another embodiment, where a patient (e.g., a patient with PNH or aHUS) is treated with a first anti-C5 antibody and then transitioned to treatment with a second distinct anti-C5 antibody, especially when the second distinct anti-C5 antibody binds to an epitope on C5, different from the epitope for the first anti-C5 antibody, the administration schedule takes into account the half-life of the first anti-C5 antibody. For example, to ensure that the first anti-C5 antibody is cleared (eg, flushed) from the patient prior to administration of the second (different) anti-C5 antibody (eg, to avoid problems associated with aggregation, immune complex formation, etc.), time the half-life of the first anti-C5 antibody is taken into account. In one embodiment, the second (different) anti-C5 antibody is not administered until the duration corresponding to 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6, 5, 7 or 7.5 times the half-life of the first anti-C5 antibody after the last administration of the first anti-C5 antibody.

In another embodiment, the patient has previously been treated with eculizumab and is then transitioned 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, where eculizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, e.g., until at least 36, 45, 54, 63, 72, 81, 90, 99, 108, 117 or 126 days after the last injection of eculizumab.

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

Additionally or alternatively, methods are used to eliminate or enhance the elimination of the first anti-C5 antibody before switching to treatment with a second (different) anti-C5 antibody. Illustrative methods include, but are not limited to, plasmapheresis or blood transfusions. In another embodiment, an anti-C5 antibody (e.g., anti-eculizumab, anti-ravulizumab, anti-7086, anti-8110, anti-305LO5, anti-SKY59, or anti-REGN3918) is administered to clear or enhancing the clearance of the first anti-C5 antibody prior to the administration of the second (different) anti-C5 antibody.

In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof (e.g., ALXN1210) is administered to a patient where the administration cycle begins at least about two weeks, at least about three weeks, at least about four weeks, at least about six weeks, at least about seven weeks, or at least about eight weeks after the patient's last dose of eculizumab. In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof (eg, ALXN1210) is administered to a patient where the administration cycle begins at least two weeks after the patient's last dose of eculizumab.

In some embodiments, patients being treated according to the methods described herein are vaccinated against meningococcal infections within 3 years prior to or at the time of initiation of treatment. In one embodiment, patients treated less than 2 weeks after administration of the meningococcal vaccine are also treated with suitable prophylactic antibiotics up to 2 weeks after vaccination. In another embodiment, patients being treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135 and/or B.

In another aspect, the described treatment regimens are sufficient to maintain a certain minimum serum concentration of anti-C5 antibody or antigen-binding fragment. For example, in one embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment thereof 50, 55, 60, 65, 70, 75,

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80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 3 50, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 mcg/ml or more. In one embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 100 μg/ml or greater. In another embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment of 150 μg/ml or more. In another embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 200 μg/ml or more. In another embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment of 250 μg/ml or more. In another embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment of 300 μg/ml or more. In another embodiment, the treatment maintains a trough serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, between 100 and 200 μg/mL. In another embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of approximately 175 μg/mL.

In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain at least 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, 195, 200, 205, 210, 215, 220, 225, 230, 2 35, 240, 245, 250, 255, or 260 micrograms of antibody per milliliter of patient blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain between 50 and 250 μg of the antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain between 100 and 200 μg of the antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain approximately 175 μg of antibody per milliliter of the patient's blood.

In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain a minimum concentration of free C5. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain a free C5 concentration of 0.2 μg/mL, 0.3 μg/mL, 0.4 μg/mL, 0.5 μg/mL, or below. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain a free C5 concentration of 0.309 to 0.5 μg/mL or lower. In another embodiment, the treatment described herein reduces the concentration of free C5 by more than 99% over the course of treatment. In another embodiment, the treatment reduces the concentration of free C5 by more than 99.5% during the treatment period.

Anti-C5 antibodies, or antigen-binding fragments thereof, may be administered to a patient by any means. In one embodiment, the antibodies are formulated for intravenous administration.

The effectiveness of the methods of treatment presented in the present description, you can evaluate using any suitable methods. In one embodiment, for a patient with PNH, the treatment produces at least one therapeutic effect selected from the group consisting of reduction or cessation of fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction. In another embodiment, for a patient with aHUS, the treatment produces at least one therapeutic effect selected from the group consisting of reduction or cessation of severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function ( such as acute renal failure).

In other embodiments, the implementation of the treatment results in inhibition of the terminal complement complex.

In other embodiments, the treatment provides a shift towards normal levels of a hemolysis-associated hematological biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, erythrocyte PNH clone (RBC), and D dimer. In another embodiment, the treatment results in an increase in hemoglobin stabilization compared to the patient's baseline prior to treatment.

In other embodiments, the treatment provides a shift towards normal levels of a chronic disease-associated biomarker selected from the group consisting of estimated glomerular filtration rate (eGFR) and albumin:creatinine ratio in a single urine sample, and brain natriuretic peptide (BNP) in plasma.

In other embodiments, the implementation of the treatment leads to a decrease in the need for blood transfusions. In another embodiment, the treatment results in a greater than 70% increase in transfusion avoidance.

In other embodiments, the implementation of the treatment leads to a decrease in abrupt hemolysis, compared with treatment using eculizumab. In another embodiment, the treatment results in

- 6 043233 exclusion of acute hemolysis during the treatment period. In another embodiment, the treatment results in a reduction in acute hemolysis compared to the baseline level of acute hemolysis prior to treatment.

In other embodiments, the implementation of the treatment leads to a decrease in major adverse vascular events (MAVE).

In other embodiments, treatment results in a change from baseline in quality of life as assessed by the Functional Evaluation of Chronic Disease Therapy (FACIT) - Fatigue Scale Version 4 and the European Organization for Research and Treatment Quality of Life Core Questionnaire-30 malignant tumors. In another embodiment, treatment results in a change from baseline in quality of life as assessed by the Fatigue Functional Assessment of Chronic Disease Therapy (FACIT) Scale Version 4 and the European Organization for Research and Cancer Treatment Quality of Life Core Questionnaire-30 , by at least 7 points, compared with the baseline score for patients without treatment.

In another embodiment, the treatment results in no change in quality of life (QoL), as assessed by the Functional Assessment of Chronic Disease Therapy (FACIT) - Fatigue, version 4, from baseline to day 183. In another embodiment, the treatment results in an increase in quality of life (QoL) as assessed by the Functional Assessment of Chronic Disease Therapy (FACIT) - Fatigue, version 4, from baseline to day 183. In another embodiment, treatment results in the elimination of transfusions from baseline to day 183. In another embodiment, treatment results in to exclude a >2 g/dL decrease in hemoglobin levels from baseline, in the absence of transfusion, from baseline to day 183.

In other embodiments, lactate dehydrogenase (LDH) levels are used to assess responsiveness to therapy (eg, reduction in hemolysis, as assessed by lactate dehydrogenase (LDH) levels, is indicative of improvement in at least one sign 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 methods described experience a decrease in LDH levels to near normal levels, or to levels within 10% or within 20% of what is considered normal (e.g., within 105- 333 IU/l (international units per liter) In another embodiment, the LDH levels of the patient are normalized during the maintenance period of treatment In another embodiment, the LDH levels of the treated patient are normalized for at least 95% of the time during the maintenance period treatment period.In another embodiment, the treated patient's LDH levels are normalized for at least 90%, 85%, or 80% of the time during the maintenance treatment period.In one embodiment, the patient's LDH levels are >1.5 times exceed the upper limit of normal (LDH > 1.5 x ULN) prior to treatment In another embodiment, treatment results in normalization of LDH levels by at least day 24 of treatment. In one embodiment, patients treated according to the methods described experience a decrease in LDH levels to levels within normal levels or to levels within 10%, 20%, 30%, 40%, or within 50% below a level considered as the upper limit. normal range (e.g., within 105-333 IU/L (international units per liter). In one embodiment, the patient's LDH levels are >1.5 times the upper limit of normal (LDH > 1.5 x ULN) before starting treatment In one embodiment, treatment results in LDH levels less than 2 x upper limit of normal (ULN).

In another aspect, the present invention provides an anti-C5 antibody, or antigen-binding fragment thereof, comprising the heavy chain variable region CDR1, CDR2 and CDR3 domains having the sequence set forth in SEQ ID NO: 12 and the light chain variable region CDR1, CDR2 and CDR3 domains, having the sequence shown in SEQ ID NO: 8, for administration to a patient having PNH or aHUS:

(a) once a day for 1 cycle of administration at a dose of: 2400 mg for a patient weighing >40-<60 kg, 2700 mg for a patient weighing >60-<100 kg, or 3000 mg for a patient weighing >100 kg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing >40-<60 kg, 3300 mg for a patient weighing >60-<100 kg, or 3600 mg for a patient weighing >100 kg.

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

In addition, the present invention provides kits comprising a pharmaceutical composition comprising an anti-C5 antibody or antigen-binding fragment thereof, such as the ravulizumab antibody, and a pharmaceutically acceptable carrier, in a therapeutically effective amount, adapted for use in the methods described herein. In one variant

- 7 043233 implementation, the set contains:

(a) a dose of an anti-C5 antibody or an antigen-binding fragment thereof containing CDR1 domains,

CDR2 and CDR3 of a heavy chain variable region having the sequence shown in SEQ ID

NO: 12, and the CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in the methods described herein.

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-<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-<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 another aspect, the present invention provides methods for treating a human patient having a complement-associated disorder. In one embodiment, the method includes treating a human patient having a complement associated disorder who has been treated with eculizumab, wherein the method includes stopping eculizumab treatment and switching the patient to treatment with a different complement inhibitor. In another embodiment, the method includes treating a human patient having a complement-associated disorder who has been treated with ravulizumab, wherein the method includes stopping treatment with ravulizumab and switching the patient to treatment with a different complement inhibitor. In one embodiment, an excellent 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, an excellent 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 their biologically active fragments. In another embodiment, the excellent complement inhibitor is an excellent anti-C5 antibody (eg, ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody).

Illustrative complement-associated conditions that can be treated in accordance with the methods described herein include, but are not limited to, rheumatoid arthritis, antiphospholipid antibody syndrome, lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense sediment disease, neuromyelitis optica, multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous fetal loss, thrombotic thrombocytopenic purpura, weak immune vasculitis, epidermosis bullosa, recurrent fetal loss, traumatic brain injury, myocarditis, cerebrovascular disorder, peripheral vascular disorder, renovascular disorder, mesenteric/enteric vascular disorder, vasculitis, Henoch-Schoenlein purpura, nephritis, systemic lupus erythematosus-associated vasculitis, rheumatoid arthritis-associated vasculitis, immune complex-associated vasculitis vasculitis, Takayasu disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki disease, venous gas embolism, restenosis after stenting, rotational atherectomy, percutaneous transluminal coronary angioplasty, myasthenia gravis, cold agglutination disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid antibody syndrome, Graves' disease, atherosclerosis , Alzheimer's disease, systemic inflammatory response, sepsis, septic shock, spinal cord injury, glomerulonephritis, transplant rejection, Hashimoto's thyroiditis, type I diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture's syndrome, Degos' disease, and catastrophic antiphospholipid syndrome antibodies. In one embodiment, the complement-associated state is PNH. In another embodiment, the complement-associated state is aHUS.

Brief description of the drawings

Fig. 1 is a schematic of the phase III ALXN1210-PNH-301 clinical trial design for PNH patients naïve to complement inhibitor treatment.

Fig. 2 is a diagram showing the distribution of patients in ALXN1210-PNH-301 Phase III.

Fig. 3 is a diagram showing baseline characteristics and patient demographics in Phase III ALXN1210-PNH-301 clinical studies.

Fig. 4 is a graphical diagram showing key performance outcomes for two joint primary endpoints.

- 8 043233

Fig. 5 is a graphical representation of the key secondary endpoints, showing that all endpoints show benefit from ravulizumab (ALXN1210) and exceed the non-inferiority margins indicated by the red triangles in the graph.

Fig. 6 is a tabular presentation of key results for both primary and secondary endpoints.

In FIG. 7 shows the results of a plurality of sensitivity analyzes of efficacy results.

Fig. 8 is a graphical diagram showing the potential for a subgroup to benefit from ravulizumab (ALXN1210) versus eculizumab.

Fig. 9 is a graphical representation of LDH levels over time for patients treated with either ravulizumab (ALXN1210) or eculizumab.

Fig. 10 is a graphical representation of the time to reach LDH normalization (LDHN) for patients treated with either ravulizumab (ALXN1210) or eculizumab.

Fig. 11 is a graphical representation of the percentage of patients who achieved normalized LDH levels using ravulizumab (ALXN1210) or eculizumab at various time points from day 8 to day 183.

Fig. 12 is a graphical representation of the percentage of patients with a 10 point improvement from baseline, at examination (complete analysis population), on the General Health Subscale of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-30 Quality of Life Questionnaire-30.

Fig. 13 is a graphical representation of the percentage of patients with a 10 point improvement from baseline, at examination (complete population for analysis), on the Functional Status subscale of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-30.

Fig. 14 is a graphical representation of the percentage of patients with a 10 point improvement from baseline, at examination (complete analysis population), on the Fatigue Subscale of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-30 Fatigue.

Fig. 15 is a tabular presentation of key safety results in ALXN1210-PNH-301 phase III clinical studies.

Fig. 16 is a tabular representation of the most common treatment-induced adverse events (TEAEs) in phase III clinical studies of ALXN1210-PNH-301.

Fig. 17 is a tabular representation of Treatment-Induced Serious Adverse Events (TESAE) in Phase III clinical studies of ALXN1210-PNH-301.

Fig. 18 is a tabular representation of treatment-induced adverse events (TEAEs) of particular interest in phase III clinical studies of ALXN1210-PNH-301.

Fig. 19 is a tabular presentation of patient compliance results in the phase III clinical studies of ALXN1210-PNH-301.

Fig. 20 is a graphical representation of the pharmacokinetics (PK) of ravulizumab (ALXN1210) and eculizumab showing the serum concentration of each drug over time (linear scale).

Fig. 21 is a graphical representation of the pharmacokinetics (PK) of ravulizumab (ALXN1210) and eculizumab showing the serum concentration of each drug over time (semi-log scale).

Fig. 22 is a graphical representation of the pharmacodynamics (PD) of ravulizumab (ALXN1210) and eculizumab showing the mean C5 concentration in the presence of each drug over time.

Fig. 23 is a graphical representation of the pharmacodynamics (PD) of ravulizumab (ALXN1210) and eculizumab showing the mean (±95% CI) percent change from baseline for total serum C5 concentration in the presence of each drug over time.

Fig. 24 is a schematic design for the ALXN1210 aHUS 311 clinical protocol.

Fig. 25 is a schematic representation of the Phase III ALXN1210-PNH-302 clinical study design in PNH patients treated with eculizumab for at least the past six (6) months, where a complement inhibitor other than eculizumab is administered to the patients.

Fig. 26 is a diagram showing the dosing schedule for patients in the ALXN1210-PNH-302 Phase III clinical study, including the actual day of infusion.

Fig. 27 is a diagram showing the distribution of patients enrolled in the phase III clinical trial ALXN1210-PNH-302.

Fig. 28 is a diagram showing the baseline characteristics and demographics of patients enrolled in the Phase III Clinical Study ALXN1210-PNH-302.

- 9 043233

Fig. 29 is a diagram showing the baseline disease characteristics of patients enrolled in the phase III clinical trial ALXN1210-PNH-302.

Fig. 30 is a graphical diagram showing key efficacy outcomes for primary and secondary endpoints from the phase III clinical trial ALXN1210-PNH-302.

Fig. 31 is a tabular presentation of key efficacy outcomes for both primary and secondary endpoints from the Phase III clinical trial ALXN1210-PNH-302.

In FIG. 32 shows the results of multiple sensitivity analyzes of efficacy results for the primary endpoint from the phase III clinical trial ALXN1210-PNH-302.

Fig. 33 is a graphical representation showing subgroup efficacy results for the primary endpoint from the phase III clinical trial ALXN1210-PNH-302.

Fig. 34 is a graphical representation of mean LDH levels over time for patients enrolled in the phase III clinical study ALXN1210-PNH-302.

Fig. 35 is a graphical representation of the percentage of patients who achieved normalized LDH levels during the phase III clinical studies of ALXN1210-PNH-302.

Fig. 36 is a graphical representation of the mean change from baseline in quality of life over time for patients enrolled in the Phase III clinical trial ALXN1210-PNH-302 as assessed using the Functional Assessment of Chronic Disease Therapy (FACIT) - Fatigue Scale.

Fig. 37 is a graphical representation of mean quality of life over time for patients enrolled in Phase III clinical study ALXN1210-PNH-302 as assessed using the Fatigue Functional Assessment of Chronic Disease Therapy (FACIT).

Fig. 38 is a tabular presentation of key safety results from the phase III clinical study ALXN1210-PNH-302.

Fig. 39 is a tabular representation of treatment-induced serious adverse events (TESAE) from the phase III clinical trial ALXN1210-PNH-302.

Fig. 40 is a tabular representation of the most common treatment-induced adverse events (TEAE) from the phase III clinical trial ALXN1210-PNH-302.

Fig. 41 is a tabular representation of upper respiratory tract infections (URTIs) from the ALXN1210-PNH-302 phase III clinical trial as determined by the standard MedDRA questionnaire (SMQ).

Fig. 42 is a tabular representation of the Treatment-Induced Adverse Events of Particular Interest (TEAESI) from the phase III clinical study ALXN1210-PNH-302.

Fig. 43 is a tabular presentation of patient compliance results from the phase III clinical study ALXN1210-PNH-302.

Fig. 44 is a graphical representation of the pharmacokinetics (PK) of ALXN1210 and eculizumab showing the serum concentration of each drug over time.

Fig. 45 is a graphical pharmacodynamic (PD) representation of ALXN1210 and eculizumab showing the mean C5 concentration in the presence of each drug over time.

Fig. 46 is a graphical representation of ALXN1210 and eculizumab showing the mean (±95% CI) change from baseline for total serum C5 concentration in the presence of each drug over time.

Detailed description

I. Antibodies against C5.

The anti-C5 antibodies described herein bind the complement component C5 (eg, human C5) and inhibit the cleavage of C5 into C5a and C5b fragments. As described above, such antibodies also have, for example, improved pharmacokinetic properties compared to other anti-C5 antibodies (eg, eculizumab) used for therapeutic purposes.

The term antibody describes polypeptides containing at least one antibody-derived antigen-binding site (eg, VH/VL or Fv region, or CDR). Antibodies include known forms of antibodies. For example, the antibody may be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. The antibody can also be a Fab, Fab' ₂ , ScFv, SMIP, Affibody®, nanobody or domain antibody. The antibody may also belong to any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD and IgE. The antibody may be a naturally occurring antibody, or may be an antibody that has been altered (eg, by mutation, deletion, substitution, conjugation to a non-antibody group). For example, an antibody may include one or more amino acid variants (compared to a natural antibody) that alter a property (e.g., functional

- 10 043233 property) antibodies. For example, many such changes are known in the art, affecting, for example, half-life, effector function, and/or a patient's immune responses to an antibody.

The term antibody also includes artificial or engineered polypeptide constructs containing at least one antibody-derived antigen-binding site.

Anti-C5 antibodies (or VH/VL domains derived therefrom) suitable for use in the invention can be generated using methods well known in the art. Alternatively, anti-C5 antibodies known in the art may be used. You can also use antibodies that compete with any of these known in the field of antibodies for binding to C5.

Eculizumab (also known as Soliris®) is an anti-C5 antibody containing heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains, having the sequences shown in SEQ ID NO: 4, 5 and 6, respectively.

Eculizumab contains a heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 7 and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 8. The variable regions of eculizumab are described in PCT/US1995/005688 and US Pat. No.: 6355245, the full explanation of the contents of which is given in the present description by reference. Eculizumab contains a heavy chain having the amino acid sequence shown in SEQ ID NO: 10 and a light chain having the amino acid sequence shown in SEQ ID NO: 11. Full length heavy and light chains of eculizumab are described in PCT/US2007/006606, a full explanation of the content of which given in the present description by reference.

An exemplary anti-C5 antibody is ravulizumab containing heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or antigen-binding fragments and variants thereof. Ravulizumab (also known as Ultomiris™, BNJ441 and ALXN1210) is described in PCT/US2015/019225 and US Patent No.: 9079949, the explanation or content of which is incorporated herein by reference. The terms ravulizumab, BNJ441, and ALXN1210 may be used interchangeably throughout this specification, but all refer to the same antibody. Ravulizumab selectively binds human complement C5 protein, inhibiting its cleavage to C5a and C5b during complement activation. This inhibition prevents the release of the inflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex C5b-9, while maintaining the proximal or early components of complement activation (eg, C3 and C3b) required for opsonization of microorganisms and clearance of immune complexes.

In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions from ravulizumab. For example, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of a VH region from ravulizumab having the sequence shown in SEQ ID NO: 12 and the CDR1, CDR2, and CDR3 domains of a VL region from ravulizumab having the sequence shown in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NO: 4, 5 and 6, respectively. In another embodiment, the antibody contains VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.

Another exemplary anti-C5 antibody is the BNJ421 heavy and light chain antibody having the sequences shown in SEQ ID NOs: 20 and 11, respectively, or antigen-binding fragments and variants thereof. BNJ421 (also known as ALXN1211) is described in PCT/US2015/019225 and US Patent No. 9079949, the explanation or content of which is incorporated herein by reference.

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

The precise boundaries of the CDR are defined in various ways, according to various methods. In some embodiments, the positions of the CDRs or framework regions within a light or heavy chain variable domain may be as defined in Kabat et al. [(1991) Sequences of Proteins of Immunological Interest. NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD]. In such cases, the CDRs may be referred to as Kabat CDRs (for example,

- 11 043233

LCDR2 according to Kabat or HCDR1 according to Kabat). In some embodiments, the CDR positions of the light or heavy chain variable region may be as defined in Chothia et al. (1989) Nature 342:877-883. Accordingly, these regions may be referred to as CDR no Chothia (eg LCDR2 by Chothia or HCDR3 by Chothia). In some embodiments, the CDR positions of the light and heavy chain variable regions may be as determined by the combined Kabat-Chothia definition. In such embodiments, these regions may be referred to as CDRs by the combined Kabat-Chothia definition. Thomas et al. [(1996) Mol Immunol 33(17/18):1389-1401] provides examples of identifying CDR boundaries as defined by Kabat and Chothia.

In another embodiment, the antibody contains VH and VL regions having the amino acid sequences shown in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises a heavy chain constant region as set forth in SEQ ID NO: 13. In another embodiment, the antibody comprises a heavy chain polypeptide as set forth in SEQ ID NO: 14 and a light chain polypeptide as set forth in SEQ ID NO: : 11. In another embodiment, the antibody comprises a human Fc constant region variant that binds the neonatal human Fc receptor (FcRn), wherein the CH3 human Fc constant region variant contains Met-429-Leu and Asn-435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of native human IgG Fc constant region, each according to EU numbering.

In another embodiment, the antibody comprises the heavy chain CDR1, CDR2, and CDR3 domains having the sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 sequences shown in SEQ ID NOs: 4, 5 and 6, respectively, and a human Fc constant region variant that binds the neonatal human Fc receptor (FcRn), wherein the CH3 human Fc constant region variant contains Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 native human IgG Fc constant region, each according to EU numbering.

In other embodiments, an anti-C5 antibody described herein comprises a heavy chain CDR1 comprising or consisting of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In another embodiment, the anti-C5 antibody described herein comprises a heavy chain CDR2 comprising or consisting of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18).

In another embodiment, the antibody binds human C5 at pH 7.4 and 25° C. with an affinity dissociation constant (K _D ) in the range 0.1 nM < K _D < 1 nM. In another embodiment, the antibody binds human C5 at pH 6.0 and 25° C. with a K _D > 10 nM. In another embodiment, [(K _D of the antibody or antigen-binding fragment for human C5 at pH 6.0 and at 25°C)/(K _{D of} the antibody or antigen-binding fragment for human C5 at pH 7.4 and at 25°C) ] antibodies is more than 25.

Another illustrative 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 from antibody 7086 (see US Pat. 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 shown in SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NOs: 24, 25 and 26, respectively. In another embodiment, the antibody or antigen-binding fragment thereof comprises a VH region from antibody 7086 having the sequence shown in SEQ ID NO: 27 and a VL region from antibody 7086 having the sequence shown in SEQ ID NO: 28.

Another exemplary anti-C5 antibody is also the 8110 antibody described in U.S. Patent Nos. 8241628 and 8883158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions from the 8110 antibody. : 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NOs: 32, 33 and 34, respectively. In another embodiment, the antibody comprises a VH region from antibody 8110 having the sequence shown in SEQ ID NO: 35 and a VL region from antibody 8110 having the sequence shown in SEQ ID NO: 36.

Another illustrative anti-C5 antibody is the 305LO5 antibody described in US 2016/0176954 A1. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions from the 305LO5 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences shown in SEQ ID NOs: 40, 41 and 42, respectively. In another embodiment, the antibody comprises a VH region from the 305LO5 antibody having the sequence shown in SEQ ID NO: 43 and a VL region from the 305LO5 antibody having the sequence shown in SEQ ID NO: 44.

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 from 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.

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.

In another embodiment, the antibody competes for binding and/or binds to the same epitope on C5 as the aforementioned antibodies (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 with the aforementioned antibodies (e.g., at least about 90%, 91, 92, 93, 94, 95, 96, 97, 98, or 99% variable region identity ).

An anti-C5 antibody described herein may, in some embodiments, comprise a human Fc constant region variant that binds a neonatal human Fc receptor (FcRn) with greater affinity than the native human Fc constant region from which the Fc constant region variant is derived. person. For example, an Fc constant region may contain one or more (e.g., two, three, four, five, six, seven, or eight or more) amino acid substitutions relative to the native human Fc constant region from which the variant human Fc constant region is derived. Substitutions can increase the binding affinity of an IgG antibody containing an Fc constant region variant to FcRn at pH 6.0 while maintaining a pH dependent interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody actually 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 illustrated in the working examples. See, for example, PCT/US2015/019225 and US Patent No. 9079949, the full content of each of which is given in the present description by reference.

Substitutions that increase the binding affinity of the Fc constant region of an antibody for FcRn are known in the art and include, for example, (1) the M252Y/S254T/T256E triple substitution described in Dall'Acqua et al. (2006) J Biol Chem 281: 23514-23524; (2) the M428L or T250Q/M428L replacements 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 pairs: P257I/Q311I, P257I/N434H and D376V/N434H are described, for example, in Datta-Mannan et al. (2007) J Biol Chem 282(3): 1709-1717, the entire content of which is incorporated herein by reference.

In some embodiments, the constant region variant has a EU amino acid residue 255 substitution for valine. In some embodiments, the constant region variant has a EU amino acid residue 309 substitution for asparagine. In some embodiments, the constant region variant has a EU amino acid residue 312 substitution for isoleucine. In some embodiments, the constant region variant has a EU amino acid residue 386 substitution.

In some embodiments, the Fc constant region variant contains no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2) amino acid substitutions, insertions or deletions, relative to the native constant region from which it originates. In some embodiments, the Fc constant region variant contains one or more amino acid substitutions selected from the group consisting of: M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V3O8F. In some embodiments, the human Fc constant region variant contains a methionine at position 428 and an asparagine at position 434, each according to EU numbering. In some embodiments, the Fc constant region variant contains a 428L/434S double substitution, as described, for example, in US Pat. 8088376.

In some embodiments, the exact localization of these mutations may be shifted relative to the position in the native human Fc constant region due to the design of the antibody. For example, the 428L/434S dual substitution, when used in a chimeric IgG2/4 Fc, can correspond to 429L and 435S, as in the M429L and N435S variants found in BNJ441 (ravulizumab) and described in US Patent No. 9,079,949, the full contents of which are given herein. as a reference.

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

Suitable anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 14 and/or a light chain polypeptide comprising the amino acid sequence shown 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 shown in SEQ ID NO: 20 and/or a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11.

In one embodiment, the antibody binds C5 at pH 7.4 and 25°C (and otherwise under physiological conditions) with an affinity dissociation constant (KD) 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 . In some embodiments, the KD of the anti-C5 antibody or antigen-binding fragment thereof is no greater than 1 (e.g., no greater than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2) nM.

In other embodiments, [(KD of C5 antibody at pH 6.0 at 25°C)/( _KD of C5 antibody at pH 7.4 at 25°C)] is greater than 21 (e.g., greater than 22, 23, 24 , 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150 , 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000 , 1500 , 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

Methods for determining whether an antibody binds a protein antigen and/or determining the affinity of an antibody for a protein antigen are known in the art. For example, binding of an antibody to a protein antigen can be detected and/or quantified using a variety of methods such as, but not limited to, Western blot, dot blot, Surface Plasmon Resonance (SPR) method (e.g., using the BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.) or enzyme-linked immunosorbent assay (ELISA). See, for example, Benny K. C. Lo (2004) Antibody Engineering: Methods and Protocols, Humana Press (ISBN: 1588290921); Johne et al. (1993) J Immunol Meth 160:191-198; Jonsson et al. (1993) Ann Biol Clin 51:19-26; and Jonsson et al. (1991) Biotechniques 11:620-627. In addition, methods for measuring affinity (eg, dissociation and binding constants) are indicated in the working examples.

- 14 043233

Within the scope of the invention, the term _ka refers to the rate constant for binding an antibody to an antigen. The term kd refers to the rate constant for the dissociation of an antibody from an antibody/antigen complex. And the term K _D refers to the equilibrium dissociation constant for an antibody-antigen interaction. The equilibrium dissociation constant is derived from the ratio of the kinetic rate constants, K _D =k _a /k _d . Such determinations are preferably carried out at 25 or 37° C. (see Working Examples). For example, antibody binding kinetics to human C5 can be determined at pH 8.0, 7.4, 7.0, 6.5, and 6.0 by surface plasmon resonance (SPR) in a BIAcore 3000 device using an anti-Fc binding method for immobilization. antibodies.

In one embodiment, the C5 antibody, or antigen-binding fragment thereof, blocks the formation or activity of active C5a and/or C5b fragments of a C5 protein (eg, human C5 protein). Through this blocking effect, the antibodies inhibit, for example, the pro-inflammatory effects of C5a and the formation of the membrane attack complex (MAC) of C5b-9 on the cell surface.

Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of the C5 component of human complement can reduce the ability of complement to lyse cells in body fluids of the subject. Such reductions in the ability to lyse cells of complement present in body fluid(s) can be measured by methods well known in the art, such as, for example, a conventional hemolytic assay, such as the hemolysis assay described in Kabat and Mayer (eds.), Experimental Immunochemistry, ^2nd Edition, 135-240, Springfield, IL, CC Thomas (1961), pages 135-139, or a conventional variation of this assay, such as the hemolysis method for chicken erythrocytes, as described, for example, in Hillmen et al. (2004) N Engl J Med 350(6):552. Methods for determining whether a candidate compound actually inhibits the cleavage of human C5 into C5a and C5b forms 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 physiological activity of C5a and C5b in body fluid can be measured by methods well known in the art. For C5b, hemolytic assays or soluble C5b-9 assays can be used as discussed herein. Other assays known in the art may also be used. Using assays of these or other suitable types, candidate agents capable of inhibiting the C5 component of human complement can be screened.

Immunological methods, such as, but not limited to, ELISA, can be used to measure the concentration of C5 protein 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, antibodies specific for the C5b-9 neoepitope are used to detect terminal complement complex formation.

Hemolytic assays can be used to determine the inhibitory activity of an anti-C5 antibody, or antigen-binding fragment thereof, with respect to complement activation. To determine the effect of an anti-C5 antibody or antigen-binding fragment thereof on classically mediated by complement activation serum hemolysis, an in vitro test solution, e.g. targets. The percentage of lysis is normalized by considering 100% lysis equal to lysis occurring in the absence of inhibitor. In some embodiments, the classic complement pathway is activated by a human IgM antibody, such as used in the Wieslab® Classic Complement Pathway Assay Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the serum to be tested is incubated with an anti-C5 antibody, or antigen-binding fragment thereof, in the presence of a human IgM antibody. The amount of C5b-9 formed is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate, and measuring the absorbance at the appropriate wavelength. As a control, test sera are incubated in the absence of anti-C5 antibody or antigen-binding fragment thereof. In some embodiments, the test serum is C5 deficient serum reconstituted using a C5 polypeptide.

To determine the effect of an anti-C5 antibody or antigen-binding fragment thereof on alternatively mediated hemolysis, non-sensitized rabbit or guinea pig erythrocytes can be used as target cells. In some embodiments, the serum solution tested is C5 deficient serum reconstituted using a C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis equal to lysis occurring in the absence of inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, for example, as used in the Wieslab® Alternative Complement Pathway Assay Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the serum to be tested is incubated with an anti-C5 antibody or antigen-binding fragment thereof in the presence of lipopolysaccharide. The amount of C5b-9 formed is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the fluorescence at the appropriate wavelength. As a control, test sera are incubated in the absence of anti-C5 antibody or antigen-binding fragment thereof.

In some embodiments, C5 activity, or inhibition thereof, is quantified using a CH50eq assay. The CH50eq assay is a way to measure the total activity of the classical complement pathway in serum. This test is a lytic assay that uses antibody-sensitized erythrocytes as an activator of the classical complement pathway and various dilutions of test serum to determine the amount needed to achieve 50% lysis (CH50). The percentage of hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measurement of terminal complement complex (TCC) formation, since the TCC itself is directly responsible for the measured hemolysis.

This analysis is well known and common practice for a person skilled in the art. Briefly, to activate the classical complement activation pathway, undiluted serum samples (eg, reconstituted human serum samples) are added to assay microplate wells containing antibody-sensitized erythrocytes to thereby generate TCC. The activated sera are then diluted in assay microplate wells coated with a binding reagent (eg, an antibody that binds one or more TCC components). The TCC present in the activated samples binds to the monoclonal antibodies coated on the surface of the assay microplate wells. The wells are washed and a detection reagent labeled with a detectable label that recognizes bound TCC is added to each well. The detectable label may be, for example, a fluorescent label or an enzyme label. The results of the analysis are expressed in CH50 unit equivalents per milliliter (CH50 units. Eq./ml).

Inhibition, for example, in relation to the activity of the terminal complement complex, includes at least 5 (for example, at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60) % reduction in terminal complement activity, eg 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. Significant inhibition, within the meaning of the invention, refers to the inhibition of a given activity (e.g., terminal complement complex activity) by at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 or more)%. In some embodiments, an anti-C5 antibody described herein contains one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs: 1-6) while still retaining 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) % complement inhibitory activity of eculizumab in a hemolytic or CH50eq assay.

An anti-C5 antibody described herein has a human serum half-life of at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55) days. In another embodiment, the anti-C5 antibody described herein has a human serum half-life of at least 40 days. In another embodiment, the anti-C5 antibody described herein has a human serum half-life of approximately 43 days. In another embodiment, the anti-C5 antibody described herein has a human serum half-life of between 39-48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof described herein has a serum half-life of at least 20 (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, 500)% greater than the serum half-life of eculizumab, for example, as measured in one of the mouse model systems, described in the working examples (eg, in C5/NOD/scid deficient mice or in a hFcRn transgenic mouse model system).

In one embodiment, the antibody competes for binding and/or binds to the same epitope on C5 as the antibodies described herein. The term binds to the same epitope, in relation to two or more antibodies, means that the antibodies bind to the same fragment of amino acid residues, as determined by this method. Methods for determining whether antibodies indeed bind to the same epitope on C5 as the antibodies described herein include, for example, epitope mapping methods such as X-ray analyzes of crystals of antigen:antibody complexes, providing atomic resolution of the epitope, and mass - hydrogen/deuterium exchange spectrometry (HDX-MS).

- 16 043233

Other methods monitor the binding of an antibody to peptide fragments of an antigen or mutant variants of an antigen, where loss of binding due to modification of an amino acid residue in the antigen sequence is often considered indicative of an epitope component. In addition, computer combinatorial epitope mapping methods can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage peptide display libraries. Antibodies having the same VH and VL sequences or the same CDR1, 2 and 3 sequences are expected to bind the same epitope.

Antibodies that compete with another antibody for binding to a target refer to antibodies that inhibit (partially or completely) the binding of another antibody to a target. Do two antibodies really compete with each other for binding to the target, i.e. whether and to what extent one antibody actually inhibits the binding of another antibody to a target can be determined using known competition experiments. In specific embodiments, the antibody competes with another antibody 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 may vary depending on which antibody is the blocking antibody (ie, cold antibody that is first incubated with the target). Competing antibodies bind the same epitope, an overlapping epitope, or adjacent epitopes (eg, as evidenced by steric hindrance).

The anti-C5 antibodies or antigen-binding fragments thereof described herein used in the methods described herein can be prepared using a variety of methods known in the art. Monoclonal antibodies can be obtained by various methods known to the person skilled in the art. Briefly, spleen cells from an animal immunized with the desired antigen are immortalized, usually by fusion with a myeloma cell (see, Kohler & Milstein, Eur. J. Immunol. 6: 511-519 (1976)). Alternative immortalization methods include transformation with Epstein-Barr virus, oncogenes, or retroviruses, or other methods well known in the art. Colonies arising from individual immortalized cells are screened for the production of antibodies with the desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by such cells can be increased by various methods, including injection into the abdominal cavity of the vertebrate host. Alternatively, DNA sequences encoding a monoclonal antibody or binding fragment thereof can be isolated by screening a DNA library from human B cells, in accordance with the general method described in Huse, et al., Science 246: 1275-1281 (1989).

II. Compositions.

The present invention also relates to compositions containing an anti-C5 antibody or an antigen-binding fragment thereof. In one embodiment, the composition comprises an anti-C5 antibody comprising the CDR1, CDR2 and CDR3 domains in the heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2 and CDR3 domains in the light chain variable region having the sequence specified in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody contains heavy and light chains having the sequences shown in SEQ ID NO: 14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences shown in SEQ ID NOs: 20 and 11, respectively.

The compositions can be formulated in the form of a pharmaceutical solution, for example, for administration to a subject for the treatment or prevention of a complement-associated disorder such as PNH or aHUS. Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. Within the scope of the invention, a pharmaceutically acceptable carrier means and includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible. The compositions may include a pharmaceutically acceptable salt, such as an acid addition salt or base addition salt, sugars, carbohydrates, polyols, and/or tonicity modifiers.

Compositions can be made in accordance with standard methods. The preparation of pharmaceutical formulations is a well developed area and is further described in, for example, Gennaro (2000) Remington: The Science and Practice of Pharmacy, ^20th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) Pharmaceutical Dosage Forms and Drug Delivery Systems, ^7th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) Handbook of Pharmaceutical Excipients American Pharmaceutical Association, ^3rd Edition (ISBN: 091733096X). In some embodiments, the composition may be formulated, for example, in the form of a buffered solution at a suitable concentration and storable at 2-8°C (eg 4°C). In some embodiments, the composition may be formulated for storage at temperatures below 0°C (eg, 20°C or -80°C). In some embodiments, the composition can be formulated for storage for up to 2 years (e.g., one month, two months, three months, four months, five

- 17 043233 months, six months, seven months, eight months, nine months, 10 months, 11 months, 1 year,

1/4 years or 2 years) at 2-8°C (eg 4°C). Thus, in some embodiments, the compositions described herein are storage stable for at least 1 year at 2-8°C (eg, 4°C).

Pharmaceutical compositions may be in a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms such as liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends, in part, on the intended route of administration and therapeutic application. For example, compositions containing a composition intended for systemic or topical delivery may be in the form of solutions suitable for injection or infusion. Accordingly, the compositions can be formulated for parenteral administration (eg, via intravenous, subcutaneous, intraperitoneal, or intramuscular injection). Parenteral administration, parenteral administration, and other grammatically equivalent phrases, as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal, 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.

In one embodiment, the composition contains ALXN1210 (also known as Ultomiris™, BNJ441 antibody, or ravulizumab) for injection. In one embodiment, the injection solution is a sterile, clear to translucent, off-white, preservative-free solution for intravenous use. In another embodiment, each single dose vial contains 300 mg of ALXN1210 for injection at a concentration of 10 mg/ml pH 7.0. In another embodiment, ALXN1210 for injection requires dilution to a final concentration of 5 mg/mL. In another embodiment, each ml additionally contains polysorbate 80 (0.2 mg) (vegetable source), sodium chloride (8.77 mg), sodium phosphate dibasic (1.78 mg), sodium phosphate monobasic (0.46 mg) and water for injection.

III. Methods of treatment.

The present invention relates to methods of 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 intended to be administered) in accordance with a specific clinical dosing regimen (i.e., e. at a specific dose level and according to a specific dosing schedule).

Within the scope of the invention, the terms induction and induction phase are used interchangeably and refer to the first phase of treatment in a clinical trial.

Within the scope of the invention, the terms maintenance and maintenance phase are used interchangeably and refer to the second phase of treatment in a clinical trial. In specific embodiments, treatment is continued for as long as clinical benefit is observed, or until uncontrolled toxicity or disease progression occurs.

Within the scope of the invention, the term subject or patient is a human patient (eg, a patient having a complement-associated condition such as PNH or aHUS).

In one embodiment, the complement-associated condition is paroxysmal nocturnal hemoglobinuria (PNH). PNH is an acquired hemolytic disorder most commonly occurring in adults (Brodsky RA., Blood. 2015; 126:2459-65). The disease begins with a clonal expansion of a hematopoietic stem cell that has acquired a somatic mutation in the PIGA gene (Brodsky RA., Blood. 2014;124:2804-1). Therefore, blood cells in PNH lack the glycophosphatidylinositol (GPI)-anchored protein and lack the membrane-associated complement inhibitory proteins CD55 and CD59. In the absence of CD55, there is an increase in the deposition of C3 complement cleavage products on the membrane surfaces of blood cells, in turn leading to the cleavage of C5 into C5a and C5b. The pathology and clinical manifestations of patients with PNH are driven by uncontrolled activation of the terminal complement complex.

C5a is an active anaphylatoxin, chemotactic factor, and cell-activating molecule that mediates a variety of 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 pp 967-95. C5b recruits terminal complement components C6, C7, C8, and C9 to form the pro-inflammatory, prothrombotic, cytolytic pore-forming molecule C5b-9, a process that, under normal conditions, can be blocked on the erythrocyte (RBC) membrane by CD59. In PNH patients, however, these end stages continue unchecked, reaching hemolysis and release of free hemoglobin, as well as platelet activation (Hill, et al., Blood 2013; 121:4985-96). Signs and symptoms of PNH can be attributed to chronic, uncontrolled breakdown of complement component C5, and release of C5a and C5b-9 leading to RBC hemolysis, which together lead to (Hill, et al., Blood 2013; 121:4985-96; Brodsky RA ., Blood. bed due to the lack of vasodilating NO, as well as possible microthrombi manifesting as abdominal pain, dysphagia and erectile dysfunction, platelet activation, and/or a proinflammatory and prothrombotic state. A significant proportion of patients with PNH experience kidney dysfunction and pulmonary hypertension (Hillmen, et al., Am J Hematol. 2010;85:553-9. [erratum in 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 at a variety of sites, including the abdomen or central nervous system (Brodsky RA., Blood. 2014;124:2804-1).

In another embodiment, the complement associated condition is an atypical hemolytic uremic syndrome (aHUS). The pathology and clinical manifestations of patients with aHUS are also controlled by the activation of the terminal complement complex. More specifically, C5 activation and dysregulation of complement activation lead to events of endothelial injury, platelet consumption, and thrombotic microangiopathy (TMA) characterized by thrombocytopenia, mechanical intravascular hemolysis, and kidney injury. Importantly, approximately 20% of patients also experience extrarenal manifestations of the disease, including involvement of the central nervous system, heart, gastrointestinal tract, distal extremities, and severe systemic organ damage (Loirat, et al., Orphanet. J. Rare Dis. 2011 ;6:60). The symptoms of aHUS are well known to those skilled in the art of rare or kidney disease medicine and include, for example, severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal dysfunction (eg, acute renal failure).

aHUS may be genetic, acquired, or idiopathic. aHUS can be considered genetic when two or more (eg, three, four, five, or six or more) members of the same family become affected at least six months apart and a common trigger is ruled out, or when one or more mutations in aHUS-associated genes (eg, one or more mutations in CFH, MCP/CD46, CFB, or CFI) are identified in the subject. For example, a subject may have a CFH-associated aHUS, a CFB-associated aHUS, a CFI-associated aHUS, or an MCP-associated aHUS. Up to 30% of genetic aHUS is associated with mutations in CFH, 12% with mutations in MCP, 5-10% with mutations in CFI, and less than 2% with mutations in CFB. Genetic aHUS can be multiplex (ie, familial; two or more affected family members) or simplex (ie, single occurrence in a family). aHUS can be considered acquired when an underlying environmental factor (eg, drug, systemic disease, or viral or bacterial agents that do not produce Shiga-like exotoxins) or trigger can be identified. aHUS can be considered idiopathic when there is no obvious trigger (genetic or environmental factor).

Laboratory tests can be performed to determine if a human subject has thrombocytopenia, microangiopathic hemolytic anemia, or acute renal failure. Thrombocytopenia may be diagnosed by a healthcare professional as one or more of: (i) a platelet count less than 150,000/mm ³ (eg, less than 60,000/mm ³ ); (ii) a decrease in platelet survival time, which decreases, reflecting increased destruction of platelets in the bloodstream; and (iii) giant platelets seen on the peripheral blood smear, consistent with secondary activation of thrombocytopoiesis. Microangiopathic hemolytic anemia may be diagnosed by a healthcare professional as one or more of: (i) hemoglobin concentrations less than 10 mg/dL (eg, less than 6.5 mg/dL); (ii) elevated serum lactate dehydrogenase (LDH) concentrations (>460 U/L); (iii) hyperbilirubinemia, reticulocytosis, circulating free hemoglobin, and low or undetectable haptoglobin concentrations; and (iv) detection of fragmented erythrocytes (schistocytes) with a typical aspect of pineal or helmet cells in a peripheral blood smear, together 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). Blood concentrations of C3 and C4 can also be used as an indicator of complement activation or dysregulation. In addition, the condition of the subject can be further characterized by identifying the subject as carrying one or more mutations in a gene associated with aHUS, such as CFI, CFB, CFH, or MCP (above). Suitable methods for detecting a mutation in a gene include, for example, DNA sequencing methods and nucleic acid arrays. See, for example, Breslin et

- 19 043233 al. (2006) Clin Am Soc Nephrol 1:88-99 and Goicoechea de Jorge et al. (2007) Proc Natl Acad Sci USA 104:240245.

In the context of the invention, an effective treatment refers to a treatment that has a beneficial effect, such as the alleviation of at least one symptom of a disease or disorder. The beneficial effect may take the form of an improvement over the starting point, ie. improvement compared to the measurement or observation made before the start of therapy in accordance with the method. In the context of PNH, for example, effective treatment may refer to the relief of one or more symptoms selected from the group consisting of fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and/or erectile dysfunction). In the context of aHUS, for example, effective treatment may refer to alleviation of one or more symptoms selected from the group consisting of severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and/or impaired renal function (e.g., acute renal failure).

The term effective amount refers to the amount of a compound that provides the desired biological, therapeutic and/or prophylactic result. This result may be a reduction, alleviation, alleviation, reduction, delay and/or attenuation of one or more of the signs, symptoms or causes of the disease, or any other desired change in the biological system. In one example, the effective amount is an amount of an anti-C5 antibody, or an antigen-binding fragment thereof, clinically shown to improve at least one symptom of PNH (eg, fatigue, abdominal pain, dyspnea, dysphagia, chest pain, or erectile dysfunction), or at least one symptom of aHUS (eg, severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function (eg, acute renal failure)). An effective amount can be administered in one or more administrations.

In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the weight of the patient. For example, in one embodiment, 2400 mg or 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >40-<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-<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 specific embodiments, dosing regimens are adjusted to provide the optimal desired response (eg, effective response).

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered over 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 eight weeks thereafter. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every eight weeks after the administration cycle for an extension period of up to two years (eg, at a dose of 3000 mg, 3300 mg or 3600 mg).

In another embodiment, the present invention relates to a method of treating a human patient with PNH or 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 heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 19 , 18, and 3, respectively, and the light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered:

(a) once daily for 1 cycle of administration at a dose of: 2400 mg for a patient weighing >40-<60 kg, 2700 mg for a patient weighing >60-<100 kg, or 3000 mg for a patient weighing >100 kg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing >40-<60 kg, 3300 mg for a patient weighing >60-<100 kg, or 3600 mg for a patient weighing >100 kg.

In another embodiment, the present invention relates to a method of treating a human patient with PNH or 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 heavy chain CDR1, CDR2 and CDR3 sequences set forth in SEQ ID NO: 19 , 18, and 3, respectively, the light chain CDR1, CDR2, and CDR3 sequences shown in SEQ ID NOs: 4, 5, and 6, respectively, and a human Fc constant region variant that binds the neonatal human Fc receptor (FcRn), where the constant region CH3 variant The human Fc contains the Met-429-Leu and Asn-435-Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 of the native human Fc constant region of human IgG, each according to EU numbering, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered:

(a) once a day for 1 cycle of administration at a dose of: 2400 mg for a patient weighing >40 - <60 kg, 2700 mg for a patient weighing >60 - <100 kg or 3000 mg for a patient weighing >100 kg: and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg for the patient

- 20 043233 weighing >40 - <60 kg, 3300 mg for a patient weighing >60 - <100 kg or 3600 mg for a patient weighing >100 kg.

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing >40-<60 kg:

(a) once a day for 1 cycle of administration at a dose of 2400 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg.

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing >60-<100 kg:

(a) once a day 1 cycle of administration at a dose of 2700 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3300 mg.

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, is administered to a patient weighing >100 kg:

(a) once a day 1 cycle of administration at a dose of 3000 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3600 mg.

In some embodiments, the patient has not previously been treated with a complement inhibitor (eg, the patient is a patient naïve to treatment with a complement inhibitor).

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

Exemplary alternative anti-C5 antibodies include, but are not limited to, (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 domains Light chain CDR1, CDR2 and CDR3 containing SEQ ID NOs: 24, 25 and 26, respectively, (iii) an antibody or antigen-binding fragment thereof containing a heavy chain variable region containing SEQ ID NO: 27 and a light chain variable region containing SEQ ID NO: 28, (iv) an antibody or antigen-binding fragment thereof, containing heavy chain CDR1, CDR2 and CDR3 domains containing SEQ ID NO: 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains containing SEQ ID NO : 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 fragment containing heavy chain CDR1, CDR2 and CDR3 domains containing SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains containing SEQ ID NOs: 40, 41 and 42, respectively, (vii) antibody or an 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 containing a heavy chain containing SEQ ID NO: 49 and a light chain containing SEQ ID NO: 50.

In some embodiments, the patient has previously been treated 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 using an anti-C5 antibody, or its antigen-binding fragment (eg, eculizumab) before switching to another anti-C5 antibody or antigen-binding fragment (eg, ravulizumab). In a specific embodiment, the patient has previously been treated for at least 6

- 21 043233 months using eculizumab.

In another embodiment, where the patient (e.g., a patient with PNH or aHUS) is treated with a first anti-C5 antibody and then transitioned to treatment with a second distinct anti-C5 antibody, especially where the second distinct anti-C5 antibody binds to an epitope on C5 other than from the epitope for the first anti-C5 antibody, the administration schedule takes into account the half-life of the first anti-C5 antibody. For example, to ensure that the first anti-C5 antibody is cleared (eg, flushed) from the patient prior to administration of the second (different) anti-C5 antibody (eg, to avoid problems associated with aggregation, immune complex formation, etc.), time the half-life of the first anti-C5 antibody is taken into account. In one embodiment, the second (different) anti-C5 antibody is not administered until the duration corresponding to 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6, 5, 7 or 7.5 times the half-life of the first anti-C5 antibody after the last administration of the first anti-C5 antibody.

In another embodiment, the patient has previously been treated with eculizumab and is then transitioned 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 where eculizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, e.g., until at least 36, 45, 54, 63, 72, 81, 90, 99, 108, 117 or 126 days after the last injection of eculizumab.

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

Additionally or alternatively, methods are used to eliminate or enhance the elimination of the first anti-C5 antibody before switching to treatment with a second (different) anti-C5 antibody. Illustrative methods include, but are not limited to, plasmapheresis or blood transfusions. In another embodiment, a first anti-C5 antibody is administered to clear or enhance the clear of a first anti-C5 antibody (e.g., anti-eculizumab, anti-ravulizumab, anti-7086, anti-8110, anti-305LO5, anti-SKY59 or an anti-REGN3918 antibody) prior to the administration of a second (different) anti-C5 antibody.

In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof (e.g., ALXN1210), is administered to a patient where the administration cycle begins at least about two weeks, at least about three weeks, at least about four weeks, at least about six weeks, at least about seven weeks, or at least about eight weeks after the patient's last dose of eculizumab. In another embodiment, the anti-C5 antibody, or antigen-binding fragment thereof (eg, ALXN1210), is administered to a patient where the administration cycle begins at least two weeks after the patient's last dose of eculizumab.

In some embodiments, patients being treated according to the methods described herein are vaccinated against meningococcal infections within 3 years prior to or at the time of initiation of treatment. In one embodiment, patients treated less than 2 weeks after administration of the meningococcal vaccine are also treated with suitable prophylactic antibiotics up to 2 weeks after vaccination. In another embodiment, patients being treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135 and/or B.

Within the scope of the invention, the term serum trough refers to the lowest level at which an agent (eg, anti-C5 antibody or antigen-binding fragment thereof) or drug is present in serum. In contrast, maximum serum level refers to the highest serum level of an agent. The mean serum level refers to the mean serum level over time.

In one embodiment, the described treatment regimens are sufficient to maintain a certain minimum serum concentration of the anti-C5 antibody or antigen-binding fragment thereof. For example, in one embodiment, treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment thereof 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, 2 55, 260 265 270 280 290 300 305 310 315 320 325 330 335 340 345 350 355 360 365 370 375 380 385 390 3 95 or 400 mcg/ml or more. In one embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment of 100 μg/ml or more. In another variant

- 22 043233 treatment maintains a minimum serum concentration of anti-C5 antibody or its antigen-binding fragment of 150 μg/ml or more. In another embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of 200 μg/ml or more. In another embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment of 250 μg/ml or more. In another embodiment, the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment of 300 μg/ml or more. In another embodiment, the treatment maintains a trough serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, between 100 and 200 μg/mL. In another embodiment, the treatment maintains a minimum serum concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of approximately 175 μg/mL.

In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain at least 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, 195, 200, 205, 210, 215, 220, 225, 230, 2 35, 240, 245, 250, 255, or 260 micrograms of antibody per milliliter of patient blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain between 50 μg and 250 μg of the antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain between 100 and 200 μg of the antibody per milliliter of the patient's blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain approximately 175 μg of antibody per milliliter of the patient's blood.

In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain a minimum concentration of free C5. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain a free C5 concentration of 0.2 μg/mL, 0.3 μg/mL, 0.4 μg/mL, 0.5 μg/mL, or below. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and at a frequency to maintain a free C5 concentration of 0.309 to 0.5 μg/mL or lower. In another embodiment, the treatment described herein reduces the concentration of free C5 by more than 99% over the course of treatment. In another embodiment, the treatment reduces the concentration of free C5 by more than 99.5% during the treatment period.

In another aspect, the present invention provides methods for treating a human patient having a complement-associated disorder. In one embodiment, the method includes treating a human patient having a complement associated disorder who has been treated with eculizumab, wherein the method includes stopping eculizumab treatment and switching the patient to treatment with a different complement inhibitor. In another embodiment, the method includes treating a human patient having a complement-associated disorder who has been treated with ravulizumab, wherein the method includes stopping treatment with ravulizumab and switching the patient to treatment with a different complement inhibitor. In one embodiment, an excellent 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, an excellent 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 their biologically active fragments. In another embodiment, the excellent complement inhibitor is an excellent anti-C5 antibody (eg, ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody).

Illustrative complement-associated conditions that can be treated according to the methods described herein include, but are not limited to, rheumatoid arthritis, antiphospholipid antibody syndrome, lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense sediment disease, neuromyelitis optica, multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous fetal loss, thrombotic thrombocytopenic purpura, weakly immune vasculitis, epidermosis bullosa, recurrent fetal loss, traumatic brain injury, myocarditis, cerebrovascular disorder, peripheral vascular disorder, renovascular disorder, mesenteric/enteric vascular disorder, vasculitis, Henoch-Schonlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, rheumatoid arthritis-associated vasculitis, immune complex-associated vasculitis , Takayasu disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki disease, venous gas embolism, restenosis after stenting, rotational atherectomy, percutaneous transluminal coronary angioplasty, myasthenia gravis, cold agglutination disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid antibody syndrome, sickness

- 23 043233

Graves, atherosclerosis, Alzheimer's disease, systemic inflammatory response, sepsis, septic shock, spinal cord injury, glomerulonephritis, transplant rejection, Hashimoto's thyroiditis, type I diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture's syndrome, Degos disease, and catastrophic antiphospholipid antibody syndrome. In one embodiment, the complement-associated state is PNH. In another embodiment, the complement-associated state is aHUS.

IV. Outcomes.

The present invention relates to methods for treating PNH or aHUS in a patient, comprising administering an anti-C5 antibody, or antigen-binding fragment thereof, to the patient.

Symptoms of PNH include, but are not limited to, fatigue (eg, fatigue, difficulty with activities of daily living, concentration problems, dizziness, weakness), pain (eg, stomach pain, leg pain or leg swelling, chest pain, chest pain, back), dark urine, difficulty breathing, 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 described herein preferably experience an improvement in at least one sign of PNH. For example, the treatment may provide at least one therapeutic effect selected from the group consisting of reduction or cessation of fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.

Symptoms of aHUS include, but are not limited to, severe hypertension, proteinuria, uremia, lethargy/fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function (eg, acute renal failure). Patients treated according to the methods described herein preferably experience an improvement in at least one sign of aHUS. For example, the treatment may have 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 impaired renal function.

In other embodiments, the implementation of the treatment results in inhibition of the terminal complement complex.

In other embodiments, the treatment provides a shift towards normal levels of a hemolysis-associated hematological biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, RBC clone at PNH, and D-dimer. In another embodiment, the treatment results in an increase in hemoglobin stabilization compared to the patient's baseline prior to treatment.

In other embodiments, the treatment provides a shift towards normal levels of a chronic disease-associated biomarker selected from the group consisting of estimated glomerular filtration rate (eGFR) and albumin:creatinine ratio in a single urine sample, and brain natriuretic peptide (BNP) in plasma.

In other embodiments, the implementation of the treatment leads to a decrease in the need for blood transfusions. In another embodiment, the treatment results in a greater than 70% increase in transfusion avoidance.

In other embodiments, the implementation of the treatment leads to a decrease in acute hemolysis, compared with treatment using eculizumab. In another embodiment, the treatment results in the elimination of acute hemolysis during the treatment period. In another embodiment, the treatment results in a reduction in acute hemolysis compared to the baseline level of acute hemolysis prior to treatment.

In other embodiments, the implementation of the treatment leads to a decrease in major adverse vascular events (MAVE).

In other embodiments, treatment results in a change from baseline in quality of life as assessed by the Functional Evaluation of Chronic Disease Therapy (FACIT) - Fatigue Scale Version 4 and the European Organization for Research and Treatment Quality of Life Core Questionnaire-30 malignant tumors. In another embodiment, treatment results in a change from baseline in quality of life as assessed by the Fatigue Functional Assessment of Chronic Disease Therapy (FACIT) Scale Version 4 and the European Organization for Research and Cancer Treatment Quality of Life Core Questionnaire-30 , by at least 7 points, compared with the baseline score for patients without treatment.

In another embodiment, the treatment results in no change in quality of life (QoL), as assessed by the Functional Assessment of Chronic Disease Therapy (FACIT) - Fatigue, version 4, from baseline to day 183. In another embodiment, the treatment results in an increase in quality of life (QoL), assessed by means of a scale of functional

- 24 043233 Chronic Disease Therapy Evaluation (FACIT) - Fatigue Version 4 from Baseline to Day 183. In another embodiment, treatment results in elimination of transfusions from Baseline to Day 183. In another embodiment, treatment results in elimination of a decrease in >

g/dl hemoglobin level, compared to baseline, in the absence of transfusion, from baseline to day 183.

In other embodiments, lactate dehydrogenase (LDH) levels are used to assess responsiveness to therapy (eg, reduction in hemolysis, as assessed by lactate dehydrogenase (LDH) levels, is indicative of improvement in at least one PNH symptom). LDH is a marker of intravascular hemolysis (Hill, A. et al., Br. J. Haematol., 149:414 25, 2010; Hillman, P. et al., N. Engl. J. Med., 350:552 9, 2004; Parker, C. et al., Blood, 106:3699-709, 2005). Erythrocytes contain large amounts of LDH, and a correlation has been published between extracellular free hemoglobin concentration and LDH 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 ). The LDH concentration obtained at baseline and then serially throughout the treatment period is an important indicator of hemolysis. Baseline plasma extracellular hemoglobin levels are greatly increased in PNH patients with LDH, >1.5 times the upper limit of normal (LDH > 1.5 x ULN), with a significant correlation between LDH and plasma extracellular hemoglobin (Hillman, P. et al., N. Engl. J. Med., 355:1233-43, 2006). The normal range for LDH values is 105-333 IU/L (international units per liter).

LDH levels can be measured using any suitable test or assay, such as those described in Ferri FF, ed. Ferri's Clinical Advisor 2014. Philadelphia: Pa: Elsevier Mosby; 2014: Section IV Laboratory tests and interpretation of results. The concentration of LDH can be measured in various samples obtained from the patient, in particular serum samples, within the scope of the invention, the term sample refers to biological material from the subject. Although the serum LDH concentration is of interest, samples can be obtained 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 samples removed for biopsy, tissue removed during resection, blood, urine, lymphatic tissue, lymphatic fluid, cerebrospinal fluid, mucus, and feces. The sample used can be varied based on the assay format, detection method, and nature of the tumors, tissues, cells, or extracts to be analyzed. Methods for obtaining samples are known in the art and can be readily adapted to obtain a sample that is compatible with the method used.

In one embodiment, the treatments described herein result in normalization of LDH levels. In another embodiment, patients treated according to the methods described experience a decrease in LDH levels to near normal levels, or to levels within 10% or within 20% of what is considered normal (e.g., within 105- 333 IU/l (international units per liter) In another embodiment, the LDH levels of the patient are normalized during the maintenance period of treatment In another embodiment, the LDH levels of the treated patient are normalized for at least 95% of the time during the maintenance period treatment period.In another embodiment, the treated patient's LDH levels are normalized for at least 90%, 85%, or 80% of the time during the maintenance treatment period.In one embodiment, the patient's LDH levels are >1.5 times exceed the upper limit of normal (LDH > 1.5 x ULN) prior to treatment In another embodiment, treatment results in normalization of LDH levels by at least day 24 of treatment. In one embodiment, patients treated according to the described methods experience a decrease in LDH levels to levels within normal levels or to levels within 10%, 20%, 30%, 40%, or within 50% below the level, considered as the upper limit of normal (e.g., within 105-333 IU/L (international units per liter). In one embodiment, the patient's LDH levels are >1.5 times the upper limit of normal (LDH > 1.5 x ULN) prior to treatment In one embodiment, treatment results in LDH levels less than 2 x upper limit of normal (ULN).

V. Kits and unit dosage forms.

The present invention also provides kits comprising a pharmaceutical composition comprising an anti-C5 antibody or antigen-binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount, adapted for use in the methods described herein. The kits may optionally also include instructions, such as including administration schedules, to allow a practitioner of skill in the art (eg, physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having PNH or aHUS. The kit may also include a syringe.

Optionally, the kits include a plurality of single dose packs of pharmaceutical compositions, each containing an effective amount of an anti-C5 antibody, or antigen-binding fragment thereof, for a single administration in accordance with the methods presented above. The tools or devices needed to administer the pharmaceutical composition(s) may also be included in kits. For example, the kit may provide one or more pre-filled syringes containing an amount of anti-C5 antibody or antigen-binding fragment thereof.

In one embodiment, the present invention relates to a kit for the treatment of 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 the heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence, specified in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody, or antigen-binding fragment thereof, in accordance with any of the methods described herein.

In one embodiment, the kit contains a dose of 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-<60 kg:

(a) once a day 1 cycle of administration at a dose of 2400 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg.

In another embodiment, the kit contains a dose of 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-<100 kg:

(a) once a day 1 cycle of administration at a dose of 2700 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3300 mg.

In another embodiment, the kit contains a dose of anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >100 kg:

(a) once a day 1 cycle of administration at a dose of 3000 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3600 mg. The following examples are illustrative only and should not be construed as limiting the scope of the present invention in any way, as many variations and equivalents will become apparent to those skilled in the art upon reading the present description.

The entire contents of all references, Genbank entries, patents, and published patent applications cited throughout this application are incorporated herein by reference.

Examples

Example 1

Randomized, open-label, phase 3, active drug-controlled study of ALXN1210 (ravulizumab) versus eculizumab in complement inhibitor-naive adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

In phase 1b/2 studies, treatment with ravulizumab at extended dosing intervals achieved a rapid and significant reduction in complement-mediated hemolysis in patients with PNH. These studies showed drug/exposure and response associations, where higher amounts of ravulizumab at minimal exposure (1800-mg-q4w cohort) were associated with a higher proportion of patients achieving plasma LDH levels considered to pose a low risk of hemolysis (normalization [or below 1.5xULN]), a decrease in free hemoglobin concentration and the absence of abrupt hemolysis, compared with all other cohorts. Based on these results and subsequent exposure response analyses, an open-label, randomized, multicentre, phase 3, active drug-controlled, study was conducted to evaluate the safety and efficacy of ALXN1210 (ravulizumab) versus eculizumab given by intravenous (IV) infusion. adult patients with PNH who are naïve to treatment with complement inhibitors. In the phase 3 study herein, patients randomized to receive ravulizumab were given a loading dose (2400 mg for patients >40 kg to <60 kg, 2700 mg for patients >60 kg to <100 kg, 3000 mg for patients >100 kg ) on day 1, followed by maintenance doses of ravulizumab (3000 mg for patients >40 kg - <60 kg, 3300 mg for patients >60 - <100 kg, 3600 mg for patients >100 kg) on day 15 and q8w thereafter.

1. Goals.

The primary aim of the study was to evaluate the non-inferiority of ALXN1210 (ravulizumab) compared to eculizumab in never exposed adult patients with PNH.

- 26 043233 treatment with a complement inhibitor.

Non-inferiority was declared if after 26 weeks of treatment: 1) the lower limit of the 95% confidence interval (CI) for the difference (ALXN1210-eculizumab) in the transfusion exclusion rate (TA) was greater than -20%, and 2) the lower limit of 95% The CI for the odds ratio for ALXN1210, compared with eculizumab, for lactate dehydrogenase (LDH-N) normalization was greater than 0.39.

Secondary objectives included characterizing the safety and tolerability of ALXN1210 in this patient population, evaluating the efficacy of ALXN1210 through supplemental pharmacokinetic/pharmacodynamic (PK/PD) and immunogenicity metrics of ALXN1210, and evaluating the long-term safety and efficacy of ALXN1210.

2. Study design.

The overall study design, treatments, and duration of the study are shown in FIG. 1. The ALXN1210-PNH-301 study is an open-label, randomized, multicentre, active-controlled, phase 3 study to evaluate the safety and efficacy of ALXN1210 compared to eculizumab given by intravenous (IV) infusion in adult patients with PNH, naive in relation to treatment with complement inhibitors. The study design included approximately 214 patients (107 patients per treatment group), but ultimately 246 subjects were enrolled and completed at least 183 days of treatment. After completion of the study, 246 subjects continued enrollment in the extension study, and 2 subjects discontinued. The study consisted of a 4-week screening period, a 26-week randomized treatment period, and an extension period up to 2 years. Patients were stratified into 1 of 6 groups based on history of transfusions (0, 1-14, or >14 pRBC units 1 year prior to first study drug dose) and LDH levels at screening (1.5-<3xULN or >3xULN) . Patients within each of the 6 groups were randomly enrolled in a 1:1 ratio to receive either ALXN1210 or eculizumab. Enrollment of patients without a history of transfusion in the past year was limited to 20%.

Prior to randomization and within 5 days prior to study drug administration on day 1, each patient's hemoglobin was assessed either by a local or central laboratory. If at that time the patient's hemoglobin was within the protocol transfusion guidelines, the patient was transfused with pRBC to a hemoglobin level above the protocol's transfusion limit to be eligible for randomization. Either the local or central laboratory confirmed that the patient's hemoglobin level after transfusion exceeded the transfusion limit specified in the protocol.

Patients randomly assigned to the ALXN1210 group received a loading dose of ALXN1210 (2400 mg for patients weighing >40-<60 kg, 2700 mg for patients weighing >60-<100 kg, 3000 mg for patients weighing >100 kg) on Day 1 , followed by maintenance doses of ALXN1210 (3000 mg for patients weighing >40-<60 kg, 3300 mg for patients weighing >60-<100 kg, 3600 mg for patients weighing >100 kg) on day 15 and every 8 weeks (q8w) thereafter for a total of 26 weeks of treatment. Patients randomly assigned to the eculizumab arm received induction treatment with 600 mg eculizumab IV on days 1, 8, 15, and 22, followed by maintenance treatment with eculizumab 900 mg on day 29 and every 2 weeks (q2w) thereafter for for a total of 26 weeks of treatment. After completion of all evaluations on day 183, patients were transferred to an expansion period during which patients were administered ALXN1210 until the product became registered or approved (according to country-specific guidelines), or for up to 2 years, whichever which comes earlier. Beginning on day 183, patients randomized to the ALXN1210 treatment arm received a maintenance dose (as described above) of ALXN1210 q8w for up to two years, and patients randomized to the eculizumab arm received a loading dose (as described above) of ALXN1210, followed by followed, at 2 weeks and q8w thereafter, a weight-based maintenance dose of ALXN1210. The pRBC transfusion was performed when the patient had a hemoglobin level of 9 g/dl or below with signs or symptoms of sufficient severity to warrant transfusion, or a hemoglobin level of 7 g/dl or below, regardless of the presence of clinical signs or symptoms.

3. Endpoints.

The co-primary efficacy endpoints of the study were (1) transfusion exclusion, defined as the proportion of patients who remained transfusion-free and did not require transfusion according to protocol guidelines up to day 183 (week 26), and (2) hemolysis, as measured directly. by LDH-N levels from day 29 (first scheduled evaluation status after maintenance dosing started) to day 183 (week 26).

Key secondary endpoints of study efficacy (tested in hierarchical order) were:

1) percent change in LDH level from baseline to day 183 (week 26);

2) change in the quality of life (QoL), assessed using a scale of functional assessment of the tera-

- 27 043233 PI Chronic Illness (FACIT) - Fatigue Version 4 from Baseline to Day 183 (Week 26);

3) Proportion of patients with acute hemolysis, defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, difficulty breathing [dyspnea], anemia [hemoglobin <10 g/dl], major adverse a vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of an elevated LDH level > 2 x upper limit of normal [ULN], after a previous decrease in LDH level - < 1.5 x ULN with therapy; And

4) Proportion of patients with stabilized hemoglobin, defined as the exclusion of a >2 g/dl decrease in hemoglobin levels from baseline in the absence of transfusion, up to day 183 (week 26).

Other secondary efficacy endpoints of the study were:

change in the European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire-30 (QLQ-C30), version 3.0, from baseline to day 183 (weeks 26);

time to first occurrence of LDH-N;

total number of units of packed red blood cells (pRBC) administered by transfusion up to day 183 (week 26);

change in the clinical manifestations of PNH (fatigue, hemoglobinuria, abdominal pain, breathing difficulties, anemia, dysphagia, and erectile dysfunction) from baseline to day 183 (week 26); and the proportion of patients experiencing MAVE up to day 183 (week 26). The pharmacokinetic and pharmacodynamic endpoints of the study were: change in serum concentration of ALXN1210 and eculizumab over time, change in hemolytic activity against chicken erythrocytes (cRBC) over time (exploratory), and change in the concentration of free complement component 5 (C5) over time .

The exploratory endpoints included patient-reported symptoms of PNH and use of healthcare resources. The safety and tolerability of ALXN1210, compared with eculizumab, is assessed through physical examinations, vital signs, electrocardiograms (ECGs), laboratory assessments, and the incidence of adverse events (AE) and serious adverse events (SAE). The proportion of patients who developed anti-drug antibodies (ADA) was also assessed.

Table 1

Schedule of examinations and assessments in the study: from screening to the end of the randomized treatment period

Period Screenshot NG Period of randomized treatment Research days -28-1 1 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183/ ET Window (day) N/A ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 informed other consent X

- 28 043233

Confirmation or administration of antimenin gococcal vaccination X X Medical history and demographic data X HIV testing X clone size PNH ^b X X X X Height X Weight X X X X X X X X X X X X X X X X X Pregnancy test ⁰ X X X X X X Registration of transfusions and transfusion parameters ⁰ X ^e X X X X X X X X X X X X X X X X symptomatology gia PNHf, g X X X X X X X X X X X X X X X X X FACIT- Fatigue g X X X X X X X EORTC ^QLQC30g X X X X X X X

- 29 043233

PNH symptom questionnaire ^g X X X X X X X X X X X X X X X X Questionnaire for patients on the use of resources ⁸ X X X X X Physical examination X Abbreviated physical examination ¹¹ X X X Vital Signs ¹ X X X X X X X X X X X X X X X X X Safety, 12-lead ECG ³ X X X Chemical analysis including LDH ^k X X X X X X X X X X X X X X X X X Hematology, including free hemoglobin and blood ^coagulation X X X X X X X X X X X X X X X X X Study X X X X X X X

- 30 043233

urine and chemical analysis of urine ^to Sampling for PK/PD ^x1 x ^{t x1} x ^t x ^t x ^t x ^{t x1} x ^t x ^t x ^{t x1} x ^t x ^t x ^{t x1} Immunogenic r (ADA) ¹¹ X X X X Safety Checklist Overview X X X X X X X X X X X X X X X X Acute hemolysis ⁰ •«—Continuous Monitoring^ Concomitant medicines X •«—Continuous Monitoring^ Adverse event X •«—Continuous Monitoring^ Randomization ^p X Introduction ALXN1210 ⁴ X X X X I Introduction of eculizumab X X X X X X X X X X X X X X X

Abbreviations: ADA=antibody against drug; ECG=electrocardiogram; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-30 Scale; ET=early termination; FACIT-Fatigue = Chronic Disease Therapy Functional Evaluation Scale - Fatigue; LDH=lactate dehydrogenase; N/A=not applicable; PD=pharmacodynamics; PK=pharmacokinetics; PNH=paroxysmal nocturnal hemoglobinuria; RBC=erythrocyte; WBC=leukocyte.

^a All patients were vaccinated against meningococcal infections within 3 years before or at the start of study drug administration. Patients initiating study drug treatment less than 2 weeks after meningococcal vaccine administration should be treated with appropriate prophylactic antibiotics up to 2 weeks after vaccination.

^b Clone size of WBC (granulocytes and monocytes) and RBC measured by high sensitivity flow cytometry at screening and day 1; only RBC clone size at day 71 and day 183.

^c For female patients of childbearing potential only. Serum pregnancy test at screening and day 183; urine pregnancy test at all other necessary time points. A negative urine test result was required prior to administration of ALXN1210 or eculizumab for female patients of reproductive potential at these examinations.

^d Transfusions given during and between visits were recorded.

^e Prior to randomization and within 5 days prior to study drug administration on Day 1, each patient's hemoglobin was assessed either by a local or central laboratory. If at that time the patient's hemoglobin was within the protocol transfusion guidelines, the patient was transfused with pRBC to a hemoglobin level above the protocol's transfusion limit to be eligible for randomization. Either the local or central laboratory confirmed that the patient's hemoglobin level after transfusion exceeded the transfusion limit specified in the protocol.

^f Investigator or designee assessment of the following events: fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.

^g Therapist-reported and patient-reported scores were obtained prior to administration of study drug.

^h An abbreviated physical examination consists of a significant examination of the body system,

- 31 043233 based on the judgment of the investigator (or authorized person) and the patient's symptoms. At least 1 body system was checked for an abbreviated physical examination.

¹ Vital signs measurements were taken after the patient rested for at least 5 minutes and included systolic and diastolic HR (millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate (breaths /minute) and oral or tympanal temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On the day of dosing, vital signs were determined prior to administration of study drug.

¹ A single 12-lead ECG is performed at screening and before dosing on day 57 and day 183. Patients should be supine for approximately 5-10 minutes prior to ECG and remain supine, but awake, during ECG.

^k Clinical laboratory measurements were performed before dosing on the day of dosing. FSH levels were measured only during screening to confirm postmenopausal status.

¹ Serum samples for PK/PD analyzes were collected before dosing (within 0.5 h before the start of the infusion) and at the end of the infusion (within 0.5 h after the end of the infusion). Samples at the end of the infusion were taken from the opposite, non-infused arm of the patient. All collection times were recorded in eCRF. At an abrupt hemolysis event, a serum sample is collected for PK/PD analysis.

^m Serum samples for PK/PD analyzes were collected before dosing (within 0.5 h prior to infusion) for patients treated with eculizumab and at any time for patients treated with ALXN1210. All collection times were recorded in eCRF. At an abrupt hemolysis event, a serum sample is collected for PK/PD analysis.

ⁿ Samples for ADA were collected before dosing. If the test results were positive, the test can be repeated every 3 months until the results are negative or stable, based on titer measurements and safety assessments.

If the predicted event of acute hemolysis occurred, the parameters LDH, PK and PD were analyzed in the central laboratory. If the predicted event of acute hemolysis does not occur at the time of the scheduled visit, conduct an off-schedule examination to assess the patient's condition and collect the necessary parameters LDH, PK and PD.

Patients were randomly enrolled for treatment based on their LDH screening result and history of blood transfusions, via an interactive system allowing access by telephone or internet (IxRS).

The dose of ALXN1210 is based on the last recorded at the time of the patient's weight study examination.

Primary efficacy endpoints are assessed prior to dosing on day 183. Dosing on day 183 marks the start of the expansion period. Additional procedures on day 183 after dosing, see table. 2 and 3.

- 32 043233

table 2

Examination and Evaluation Schedule: Expansion Period - Patients Transferred from ALXN1210_________________

Period Expansion period Days of research 183 ^a 239 295 351 407 463 519 575 631 687 743 799 855 911 EO S/E T Window (day) ±2 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 PNH clone size ^b X X X X X X X X X X X X X Weight X X X X X X X X X X X X X Pregnancy test X X X X X X X X X X X X X Registration of transfusions and transfusion parameters ⁰ X X X X X X X X X X X X X Symptomatology PNH ^e X X X X X X X X X X X X X FACI Fatigue b ^f X X X X EORTC QLQ-C30 ^f X X X X PNH symptom questionnaire ^f X X X X X X X X X X X X X Questionnaire for patients on the use of ^resources X X X X X X X X X X X X X Abbreviated physical examination g X X X X X X X Vital Signs ¹¹ X X X X X X X X X X X X X Safety , 12 lead ECG ¹ X Chemical analysis including LDH ^j X X X X X X X X X X X X X Hematology, including free X X X X X X X X X X X X X

- 33 043233

hemoglobin and blood clotting ¹ Urinalysis and chemical analysis of urine ¹ X X X X X X X X X X X X X Sampling for PK/PD ^k X X X X X Immunogenicity (ADA) ¹ X X X X X X X Safety Checklist Overview X X X X X X X X X X X X X Acute hemolysis ¹¹¹ •«—Continuous Monitoring^ Concomitant medicinal products •«—Continuous Monitoring^ Adverse events •"—Continuous Monitoring—"· Introduction ALXN1210 ¹¹ X X X X X X X X X X X X X

Abbreviations: AOA=anti-drug antibody; ECG=electrocardiogram; EORTC QLQ-C30=IIlKana of the main questionnaire-30 of the quality of life of the European Organization for Research and Treatment of Malignant Tumors; EO8=end of study; ET=early termination; FACI Fatigue = Chronic Disease Therapy Functional Evaluation Scale - Fatigue; EBH=lactate dehydrogenase; PO=pharmacodynamics; PK=pharmacokinetics; PKN=paroxysmal nocturnal hemoglobinuria; RBC = erythrocyte.

^a All patients enrolled for the expansion period received ALXN1210 on Day 183 after all evaluations.

^b Clone size of granulocytes and RBC measured by high sensitivity flow cytometry on days 351 and 743; only the size of the RBC clone at other examinations.

^c For female patients of childbearing potential only. Serum pregnancy test only for ET; urine pregnancy test at all other time points. A negative urine test result is required prior to administering ALXN1210 to female patients of childbearing potential on the day of dosing.

^d Transfusions given during and between visits were recorded.

^e Investigator's or designee's evaluation of the following events: fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.

^f Therapist-reported and patient-reported scores were obtained prior to administration of study drug.

^g An abbreviated physical examination consists of a meaningful body system examination based on the judgment of the investigator (or designee) and the patient's symptoms. At least one body system must be checked for a reduced physical examination.

^h Vital signs measurements were taken after the patient rested for at least 5 minutes and included systolic and diastolic HR (millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate (breaths /minute), and oral or tympanal temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). Vital signs were determined prior to administration of each study drug.

¹ A single 12-lead ECG is performed on day 911 or ET. Patients should lie supine for approximately 5-10 minutes prior to the ECG and remain supine but awake during the ECG.

^J Clinical laboratory measurements were performed before dosing on the day of dosing.

^k Serum samples for PK/PD analyzes were collected at the end of the infusion on day 183; before dosing (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) on days 351, 575 and 743; and at any time on the day 911 or ET. Samples at the end of the infusion were taken from the opposite, non-infused arm of the patient. All collection times were recorded in eCRF. At an abrupt hemolysis event, a serum sample is collected for PK/PD analysis.

¹ Samples for ADA were collected before dosing. If the test results were positive, the test can be repeated every 3 months until the results are negative or stable.

-34043233 baths, based on titer measurements and safety assessments.

^m If the predicted event of acute hemolysis occurred, the parameters LDH, PK and PD were analyzed in the central laboratory. If the predicted event of acute hemolysis does not occur at the time of the scheduled visit, conduct an off-schedule examination to assess the patient's condition and collect the necessary parameters LDH, PK and PD.

ⁿ The dose of ALXN1210 is based on the last recorded at the time of the patient's weight study visit.

Table 3

Study Review and Evaluation Schedule: Extension Period - Patients Transferred from Eculizumab Arm

Period Study days Window (days) PNH clone size ^b Weight Pregnancy test c Transfusion ^records and transfusion parameters ⁰ Symptomatology PNH ^e FACI Fatigue b ^f EORTC QLQ-C30 ^f PNH Symptom Patient Questionnaire ^f Resource Utilization Patient Questionnaire ^d Abbreviated physical examination g Vital signs ¹¹ 183 ^a ±2 197±3 X X X X X X X X X 253±7 X X X X X X X X X 309±7 X X X X X X X X 365±7 X X X X X X X X X X X Per 421±7 X X X X X X X X iodine p 477±7 X X X X X X X X X asshi 533±7 X X X X X X X X reni 589±7 X X X X X X X X X X X I 645±7 X X X X X X X X 701±7 X X X X X X X X X 757±7 X X X X X X X X X X 813±7 X X X X X X X X X 869±7 X X X X X X X X 925 EO S/E T ±7 X X X X X X X X X X X Safety , 12 lead ECG ¹ X chemical analysis, X X X X X X X X X X X X X X

- 35 043233

including LDH ^j Hematology, including free hemoglobin and blood coagulation ¹ X X X X X X X X X X X X X X Urinalysis and chemical analysis of urine ¹ X X X X X X X X X X X X X X Sampling for PK/PD ^k X X X X X X Immunogenicity (ADA) ¹ X X X X X X X Safety Checklist Overview X X X X X X X X X X X X X X Acute hemolysis ¹¹¹ <—Continuous monitoring—”· Concomitant medicinal products <—Continuous monitoring—” Adverse events •«—Continuous Monitoring^ Introduction ALXN1210 ¹¹ X X X X X X X X X X X X X X

Abbreviations: ADA=antibody against drug; ECG=electrocardiogram; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-30 Scale; EOS=end of study; ET=early termination; FACI Fatigue = Chronic Disease Therapy Functional Evaluation Scale - Fatigue; LDH=lactate dehydrogenase; PD=pharmacodynamics; PK=pharmacokinetics; PNH=paroxysmal nocturnal hemoglobinuria; RBC=erythrocyte.

^a All patients registered for the expansion period were administered ALXN1210 on day 183 after all evaluations.

^b Clone size of granulocytes and RBC measured by high sensitivity flow cytometry on days 365 and 757; only the size of the RBC clone at other examinations.

^c For female patients of childbearing potential only. Serum pregnancy test only for ET; urine pregnancy test at all other time points. A negative urine test result is required prior to administering ALXN1210 to female patients of childbearing potential on the day of dosing.

^d Transfusions given during and between visits were recorded.

^e Investigator or designee assessment of the following events: fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.

f

Therapist- and patient-reported assessments are made prior to administration of study drug.

^g An abbreviated physical examination consists of a meaningful body system examination based on the judgment of the investigator (or designee) and the patient's symptoms. At least one body system is tested for a reduced physical examination.

^h Vital signs measurements were taken after the patient rested for at least 5 minutes and included systolic and diastolic HR (millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate (breaths /minute), and oral or tympanal temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). Vital signs were determined prior to administration of each study drug.

¹ A single 12-lead ECG is performed on day 925 or ET. Patients should lie supine for approximately 5-10 minutes prior to the ECG and remain supine but awake during the ECG.

j Clinical laboratory measurements were taken before dosing on the day of dosing.

^k Serum samples for PK/PD analyzes were collected before dosing (within 0.5 h before the start of the infusion) and at the end of the infusion (within 0.5 h after the end of the infusion) on days 197, 365, 589 and 757; at the end of the infusion on day 183; and at any time on the day 925 or ET. Samples were taken at the end of the infusion

- 36 043233 from the patient's opposite, non-infused hand. All collection times were recorded in eCRF. At an abrupt hemolysis event, a serum sample is collected for PK/PD analysis.

^l Samples for ADA were collected before dosing. If the test results were positive, the test can be repeated every 3 months until the results are negative or stable, based on titer measurements and safety assessments.

^m If the predicted event of acute hemolysis occurred, the parameters LDH, PK and PD were analyzed in the central laboratory. If the predicted event of acute hemolysis does not occur at the time of the scheduled visit, an off-schedule visit should be performed to assess the patient's condition and collect the necessary LDH, PK, and PD parameters.

ⁿ The dose of ALXN1210 is based on the last recorded at the time of the patient's weight study visit.

4. Study population.

In total, approximately 246 patients with documented PNH are included and randomly enrolled for treatment with either ALXN1210 or eculizumab at approximately 300 study sites worldwide. Individuals who were not eligible for this study (not screened) may be rescreened. Prospective approval of protocol deviations based on invitation and registration criteria, also known as permissions for protocol deviations or exemptions from protocol restrictions, was not allowed.

Patients were eligible for study enrollment 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 as assessed by high sensitivity flow cytometry (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) RBC and leukocyte (WBC), with a clone size of granulocytes or monocytes >5%.

3. Presence of 1 or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, difficulty breathing (dyspnea), anemia (hemoglobin <10 g/dl), major adverse vascular event a history (including thrombosis), dysphagia or erectile dysfunction; or pRBC transfusion due to a history of PNH.

4. LDH level > 1.5 x ULN at screening.

5. To reduce the risk of meningococcal infections (Neisseria meningitidis), all patients should be vaccinated against meningococcal infections within 3 years before or at the start of study drug administration. Patients initiating study drug treatment less than 2 weeks after meningococcal vaccine administration should be treated with appropriate prophylactic antibiotics up to 2 weeks after vaccination.

6. Female patients of reproductive potential and male patients with female partners of reproductive potential should follow protocol guidance to prevent pregnancy during treatment and for 8 months after the last dose of study drug.

7. Patients must provide written informed consent and comply with the schedule for all exam examinations and procedures, including the use of any data collection device(s) for direct recording of patient data.

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 ³ (30 x 10 ⁹ /l) at screening.

3. Absolute neutrophil count < 500/µl (0.5 x 10 ⁹ /l) at screening.

4. Bone marrow transplantation in history.

5. Body weight < 40 kg at screening.

6. History of N. meningitides infection.

7. Unspecified, history of recurrent infection.

8. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug administration on day 1.

9. Presence of fever >38°C (100.4°F) within 7 days prior to study drug administration on day 1.

10. Human immunodeficiency virus (HIV) infection (as proven by anti-HIV-1 or anti-HIV-2 antibody titer).

11. Immunization with live attenuated vaccine 1 month prior to study drug administration on day 1 within 5 years of screening.

- 37 043233

12. History of malignancy within 5 years of screening, excluding treated non-melanoma skin cancer or carcinoma in situ of the cervix, with no evidence of recurrence.

13. A history of or current underlying heart, lung, kidney, endocrine, or hepatic disease (eg, active hepatitis) that, in the opinion of the investigator or sponsor, prevents the patient from participating in exploratory clinical trials.

14. Unstable medical conditions (eg, myocardial ischemia, active gastrointestinal bleeding, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, concomitant chronic non-PNH anemia) that make them less likely to tolerate protocol requirements (eg transfusion guidelines).

15. Concomitant use of any of the following medicinal products is prohibited unless administered on a stable regimen within the specified time 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 (eg warfarin) with a stable international normalization ratio (INR) for at least 4 weeks;

d) Dietary supplements containing iron or folic acid for at least 4 weeks;

e) LMW heparin for at least 4 weeks.

16. Hypersensitivity to mouse proteins or to any excipients for the study drug in history (for example, polysorbate 80).

17. Women who are planning a pregnancy, or who are pregnant or currently breastfeeding.

18. Women who have a positive pregnancy test at screening or on day 1.

19. Participation in another interventional treatment study or use of any experimental therapy within 30 days prior to the start of study drug administration on Day 1 in that study or within 5 half-lives of that study product, whichever is greater.

20. Known or suspected history of drug or alcohol addiction or dependence within 1 year prior to screening.

21. Known medical or psychological condition(s) or risk factor which, in the opinion of the Investigator, may prevent the patient from participating fully in the study, pose any additional risk to the patient, or distort the patient's assessment or study outcome.

The patient has the right to withdraw from the study at any time. If the patient withdrew consent, the scores indicated for the early termination (ET) review were performed. Patients withdrawn from the study were not replaced.

It is possible for a patient to discontinue the study drug if it is in the patient's best interest to discontinue treatment. If the patient is discontinued from the study drug, the patient is encouraged to return to the remaining examinations in his or her schedule prior to starting excellent complement-targeted therapy.

If the study was terminated for a patient with a current adverse event or unresolved laboratory result that is significantly outside the reference range and clinically significant, the investigator has made efforts to ensure follow-up until a satisfactory clinical resolution of the laboratory result or adverse event is achieved.

The sponsor or competent authority may terminate the study for reasonable cause. The end of the study is defined as the date of the last examination of the last patient in the expansion period.

5. Investigational drug.

The study drugs in this study were ALXN1210 (ravulizumab) and eculizumab (active control). Both ALXN1210 and eculizumab were humanized anti-C5 monoclonal antibodies.

Eculizumab is an IgG2/4 kappa immunoglobulin consisting of human constant regions and murine complementarity determining regions grafted onto a human light and heavy chain variable region framework. For the sake of clarity, IgG2/4 is a shorthand way of describing a non-natural, protein engineered heavy chain containing elements from both IgG2 and IgG4 heavy chains. This unique heavy chain is first described for use in an anti-C5 antibody for eculizumab. Eculizumab consists of two 448 amino acid heavy chains and two 214 amino acid light chains.

ALXN1210 is produced by minimally targeted modification of eculizumab by introducing 4 unique amino acid substitutions in its heavy chain to increase the half-life of the antibody. ALXN1210 and eculizumab share over 99% primary amino acid sequence identity and have very similar pharmacology.

ALXN1210 and eculizumab formulations were supplied for clinical trials as sterile preservative-free solutions of 10 mg/ml in disposable vials and developed for infusion by dilution in commercially available saline (0.9% sodium chloride for injection; country-specific pharmacopeia) for administration by IV infusion. In table. 4, the current IB ALXN1210 and the approved local labeling of eculizumab or the current IB eculizumab provides additional information.

Table 4

Investigational drug Investigational drug Product name ALXN1210 Eculizumab Dosage form Concentrated solution (10 mg/ml) for infusion Concentrated solution (10 mg/ml) for infusion Method of administration IV infusion IV infusion Physical Description Clear to translucent, whitish, practically free of particles Clear, colorless solution, practically free of particles Manufacturer Alexion Pharmaceuticals Inc. or an organization that manufactures under a contract Alexion Pharmaceuticals Inc. or an organization that manufactures under a contract

ALXN1210 and eculizumab were packaged in USP/EPS Type 1 borosilicate glass vials and sealed with butyl rubber stoppers with an aluminum crimp cap and flip cap. The study drug is supplied in kits. The investigational medicinal product is distributed to each center after receipt of all required necessary documents based on the current regulations.

Upon arrival of the investigational drug kits at the study site, the pharmacist or authorized person immediately removes the investigational drug kits from the transport refrigerator and stores them in their original boxes under refrigerated conditions at 2-8°C (35-47°F) and protected from light . ALXN1210 and eculizumab were not designed for freezing. The investigational medicinal product is kept in secure storage with limited access, and the temperature must be monitored daily.

The drug is at room temperature until administration. The material is not heated (eg using microwaves or other heat source) in a manner other than using ambient temperature.

Eculizumab or ALXN1210 was not administered as an IV bolus or bolus injection. Study drug infusions were prepared using an aseptic technique. The required patient dose of ALXN1210 or eculizumab is then diluted in commercially available saline (0.9% sodium chloride; country-specific Pharmacopoeia) in the volume shown in Table 1. 5 for ALXN1210, or in table. 6 for eculizumab (see also approved local labeling or current IB for eculizumab). A solution of ALXN1210 or eculizumab in diluent is administered to the patient using an IV tubing set via an infusion pump. Use of the built-in filter for infusion is necessary.

Table 5

Dosing Reference Chart for Dose Preparation ALXN1210

Dose type Body weight (kg) ^a Dose (mg) Volume ALXN121 0 (ml) Salt solution volume (ml) Total volume (ml) Minimum duration of infusion, minutes (hour) Maximum infusion rate (ml/hour) load > 40 - < 60 2400 240 240 480 114(1.9) 253 > 60 - < 100 2700 270 270 540 102 (1.7) 333 > 100 3000 300 300 600 108 (1.8) 333 Supporting > 40 - < 60 3000 300 300 600 138 (2.3) 267 > 60 - < 100 3300 330 330 660 120 (2.0) 333 > 100 3600 360 360 720 132 (2.2) 333

Note: See the Pharmaceutical Manual for additional instructions for dose preparation.

^a Body weight, as recorded at the last examination in the study.

- 39 043233

Table 6

Dosing reference chart for eculizumab dose preparation_______

Dose type Dose (mg) Volume of eculizumab a (ml) Salt solution volume (ml) Total volume (ml) Duration of infusion (minutes) Approximate infusion rate (ml/hour) induction 600 60 60 120 35 200 Supportive 900 90 90 180 35 300

Only a pharmacist or qualified healthcare professional prepared and dispensed study drug doses. Investigational medicinal product is distributed only to registered patients who are confirmed to be eligible for this study. After preparation of an investigational medicinal product for a patient, it is administered only to that patient. The study drug vials were for single use only and no drug remaining in the vial was used for another patient. No drug remaining in the infusion tubing or infusion bag was used on another patient.

This study includes a direct comparison of ALXN1210 with the active control, eculizumab. Patients were randomly enrolled in a 1:1 ratio to receive either ALXN1210 or eculizumab for 26 weeks. Study drug was administered as a slow IV infusion (see Tables 5 and 6).

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

Table 7

Doses of ALXN1210 based on weight

ALXN1210 treatment group, body weight Loading dose maintenance dose > 40 - < 60 kg 2400 mg 3000 mg > 60 - < 100 kg 2700 mg 3300 mg > 100 kg 3000 mg 3600 mg

Patients were randomly assigned to the eculizumab arm receiving eculizumab according to the approved PNH indication dosing regimen of 4 weekly induction doses followed by q2w maintenance doses starting at week 5 (Table 8).

Table 8 ____________________________ Doses of eculizumab ___________________________

Eculizumab treatment group Induction dose maintenance dose All patients 600 mg 900 mg

After the randomized treatment period, all patients entered the expansion period and were administered ALXN1210 until the product became registered or approved (according to country-specific guidelines), or for up to 2 years, whichever came first. Beginning on day 183, patients randomized to the ALXN1210 treatment arm received their weight-based maintenance dose of ALXN1210 q8w, and patients randomized to the eculizumab arm received the weight-based loading dose of ALXN1210, followed by 2 weeks and q8w thereafter. , weight-based maintenance dose of ALXN1210 (Table 7).

The actual time of administration of all doses was recorded in the patient's eCRF.

Patients meeting all enrollment criteria were randomly enrolled for study treatment with ALXN1210 or eculizumab at baseline (Day 1). Assignment to a treatment group was determined by a computer-generated random sequence using an interactive system allowing access by phone call or via the Internet (IxRS). Randomization was a stratified randomization. Patients were stratified into groups 1-6 based on a history of transfusions (0, 1-14, or >14 pRBC units 1 year prior to the first dose of study drug) and lactate dehydrogenase (LDH) levels at screening (1.5 - < 3 x ULN or > 3 x ULN). Patients within each of the 6 groups were then randomly enrolled in a 1:1 ratio to receive either ALXN1210 or eculizumab during a 26-week randomized treatment period.

Weight-based doses of ALXN1210 in this study (Table 7) were based on PK/PD data from early development studies in healthy adult volunteers, as well as available data for patients with PNH in the current phase 1b dose-finding study (ALXN1210 -PNH-103) and in the current phase 2 proof-of-concept study (ALXN1210-PNH-201). The choice of ALXN1210 dosing regimen is based on target immediate, complete, and long-term inhibition.

-40043233 on the development of the terminal complement complex in patients with PNH.

The eculizumab dose is the stated dose for the treatment of patients with PNH (Soliris® USPI and SmPC).

Infusion of other monoclonal antibodies is associated with infusion reactions, usually onset during or shortly after completion of the infusion. Prior medicinal products (including vitamins and herbal preparations) - including those discussed in the Exclusion Criteria and Procedures section (any therapeutic intervention such as surgery/biopsy or physical therapy) that the patient was administered or administered within 28 days (or 3 years for documentation of meningococcal vaccination) prior to screening, up to the first dose of study drug, were recorded in the patient's eCRF.

Transfusions of pRBCs within 1 year prior to the first study drug administration were recorded in the patient's eCRF.

All drug use and procedures performed during the course of the trial are recorded on the clinical trial participant registration form/medical record and the patient's eCRF. This registration includes all prescription drugs, herbal products, vitamins, minerals, over-the-counter drugs, and current PNH drugs. Concomitant medicinal products were registered from the first infusion of investigational medicinal product until 56 days after the last dose of investigational medicinal product administered to the patient. Any changes to concomitant medications were also recorded on the clinical trial participant registration form/medical record and the patient's eCRF. Any concomitant drug deemed necessary for the standard of care of the patient during the course of the study or for the treatment of any AE, together with the eligible drugs described below, is administered at the discretion of the investigator. However, it is the investigator's responsibility to ensure that the details, for all medicinal products, are fully recorded on the clinical trial participant registration form/medical record and the patient's eCRF.

The following concomitant medicinal products are approved if the following conditions occur and dose adjustments are not expected during the randomized treatment period:

Erythropoietin if the patient has been on a stable dose for at least 8 weeks prior to screening.

Immunosuppressants if the patient has been on a stable dose for at least 8 weeks prior to screening.

Corticosteroids if the patient has been on a stable dose for at least 4 weeks prior to screening.

Vitamin K antagonists (eg, warfarin) with stable INR for at least 4 weeks prior to screening.

Dietary supplements containing iron or folic acid if the patient is on a stable dose for at least 4 weeks prior to screening.

LMW heparin if the patient is on a stable dose for at least 4 weeks prior to screening.

If this seems to be in the best interest of the patient, the frequency or dose level of any of the above drugs may be adjusted.

Due to their mechanism of action, the use of eculizumab or ALXN1210 increases the patient's susceptibility to N. meningitidis infection. To reduce the risk of meningococcal infections, all patients were vaccinated against meningococcal infections within 3 years before or at the start of study drug administration. Patients initiating study drug treatment less than 2 weeks after meningococcal vaccine administration were treated with appropriate prophylactic antibiotics up to 2 weeks after vaccination. Vaccines against serotypes A, C, Y, W135 and B, when available, are recommended to prevent infection with common pathogenic meningococcal serotypes. Patients were vaccinated or revaccinated according to current national vaccination guidelines or local practice for the use of vaccination with complement inhibitors (eg, eculizumab).

Vaccination may not be sufficient to prevent meningococcal disease. Consider official guidance and local practice for the appropriate use of antibacterial agents. All patients were monitored for early signs of meningococcal infections, evaluated immediately if infection was suspected, and treated with appropriate antibiotics as needed.

6. Performance evaluations.

The pRBC transfusion was performed when the patient had a hemoglobin level of 9 g/dl or below with signs or symptoms of sufficient severity to warrant transfusion, or a hemoglobin level of 7 g/dl or below, regardless of the presence of clinical signs or symptoms.

Signs or symptoms usually associated with the patient's need for transfusion

- 41 043233 or provoking it, documented in eCRF for each individual patient. Typical anemia-related symptoms warranting transfusions included angina pectoris, altered mental status (eg, syncope, dizziness, confusion, stroke, transient ischemic attack), severe or worsening difficulty breathing, and severe or worsening fatigue.

If a patient met any of the transfusion criteria during the course of the study, the investigator determined the appropriate number of pRBC units to be administered via transfusion. It was recommended that the transfusion be performed within 48 hours of determining the hemoglobin level leading to the transfusion. The conduct of the transfusion, including the hemoglobin result and symptoms triggering the transfusion, and the number of units administered by transfusion, were documented in the eCRF.

Prior to randomization and within 5 days prior to study drug administration on day 1, each patient's hemoglobin was assessed either by a local or central laboratory. If the patient's hemoglobin level met this transfusion guideline at that time, the patient was transfused with pRBC to a hemoglobin level above the transfusion limit to be eligible for randomization. Either the local or central laboratory confirmed that the patient's hemoglobin level after transfusion exceeded the transfusion limit.

A. LDH and other disease-related laboratory parameters.

Blood and urine samples were collected. The following disease-related laboratory parameters were measured during the study: LDH, free hemoglobin, occult blood, urinalysis, total C5, haptoglobin, reticulocyte count, RBC clone size at PNH estimated by high sensitivity flow cytometry, D-dimer concentration, estimated rate glomerular filtration rate (calculated using the kidney failure diet modification formula), urine albumin:creatinine ratio, and C-reactive protein.

B. Patient-reported outcome measures.

Two validated QoL scales were offered to patients prior to study drug administration. The FACIT Fatigue Scale, version 4.0, is a collection of QoL questionnaires related to the management of symptoms of fatigue due to chronic disease. FACITatigue is a 13-item questionnaire assessing patient-reported fatigue and its impact on daily activities and functions during the previous 7 days. Patients rated each item on a 5-point scale: 0 (not at all) - 4 (very strongly). The overall score ranges from 0 to 52, with a higher score indicating a better QoL score.

The European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire-30 Scale (QLQ-C30), version 3.0, is a questionnaire designed to assess the QoL of patients with malignant tumors. The questionnaire includes the following subscales: general health, functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social activity), symptom scales (fatigue, nausea and vomiting, and pain), and individual items (dyspnea, insomnia, loss of appetite, constipation, diarrhea and financial difficulties). Thirty questions are related to QoL, where the first 28 questions are rated on a 4-point scale (1=not at all - 4=very bad), and the last 2 questions, analyzing the patient's general health and QoL, are rated on a scale of 1 (very bad) - 7 (excellent). Each subscale has a range of 0-100%, where a high score represents a higher level of response. Thus, a high score on the functional scale represents a high level of functioning, but a high score on the symptom scale represents a high level of symptomatology/problem.

Patients completed two additional questionnaires to assess disease burden. These questionnaires were administered to patients prior to study drug infusion. The PNH symptom questionnaire lists the following symptoms: yellowing of the eyes, discoloration of urine, chest pain, difficulty breathing, headache, fatigue, abdominal pain, confusion, erectile dysfunction, difficulty swallowing, and others. Patients indicate whether they experienced each of the symptoms in the past week, and if so, rate frequency (on a 4-point scale ranging from rare to almost always), severity (on a 4-point scale ranging from mild to very severe) and associated the degree of stress/anxiety (on a 5-point scale in the range not at all - very much).

The Resource Utilization Questionnaire asks patients to provide the number of times during the last month they had to: visit their healthcare provider, primarily for PNH treatment (excluding protocoled study visits), go to the emergency room, primarily for PNH treatment, admitted to hospital for PNH treatment primarily, had dark urine and/or missed a day of work as a result of PNH symptoms.

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C. Major adverse vascular events.

Major adverse vascular events (MAVE) were assessed as part of a routine assessment of adverse events (AE). Description of MAVE, anatomical location, method of diagnosis (eg, magnetic resonance imaging, ultrasound, angiogram), date of diagnosis, and date of resolution (or current) 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 occlusion of peripheral vessels;

h) thrombosis or infarction of mesenteric/visceral veins;

i) thrombosis or infarction of the mesenteric/visceral arteries;

j) hepatic/portal vein thrombosis (Budd-Chiari syndrome);

k) cerebral artery occlusion/acute cerebrovascular accident;

l) cerebral vein occlusion;

m) renal artery thrombosis;

n) gangrene (non-traumatic; non-diabetic);

o) amputation (non-traumatic; non-diabetic);

p) dermal thrombosis;

q) other, please specify.

D. Major adverse vascular events.

Demographic parameters were reviewed, including age, gender, race and ethnicity. A complete medical history was collected and documented. Weight and height were recorded. Growth was measured only at screening.

The medical history of the patient with PNH, including the onset of the first symptom of PNH, date of diagnosis, PNH clone size, pRBC transfusions, and any history of MAVE, was documented at the screening examination.

The patient's medical history, including prior and comorbid conditions/disorders and history of transfusions, was recorded at the screening examination. Drug use (prescription or nonprescription, including vitamins and/or herbal supplements) within 28 days (or 3 years for documentation of meningococcal vaccination) prior to screening was also recorded, in addition to meningococcal vaccination.

The physical examination included the following assessments: general appearance; skin; head, ears, eyes, nose and throat; neck; lymph nodes; chest; hearts; abdominal cavity; limbs; central nervous system; and the musculoskeletal system. The abbreviated physical examination consisted of a meaningful body system examination based on the investigator's judgment and the patient's symptoms.

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

Samples were collected for a serum pregnancy test, hematological analysis, chemical analysis, blood coagulation analysis, and urinalysis. Samples for laboratory evaluations were collected prior to the administration of each study drug. If the predicted event of acute hemolysis occurs, an off-schedule inspection is performed in which a sample is collected for LDH and PK/PD analysis at a central laboratory.

It is understood that some laboratory values may be outside the normal range due to comorbidity. Researchers use their own judgment when assessing the clinical significance of these values. Clinical significance is defined as any deviation in laboratory measurements that is of medical significance and that results in a change in medical care. If there were clinically significant laboratory changes from baseline, the changes were documented as AEs in the AE eCRF. The investigator also assessed association with study treatment for all clinically relevant values outside the range. The Investigator continued to monitor the patient through additional laboratory evaluations until (1) values returned to the normal range or baseline, or (2) the Investigator expressed the opinion that values outside the normal range are not related to study drug administration or other protocol-specific procedures .

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Blood samples were analyzed for serum chemistry. Indirect bilirubin is calculated from the levels of total and direct bilirubin; thus, results for indirect bilirubin were not available if direct bilirubin was below the limit of quantitation. Serum FSH levels were measured during screening for postmenopausal female patients to confirm their postmenopausal status. Conducted chemical evaluations. Estimated glomerular filtration rate was calculated using the Renal Failure Diet Modification formula at all examinations at which serum chemistries were performed. Blood samples were analyzed for blood coagulation parameters.

Urine samples were analyzed. Microscopic examination of urine samples was performed if the results of macroscopic analysis were abnormal. Urine samples were also analyzed to measure the level of proteins and creatinine to calculate the ratio of protein:creatinine in the urine.

HIV testing for human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2) is required for all patients prior to enrollment. No known HIV-positive patients were registered.

For each patient, a single digital 12-lead ECG was performed. Patients should lie supine for approximately 5-10 minutes prior to the ECG and remain supine but awake during the ECG.

Blood samples were collected to test for the presence and titer of anti-ALXN1210 ADA or eculizumab in serum prior to study drug administration. If the test results were positive, the test was repeated every 3 months until the results became negative or stabilized based on titer measurements and safety assessments. Additional characterization of antibody responses was performed as needed, including binding and neutralizing antibodies, PK/PD, safety and potency of ALXN1210 or eculizumab.

AE is any adverse medical event in a patient who is administered a pharmaceutical product and does not need to be causally related to this treatment. An AE may thus be any adverse or unintended sign (eg, an abnormal laboratory finding), symptom, or disease associated in time with drug use, whether or not considered drug-related.

Situations in which an adverse medical event did not occur (eg, hospitalization for elective surgery if planned prior to study entry, hospitalization for social or convenience reasons), and envisaged daily fluctuations in preexisting disease(s) or condition(s) ) present or detected at the start of the study that did not worsen were not AEs.

No effect of a drug is not an AE in clinical trials because the purpose of a clinical trial is to determine the effect of a drug.

An error in the administration of a medicinal product (including intentional misuse, abuse and overdose of the product) or use other than that specified in the protocol is not considered as an AE, unless an adverse medical event is present as a result of an error in the administration of the medicinal product.

Pregnancies occurring during maternal or paternal exposure to study product were recorded within 24 hours of notification to the investigator/centre. Data on fetal outcome and breastfeeding are being collected for reporting to regulatory authorities and safety assessments.

Adverse events were recorded from the time the consent was signed. AE reported after informed consent but prior to administration of the investigational medicinal product is considered to be pre-treatment AE.

C5 inhibition is known to increase susceptibility to infections caused by encapsulated bacteria, in particular N. meningitidis. The following events were important identified risks in this study: meningococcal infections, sepsis, serious infections, Aspergillus infection, and infusion reactions. Additional events of interest in this study included the following: serious skin adverse reactions, cardiac events (including ventricular fibrillation), and angioedema.

The severity of AEs was ranked using the Common Criteria for Adverse Events Terminology (CTCAE) version 4.03 or higher. A ranking (severity) scale is provided for each AE term. Each CTCAE term is a Low Level Term (LLT) according to the Medical Dictionary for Regulatory Activities (MedDRA®). Each LLT is coded by a MedDRA Preferred Term (PT).

Grade refers to the severity of the AE. CTCAE assigns grades 1-5, with unique clinical descriptions of severity for each AE (Table 9).

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Table 9

Adverse Event Severity Ranking Scale

Degree Description Degree 1 soft; asymptomatic or mild symptoms; only clinical or diagnostic observations; no intervention shown. Degree 2 moderate; minimal, local or non-invasive intervention is indicated; restriction of age-appropriate instrumental activity in activities of daily living (ADL) ^a Grade 3 Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization is indicated; disabling; limiting self-service ADL ^b Degree 4 Life-threatening consequences; urgent intervention is indicated. Degree 5 AE-related death.

Abbreviations: ADL=activity in daily activities; AE=adverse event.

Instrumental ADL refers to cooking, shopping for groceries or clothes, using the phone, managing money, and so on.

Self care ADL refers to washing, dressing and undressing, eating, using the toilet, taking medication, and staying out of bed.

The investigator should provide an estimate of causality (no association, unlikely, possible, probable, or certain) for all AEs (both serious and non-serious), based on the investigator's judgment and observed symptoms associated with the event (Table 10). This score was recorded in the eCRF and any additional forms as needed.

Table 10

Descriptions of causality assessment

Grade Description Not connected/no connection Assumes no causal relationship between the product under investigation and the reported event. unlikely to be associated Assumes that the clinical picture is highly consistent with a cause other than the investigational product, but the correlation cannot be made with absolute certainty, and an association between the investigational product and AE cannot be ruled out with absolute certainty. Possibly related Suggests that treatment with the investigational product may cause or contribute to AE (i.e., the event follows a reasonable time sequence from the time of drug administration and/or follows a known pattern of response to the investigational product, but may also be caused by other factors) . Probably related Assumes that there is a reasonable temporal sequence of the event with the introduction of the investigational product, and a probable causal relationship of the event to the investigational product. This is based on the known pharmacological activity of the investigational product, known or previously reported adverse reactions to the investigational product or drug class, or an opinion based on the investigator's clinical experience. Definitely related Temporal association with study product, other conditions (comorbid illness, reaction to concomitant drug, or progression/manifestation of a disease state) do not appear to explain the event, consistent with known pharmaceutical profile, improvement on discontinuation, recurrence on re-exposure.

A serious adverse event (SAE) is any adverse medical event that: results in death, is life-threatening (i.e. the patient is at risk of death at the time of the event), requires hospitalization of the patient or prolongation of existing hospitalization, results in permanent or significant disability/incompetence and/or is a congenital malformation of the fetus/birth pathology.

Significant medical events that may not be fatal, not directly life-threatening, or not requiring hospitalization may be considered a serious adverse event when, based on appropriate medical judgment, they may put the patient at risk or require intervention to prevent one of the outcomes listed above.

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Suspected Unanticipated Serious Adverse Reactions (SUSARs) were serious events that were not listed in the IB and which the Investigator identifies as being related to the investigational product or method.

All AEs (serious and non-serious) were collected from signing the ICF 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.

7. Pharmacokinetics and pharmacodynamics.

Blood samples for determination of serum drug concentrations and PD estimates were collected before and after study drug administration. Record the actual date and time (24 hour clock) of each sampling. The number of PK sampling time points for any given patient did not exceed the currently planned number of time points; in an acute hemolysis event, an additional sample for PK/PD was necessary.

Blood samples for PK and PD assessment were taken from the arm opposite the arm used for drug infusion.

PK/PD scores were as follows: change in serum concentration of ALXN1210 and eculizumab over time, change in hemolytic activity in cRBC over time (exploratory), and change in free C5 and total C5 over time.

8. Statistical methods and planned analyzes.

All collected data are presented in tabular summaries. All data, as well as any outcomes inferred from the data, are presented in detailed data sheets. Graphical representations are also provided where appropriate. All analyzes were performed using SAS® Release 9.4 or later (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. Continuous variables were summarized using descriptive statistics, including number of observations and mean, standard deviation, median, minimum and maximum values. Categorical variables were summarized by frequency and percentage of patients. All statistical tests performed were based on a 2-tailed 5% significance level unless otherwise noted. Before finalizing and closing access to the database, all decisions regarding the inclusion or exclusion of data from the analysis for each patient were made by the relevant specialists in the field of medicine and statistics. Exceptions, without exception, were documented in the patient lists.

The details of the statistical analyzes described below were specified in a separate Statistical Analysis Plan (SAP) prior to the database being closed and analyzed. Any change to the data analysis methods described in the protocol requires improvement only if it changes the primary or key secondary objectives, or the conduct of the study. Any other change to the data analysis methods described in the protocol or SAP, and the rationale for making the change, is described in the Clinical Study Report (CSR). Additional exploratory data analyzes were performed as deemed necessary.

CSR was generated based on efficacy, safety, PK and PD data collected up to the end of the 26 week randomized treatment period (day 183). The final CSR to summarize the parameters of long-term efficacy, safety, PK and PD was obtained at the end of the study.

Approximately 246 patients were randomly enrolled in a 1:1 ratio to receive either ALXN1210 (N=107) or eculizumab (N=107) to provide at least 193 eligible patients (assuming a dropout rate of no more than 10%). The sample size estimate was based on a non-inferiority design comparing ALXN1210-treated patients with eculizumab-treated patients. The joint primary hemolysis endpoints, as measured directly by LDH normalization (LDH-N) from day 29 to day 183, and the proportion of patients achieving transfusion exclusion (TA) up to day 183, were used to assess non-inferiority. The sample size is based on the endpoint requiring more patients.

For the LDH-N co-primary endpoint, using a non-inferiority margin (NIM) based on relative benefit of eculizumab versus placebo, 0.39 and a Type I 1-sided error of 2.5%, a minimum of 142 patients provides 80% power to demonstrate non-inferiority of ALXN1210 relative to eculizumab. NIM was determined based on a placebo-controlled randomized trial (Hillmen P., et al., N. Engl. J. Med., 2006;355:1233-1243), which showed the relative advantage of eculizumab, compared with placebo, with the ratio 6.5 chances. This was based on several factors. Because baseline LDH is a predictor of normalization rate, to keep the assumption constant, LDH-N rates were calculated by adjusting for observed baseline LDH-N from the current ALXN1210 phase 1b and 2 study. The estimated LDH-N for eculizumab was then calculated as a weighted average of the proportion LDH-N from day 29 to day 183, consistent with the proposed analysis plan for this study. Because the proportion of LDH-N for those treated

- 46 043233 placebo patients was 0% at all examinations, the upper limit of 95% CI was used to allow the calculation of the odds ratio. The final benefit estimate was based on an LDH-N proportion of 42% for patients treated with eculizumab and 10% for placebo. The traditional NIM choice is one with <50% loss of advantage resulting in a NIM odds ratio of 0.39. The NIM calculation is followed by Ng TH (Statist. Med. 2008; 27:5392-5406) in which NIM is given by 1/{OR ^0.5 } where OR is the odds ratio of eculizumab versus placebo and is given by [ 0.42/(1-0.42)]/[0.1/(1-0.1)], and 0.5 represents the share of benefit to be retained. This method selects NIM on a log odds ratio scale as described in Section IV of the 2010 Food and Drug Administration (FDA) Industry Guidelines: Clinical Studies of No Less Efficacy. While more conservative methods can be used to design NIM, such as using a lower bound of 95% CI for eculizumab, the resulting estimated sample size makes this study operationally unfeasible in light of the rarity of PNH and the paucity of eculizumab-naive patients.

For the other co-primary endpoint, the proportion of patients not transfused by day 183, using NIM -20% and a 1-sided Type I error of 2.5%, a minimum of 193 patients provide 80% power to demonstrate non-inferiority between treatment groups . NIM was determined from the Global PNH Registry for eculizumab treated patients registered in 2012 or later (Soliris Type II Variation Procedure No. EMEA/H/C/000791/P/66). History of transfusions is a predictor of on-treatment transfusions, thus, to keep the assumption constant, NIM was assessed based on available data from treated and untreated patients in proportion to expected enrollment in the current study. Eculizumab-treated patients (TA rate 57.1%) showed an advantage over untreated patients (TA rate 18.6%) with a difference of approximately 40% (38.5%) after adjusting for the number of transfusions in history in the 12 months prior to enrollment. The correction was obtained from the expected proportion of patients without a history of transfusions no more than 20%. Patient enrollment for this study was limited to 20% for patients with no history of transfusion to ensure consistency satisfaction.

The traditional NIM choice is one with <50% loss of advantage resulting in a NIM of approximately -20%. A more conservative NIM can be used using a lower bound of 95% CI for difference in frequency, however, the resulting estimated sample size makes this study operationally unfeasible in light of the rarity of PNH and the paucity of eculizumab-naive patients with and without a history of transfusion. In addition, given the proportion of patients with TA observed in the phase 1b/2 program preliminary results, no less efficacy can be shown using more conservative NIMs for a given sample size with limited power loss.

Since the sample size estimate based on LDH-N is smaller than the estimate based on TA (Table 11), the final sample size estimate chosen for this study was based on the TA endpoint. Adjusting for a possible 10% dropout rate, approximately 246 patients were enrolled in this study.

Table 11

Generalization of parameters used in sample size estimation with joint primary endpoints

Options LDH normalization (LDH-N) Transfusion Avoidance (TA) Power 80% 80% Type I error 1-sided 0.025 1-sided 0.025 Limit of no less efficiency 0.39 -0.20 distribution ratio 1:1 1:1 Average response to eculizumab 0.42 ^a 0.57 ^b Standard deviation for response to eculizumab NA NA Alleged difference in treatments 1 0 Estimated Sample Size (SS) 142 193 Adjusted SS for 10% dropout 158 214

Note: Software package: Hintze, J. (2011). PASS 11. NCSS, LLC. Kaysville, Utah, US. www.ncss.com.

^a Response rate from the TRIUMPH study adjusted for baseline LDH.

^b Response rate from the PNH Global Registry adjusted for history of transfusions.

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Efficacy analyzes were performed on the complete analysis population (FAS). Analyzes of joint primary efficacy endpoints, as well as analyzes of key secondary endpoints, were performed on the per-protocol analysis (PP) population. FAS is the primary population for all efficacy analyses. FAS includes all patients who received at least 1 dose of ALXN1210 or eculizumab and who have at least 1 efficacy score after the first infusion.

The RR population finalized prior to database closure consists of FAS patients who meet all of the following criteria:

a) Missed no doses of ALXN1210 or missed no more than 1 dose of eculizumab during the 26-week randomized treatment period;

b) Satisfy inclusion criteria #2, 3 and 4;

c) Did not meet exclusion criteria #1, 2, 3, or 4;

d) Never been subjected to incorrect randomized treatment;

f) Follow the transfusion guidelines specified in the protocol.

Safety analyzes were performed on a safety population defined as all patients who received at least 1 dose of study drug. Pharmacokinetic and PD analyzes were performed on all patients treated with at least 1 dose of study drug and who have measurable PK and PD data.

Patient demographics and baseline characteristics, including medical and transfusion history, were summarized by treatment stratum and combined for the FAS, safety, and PP populations. No formal statistical comparisons were made.

All patients were included in patient distribution summaries describing the frequency and percentage of patients who were screened and treated and who completed or discontinued the study, along with the reason for discontinuation, by treatment stratum. All patients for whom the study was terminated were identified and the extent of their participation in the study was recorded. If known, the reason for termination is given. The number of patients treated, treatment discontinuation (together with reason for discontinuing treatment), transfer to expansion period, and termination of expansion period (together with reason for discontinuation) were tabulated by treatment strata and cumulatively.

The use of prior and concomitant medications for each patient was coded using the World Health Organization Dictionary of Medicines, and the frequency and percentage of administration of concomitant medications were summed. Drugs were summarized by Anatomic Therapeutic Chemical (ATC) system class and preferred drug name using frequency and percentage of patients in the FAS, safety, and PP populations.

The joint primary efficacy endpoints were 1) the difference between treatment groups in the proportion of patients who achieved TA by day 183, and 2) the relative effect between treatment groups on LDH-N from day 29 to day 183, expressed as an odds ratio.

Transfusion exclusions were only achieved for those patients who were not transfused and who did not comply with the transfusion guidelines specified in the protocol. The percentage of patients who achieved TA with a 95% CI is calculated on day 183 for both ALXN1210 and eculizumab treatment arms and the randomization stratum. The difference in percentage of patients reaching TA in the 2 treatment groups is calculated between the ALXN1210 and eculizumab treatment groups, together with a 95% CI for the difference. The difference between the ALXN1210 and eculizumab treatment groups is calculated as the weighted combination of the differences between the ALXN1210 and eculizumab treatment groups within the stratification groups (using the Mantel-Haensel method). The 95% CI for the difference between the ALXN1210 and eculizumab treatment groups is calculated using the Newcomb stratified confidence interval.

LDH-N was analyzed using the General Estimating Equation (GEE) method, which takes into account repeated measurements of LDH-N at each visit (Liang K-Y, et al., Biometrika. 1986;73(1):13-22). The GEE method provides odds ratios and CIs for treatment effect while controlling for the correlation between visits for a given patient and other input factors. LDH-N from day 29 to day 183 is used as the dependent variable and indicator variable for treatment, history of transfusions (as a categorical variable based on stratification factor levels) and baseline LDH level (as a continuous variable) are included in the model as influencing variables. To correlate data for one patient, a first-order autoregressive structure is adopted, in which the highest correlation between examinations that were closest in time is assumed. Day 29 was the first scheduled assessment after the start of maintenance dosing, and experience with eculizumab and ALXN1210 phase 1b/2 data show near maximal LDH suppression after 4 weeks of treatment. The results for the model were presented as odds ratios with 95% confidence intervals.

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To conclude that ALXN1210 is non-inferior to eculizumab, both joint primary endpoints individually must be shown to be equally effective. If the lower limit of 95% CI for the difference (ALXN1210-eculizumab) exceeded the NIM of -20% for TA, and the lower limit of 95% CI for the odds ratio of ALXN1210, compared with eculizumab, exceeded the NIM of 0.39 for LDH-N, then it was concluded, that ALXN1210 treatment is not inferior to eculizumab. If no inferior efficacy was observed for both joint primary endpoints, and a greater effect for ALXN1210 was observed at any joint primary endpoint, then superiority was assessed using the Hochberg multiple comparison method.

key secondary efficacy endpoints were summarized by randomization strata and by treatment strata at baseline and at study visits, where these scores were collected during the 26-week randomized treatment period. The change in FACIT fatigue (and percent change in LDH) from baseline to week 26 is analyzed using a repeated measures mixed effects model (MMRM; see, e.g., Mallinckrodt CH, et al., J. Biopharm. Stat. 2001;11 :9-21 and Mallinckrodt CH, et al., Clinical Trials 2004;1:477-489) with fixed, categorical treatment effects, stratified randomization rates for history of transfusions (0, 1-14, or >14 pRBC units per 1 year prior to first dose of study drug) and LDH levels at screening (1.5-<3xULN or >3xULN), study visit, and study visit interaction with treatment group, as well as continuous, fixed covariances of baseline FACIT -fatigue (or LDH) and the interaction of baseline FACITatigue (or LDH) with examination as covariates. For percent change in LDH level, include baseline LDH level as a continuous variable. The Kenward-Roger approximation is used to estimate the degrees of freedom of the denominator. The difference between the ALXN1210 and eculizumab treatment groups is calculated along with a 2-sided 95% CI.

For rapid hemolysis and stabilized hemoglobin, the same method used for TA was used. These key secondary endpoints were tested in a hierarchical order, provided that no lesser performance was claimed for the joint primary endpoints. If no less efficacy is obtained for the key secondary endpoint, and a greater effect is observed for ALXN1210, then superiority was assessed using a 2-tailed test of 0.05 for each parameter.

When conducting analyzes of key secondary efficacy endpoints, a closed-loop testing method was used, so the lack of test significance prevents the analysis of subsequent tests. Scores and CIs were calculated for all of these key secondary efficacy endpoints, whether or not the lack of test significance prevents analysis of subsequent tests. If the upper limit of the 95% CI for the difference between ALXN1210 and eculizumab treatment groups in percent change from baseline to week 26 in LDH was less than 20% NIM, then ALXN1210 was declared non-inferior in that parameter and the next parameter was tested. If the lower limit of 95% CI for the difference between ALXN1210 and eculizumab treatment groups in change from baseline on the FACIT fatigue score was greater than NIM -5, then ALXN1210 was declared non-inferior in that parameter and the next parameter was tested. If the upper limit of 95% CI for the difference between ALXN1210 and eculizumab treatment groups in the proportion of patients with acute hemolysis was less than 20% NIM, then ALXN1210 was declared non-inferior in this parameter and the next parameter was tested. If the lower limit of 95% CI for the difference between the ALXN1210 and eculizumab treatment groups in the proportion of patients with stabilized hemoglobin exceeded the NIM of -20%, then ALXN1210 was said to be non-inferior in this parameter. Due to the predefined testing in hierarchical order, no Type I error correction was required.

Changes from baseline in EORTC-QLQ-C30 were summarized by treatment group at baseline and at the study visits where these scores were collected. Changes from baseline in the clinical manifestations of PNH were summarized by treatment group and at the study visits where these scores were collected. The number of any treatment-induced MAVE (n) and the number of patients with events (n, %) were displayed by treatment group. The total number of pRBC units administered by transfusion during treatment was summed by treatment group. Kaplan-Meier curves were generated for both treatment groups and estimates of time to first occurrence of LDH-N since first administration of study drug. Statistical inferences from these parameters are not planned.

All safety analyzes were performed on the safety population, defined as all patients who received at least 1 dose of ALXN1210 or eculizumab. Up to day 183, safety results were recorded per treatment group.

The following definitions were used for AE:

a) Pre-Treatment Adverse Events: Any AE that begins after informed consent is given but before the first infusion of study drug.

b) Treatment-induced adverse event: any AE that begins during or after the first infusion of study drug.

c) Treatment-induced SAE: Treatment-induced AE (TEAE) that is serious.

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The incidence of TEAE, discontinuation due to TEAE associated with TEAE drug administration, TEAE during study drug administration, severe TEAE, and SAE were summarized. All AEs were coded using MedDRA version 18 or higher and summarized by organ system class (SOC) and PT. A detailed patient list was obtained for TEAE, SAE, TEAE, associated TEAE, TEAE during study drug administration and discontinuation due to TEAE. Adverse changes from baseline in physical examination findings were classified as AEs and analyzed accordingly.

Vital signs were summarized descriptively at baseline and time points after baseline, and by change from baseline across the treatment group. Received lists of data on patients.

Changes in clinical chemistry, hematology, and urinalysis results from baseline to time points within the study after baseline were summarized descriptively by treatment group. Tables of shifts over time were presented for all central laboratory values, where applicable, using the ranking criteria from CTCAE v4.03. Received lists of patients with abnormal results.

Received data lists for ECG parameters by patient. Changes from baseline in electrocardiogram intervals (PR, RR, QT and QTcF) were presented by treatment group. The QT interval is corrected for heart rate using the Friederick formula (QTcF).

Abnormal immunogenicity findings, including incidence and titers of ADA against ALXN1210 or eculizumab, were summarized in a tabular format by treatment group. The proportion of patients ever positive and the proportion of patients always negative were analyzed.

Individual serum concentration data for all patients treated with at least 1 dose of study drug (i.e., ALXN1210 or eculizumab) and who had measurable PK data were used to derive PK parameters for ALXN1210 and eculizumab. Build graphs of profiles of the average concentration in serum depending on time. Serum concentration profiles versus time were also plotted for individual patients. The actual timing of dosing and sampling was used for all calculations. Descriptive statistics were calculated for serum concentration data at each sampling time point, as appropriate. Population PK estimates were considered using data from this study or in combination with data from other studies.

PD analyzes were performed on all patients who received at least 1 dose of ALXN1210 or eculizumab and had measurable PD data. Descriptive statistics were presented for all ALXN1210 and eculizumab PD endpoints at each sampling time point. The effects of PD of ALXN1210 and IV eculizumab were assessed by evaluating absolute values and changes, and percent change from baseline, for total serum C5 and free C5 serum concentrations, and cRBC hemolysis over time, as needed.

Example 2

Results of a randomized, open-label, phase 3, active drug-controlled study of ALXN1210 (ravulizumab) versus eculizumab in complement inhibitor-naive adult patients with PNH.

The following is a summary of the data from the current phase 3 open label clinical trial conducted according to the protocol described in Example 1 above. A summary of the results for efficacy and safety is presented below.

1. Generalization of the study.

This Phase III Human Clinical Trial was a randomised, open label, active drug controlled trial comparing non-inferiority of ALXN1210 versus Soliris® (eculizumab) in adult patients, for patients with PNH who were naïve to treatment using a complement inhibitor. The study enrolled a total of 246 patients. A total of 244 patients completed the study and were included in this per-protocol analysis. Only 2 subjects discontinued the study during the course of the study.

This Phase III study achieved its primary goal of showing that ALXN1210 (ravulizumab) was non-inferior to Soliris® (eculizumab). Specifically, the study achieved pre-assigned non-inferiority (NIM) limits for LDH normalization (LDH-N) and transfusion avoidance (TA), with values better than the 10% limits required by the FDA. In addition, less than 5% NIM is achieved at the TA endpoint. In addition, all 4 key secondary endpoints were shown to be superior to ALXN1210 and showed non-inferiority compared to Soliris® (eculizumab). For acute hemolysis (SHH), a quantitative trend towards ravulizumab advantage over eculizumab was also shown, with 4% vs. 10.7%, respectively, but it did not quite reach inclusion in the table in this study (p<0.074). The incidence of acute hemolysis was more than 2-fold higher in the Soliris® group than in the ALXN1210 group, and the difference was associated with suboptimal C5 inhibition in the Soliris® group, suggesting that AXLN1210 reduces the risk of acute hemolysis for the patient, through permanent complete inhibition of C5.

In sum, ravulizumab was not statistically significantly inferior to eculizumab for both joint primary and all key secondary endpoints: transfusion exclusions (73.6% vs 66.1%; difference 6.8% [95% CI, -4.7, 18, 1]), normalization of LDH (53.6% vs. 49.4%, odds ratio [1.19 (0.80, 1.77)]), percentage reduction in LDH (76.8% vs. 76.0%; difference [95% CI], -0.83% [-5.2, 3.6]), changes in FACIT fatigue score (7.1 vs 6.4; difference [95% CI], 0.67 [-1 .2, 2.6]), acute hemolysis (4.0% vs. 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68 .0% vs 64.5% difference [95% CI], 2.9 [-8.8, 14.6]). Importantly, the sensitivity analysis showed reliable results for all efficacy endpoints. The data are presented in the accompanying figures and tables and are discussed more fully below.

The non-inferiority study design comparing ALXN1210 and eculizumab is shown in FIG. 1. The study compared an individualized weight-based dosing regimen for ALXN1210 with an existing approved dosing regimen for eculizumab in PNH in an attempt to demonstrate non-inferiority in PNH patients naïve to complement inhibitor treatment. The dose selected for ALXN1210 is based on weight and includes a loading dose (2400 mg for patients >40 kg - <60 kg, 2700 mg for patients >60 kg -<100 kg, 3000 mg for patients >100 kg) on day 1, followed by maintenance doses of ALXN1210 (3000 mg for patients >40 kg - <60 kg, 3300 mg for patients >60 -<100 kg, 3600 mg for patients >100 kg) on day 15 and q8w thereafter. See fig. 1. In contrast, the eculizumab dose includes four induction doses of 600 mg on days 1,8, 15, and 22, followed by a maintenance dose of 900 mg administered IV on days 29 and every 2 weeks thereafter. See fig. 1.

The study enrolled more patients than originally planned. Specifically, 246 patients were enrolled in the study and randomized to either ALXN1210 or eculizumab. See fig. 2. A total of 39 subjects were not screened. Of the 246 patients to be included in the 26-week treatment period and completed, 243 were transferred to the current extension study. See fig. 2. Baseline characteristics and demographics for the study population are shown in FIG. 3.

All 246 treated patients (125 patients in the ALXN1210 arm and 121 patients in the eculizumab arm) are included in the FAS and safety populations as indicated in Table 1. 12. Two patients were excluded from the RR population. One patient in the ALXN1210 arm and 1 patient in the eculizumab arm met the protocol-specified criteria for pRBC transfusion (hemoglobin <7 g/dL), but were not transfused at this time or at any other time during the initial evaluation period. Although other patients were eligible for transfusion at a particular examination but did not receive a transfusion, these patients are included in the RR population because they received at least 1 transfusion according to the criteria for transfusion.

Table 12

Populations for data analysis (all randomized patients)

ALXN1210, η (%) Eculizumab, n(%) Total, η (%) Number of randomized patients 125(100) 121 (100) 246(100) Number of patients in FAS 125(100) 121 (100) 246(100) Number of patients excluded from FAS 0 0 0 Number of patients in the RR population 124 (99.2) 120 (99.2) 244 (99.2) Number of patients excluded from the RR population 1 (0.8) 1 (0.8) 2 (0.8) Number of patients in the safety population 125 (100) 121 (100) 246(100) Number of patients excluded from the safety population 0 0 0 Number of patients in the population for PK analysis 125(100) 121 (100) 246(100) Number of patients excluded from the population for PK analysis 0 0 0

Abbreviations: PA8=complete population for analysis; PP = according to the protocol. There was no difference in actual stratification at time of randomization compared to observed stratification for the LDH groups (LDH 1.5 - < 3 x ULN vs. LDH > 3 x ULN) (see Table 13). Of the 44 patients stratified for 0 pRBC units, 1 patient was observed to receive 1-14 pRBC unit(s). Of 157 patients stratified for 1-14 pRBC unit(s), 3 patients were observed to receive >14 pRBC units. Of 45 patients stratified for >14 pRBC units, 1 patient was observed to receive 1-14 pRBC unit(s).

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Table 13

Stratification groups at randomization and observation (complete population for analysis)

Variable ALXN1210 (N=125) Eculizumab (N=121) Total (N=246) LDH stratification groups at randomization, η (%) 1.5-<3xULN 18 (14.4) 16(13.2) 34(13.8) >3><ULN 107 (85.6) 105 (86.8) 212 (86.2) Observed LDH stratification groups, η (%) 1.5-<3xULN 18 (14.4) 16(13.2) 34(13.8) >3xULN 107 (85.6) 105 (86.8) 212 (86.2) Stratification groups pRBC at randomization, η (%) 0 units 23 (18.4) 21 (17.4) 44 (17.9) 1-14 units 79 (63.2) 78 (64.5) 157 (63.8) >14 units 23 (18.4) 22(18.2) 45(18.3) Observed stratification groups pRBC, η (%) 0 units 22(17.6) 21 (17.4) 43 (17.5) 1-14 units 80 (64.0) 76 (62.8) 156 (63.4) >14 units 23 (18.4) 24 (19.8) 47(19.1) Overall stratification grouping at randomization, η (%) pRBC=0 units, and LDH=1.5 - < 3xULN 9 (7.2) 8 (6.6) 17 (6.9) pRBC=l-14 units, and LDH=1.5 - < 3xULN 6 (4.8) 6 (5.0) 12 (4.9) pRBC > 14 units, and LDH=1.5 - < 3xULN 3 (2.4) 2(1.7) 5 (2.0) pRBC=0 units, and LDH > 3xULN 14(11.2) 13 (10.7) 27(11.0) pRBC=l-14 units, and LDH > 3xULN 73 (58.4) 72 (59.5) 145 (58.9) pRBC >14 units, and LDH > 3xULN 20(16.0) 20 (16.5) 40(16.3) Observed total stratification grouping, η (%) pRBC=0 units, and LDH=1.5 - < 3xULN 8 (6.4) 8 (6.6) 16 (6.5) pRBC=l-14 units, and LDH=1.5 - < 3xULN 7 (5.6) 6 (5.0) 13 (5.3) pRBC > 14 units, and LDH=1.5 - < 3xULN 3 (2.4) 2(1.7) 5 (2.0) pRBC=0 units, and LDH > 3xULN 14(11.2) 13 (10.7) 27(11.0) pRBC=l-14 units, and LDH > 3xULN 73 (58.4) 70 (57.9) 143 (58.1) pRBC >14 units, and LDH > 3xULN 20(16.0) 22(18.2) 42(17.1)

Note: Baseline was defined as the last non-missing value prior to the first dose of study drug. The ULN for LDH is 246 U/L.

Abbreviations: LOH=lactate dehydrogenase; pFBC=erythrocyte mass; ULK=upper limit of normal.

Baseline disease characteristics were similar between the 2 treatment groups (Table 14). In the general population, the median time from diagnosis of PNH to informed consent was 6.6 years (median = 3.9 years).

All patients had a PNH diagnosis confirmed by flow cytometry at screening. The mean overall RBC clone size at PNH was 38.57%; the average total granulocyte clone size at PNH was 84.74%, and the average total monocyte clone size at PNH was 87.99%.

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Table 14

Disease characteristics (total population for analysis)

Variable category ALXN1210 (Ν=125) Eculizumab (Ν=121) Total (N=246) Age (years) at time of diagnosis PNH η Average (SD) Median Min, Max 123 37.9 (14.90) 34.0 15, 81 118 39.6 (16.65) 36.5 13, 82 241 38.7(15.77) 35.0 13, 82 Method of initial diagnosis PNH, η (%) Flow cytometry Ham test Sucrose hemolysis test Other ^a 94 (75.2) 10 (8.0) 0 (0.0) 21 (16.8) 96 (79.3) 5 (4.1) 2(1.7) 18(14.9) 190 (77.2) 15 (6.1) 2 (0.8) 39 (15.9) Years from diagnosis to informed consent η Average (SD) Median Min, max 123 6.7 (8.14) 3.8 0.41 118 6.4 (7.54) 3.9 0.34 241 6.6 (7.84) 3.9 0.41 Clone size at ΡΝΗ at the starting point Type II RBC clone size at ΡΝΗ (%) η Average (SD) 124 12.36 (20.539) 120 13.70 (17.672) 244 13.02(19.155) Median Min, max 4.00 0.1, 99.5 6.15 0.1.95.3 5.00 0.1.99.5 Clone size RBC type III pi ΡΝΗ (%) η Average (SD) Median Min, max 124 26.29 (17.246) 26.35 0.1, 82.0 120 25.21 (16.944) 21.20 0.4, 75.6 244 25.76 (17.071) 24.10 0.1, 82.0 Total RBC clone size at ΡΝΗ (%) η Average (SD) Median Min, max 125 38.40 (23.748) 33.60 3.0, 99.6 121 38.74 (23.194) 34.20 2.2, 98.0 246 38.57 (23.430) 33.75 2.2, 99.6 Total clone size of granulocytes at ΡΝΗ (%) η Average (SD) Median Min, max 125 84.22 (20.956) 93.80 4.2, 99.9 121 85.28 (18.977) 92.40 8.0, 100.0 246 84.74 (19.973) 92.55 4.2, 100.0 Total clone size of monocytes at ΡΝΗ (%) η Average (SD) Median Min, max 125 86.86 (18.078) 94.00 8.5, 99.9 121 89.15 (15.189) 95.10 17.0, 99.9 246 87.99 (16.725) 94.80 8.5, 99.9

Note: Total size of RBC clone, granulocytes, monocytes = sum of sizes of type II and type III RBC clones, granulocytes, monocytes respectively. Baseline was defined as the last non-missing value prior to the first dose of study drug.

Another category included Coombs' test, Flaer's test, clinical signs/symptoms (i.e., clinical findings, presentation, or diagnosis), immunophenotyping, combination of methods used for diagnosis, osmotic fragility test, diagnosis at another hospital, and unknown.

Abbreviations: max=maximum; min=minimum; SD=standard deviation; PNH=paroxysmal nocturnal hemoglobinuria; RBC=erythrocyte.

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Enrollment in the previous administration stratum of 0 RBC units was closed when the protocol-specified 20% enrollment limit for patients without a history of transfusions in the previous year was reached. Thus, the majority of patients (82.5%) had a history of pRBC transfusions within a year prior to the first dose of study drug, as shown in Table 1. 15. In the general population, there were an average of 6.2 transfusions of pRBC/whole blood, and an average of 8.8 units were administered via transfusion during the 12 months prior to the first dose. The number of transfusions and the number of units administered via transfusion were similar between the 2 treatment groups.

Table 15

RBC transfusions within 12 months prior to first dose (complete population for analysis)

Variable Category ALXN1210 (Ν=125) Eculizumab (Ν=121) Total (N=246) Number of patients with pRBC/whole blood transfusions within 12 months prior to first dose, η (%) 103 (82.4) 100 (82.6) 203 (82.5) pRBC/whole blood transfusions within 12 months prior to first dose Total Average (SD) Median Min, Max 677 6.6 (6.04) 4.0 1.28 572 5.7 (5.53) 3.0 1.28 1249 6.2 (5.80) 4.0 1.28 Units of pRBC/whole blood transfused within 12 months prior to first dose Total Average (SD) Median Min, Max 925 9.0 (7.74) 6.0 1.44 861 8.6 (7.90) 6.0 1.32 1786 8.8 (7.81) 6.0 1.44

Abbreviations: max=maximum; min=minimum; pRBC=erythrocyte mass; SD=standard deviation.

As required by the protocol, all patients had at least 1 PNH-associated symptom at baseline. The types of PNH symptoms experienced by patients prior to informed consent were similar between treatment groups, with the most common (>20% of all patients) being fatigue or asthenia (general weakness), red or dark urine, shortness of breath (dyspnea), biliary spillage ( yellowing of the skin or eyes), abdominal pain, and CNS-related symptoms such as headache, dizziness, or difficulty concentrating.

In the general population, 98.0% of patients had documented PNH-associated conditions diagnosed prior to informed consent, as shown in Table 1. 16. Most (84.6%) patients 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

PNH-associated conditions diagnosed at any time prior to informed consent (full population for analysis)

ΡΝΗ-associated states, n(%) ALXN1210 (Ν=125) Eculizumab (Ν=121) Total (N=246) Patients with any associated 121 (96.8) 120 (99.2) 241 (98.0) with ΡΝΗ states up to informed consent Anemia 103 (82.4) 105 (86.8) 208 (84.6) Hematuria or hemoglobinuria 81 (64.8) 75 (62.0) 156 (63.4) aplastic anemia 41 (32.8) 38(31.4) 79 (32.1) kidney failure 19(15.2) 11(9.1) 30(12.2) myelodysplastic syndrome 7 (5.6) 6 (5.0) 13 (5.3) Complication during pregnancy 3 (2.4) 4 (3.3) 7 (2.8) Other ^a 27 (21.6) 13 (10.7) 40(16.3)

Note: Patients can be counted in more than one category.

^a The other category included the most frequently (n>2) reported conditions in the other category that had a history of at least 1 other PNH-associated condition, including thrombocytopenia (n=5), chronic renal failure (n=4), pancytopenia (n=3), elevated AST (n=2), renal parenchymal disease (n=2), leukopenia/thrombocytopenia (n=2), gallstones (n=2), and for 1 patient each history of hepatosplenomegaly, myeloid and megakaryocytic hypoplasia, hemolytic event, bone marrow hypocellularity, pancytopenia, bone marrow hypoplasia, signs of hemolysis, chronic

- 54 043233 hemolysis, bilateral renal parenchymal disease / hypokalemia, suspected aplastic anemia, miscarriage, ischemic stroke / chronic renal failure, bone marrow hyperplasia, thrombocytopenia / epistaxis, increased bilirubin, bone marrow aplasia or leukopenia / thrombocytopenia / splenectomy.

Abbreviation: PNH=paroxysmal nocturnal hemoglobinuria.

All 246 patients had a history of prior drug use. All patients received the meningococcal vaccine no later than day 1. The most commonly reported (>10% of patients) prior drug groups other than meningococcal vaccine were vitamin B12 and folic acid (52.8%), antithrombotics (29, 7%), systemic corticosteroids (24.8%), drugs for peptic ulcer and gastroesophageal reflux disease (22.8%), iron preparations (15.4%), beta-lactam antibacterials (penicillins) (15.0%), antihistamines for systemic use (13.0%), selective calcium channel blockers with major vascular effects (11.4%) and other analgesics and antipyretics (11.0%).

In total, 95.9% of patients (98.4% in the ALXN1210 group and 93.4% in the eculizumab group) received at least one concomitant drug. The most commonly reported (>10% of patients) antecedent groups were vitamin B12 and folic acid (54.9%), other analgesics and antipyretics (38.6%), beta-lactam antibacterials (penicillins) (38.6 %), antithrombotics (31.3%), drugs for peptic ulcer and gastroesophageal reflux disease (29.3%), quinolone antibacterials (26.0%), antihistamines for systemic use (24.8% ), systemic corticosteroids (24.4%), anti-inflammatory and antirheumatic agents (21.1%), iron preparations (17.1%), other beta-lactam antibacterials (13.0%), expectorants, excluding combinations with cough suppressants (11.4%), selective calcium channel blockers, mainly for vascular events (12.6%), and immunosuppressants (10.2%). During the study, only 30.9% of patients underwent a non-pharmacological medical procedure.

2. Primary/secondary endpoints and disease-related parameters.

The two co-primary efficacy endpoints of transfusion avoidance (TA) and LDH normalization (LDH-N) had very clear agreement and superiority as shown in FIG. 4. The red triangle in FIG. 4 denotes the FDA's limit of non-inferiority. Both endpoints, TA and LDH-N, significantly exceeded the 20% non-inferiority limits. In fact, the TA endpoint didn't just meet the 20% limit, it met the 5% limit. Similarly, LDH-N exceeded the 20% limit, and further satisfied the equivalent of the 10% limit. See fig. 4.

The key secondary endpoints, percent change in LDH (LDH-PCHG), change in FACIT fatigue scores, acute hemolysis (HTH), and hemoglobin stabilization (HGB-S) were also positive and showed a benefit of ALXN1210 compared to eculizumab. See fig. 5. Moreover, all secondary endpoints not only showed the benefit of ALXN1210, but they all significantly exceeded the limits of non-inferiority shown by the red triangles in the graph. See fig. 5.

Key primary and secondary endpoints are presented in tabular form in FIG. 6. The benefit of the treatment effect for each endpoint for ALXN1210 was also shown over the effect for eculizumab. For example, the first row shows that the treatment effect for avoiding transfusions for ALXN120 compared to eculizumab was 6.8%, far greater than the required non-inferiority margin of -20%, and presents the discovery of a non-inferiority drug. Similarly, all primary and secondary endpoints led to the same conclusion of non-inferiority of ALXN1210 compared to eculizumab. In other words, ALXN1210 was found to be superior to eculizumab, but the sample size was insufficient to reach a statistical conclusion of superiority. See fig. 6.

The efficacy data for this study were subjected to a variety of different sensitivity analyses. The results are shown in FIG. 7. For example, the treatment effect (point estimate) for 1210 was 6.8% better than for eculizumab, with a 95% confidence interval (CI) of -4.7-18.1%. The number -4.7% is significantly better than the pre-defined limit of no less efficiency -20%. This table shows a variety of sensitivity assays that all support robust primary assay detections. It is worth noting that this consistency is unusual for clinical studies of this type and supports the idea that this study was of very high quality.

The efficacy results for the primary endpoint of LDH-N were analyzed in the form of subgroups of the patient population and are shown in FIG. 8. LDH-N (lactate dehydrogenase normalization) refers to LDH levels less than or equal to 1xULN from day 29 to day 183. Subgroup analyzes for

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LDH-N found that stronger evidence showed a benefit for ALXN1210. Gray lines are 95% confidence intervals and blue squares are point estimates. The evaluation was based on the General Estimating Equations (GEE) method. The model included the following terms: treatment group, history of transfusions, and baseline LDH levels. The scores to the right of 1 show the benefit of ALXN1210 and the scores to the left show the benefit of eculizumab. All point estimates were to the right of a predefined limit of non-inferiority (red triangle) (-20%). There were only 3 endpoints showing the benefit of eculizumab that were not there, and two of them had a small sample size. In conclusion, ALXN1210 is clearly superior to eculizumab for most subgroups. See fig. 8.

As shown in FIG. 9, mean values for LDH normalized in the patient population to the upper limit of normal (1 x ULN LDH) from about day 22 to day 24 and remained at this level throughout the study. The dotted line in Fig. 9 shows the value of the upper limit of normal for LDH or 1x ULN LDH. The box below the graph shows the number of patients in each group, which contributes to that day's average. In conclusion, it is clear that the mean LDH in patients treated with ALXN1210 remained below the critical level of 1.5x ULN. See fig. 9.

The time to reach LDH normalization is shown in FIG. 10 for both ALXN1210 and eculizumab treatment groups. Patients treated with ALXN1210 achieved normalization approximately 5 days sooner than patients treated with eculizumab. See fig. 10. Mean of the number of patients treated with ALXN120 reached normalization on day 24 versus day 29 for patients treated with eculizumab. The box with numbers below the graph for LDH patients from each group was used to calculate the average for that day. See fig. 10.

The percentage of patients who achieved LDH normalization at various time points during the course of the study is shown in FIG. 11. In general, more than 50% of patients treated with ALXN120 remained in the normal range throughout the study, while less than 50% of eculizumab-treated patients remained in the normal range during the study and up to day 183. See FIG. eleven.

In addition, at baseline, mean scores on the EORTC QLQ-C30 general health subscale were 56.13 for the ALXN1210 group and 57.51 for the eculizumab group. An improvement of >10 points on the 3 EORTC QLQ-C30 subscales, general health, functional status, and EORTC fatigue, is considered an indicator of clinically significant improvement (King, 1996; Osoba, 1998). A higher percentage of patients in the ALXN1210 group had an improvement of at least 10 points on the EORTC QLQ-C30 subscales, general health, functional status, and fatigue on Day 29 and throughout the initial evaluation period, compared to the eculizumab group, as shown in FIG. . 12, 13 and 14.

3. Safety.

There were no notable safety differences for observed adverse events (AEs) or serious adverse events (SAEs) between patients treated with ALXN1210 and eculizumab. See fig. 15 and 16. In addition, there were no meningococcal infections, terminations due to AE, and deaths observed during the initial evaluation period. See fig. 17 and 18. The most common AE was headache in 35%. See fig. 16.

A history of one or more MAVEs was recorded in only 17.1% of patients, as indicated in Table 1. 17.

Table 17 History of major adverse vascular events (complete population for analysis)

Category MAVE ALXN1210 (N=125) Eculizumab (N=121) Total (N=246) Patients with a history of MAVE 17(13.6) 25 (20.7) 42(17.1) Thrombophlebitis / deep vein thrombosis 4 (3.2) 8 (6.6) 12 (4.9) Hepatic/portal vein thrombosis (Budd-Chiari syndrome) 4 (3.2) 4 (3.3) 8 (3.3) Cerebral artery occlusion/acute cerebrovascular accident 4 (3.2) 2(1.7) 6 (2.4) Thrombosis or infarction of mesenteric/visceral veins 3 (2.4) 2(1.7) 5 (2.0)

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Cerebral vein occlusion 1 (0.8) 3 (2.5) 4(1.6) Pulmonary embolism 0 4 (3.3) 4(1.6) Dermal thrombosis 2(1.6) 1 (0.8) 3 (1.2) myocardial infarction 0 3 (2.5) 3 (1.2) Acute peripheral vascular occlusion 1 (0.8) 1 (0.8) 2 (0.8) thrombosis or infarction mesenteric/visceral arteries 0 2(1.7) 2 (0.8) Transient ischemic attack 1 (0.8) 1 (0.8) 2 (0.8) Amputation (non-traumatic; non-diabetic) 0 0 0 Gangrene (non-traumatic; non-diabetic) 0 0 0 Thrombosis of the renal arteries 0 0 0 Thrombosis of the renal veins 0 0 0 Unstable angina 0 0 0 Other 0 2(1.7) 2 (0.8)

Note: Patients can be counted in more than one category.

Abbreviation: MAVE=major adverse vascular event.

There was one case of treatment-induced anti-drug antibody (ADA) formation observed for each of ALXN1210 and eculizumab. In no case did neutralizing antibodies form and there was no effect on PK, PD, efficacy or safety of these apparently transient ADAs.

Fig. 15 is a tabular presentation of the key safety results in the ALXN1210-PNH-301 phase III clinical study.

Patient compliance with the drug regimen was nearly perfect for this clinical study, as shown in FIG. 19. There was only one case of patient non-compliance in the eculizumab group, as shown in FIG. 19.

4. Pharmacokinetic results.

The mean (± SD) serum concentration profile of ALXN1210 and eculizumab versus time for the respective treatment groups (linear scale) is shown in FIG. 20. The mean (± SD) serum concentration profile of ALXN1210 and eculizumab versus time for the respective treatment groups (semi-log scale) is shown in FIG. 21.

Pharmacokinetic parameters for ALXN1210 are summarized in Table 1. 18 and tab. 19 for the first (induction) and last (maintenance) doses, respectively. The geometric mean (geometric CV%) C _max and C _min of ALXN1210 after the first dose in all patients was 753.7 (22.45) and 376.44 (26.17) µg/mL, respectively. After the last dose of ALXN1210, the geometric mean (%CV) of _Cmax and _Cmin in all patients was 1350.5 (20.8) and 446.1 (36.2) µg/mL, respectively.

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Table 18

Pharmacokinetic parameters of ALXN1210 (C _max and C _min ) after the first (loading) dose of ALXN1210 (PK assay population)

Parameter Statistics All patients (N=125) > 40 - < 60 kg (N=41) > 60 - < 100 kg (N=79) > 100 kg (N=5) With ^max (µg/ml) Average 771.4 846.7 740.3 645.0 SD 165.89 174.34 146.62 181.25 cv% 21.51 20.59 19.80 28.10 Median 761.0 846.0 736.0 656.0 Minimum 403 470 414 403 Maximum 1310 1160 1310 905 Geometric mean 753.7 828.6 726.2 623.9 Geometric CV% 22.45 21.60 20.99 29.96 Cmin (µg/ml) Average 391.21 424.15 377.8 333.6 SD 136.774 116.191 146.30 93.26 cv% 34.96 27.39 38.73 27.96 Median 358.00 412.00 351.0 308.0 Minimum 199.0 199.0 257 252 Maximum 1500.0 775.0 1500 482 Geometric mean 376.44 409.51 363.8 324.2 Geometric CV% 26.17 27.30 24.56 26.71

Abbreviations: C _max = maximum serum concentration; C _min =minimum serum concentration; CV=coefficient of variation; SD=standard deviation.

Table 19

Pharmacokinetic parameters of ALXN1210 (C _max and C _min ) after the last maintenance dose of ALXN1210 (PK assay population)

Parameter Statistics All patients (N=124) > 40 - < 60 kg (N=41) > 60 - < 100 kg (N=77) > 100 kg (N=6) with ^max (µg/ml) Average 1378.5 1528.8 1292.9 1450.0 SD 275.94 279.47 242.83 219.00 cv% 20.02 18.28 18.78 15.10 Median 1365.0 1520.0 1280.0 1365.0 Minimum 780 909 780 1260 Maximum 2100 2100 1790 1790 Geometric mean 1350.5 1502.8 1269.6 1436.9 Geometric CV% 20.80 19.17 19.63 14.63 Cmin (µg/ml) Average 472.7 548.3 438.8 391.8 SD 157.94 167.99 139.25 143.75 cv% 33.41 30.64 31.74 36.69 Median 463.5 538.0 433.0 353.5 Minimum 135 257 135 250 Maximum 1000 1000 790 579 Geometric mean 446.1 524.0 415.5 370.8 Geometric CV% 36.22 31.47 35.61 37.44

Abbreviations: Cmax=maximum serum concentration; Cmin=minimum serum concentration; CV=coefficient of variation; SD=standard deviation.

Non-compartmental PK parameters were measured only for the ALXN1210 group. Results after the last maintenance dose of ALXN1210 are shown in Table 1. 20. PK ALXN1210 at equilibrium was obtained after administration of multiple doses, for all maintenance doses on a weight basis (Table 21).

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Table 20

Summary of non-compartmental analysis of pharmacokinetic parameters of ALXN1210 after the last maintenance dose of ALXN1210 (PK assay population)

All patients (N=124) > 40 - < 60 kg (N=41) > 60 - < 100 kg (N=77) > 100 kg (N=6) RK parameter (units) Mean±8P (%CV) Mean±8P (%CV) Mean±8P (%CV) Mean±8P (%CV) 1max (hour) 2.5 (2.0, 335.8) 2.75 (2.4, 309.1) 2.3 (2.0, 335.8) 2.6 (2.3, 2.9) With '-Max (µg/ml) 1378.5±275.9 (20.0) 1528.8±279.5 (18.3) 1292.9±242.8 (18.8) 1450.0±219.0(15.1) C MIN (mcg/ml) 472.7±157.9 (33.4) 548.3±168.0 (30.6) 438.8±139.25 (31.7) 391.8±143.75 (36.7) AUC _T (hour mcg/m l) 1007169.4±237539.3 (23.6) 1148146.3±235621.5 (20.5) 939779.2±205402.5 (21.9) 908666.7±240977.7 (26.5) CL (ml/hour) 2.0±0.8 (41.6) 1.5±0.5 (34.3) 2.2±0.9 (38.9) 2.5±0.9 (36.6) _Vz (ml) 2989.4±715.0 (23.9) 2494.8±568.0 (22.8) 3194.7±646.0 (20.2) 3653.3±691.1 (18.9)

Note: Mean elimination half-life cannot be reliably estimated due to continuous therapeutic maintenance dosing.

a t _max values are presented as median (minimum, maximum). Abbreviations: AUC _τ = area under the serum concentration-time curve over the dosing interval; C _max = maximum observed serum concentration; C _min = concentration at end of dosing interval; CL=total clearance; CV=coefficient of variation; SD=standard deviation; t _max = time to maximum observed serum concentration; V _z =volume of distribution at equilibrium.

Table 21

ALXN1210 PK Equilibrium Assessment (PK Assay Population)

Achieving a state of equilibrium Maintenance dose in mg (body weight group) Tilt angle Lower 95%C1 Upper 95%C1 Has a state of equilibrium been reached? Days 15, 71, 127, 183 3000 (> 40 - < 60 kg) 0.00007432 -0.00010259 0.00025123 Yes Day 15, 71, 3300 (> 60 - < 100 0.00000884 -0.00008491 0.00010259 Yes 127, 183 kg) Days 15, 71, 127, 183 3600 (> 100 kg) 0.00001494 -0.00026602 0.00029591 Yes Days 15, 71, 127, 183 All patients 0.00001751 -0.00007316 0.00010817 Yes

Abbreviations: O=confidence interval.

5. Pharmacodynamic results.

Treatment with ALXN1210 resulted in immediate, complete and sustained inhibition of complement component C5 over the entire 8 week dosing interval. See fig. 19. Weight-based dosing every 8 weeks resulted in maximum exposure at equilibrium and minimum exposure as shown in FIG. 19.

In table. 22 summarizes the mean percent change from baseline in free C5 serum concentrations following treatment with ALXN1210 (dose based on q8w weight) or eculizumab (900 mg q2w). Some samples of free C5 were excluded because they were considered biologically implausible. Exclusions were confirmed using paired PK data, as samples for PK and free C5 were collected at the same blood draw. These exceptions were as follows: ALXN1210 group: for 3 (2.4%) patients, on day 1 free C5 samples at the end of the infusion had values similar to pre-treatment values. Eculizumab arm: For 3 (2.5%) patients, on day 1 free C5 samples were below the pre-treatment limit of quantitation (BLQ); for 5 (4.1%) patients, on day 1 free C5 samples at EOI had values similar to those before treatment.

The mean serum concentration of free C5 as early as at the end of the first infusion and at all subsequent troughs was <0.5 μg/mL in the ALXN1210 group. This threshold was not consistently observed in the eculizumab group. In addition, more individual free C5 values above the target free C5 threshold of 0.5 µg/ml were noted in the eculizumab group than in the ALXN1210 group. This disequilibrium in free C5 control appears to be responsible for the differences noted in acute hemolysis events between treatment groups (ALXN1210: n=5, eculizumab: n=15).

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Table 22

Mean free C5 serum concentration and number (percentage) of patients with free C5 serum concentration > 0.05 µg/mL over time (complete analysis population)

Inspection ^a ALXN1210 Eculizumab η Mean serum concentration of free C5, mcg/ml n(%) of patients with free C5 serum concentration > 0.5 µg/mL η Mean serum concentration of free C5, mcg/ml n(%) of patients with serum free C5 > 0.5 µg/mL Day 1 122 0.01 0 114 0.01 10 (8.62) Day 8 120 0.04 0 116 3.60 1 (0.85) Day 15 125 0.05 0 117 0.28 0 Day 22 124 0.03 0 117 0.05 0 Day 29 125 0.03 0 116 0.05 0 Day 43 125 0.04 0 116 0.05 1 (0.87) Day 57 124 0.05 0 115 0.26 2 (1.74) Day 71 125 0.06 0 115 0.76 1 (0.88) Day 85 124 0.03 0 114 0.18 3 (2.61) Day 99 124 0.04 0 115 0.70 2 (1.74) Day 113 124 0.05 0 115 0.22 2 (1.72) Day 127 124 0.06 0 116 0.29 1 (0.86) Day 141 125 0.04 0 116 0.15 4 (3.45) Day 155 125 0.05 0 116 0.53 4 (3.48) Day 169 123 0.06 0 115 0.94 5(4.31) Day 183 125 0.07 0 116 3.00 10 (8.62)

Mean free C5 levels were more than 99% inhibited by the end of the first ALXN1210 infusion and remained more than 99% inhibited throughout the treatment period in the study. In contrast, free C5 levels did not remain more than 99% inhibited at all time points in the eculizumab group (see FIG. 22).

Overall C5 levels were similar for both ALXN1210 and eculizumab groups. The mean (±95% CI) percent change from baseline for the profile of total serum C5 over time is shown in FIG. 23. The rate and range of change in total serum C5 were similar between treatments. Baseline was defined as the last non-missing score prior to the first dose of study drug. l shows that data for day 1 referred to the end of the infusion, while on days 8, 22, 29, 43, 57, 85, 99, 113, 141, 155 and 169, data were obtained at any time for the ALXN1210 group and before dosing for the eculizumab group; on days 15, 71 and 127, data were obtained before dosing for both treatment groups; and on day 183, data were obtained at the end of the randomized treatment period for both treatment groups.

Example 3

Multicenter Phase 3, single arm study for ALXN1210 in complement inhibitor-naive adult patients with atypical hemolytic uremic syndrome (aHUS).

A single arm study of ALXN1210 (ALXN1210 aHUS 311) is performed on complement inhibitor-naive adult and adolescent patients with atypical hemolytic uremic syndrome (aHUS).

aHUS is a thrombotic microangiopathy (TMA) most commonly caused by mutations in genes encoding proteins involved in the alternative complement pathway (APC) or by autoantibodies against APC-regulating proteins (Noris, et al., Clin. J. Am. Soc. Nephrol. 2010;5:184459). Patients with aHUS are at risk for life-threatening disease manifestations resulting from endothelial injury, including thrombocytopenia, intravascular hemolysis, acute renal failure, and damage to extrarenal tissues. Importantly, approximately 20% of patients experience extrarenal disease manifestations, including involvement of the central nervous system, heart, GI, distal extremities, and severe systemic organ damage (Loirat, et al., Orphanet J. Rare Dis. 2011;6:60 and Brodsky, Blood 2015;126:2459-65). Prior to the availability of eculizumab, mortality rates among patients with aHUS were as high as 15% during the acute phase of disease progression (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 experienced progression to end-stage kidney disease (ESKD), often within one year of onset, and required dialysis or a kidney transplant to sustain life. Chronic, uncontrolled activation of the terminal complement complex, specifically the activation of complement component 5 (C5) and dysregulation of complement activity, is central to the pathogenesis of aHUS and the debilitating manifestations of this disease. As a result, targeted blocking of C5, with selective inhibition of C5a and C5b 9 formation, represents an important therapeutic treatment mechanism.

1. Goals.

The primary aim of the study was to evaluate the efficacy of ALXN1210 in complement inhibitor-naive adolescent and adult patients with aHUS to inhibit complement-mediated TMA as characterized by thrombocytopenia, hemolysis, and liver injury.

The secondary objectives of the study were (1) to characterize the safety and tolerability of ALXN1210 in this patient population, (2) to evaluate the efficacy of ALXN1210 through additional measures (e.g., dialysis need status, time to complete TMA response, TMA complete response status over time, observed value, and change from baseline in estimated glomerular filtration rate (eGFR), stage of chronic kidney disease (CKD) (as assessed on selected target days and classified as improved, stable (no change), or worsened from baseline), observed value and a change from baseline in hematological parameters (platelets, LDH, hemoglobin), an increase in hemoglobin > 20 g/l from baseline (maintained for at least 2 consecutive measurements taken at least 4 weeks apart), change , compared to baseline, quality of life (QoL) (as measured by EuroQol in 5 categories across 3 levels (EQ-5D-3L; all patients), the Functional Assessment of Chronic Disease Therapy (FACIT) Fatigue Scale Version 4 (patients > 18 years of age), and the FACIT Pediatric Fatigue Scale (patients < 18 years of age))), (3) characterization of PK/ pharmacodynamics (PD) of ALXN1210 by changes in serum concentration of ALXN1210 over time and changes in free C5 concentration over time, and (4) assessing the long-term safety and efficacy of ALXN1210.

2. Endpoints.

The primary efficacy endpoint of the study is a complete TMA response during the 26-week baseline period, as evidenced by normalization of hematological parameters (platelet count and LDH) and >25% improvement in serum creatinine from baseline, and confirmed by 2 consecutive measurements obtained with at least 4 weeks apart.

The secondary efficacy endpoints of the study were as follows:

A. Dialysis need status;

B. Time to complete TMA response;

C. TMA complete response status over time;

D. Observed value and change from baseline in eGFR;

E. CKD stage as assessed by the investigator on the selected target day and classified as improved, stable (no change), or worsened from baseline;

F. Observed value and change from baseline in hematological parameters (platelets, LDH, hemoglobin);

G. An increase in hemoglobin level > 20 g/l from baseline, maintained for at least 2 consecutive measurements taken at least 4 weeks apart;

H. Change from baseline QoL as measured by EQ-5D-3L (all patients), FACIT Fatigue Scale Version 4 (patients > 18 years of age), and FACIT Pediatric Fatigue Scale (patients < 18 years of age).

The pharmacokinetic (PK) and pharmacodynamic (PD) endpoints of this study are changes in serum concentration of ALXN1210 over time and changes in free C5 concentration over time.

The safety and tolerability of ALXN1210 is assessed through physical examinations, vital signs, electrocardiograms (ECGs), laboratory evaluations, and the incidence of AEs and SAEs. The proportion of patients who develop anti-drug antibodies (ADA) is also assessed.

Target biomarkers of the effect of PD include, but are not limited to, change from baseline in markers of complement dysregulation (eg, factor Ba), vascular inflammation (eg, soluble tumor necrosis factor receptor 1 [sTNFR1]), endothelial activation/damage ( for example, soluble vascular endothelial adhesion molecule 1 [sVCAM1], thrombomodulin), blood clotting (eg, D-dimer), and kidney injury (eg, cystatin C). Additional assessments may include measurements of ALXN1210 urinary excretion, chicken erythrocyte hemolysis (cRBC), total C5, autoantibodies against complement proteins (eg, against factor H), and APC activity (eg, modified Ham test, complement deposition assays).

Exploratory genetic studies can be conducted to investigate genetic variants in genes known to be associated with aHUS, as well as to identify new genetic variants associated with aHUS, complement dysregulation, or ALXN1210 metabolism or efficacy. Patients may choose not to provide a sample for exploratory genetic testing and still participate in the study.

3. Summary of study design.

The ALXN1210 aHUS 311 study is an open-label, multicenter, phase 3, single arm study to evaluate the safety and efficacy of ALXN1210 given by intravenous (IV) infusion in adolescent (aged 12-<18 years) and adult (aged >18 years) patients. years) with aHUS. The study enrolled approximately 55 patients for ALXN1210 administration. Fig. 24 illustrates the study design. All patients are naïve to complement inhibitor treatment and include at least 6 and up to 10 adolescent patients (aged 12 to <18 years at screening) and at least 10 and up to 25 patients with prior kidney transplantation.

The study consists of a screening period of up to 7 days, a 26-week initial evaluation period, and an extension period of up to 2 years. Doses are based on the patient's last recorded body weight at the study visit (Table 27). Patients are given a loading dose of ALXN1210 IV (2400 mg for patients weighing >40-<60 kg, 2700 mg for patients weighing >60-<100 kg, 3000 mg for patients weighing >100 kg) on Day 1, followed by maintenance doses of ALXN1210 IV (3000 mg for patients weighing >40-<60 kg, 3300 mg for patients weighing >60-<100 kg, 3600 mg for patients weighing >100 kg) on Day 15 and once every 8 weeks (q8w) thereafter for for a total of 26 weeks of treatment. After the Initial Evaluation period, patients are moved into an expansion period and given ALXN1210 until the product is registered or approved (according to country-specific guidelines), or for up to 2 years, whichever comes first. The end of the study is defined as the last examination of the last patient.

This is an open-label, phase 3, single arm study evaluating the safety and efficacy of treatment using ALXN1210. Although no formal comparison analyzes are planned for this study, the results for ALXN1210-treated patients are evaluated in the context of the results observed in the historical control group of patients treated with eculizumab. The historical control group contains patients with aHUS who were treated with eculizumab in prospective drug registration studies C08 002A/B, C10 003 and C10 004 for whom the study design and accompanying features of interest that may influence the effect size were similar with current research. In addition, the control group is limited to patients aged >12 years and with PE/PI for 4 weeks or less on prior eculizumab treatment, to further meet inclusion criteria for the current study.

The assessment schedule for the screening and initial assessment period is shown in Table 1. 23. The schedule of assessments for the expansion period is shown in Table. 24. Additional (off-schedule) examinations outside of these examinations are permitted at the discretion of the investigator. Procedures, tests and evaluations are at the discretion of the investigator. Any tests, procedures, or assessments performed during out-of-schedule visits are recorded on the Electronic Clinical Study Participant Record (eCRF). Laboratory analysis in a local laboratory or in a central laboratory is used for tests at out-of-schedule visits. However, if it is necessary to use tests in a local laboratory, duplicate samples are collected for testing at off-schedule examinations at the central laboratory.

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Schedule of examinations and assessments during the study: from screening to the end of the period of initial assessment

Period

Study days Window (days)

Informed Consent

Confirmation or administration of antimeningo-coccal vaccination

Medical history and demographics

AD AMTS 13

Screening for HIV ^b

Streptococcal pneumoniae HUS testing STHUS screening ⁰

±2 ±3 ±3 ±3

Initial evaluation period

113

127

141

155

169 ±3 ±3 ±3 ±3 ±5 ±5 ±5 ±5 ±5 ±5

Table 23

183 ^V /E T ±2

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Height Weight Pregnancy Test ⁰ FACIT Fatigue Questionnaire/Pediatric FACET Fatigue Questionnaire ^e ' ^f EQ5D-3L Questionnaire ^f Patient Reported Symptoms Questionnaire aHUS Patient Utilization Questionnaire ^d Physical Examination Abbreviated Physical Examination ⁸ Assessment of Extrarenal Signs or Symptoms aHUS Vital Signs ¹¹ ECG Safety in 12 leads ¹ Chemical analysis ³ LDH isozymes ^k Hematology, including free hemoglobin and blood coagulation ¹ X X X X X X X X ^th X X ^th X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X Urinalysis and X X X X X X X X X

- 64 043233

chemical Analysis of urine Sampling for PK/PD ^m X ^t x ^t x ^t x ^t x ^t x ^t x ^t x ^t x ^t x ^t x ^t x ^t x ^t x ^t Urine sample ¹¹ X X X X Search activity APC° X X X X X X X X Search biomarkers ^p X X X X X Search genetic sample ⁴ X Immunogenicity (ADA) ^r X X X X Safety Checklist Overview X X X X X X X X X X X X X X X X Concomitant medicines ⁵ •«—Continuous monitoring> Registration of plasma exchange "—Continuous Monitoring—"· Adverse Events "—Continuous Monitoring—" Introduction ALXN1210 ¹ X X X X

Abbreviations: ADA=antibody against drug; ADAMTS13=ge3UHmerpuH and type 1 thrombospondin metalloproteinase, family member 13; aHUS=atypical hemolytic uremic syndrome; APC=alternative complement pathway; ECG=electrocardiogram; EQ-5D3L=EuroQol in 5 categories at 3 levels; ET=early termination; FACIT=functional evaluation of chronic disease therapy; HUS=hemolytic uremic syndrome; LDH=lactate dehydrogenase; N/A=not applicable; PD=pharmacodynamics; PK=pharmacokinetics; QoL=quality of life; STHUS = Shiga toxin-associated hemolytic uremic syndrome.

^a All patients vaccinated against meningococcal infections within 3 years before or at the time of initiation of study drug administration. Patients initiating study drug treatment less than 2 weeks after meningococcal vaccine administration are treated with appropriate prophylactic antibiotics for up to 2 weeks after vaccination. Patients not vaccinated prior to initiation of ALXN1210 treatment are treated with prophylactic antibiotics before and for at least 2 weeks after meningococcal vaccination.

^b Screening for human immunodeficiency virus type 1 and human immunodeficiency virus type 2.

^c Fecal sample for Shiga toxin enzyme immunoassay.

^d For female patients of childbearing potential only. Serum pregnancy test at screening and day 183; urine pregnancy test at all other necessary time points. A negative urine test result is required prior to administration of investigational medicinal product for female patients of reproductive potential at potential study visits.

^e The FACIT Fatigue Score version 4 is used for patients > 18 years of age at screening. The FACIT Pediatric Fatigue Scale version 4 is used for patients < 18 years of age at screening.

^f On the day of dosing, patient-reported scores are obtained prior to dosing.

^g An abbreviated physical examination consists of a meaningful body system examination based on the judgment of the investigator (or designee) and the patient's symptoms. At least 1 body system is checked for an abbreviated physical examination.

^h Vital signs measurements are taken after the patient has rested for at least 5 minutes and includes systolic and diastolic VR (millimeters of mercury [mmHg]), pulse oximetry, heart rate (beats/minute), respiratory rate (breaths/minute), and oral or tympanic temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On the day of dosing, vital signs are determined before dosing.

¹ A single 12-lead ECG is performed at screening, prior to dosing on day 57 and day 183. Patients lie supine for approximately 5-10 minutes prior to ECG and remain supine but awake during ECG.

^j Clinical laboratory safety measurements are performed prior to dosing on the day of dosing. LDH to assess the possibility of incorporation is determined by chemical evaluation. FSH levels are measured only during screening to confirm postmenopausal status.

^k Serum sample for LDH isozyme testing is collected only at selected sites at any/all time points prior to ALXN1210 dosing, depending on sample testing availability.

¹ Security assessment, as well as primary and secondary endpoints.

^m Serum samples for PK/PD analyzes are collected pre-dosing (within 0.5 h before infusion) and at the end of infusion (EOI) (within 0.5 h after 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 before dosing on day 183 (note that additional samples for PK/PD are collected on day 183 as part of the expansion period). Samples at the end of the infusion are taken from the opposite, non-infused arm of the patient. All collection times are recorded in the eCRF.

ⁿ A urine sample for drug level measurement is collected and at the end of infusion (EOI) (within 0.5 h after EOI) on days 1, 15 and 71; and at any time on day 29.

⁰ Serum samples are collected before dosing on the day of dosing and on the day without dosing at any time of the day. All collection times are recorded in the eCRF.

^p Serum, plasma, and urine collections for exploratory biomarker analysis are performed at baseline and post-treatment time points immediately prior to ALXN1210 dosing.

^q A single collection of whole blood from patients who consented to genetic testing may be performed at any time during the course of the study.

^d Serum samples for ADA are collected prior to dosing on days 1, 71, and 127. Collection on day 183 is prior to the first dose in the expansion period. All collection times are recorded in the eCRF. If the test results are positive, the test is repeated every 3 months until the results are negative or stabilized based on titer measurements and safety assessments.

^s Concomitant drug information should be collected at all study visits and checked against the Prohibited Drug List.

¹ The dose of ALXN1210 is based on the last recorded at the time of the patient's weight study visit.

^u Analysis at a local laboratory or at a central laboratory can be used to determine eligibility for inclusion in screening. However, if local laboratory tests are used, duplicate samples for analysis of LDH, platelet count, hemoglobin, and serum creatinine are collected at this examination for testing at the central laboratory.

^v Primary efficacy endpoints are assessed prior to dosing on day 183. Dosing on day 183 is the start of the expansion period.

Table 24

Examination Schedule and Assessments: Expansion Period_____

Period Expansion period Research days 183' 239 295 351 407 463 519 575 631 687 743 799 855 911/ET/E OS Window (day) ±2 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 Weight X X X X X X X X X X X X X Pregnancy test ²¹ X X X X X X X X X X X X X Questionnaire X X X X

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FACITfatigue/Fatigue Pediatric Questionnaire FACITatigue ^b ' ^c Questionnaire EQ5D-3L ^C Patient Reported Symptoms Questionnaire aHUS ^c Resource Use Questionnaire for Patients ⁰ Physical Examination Abbreviated Physical Examination ⁰ Assessment of Extrarenal Signs or Symptoms of aHUS Vital Signs ⁶ 12-Lead ECG Safety ^d Chemical analysis Hematology and blood coagulation ⁸ Urinalysis and urinalysis sampling for PK/PD ^h Search biomarkers ¹ Immunogenicity (ADA) ^j Safety leaflet overview Concomitant medicinal products ¹⁰ Plasma exchange recording X XXX XXXXXXXXXXXXXXXXXX X XXXXXXXXXXXX X X XXXXXXXXXXXXXX XXXXXXXXXXXXXXXXX X _X XXXXXXXXXXXXXX X XXXXXXXXXXXXXXX X XXXXXXXXXXXXXX X X X _J ^X _J ^X _J ^{X J} XXXXXXXXXXXXXXXXX X •“—Continuous _monitoring ^ •“—Continuous monitoring^ Adverse Events •"—Continuous Monitoring—" Introduction ALXN1210 ^{1 x1} X X X X X X X X X X X X

Abbreviations: ADA=antibody against drug; aHUS = atypical hemolytic uremic syndrome; ECG=electrocardiogram; EOS=end of study; EQ-5D=EuroQol in five categories; ET=early termination; FACIT=functional assessment of chronic disease therapy; PD=pharmacodynamics; PK=pharmacokinetics; QoL=quality of life.

^a Only for female patients of reproductive potential. Serum pregnancy test only for ET; urine pregnancy test at all other necessary time points. A negative urine test result is required prior to administration of ALXN1210 to female patients of reproductive potential at the indicated study visits.

- 67 043233 ^b The FACIT fatigue score version 4 is used for patients > 18 years of age at screening. The FACIT Pediatric Fatigue Scale version 4 is used for patients < 18 years of age at screening.

^c On the day of dosing, patient-reported scores are obtained prior to dosing.

^d An abbreviated physical examination consists of a meaningful examination of the body system, based on the judge's judgment and the patient's symptoms.

^e Vital signs measurements are taken after the patient has rested for at least 5 minutes and includes systolic and diastolic VR (millimeters of mercury [mmHg]), pulse oximetry, heart rate (beats/minute), respiratory rate (breaths/minute) and oral or tympanal temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On the day of dosing, vital signs are determined before dosing.

f A single 12-lead ECG is performed on day 911 or ET. Patients should lie supine for approximately 5-10 minutes prior to the ECG and remain supine but awake during the ECG.

^g Security assessment, as well as primary and secondary endpoints.

^h Serum samples for PK/PD analysis are collected before dosing (within 0.5 h before infusion) and EOI (within 0.5 h after EOI) on days 351, 575, and 743; EOI (within 0.5 h after EOI) on day 183; and at any time on the day 911 or ET. Samples at the end of the infusion are taken from the opposite, non-infused arm of the patient. All collection times are recorded in the eCRF.

¹ Serum, plasma, and urine collection for exploratory biomarker analysis is performed at the indicated time points immediately prior to ALXN1210 dosing; and at any time on the day 911 or ET. All collection times are recorded in the eCRF.

- ¹ Pre-dose serum sample is collected on days 351, 575 and 743. Serum sample is also collected at any time on day 911 or ET. All collection times are recorded in the eCRF. If the test results are positive, the test is repeated every 3 months until the results are negative or stabilized based on titer measurements and safety assessments.

^k Concomitant drug information is collected at all study visits and checked against the Prohibited Drug List.

¹ The expansion period begins at the start of dosing on day 183. The dose of ALXN1210 is based on the patient's last recorded body weight at the time of the study visit.

4. Study population.

In total, approximately 55 patients with documented aHUS are registered and scheduled for treatment with ALXN1210 at approximately 200 study sites worldwide. The study enrolled at least 6 and up to 10 adolescent patients (aged 12 - < 18 years at screening) and at least 10 and up to 25 patients with prior kidney transplantation.

Individuals who are not eligible for this study (not screened) may be rescreened. Patients can be rescreened a maximum of 2 times. Prospective approval of protocol deviations based on invitation and registration criteria, also known as permissions for protocol deviations or exemptions from protocol restrictions, was not allowed.

Patients were eligible for enrollment in the study if they met all of the following criteria and none of the exclusion criteria:

Male or female patients aged >12 years and weighing >40 kg at time of consent.

Evidence of TMA, including thrombocytopenia, evidence of hemolysis, and kidney dysfunction, based on the following laboratory findings at screening examination: Platelet count < 150,000 per microliter (μL) and LDH > 1.5 x upper limit of normal (ULN), and hemoglobin < lower limit norms (LLN) according to age and sex, and serum creatinine level > ULN in adults (aged >18 years), or >97.5th percentile according to age at screening in adolescents (aged 12 - <18 years) (patients requiring dialysis due to kidney damage are also eligible).

Among kidney transplant patients: a history of known aHUS prior to current kidney transplantation, or no known history of aHUS, and persistent evidence of TMA after dosing a suspension of a calcineurin inhibitor ([CNI]; eg, cyclosporine, tacrolimus) or mammalian target inhibitor rapamycin ([ mTORi]; eg sirolimus, everolimus) for a minimum of 4 days and a maximum of 7 days.

Among patients with TMA onset in the postpartum period, persistent evidence of TMA for >3 days postpartum.

To reduce the risk of meningococcal infections (Neisseria meningitidis), all patients should be vaccinated against meningococcal infections within 3 years before or at the start of study drug administration. Patients who receive a meningococcal vaccine less than 2 weeks prior to initiation of ALXN1210 treatment are treated with appropriate prophylactic antibiotics up to 2 weeks after vaccination. Patients not vaccinated prior to initiation of ALXN1210 treatment are treated with prophylactic antibiotics before and for at least 2 weeks after meningococcal vaccination.

Patients <18 years of age should be vaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae, in accordance with national and local vaccination schedule guidelines.

Female patients of reproductive potential and male patients with female partners of reproductive potential should follow protocol guidance to prevent pregnancy during treatment and for 8 months after the last dose of study drug.

Willingness and ability to give informed consent and adhere to study schedules. For patients < 18 years of age, the patient's legal representative must be willing and able to give informed consent, and the patient must be willing and able to provide the minor's written informed consent form.

Screening samples can be tested either at a local or central laboratory. If local laboratory tests are used to analyze LDH, platelet count, hemoglobin, and serum creatinine, duplicate samples are collected for testing at the central laboratory to obtain baseline and postbaseline measurements from the central laboratory. While results from a local laboratory can be used to expedite eligibility assessment, the final determination of these inclusion criteria should be based on results from a central laboratory.

Patients are excluded from enrollment in the study if they meet one of the following criteria:

A. Known deficiency of disintegrin and metalloproteinase with thrombospondin motif type 1, family member 13 (ADAMTS13) (<5% activity).

B. Shiga toxin-associated hemolytic uremic syndrome (ST-HUS).

C. Streptococcal pneumoniae-associated hemolytic uremic syndrome (HUS), as proven by a positive direct Coombs test, and Streptococcal pneumoniae infection (eg, culture, antigen test).

D. Known human immunodeficiency virus (HIV) infection.

E. Unresolved systemic meningococcal disease.

F. Patients with a confirmed diagnosis of current sepsis, defined as positive blood cultures within 7 days prior to screening and not being treated with antibiotics.

G. The presence or suspicion of an active and untreated systemic bacterial infection that, in the opinion of the investigator, makes it difficult to accurately diagnose aHUS or interferes with the ability to control aHUS disease.

N. Pregnancy or lactation.

I. Heart, lung, small intestine, or liver transplant.

J. Among kidney transplant patients, any of the following:

a. Acute kidney dysfunction within 4 weeks of transplant consistent with a diagnosis of acute antibody-mediated rejection (AMR) according to the Banff 2013 criteria, or

b. Acute kidney dysfunction within 4 weeks of transplantation and an increase in donor-specific antibodies (DSA) consistent with the clinical diagnosis of acute AMR.

c. History of polycystic kidney disease.

K. Among patients aged >18 years, the manifestation of systolic blood pressure (SBP) >170 mm Hg. Art., or, among patients aged 12 to <18 years, manifestation of a clinical diagnosis of hypertension, any of the following:

a. Permanent evidence of TMA (inclusion criterion number 2) in less than 4 days from a decrease in blood pressure (BP) to < 140 mmHg. Art.

b. Known left ventricular hypertrophy.

c. Known small and hyperechoic kidneys on ultrasound.

L. Identified drug-related HUS.

M. Exposure to PE/PI, within 28 days or longer, prior to screening due to current TMA.

N. History of malignancy within 5 years of screening, excluding treated non-melanoma skin cancer or carcinoma in situ of the cervix, with no evidence of recurrence.

A. Bone marrow transplantation (BMT)/hematopoietic stem cell transplantation (HSCT) within the last 90 days prior to screening.

R. HUS-related vitamin B12 deficiency.

Q. Known systemic scleroderma (scleroderma), systemic lupus erythematosus (SLE) or

- 69 043233 antiphospholipid antibody denial, or antiphospholipid antibody syndrome.

R. Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy against ESKD).

S. Patients on chronic intravenous immunoglobulin (IVIg) within 8 weeks prior to screening, unless due to an unrelated medical condition (eg, hypogammaglobulinemia); or chronic rituximab therapy within 12 weeks prior to screening.

T. Patients undergoing other immunosuppressive therapies such as steroids, mTORi (eg, sirolimus, everolimus), CNI (eg, ciclosporin or tacrolimus) are excluded unless: a) the therapy is part of an established post-rejection treatment regimen transplant, or b) the patient has a confirmed anti-complement factor antibody requiring immunosuppressive therapy, or c) steroids are being used due to a condition other than aHUS (eg, asthma).

U. Participation in another interventional treatment study or use of any experimental therapy within 30 days prior to the start of study drug administration on Day 1 in that study, or within 5 half-lives of that study product, whichever is greater .

V. Previous use of eculizumab or other complement inhibitors.

W. Hypersensitivity to mouse proteins or to any of the excipients.

X. Any medical or psychological condition that, in the opinion of the Investigator, may increase the risk to the patient due to participation in the study or confound the outcome of the study.

Y. Known or suspected history of drug or alcohol addiction or dependence within 1 year prior to screening.

Laboratory results for exclusion criterion number 1 may not be available until the first dose. Late results for exclusion criterion number A may result in termination of the study for the patient and replacement.

The patient has the right to withdraw from the study at any time. If the patient withdraws consent, perform the assessments indicated for the early termination (ET) review. Patients withdrawn from the study are not replaced. It is possible for a patient to discontinue the investigational medicinal product if the investigator or sponsor has reason to believe that it is in the patient's best interest to discontinue treatment.

Patients with a previous kidney transplant who developed AMR (C4d-positive kidney biopsy) and patients for whom rituximab appears to be an appropriate therapy should withdraw from the study and receive standard therapy. The primary reason and any other reason(s) for termination are recorded in the eCRF.

If a study is terminated for a patient with a current AE or an unresolved laboratory result that is significantly outside the reference range and is clinically significant, the investigator makes efforts to ensure follow-up until satisfactory clinical resolution of the laboratory result or adverse event is achieved.

The sponsor or competent authority may terminate the study for reasonable cause. Conditions justifying termination of a study include, but are not limited to: (1) discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the study, (2) sponsor's decision to suspend or stop investigational drug testing, evaluation, or development, (3) failure to investigator to comply with an approved protocol, appropriate guidelines and/or regulations, and (4) knowingly misrepresenting information from an investigator to a sponsor and/or regulatory authorities.

If, at any point, it is determined that the screening data for a patient does not meet one or more of the following inclusion/exclusion criteria (inclusion criterion number 2 or exclusion criterion number 1), after at least 1 dose of investigational product has been administered (for example, if the patient data from the local laboratory used to validate the eligibility criteria are subsequently determined by the central laboratory that they no longer meet the eligibility criteria), the patient is terminated from the study and can be replaced. Early termination procedures are performed on patients undergoing early termination, and information on all AEs is collected up to 60 days after the last dose of study drug administered to the patient.

The end of the study is defined as the date of the last examination of the last patient in the expansion period.

5. Investigational drug.

ALXN1210, a humanized anti-C5 monoclonal antibody consisting of two 448 amino acid heavy chains and two 214 amino acid light chains, is an IgG2/4 kappa immunoglobulin composed of human constant regions and murine complementarity determining regions grafted into a human lung variable region framework. and heavy chain.

ALXN1210 and eculizumab share over 99% primary amino acid sequence identity and have very similar pharmacology.

ALXN1210 is supplied for clinical trials as a sterile 10 mg/ml preservative-free solution in disposable vials and is designed to be infused by diluting into commercially available saline (0.9% sodium chloride injection; country-specific pharmacopoeia) for administration by IV infusion. In table. 25 and modern IB provides additional information.

Table 25

Investigational drug

Product name ALXN1210 Dosage form Concentrated solution (10 mg/ml) for infusion Method of administration IV infusion Physical Description Clear to translucent, whitish, practically free of particles Manufacturer Alexion Pharmaceuticals Inc. or an organization that manufactures under a contract

ALXN1210 is packaged in USP/EPS Type 1 borosilicate glass vials and sealed with butyl rubber stoppers with an aluminum crimp cap and flip top cap. The study drug is supplied in kits. ALXN1210 is distributed to each center after receipt of all required necessary documents based on current regulations.

Upon arrival of the investigational drug kits at the study site, the pharmacist (or qualified authorized person) immediately removes the investigational drug kits from the transport refrigerator and stores them in their original boxes under refrigerated conditions at 2-8°C (35-47°F) and protection from light. ALXN1210 is not frozen. The investigational medicinal product is kept in secure storage with limited access, and the temperature is monitored daily.

The drug is at room temperature until administration. The material is not heated (eg using microwaves or other heat source) in a manner other than using ambient temperature.

ALXN1210 is not administered as an IV bolus or bolus injection. Investigational drug infusions are prepared using an aseptic technique. The required patient dose of ALXN1210 is further diluted in commercially available saline (0.9% sodium chloride; country-specific Pharmacopoeia) in the volume shown in Table 1. 26. A solution of ALXN1210 in diluent is administered to the patient using a set of IV tubing via an infusion pump. Use of the built-in filter for infusion is necessary.

Table 26

Dosing Reference Chart for Dose Preparation ALXN1210

Dose type Body weight (kg) ^a Dose (mg) Volume ALXN 1210 (ml) Salt solution volume (ml) Total volume (ml) Min. continuous infusion minutes (hour) Max. infusion rate (ml/hour) load > 40 - < 60 2400 240 240 480 114(1.9) 253 > 60 - < 100 2700 270 270 540 102(1.7) 333 > 100 3000 300 300 600 108(1.8) 333 Supportive > 40 - < 60 3000 300 300 600 138 (2.3) 267 > 60 - < 100 3300 330 330 660 120 (2.0) 333 > 100 3600 360 360 720 132 (2.2) 333

See the Pharmaceutical Guide for additional instructions for dose preparation.

^a Body weight, as recorded at the last examination in the study.

Only a pharmacist or qualified healthcare professional prepares and dispenses doses of investigational medicinal product. Investigational medicinal product is distributed only to registered patients who are confirmed to be eligible for this study. After preparation of an investigational medicinal product for a patient, it is administered only to that patient. The study drug vials are for single use only and no drug remaining in the vial is to be used for another patient. Any drug left in the infusion tubing or infusion bag should not be used on another patient.

- 71 043233

Any material for clinical investigation is kept in a safe place and assigned and distributed by appropriately qualified persons. Maintain detailed records of quantities received, distributed and destroyed of investigational product. Unless otherwise indicated, empty vials and vials with remaining materials are retained for review and reporting to the Study Supervisor until they are destroyed, or manipulated according to local pharmacology standard operating procedures (SOPs) for medicinal products in clinical trials. To meet regulatory requirements for drug reporting, at the end of the study, all remaining stocks of ALXN1210 are verified and destroyed or returned to Alexion, in accordance with acceptable regulations.

Patients are driven ALXN1210 for 26 weeks. ALXN1210 is administered as a slow IV infusion over approximately 2 hours. ALXN1210 is not administered as an IV bolus or bolus injection.

The dosing regimen for ALXN1210 during the initial evaluation period is based on the patient's last recorded body weight during the study visit (Table 27). Patients are given a loading dose of ALXN1210 IV on day 1, followed by maintenance dosing of ALXN1210 IV on day 15 and q8w (every eight weeks) thereafter.

Table 27

Modes of loading and maintenance treatment

Body weight ^a Loading dose (day 1) Maintenance dose (days 15, 71 and 127) > 40 - < 60 kg 2400 mg 3000 mg > 60 - < 100 kg 2700 mg 3300 mg > 100 kg 3000 mg 3600 mg

a Body weight, as recorded at the last examination in the study.

After the initial evaluation period, all patients are transferred to an expansion period of up to 2 years, during which all patients are administered ALXN1210 q8w (every eight weeks). The actual time of administration of all doses is recorded in the patient's eCRF.

This is an open study. Patients who meet all eligibility criteria are assigned to study treatment using ALXN1210 at baseline (Day 1). An interactive system allowing access by phone call or via the Internet (IxRS) is used to assign vials containing ALXN1210 to each patient.

The weight-based doses of ALXN1210 in this study (Table 27) are based on PK/PD data from early development studies in healthy adult volunteers, as well as available data for patients with PNH in the current phase 1b dose-finding study (ALXN1210- PNH-103) and in the current phase 2 proof-of-concept study (ALXN1210-PNH-201). The choice of ALXN1210 dosing regimen for patients with aHUS is based on targeted immediate, complete, and long-term inhibition of the terminal complement complex in PNH patients, as expected, consistent with immediate, complete, and long-term inhibition of the terminal complement complex in aHUS patients, as shown using data from clinical studies of eculizumab in patients with PNH and aHUS.

Infusion of other monoclonal antibodies is associated with infusion reactions, usually onset during or shortly after completion of the infusion.

Prior medicinal products (including vitamins and herbal preparations) - including those discussed in the Exclusion Criteria and Procedures section (any therapeutic intervention such as surgery/biopsy or physical therapy) that the patient was administered or administered within 28 days ( or 3 years for documentation of meningococcal vaccination) prior to screening, up to the first dose of ALXN1210, is recorded in the patient's eCRF.

For analytical purposes, any dialysis within a period of 14 days immediately following the first dose of ALXN1210 is not considered new dialysis.

All drug use and procedures performed during the course of the trial are recorded on the clinical trial participant registration form/medical record and the patient's eCRF. This registration includes all prescription drugs, herbal products, vitamins, minerals, over-the-counter drugs, and current drugs. Concomitant medicinal products are registered from the first infusion of investigational medicinal product until 56 days after the last dose of investigational medicinal product administered to the patient. Any changes to concomitant medications are also recorded on the clinical trial participant registration form/medical record and the patient's eCRF. Any concomitant medicinal product deemed necessary for the patient's standard of care during the course of the study, or for the treatment of any AE, together with the eligible medicinal products described below,

- 72 043233 administered at the discretion of the investigator. However, it is the investigator's responsibility to ensure that the details, for all medicinal products, are fully recorded on the clinical trial participant registration form/medical record and the patient's eCRF.

Patients are prohibited from using any of the following medicines and procedures at any time after the first dose of investigational medicinal product: eculizumab or other complement inhibitors, use of any other investigational medicinal product or device as part of clinical trials, IVIg (except for unrelated medical necessity, e.g., due to hypogammaglobulinemia), rituximab, PE/PI after the first dose, and new dialysis with the first 48-hour period after the first dose of ALXN1210, unless there is a compelling medical reason, as assessed by (1) hypervolemia not responding to diuretics, (2 ) refractory electrolyte imbalance or (3) new onset uremic encephalopathy. Exceptions must be approved by the sponsor prior to dialysis on a case-by-case basis.

The following concomitant drugs and procedures are acceptable under specific conditions and with the following restrictions: Use of other immunosuppressive drugs (such as steroids, mTORi [eg, sirolimus, everolimus], CNI [eg, cyclosporine or tacrolimus]) before screening or during the study is not acceptable unless: a) they are part of an established transplant anti-rejection regimen, or b) the patient has a confirmed anti-complement factor antibody requiring immunosuppressive therapy, or c) steroids are being used for a condition other than aHUS (for example, asthma).

All patients receiving other complement inhibitors (including eculizumab) or undergoing PE/PI after the first dose of study drug are excluded from the study.

Due to its mechanism of action, the use of ALXN1210 increases the patient's susceptibility to infection. To reduce the risk of infection, all patients are vaccinated against N. meningitidis, Hib, and Streptococcus pneumoniae.

Patients are vaccinated against N. meningitidis within 3 years before or at the time of the first dose of ALXN1210. Patients treated with the drug less than 2 weeks after administration of the meningococcal vaccine are treated with suitable prophylactic antibiotics for up to 2 weeks after vaccination. Vaccines against serotypes A, C, Y, W135 and B, when available, are recommended to prevent infection with common pathogenic meningococcal serotypes. Patients are vaccinated or revaccinated according to current national vaccination guidelines or local practice for the use of vaccination with complement inhibitors (eg, eculizumab).

It is understood that some patients not vaccinated against N. meningiditis within 3 years prior to the first dose of ALXN1210 may not be able to be vaccinated at the time of the first dose. Patients not vaccinated prior to initiation of ALXN1210 treatment are treated with prophylactic antibiotics before and for at least 2 weeks after meningococcal vaccination.

Vaccination may not be sufficient to prevent meningococcal disease. Consideration should be given to official guidance and local practice for the appropriate use of antibacterial agents. All patients are monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics as needed.

To increase risk awareness and facilitate rapid reporting of any potential signs or symptoms of infection experienced by patients during the course of the study, patients are provided with a safety card to carry with them at all time points. Additional discussion and explanation of potential risks, signs, and symptoms occurs at specific time points as part of the patient safety leaflet review and throughout the study, as described in the evaluation schedule (Tables 23 and 24).

Patients are vaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae in accordance with national and local vaccination schedule guidelines, before or at the time of the first dose of ALXN1210. The vaccination status against N. meningitidis, Hib and S. pnemoniae is recorded in the patient's eCRF.

Patients are administered the investigational medicinal product under controlled conditions under the direction of the investigator or authorized person, thus ensuring compliance with the regimen of administration of the investigational medicinal product. The investigator or designee ensures that all patients are adequately informed of the specific dosing regimen required to comply with the study protocol, ensures that the patient is administered the appropriate dose at the designated time points during the course of the study, and that adequate safety monitoring occurs during the infusion.

- 73 043233

Prior to study drug administration, female patients who consider themselves postmenopausal must provide evidence of menopause based on a combination of at least 1 year of amenorrhea and an elevated follicle-stimulating hormone (FSH) level (>30 IU/L) (eg, in the absence of hormone replacement therapy, dietary phytoestrogens).

Female patients of childbearing potential use a highly effective method of contraception (as defined below) starting at screening and continuing for at least 8 months after the last dose of study drug. Highly effective method of contraception* includes: hormonal contraception associated with ovulation suppression, intrauterine device, intrauterine hormone release system, bilateral tubal occlusion, vasectomy partner (assuming the partner is the patient's only sexual partner), sexual abstinence (defined as abstinence from heterosexual sexual intercourse throughout the period of risk associated with treatment with the investigational medicinal product; the reliability of sexual abstinence must be assessed in relation to the duration of the clinical study and the patient's preferred and usual lifestyle), the combination of a male condom with a cap, diaphragm or sponge with spermicide (double barrier ways). Male patients with a spouse/female partner of reproductive potential or a pregnant or breastfeeding spouse or partner consent to the use of dual barrier contraception (male condom plus an appropriate barrier method for female partner) during treatment and for at least 8 months after the last dose of study drug. Double barrier contraception is essential, even with documented medical evaluation of a successful surgical vasectomy.

Male patients do not donate sperm during treatment and for at least 8 months after the last dose of study drug.

6. Performance evaluations.

The primary measure of efficacy is the complete TMA response over the 26-week initial evaluation period. Criteria for a complete TMA response are (1) normalization of platelet count, (2) normalization of LDH, and (3) >25% improvement in serum creatinine from baseline.

Patients meeting all criteria for a TMA complete response, confirmed by 2 consecutive measurements obtained at least 4 weeks apart, are classified as meeting the primary efficacy endpoint.

The following secondary efficacy measures are measured during the course of the study:

A. Dialysis need status.

B. Time to complete TMA response.

C. TMA complete response status over time.

D. Observed value and change from baseline in eGFR.

E. CKD stage as assessed by the investigator on the selected target day and classified as improved, stable (no change), or worsened from baseline.

F. Observed value and change from baseline in hematological parameters (platelets, LDH, hemoglobin).

G. An increase in hemoglobin level > 20 g/l from baseline, maintained for at least 2 consecutive measurements taken at least 4 weeks apart.

H. Change from baseline QoL as measured by EQ-5D-3L (all patients), FACIT Fatigue Scale Version 4 (patients >18 years of age), and FACIT Pediatric Fatigue Scale (patients <18 years of age).

7. Safety assessments.

The Investigator or his/her designee meets with patients to discuss the potential safety risks of ALXN1210 and to give the Investigator an opportunity to address any patient concerns regarding the study.

The AE set is monitored from the time of obtaining informed consent until completion of the study. Investigators track any AEs until they are resolved (resolved or stabilized). If a patient is withdrawn from the study, AE monitoring continues until the last visit of the last patient in the study, if possible. The timing of clinical and laboratory evaluations is established by the evaluation schedule (Tables 23 and 24). Any clinically significant abnormal findings are monitored until resolution or stabilization.

Conduct a demographic survey, including age, gender, race, and ethnicity. A complete medical history is collected and documented. Record weight and height. Growth is measured only at screening.

The medical history of the patient with aHUS, including the onset of the first symptom of aHUS and the date of diagnosis, is documented at the screening examination.

The patient's medical history, including prior and comorbid conditions/disturbances, is recorded at the screening examination. Drug use (prescription or non-prescription, including vitamins and/or herbal supplements) within 28 days (or 3 years for documentation of meningococcal vaccination) prior to screening is also recorded, in addition to meningococcal vaccination.

The physical examination includes the following assessments: general appearance; skin; head, ears, eyes, nose and throat; neck; lymph nodes; chest; hearts; abdominal cavity; limbs; central nervous system; and the musculoskeletal system. The abbreviated physical examination consists of a meaningful examination of the body system, based on the judge's judgment and the patient's symptoms. Vital signs measurements are taken after the patient has rested for at least 5 minutes and includes systolic and diastolic HR (millimeters of mercury [mmHg]), pulse oximetry, heart rate (beats/minute), respiratory rate ( breaths/minute) and oral or tympanal temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]).

Sample collection for serum pregnancy test, haematological analysis, chemical analysis, blood coagulation analysis and urinalysis is carried out at the time points indicated in the assessment schedule (Tables 23 and 24). Samples for laboratory evaluations are collected prior to the administration of each study drug.

Screening samples can be tested either at a local or central laboratory. If local laboratory tests are used to analyze LDH, platelet count, hemoglobin, and serum creatinine, duplicate samples are collected for testing at the central laboratory to obtain baseline and postbaseline measurements from the central laboratory. In case of duplication of samples from the local and central laboratory, the results from the central laboratory are used for analysis.

It is understood that some laboratory values may be outside the normal range due to comorbidity. Investigators should use physician judgment when evaluating the clinical significance of these values. Clinical significance is defined as any deviation in laboratory measurements that is of medical significance and that results in a change in medical care. If there are clinically significant laboratory changes from baseline, the changes are documented as AE in AE eCRF. The investigator assesses association with study treatment for all clinically relevant values outside the range. The Investigator continues to monitor the patient through additional laboratory evaluations until (1) values return to the normal range or baseline, or (2) the Investigator expresses the opinion that values outside the normal range are not related to administration of investigational medicinal product or other protocol-specific procedures .

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

Blood samples are analyzed for serum chemistry. Indirect bilirubin is calculated from the levels of total and direct bilirubin; thus, results for indirect bilirubin are not available if direct bilirubin is below the limit of quantitation. Serum FSH levels are measured during screening for postmenopausal female patients to confirm their postmenopausal status.

Chemical evaluations are carried out at the time points specified in the evaluation schedule (Tables 23 and 24). eGFR is calculated for all visits at which serum chemistries were performed using the renal disease diet modification formula in patients >18 years of age and the Schwartz renal disease diet modification formula in patients < 18 years of age.

Blood samples are analyzed for blood coagulation parameters.

Analyze urine samples. Microscopic examination of urine samples is carried out if the results of macroscopic analysis are abnormal. Urine samples are also analyzed to measure protein and creatinine levels to calculate the urinary protein:creatinine ratio.

For each patient, a single digital 12-lead ECG is performed according to the assessment schedule (Tables 23 and 24). Patients should lie supine for approximately 5-10 minutes prior to the ECG and remain supine but awake during the ECG. The investigator or authorized person responsible for reviewing the ECG evaluates whether the ECG is within normal limits and determines the clinical significance of the results. These scores are indicated in the CRF.

Blood samples were collected to test for the presence and titer of anti-ALXN1210 ADA in serum prior to study drug administration as indicated in the evaluation schedule (see Tables 23 and 24). If the test results are positive, the test can be repeated every 3 months until the results are negative or stable based on titer measurements and safety assessments. Additional characterization of antibody responses can be performed as needed,

- 75 043233 including binding and neutralizing antibodies, PK/PD, safety and activity of ALXN1210.

AE is any adverse medical event in a patient who is administered a pharmaceutical product and does not necessarily have a causal relationship with this treatment. An AE may thus be any adverse or unintended sign (eg, an abnormal laboratory finding), symptom, or disease associated in time with drug use, whether or not considered drug-related.

Situations in which an adverse medical event did not occur (eg, hospitalization for elective surgery if planned prior to study entry, hospitalization for social or convenience reasons), and envisaged daily fluctuations in preexisting disease(s) or condition(s) ) present or detected at the start of the study that did not worsen are not AEs.

No effect of a drug is not an AE in clinical trials because the purpose of a clinical trial is to determine the effect of a drug.

An error in the administration of a medicinal product (including intentional misuse, abuse and overdose of the product) or use other than that specified in the protocol is not considered as an AE, unless an adverse medical event is present as a result of an error in the administration of the medicinal product.

Pregnancies occurring during maternal or paternal exposure to study product must be reported within 24 hours of notification to the investigator/centre. Data on fetal outcome and breastfeeding are being collected for reporting to regulatory authorities and safety assessments.

Adverse events are recorded from the time the consent was signed. AE reported after informed consent but prior to administration of the investigational medicinal product is considered to be pre-treatment AE.

The following events represent important identified risks in this study: meningococcal infections.

The severity of AEs is ranked using the Common Criteria for Adverse Events Terminology (CTCAE) version 4.03 or higher. A ranking (severity) scale is provided for each AE term. Each CTCAE term is a Low Level Term (LLT) according to the Medical Dictionary for Regulatory Activities (MedDRA®). Each LLT is coded by the preferred MedDRA term. Grade refers to the severity of the AE. CTCAE assigns grades 1-5, with unique clinical descriptions of severity for each AE (Table 28).

Table 28

Adverse Event Severity Ranking Scale

Degree Description Degree 1 soft; asymptomatic or mild symptoms; only clinical or diagnostic observations; no intervention shown. Degree 2 moderate; minimal, local or non-invasive intervention is indicated; restriction of age-appropriate instrumental activity in activities of daily living (ADL) ^a Degree 3 Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization is indicated; disabling; limiting self-service ADL ^b Degree 4 Life-threatening consequences; urgent intervention is indicated. Degree 5 AE-related death.

Abbreviations: ADL=activity in daily activities; AE=adverse event.

^a Instrumental ADL refers to cooking, shopping for groceries or clothes, using the phone, managing money, etc.

^b Self care ADL refers to washing, dressing and undressing, eating, using the toilet, taking medication, and not being bedridden.

Any change in AE severity is documented based on specific guidance in the eCRF completion instructions. Severity and severity are distinguished: severity describes the intensity of the AE, while the term severity refers to an AE that meets the specific criteria for a serious adverse event (SAE).

The investigator should provide an estimate of causality (no association, unlikely, possible, probable, or certain) for all AEs (both serious and non-serious), based on the investigator's judgment and observed symptoms associated with the event (Table 29). This score was recorded in the eCRF and any additional forms as needed.

- 76 043233

Table 29

Descriptions of causality assessment

Grade Description Unconnected/No connection Assumes no causal relationship between the product under investigation and the reported event. unlikely to be associated Assumes that the clinical picture is highly consistent with a cause other than the investigational product, but the correlation cannot be made with absolute certainty, and an association between the investigational product and AE cannot be ruled out with absolute certainty. Possibly related Suggests that treatment with the investigational product may cause or contribute to AE (i.e., the event follows a reasonable time sequence from the time of drug administration and/or follows a known pattern of response to the investigational product, but may also be caused by other factors) . Probably related Assumes that there is a reasonable temporal sequence of the event with the introduction of the investigational product, and a probable causal relationship of the event to the investigational product. This may be based on the known pharmacological activity of the investigational product, known or previously published adverse reactions to the investigational product or drug class, or an opinion based on the investigator's clinical experience. Definitely related Temporal association with study product, other conditions (comorbid illness, reaction to concomitant drug, or progression/manifestation of a disease state) do not appear to explain the event, consistent with known pharmaceutical profile, improvement on discontinuation, recurrence on re-exposure.

A serious adverse event (SAE) is any adverse medical event that results in death.

Is life-threatening (i.e. the patient is at risk of death at the time of the event) Requires hospitalization of the patient or extension of existing hospitalization Leads to permanent or significant disability/incapacity Is a congenital malformation of the fetus/birth abnormality Major medical events that may not result in death that is not directly life-threatening or does not require hospitalization may be considered a serious adverse event when, based on the appropriate medical opinion, they may put the patient at risk or require intervention to prevent one of the outcomes listed above.

Suspected Unanticipated Serious Adverse Reactions (SUSARs) are serious events not listed in the IB that the investigator identifies as being related to the investigational product or method. US Code of Federal Regulations (CFR) Record 21 312.32 and European Union Clinical Research Directive 2001/20/EC, and related detailed guidelines or national regulations in participating countries require SUSAR registration.

All AEs (serious and non-serious) are collected from signing the ICF up to 60 days after the last dose of investigational drug for patients with ET, or up to 56 days after the last dose of investigational drug for patients who complete the study. All AEs are registered in the eCRF after the investigator or his/her staff is informed of their occurrence.

All SAEs are recorded, regardless of the investigator's assessment of causality. There is no time limit for registering SAEs that are considered to be causally related to an investigational medicinal product. Researchers have the right to register SAE, regardless of causation, at any time.

For all SAEs, the investigator must provide the following: relevant and requested tracking information, SAE (multiple SAE) causality, SAE (multiple SAE) treatment/intervention, SAE (multiple SAE) outcome, and accompanying medical records and laboratory/ diagnostic information.

Pregnancy data is collected during this study for all patients and female spouses/partners of male patients. Exposure during pregnancy (also

- 77 043233 meaning in utero exposure) may result either from maternal exposure or from transfer of the drug through semen after paternal exposure. Pregnancy itself is not considered an AE unless there is suspicion that the investigational product may interfere with the effectiveness of the contraceptive medicinal product. However, pregnancy complications and abnormal pregnancy outcomes are AEs and may meet SAE criteria (eg, ectopic pregnancy, miscarriage, intrauterine fetal death, neonatal death, or congenital anomaly). Voluntary termination of pregnancy without complications should not be registered as AE.

8. Assessments of pharmacokinetics and pharmacodynamics.

Blood samples for serum drug concentrations and PD assessments are collected before and after study drug administration at the time points indicated in the assessment schedule (see Tables 23 and 24). Record the actual date and time (24 hour clock) of each sampling. The number of time points for PK sampling for any given patient does not exceed the number of time points currently planned.

Blood samples for PK and PD assessment are collected from the arm opposite the arm used for drug infusion. The PK/PD scores are as follows: (1) changes in ALXN1210 serum concentration over time and (2) changes in free C5 concentration.

9. Search ratings.

For exploratory biomarker analyses, summary statistics are presented for actual change and percent change from baseline.

The relationship between ALXN1210 concentration and retrieval biomarkers or the correlation between clinical benefit and key retrieval biomarkers can be assessed via graphical representation. Exploratory analyzes and analyzes of potential relationships between clinical outcomes, PK/PD, genetic profile, and biomarker levels can also be performed. APC activity and autoantibody results are summarized if evaluated.

Exploratory genetic studies can be conducted to investigate genetic variants in genes known to be associated with aHUS, as well as to identify new genetic variants associated with aHUS, complement dysregulation, or ALXN1210 metabolism or efficacy.

Genetic mutations of known clinical significance in aHUS are reported to the patient or the patient's caregiver by the investigator, along with appropriate genetic counseling. Genetic variants of unknown clinical significance are not reported by the investigator to patients or their caregivers.

Additional signs or symptoms of aHUS are assessed using the Patient Use of Resources Questionnaire and the Patient Reported Symptoms of aHUS Questionnaire.

The components of extrarenal signs or symptoms of aHUS, including vital signs and clinical laboratory parameters, can be summarized descriptively at baseline and time points after baseline, and by change from baseline. You can provide a list of patients.

Analysis of signs, symptomology, and resource use may include standardized measures for categorical outcomes in the presence or absence of repetitive measurements.

If there is no score on day 1, the screening score is used as the baseline score.

To assess TMA complete response over the 26-week baseline period (primary endpoint), for patients with no efficacy evaluation as part of the TMA complete response determination still on study, last follow-up data forward (LOCF) is performed. For patients who completed the study before week 26, data up to the time of discontinuation is used to evaluate the complete TMA response.

Manipulations of missing data for QoL tools are performed as specified in the instructions for each tool.

An interim analysis is scheduled for this study at the end of the 26-week baseline period, after all patients have completed or discontinued the 26-week baseline period. In addition, a second analysis to summarize long-term efficacy, safety and PK parameters is performed at the end of the 2-year expansion period.

Example 4

Randomized, open-label, phase 3, active drug-controlled study of ALXN1210 versus eculizumab in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) previously treated with eculizumab.

An open-label, randomized, multicentre, active-controlled, Phase 3 study was conducted to evaluate the safety and efficacy of ALXN1210 (also known as Ultomiris™, BNJ441 antibody, or ravulizumab) compared to eculizumab given by intravenous (IV) infusion in adult patients with PNH who have been treated with eculizumab for at least 6 months.

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1. Goals and end points.

The primary objective was to evaluate the non-inferiority of ALXN1210 (ravulizumab) compared to eculizumab in adult patients with PNH treated with eculizumab for at least 6 months.

Non-inferiority was declared if, after 26 weeks of treatment, the upper limit of the 95% confidence interval (CI) for the difference (ALXN1210-eculizumab) in percent change in LDH level (LDHPCHG) was less than 15%.

Secondary objectives included characterizing the safety and tolerability of ALXN1210 in patients switched from eculizumab to ALXN1210, evaluating the efficacy of ALXN1210 through supplemental pharmacokinetic/pharmacodynamic (PK/PD) and immunogenicity metrics of ALXN1210, and evaluating the long-term safety and efficacy of ALXN1210.

The primary study efficacy endpoint was hemolysis, as measured directly by the percentage change in lactate dehydrogenase (LDH-PCHG) from baseline to day 183. Key secondary study efficacy endpoints (to be tested in a hierarchical order) were:

1. Proportion of patients with acute hemolysis, defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, difficulty breathing (dyspnea), anemia (hemoglobin <10 g/dl), major adverse event vascular event (MAVE) (including thrombosis), dysphagia, or erectile dysfunction) in the presence of elevated LDH > 2 x upper limit of normal (ULN).

2. Change in quality of life (QoL), as assessed by the Functional Assessment of Chronic Disease Therapy (FACIT) - Fatigue, version 4, from baseline to day 183.

3. Transfusion exclusion (TA), defined as the proportion of patients who remained transfusion-free and did not require transfusion, as per protocol guidelines, from baseline to day 183.

4. Proportion of patients with stabilized hemoglobin, defined as the exclusion of a >2 g/dl decrease in hemoglobin levels from baseline in the absence of transfusion, from baseline to day 183.

Other secondary efficacy endpoints included assessment of: (1) total number of red cell mass units (pRBC) administered via transfusion from baseline to day 183, (2) proportion of patients with LDH in the normal range at day 183, (3) change in European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire-30 (QLQ-C30), version 3.0, from baseline to day 183, (4) changes in the clinical manifestations of PNH (fatigue, hemoglobinuria, pain in the area abdomen, breathing difficulties, anemia, dysphagia and erectile dysfunction) from baseline to day 183 and (5) the proportion of patients experiencing MAVE from baseline to day 183.

Pharmacokinetic and pharmacodynamic endpoints included an assessment of:

(1) changes in serum concentrations of ALXN1210 and eculizumab over time, (2) changes in hemolytic activity against chicken erythrocytes (cRBC) over time (exploratory), and (3) changes in free C5 concentration over time.

Exploratory endpoints included an assessment of patient-reported PNH symptoms and healthcare resource use.

The safety and tolerability of ALXN1210, compared with eculizumab, was assessed through physical examinations, vital signs, electrocardiograms (ECGs), laboratory evaluations, and the incidence of adverse events (AE) and serious adverse events (SAE). At the end of the study, the proportion of patients who developed anti-drug antibodies (ADA) was also assessed.

2. Study design.

This study was designed to evaluate the safety and efficacy of ALXN1210 (ravulizumab) compared with eculizumab given by intravenous (IV) infusion in adult patients with PNH treated with eculizumab for at least the past 6 months. Approximately 192 patients (96 patients per treatment arm) were expected to be included in the study by design, but ultimately 195 subjects were enrolled in the study and 186 subjects were analyzed as part of the protocol analysis. The study included a 4-week screening period, a 26-week randomized treatment period, and an extension period up to 2 years. Patients were stratified into 1 of 2 groups based on a history of transfusion (RBC transfusion exposure within 12 months to day 1, yes or no). Patients within each of the 2 groups were randomly enrolled in a 1:1 ratio to either continue eculizumab or switch to ALXN1210. 97 patients were enrolled in the ALXN1210 group and 98 patients were enrolled in the eculizumab group. After completion of the study, 191 subjects were transferred to enroll in the expansion study, as 4 subjects

- 79,043,233 patients (1 in the ALXN1210 group and 3 in the eculizumab group) stopped treatment.

Prior to randomization and within 5 days prior to study drug administration on day 1, each patient's hemoglobin was assessed either by a local or central laboratory. If at that time the patient's hemoglobin was within the protocol transfusion guidelines, the patient was transfused with pRBC to a hemoglobin level above the protocol's transfusion limit to be eligible for randomization. Either the local or central laboratory confirmed that the patient's hemoglobin level after transfusion exceeded the transfusion limit specified in the protocol.

Day 1 of study treatment occurred 2 weeks after the last dose of eculizumab was administered to the patient. Patients randomly assigned to the ALXN1210 group received a loading dose (see Table 7) of ALXN1210 on day 1, followed by maintenance doses of ALXN1210 on day 15 and every 8 weeks (q8w) thereafter for a total of 26 weeks of treatment. Patients randomly assigned to eculizumab continued to receive the approved dose of eculizumab for the treatment of PNH (900 mg every 2 weeks [q2w]) for a total of 26 weeks of study treatment.

After completion of all evaluations on day 183, patients are transferred to the expansion period and continue to receive ALXN1210 until the product is registered or approved (according to country-specific guidelines), or for up to 2 years, whichever will come earlier. Beginning on day 183, patients randomized to the ALXN1210 treatment arm received a maintenance dose (as described above) of ALXN1210 every 8 weeks (q8w) and patients randomized to the eculizumab arm received a loading dose (as described above) of ALXN1210 2 weeks later and every 8 weeks (q8w) thereafter, as per weight-based maintenance dose of ALXN1210. Fig. 25 and 26 illustrate the study design.

The pRBC transfusion was performed when the patient had a hemoglobin level of 9 g/dl or below with signs or symptoms of sufficient severity to warrant transfusion, or a hemoglobin level of 7 g/dl or below, regardless of the presence of clinical signs or symptoms.

The schedule of assessments is presented in Table. 30 for screening and randomized treatment period, and in table. 31 (patients transferred from the ALXN1210 group), and in table. 32 (patients transferred from the eculizumab group) for the expansion period.

Additional (off-schedule) examinations outside of these examinations are permitted at the discretion of the investigator. Procedures, tests, and evaluations were at the discretion of the investigator. Any tests, procedures, or assessments performed at out-of-schedule visits were recorded in the Electronic Clinical Study Participant Records (eCRF).

In addition, if the predicted event of abrupt hemolysis occurred, the parameters LDH, PK and PD were analyzed in the central laboratory. If the predicted event of acute hemolysis did not occur at the time of the scheduled visit, an off-schedule visit was performed to assess the patient's condition and collect the necessary LDH, PK, and PD parameters. For the purposes of defining acute hemolysis, the LDH score is based on the value obtained from the central laboratory.

Table 30

Schedule of examinations and assessments in the study: from screening to the end of the randomized treatment period

Period Screening g Period of randomized treatment Research days -28-1 1 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183/E T Window (day) N/A ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 ±2 Informed other consent X

- 80 043233

Confirmation or administration of antimenin gococcal vaccination X X Medical history and demographic data X HIV testing X clone size PNH ^b X X X X Height X Weight X X X X X X X X X X X X X X X X X Pregnancy test ⁰ X X X X X X Registration of transfusions and transfusion parameters ⁰ X ^e X X X X X X X X X X X X X X X X Symptomatology PNHf, g X X X X X X X X X X X X X X X X X FACIT- Fatigue ⁸ X X X X X X X EORTC ^QLQC30g X X X X X X X PNH symptom questionnaire ^g X X X X X X X X X X X X X X X X Questionnaire for patients on the use of resources ⁸ X X X X X Physical examination X Abbreviated physical examination ¹¹ X X X Vital Signs ¹ X X X X X X X X X X X X X X X X X

- 81 043233

Safety, 12-lead ECG ¹ X X X Chemical analysis including LDH ^k X X X X X X X X X X X X X X X X X Hematology, including free hemoglobin and blood clotting X X X X X X X X X X X X X X X X X Urinalysis and chemical analysis of urine X X X X X X X sampling for PK/PD ^x1 x ^{t x1} x ^t x ^t x ^t x ^{t x1} x ^t x ^t x ^{t x1} x ^t x ^t x ^{t x1} Immunogenicity (ADA) ¹¹ X X X X Safety Checklist Overview X X X X X X X X X X X X X X X X Acute hemolysis ⁰ "—Continuous Monitoring—"· Concomitant medicines X "—Continuous Monitoring—" Adverse Events X •«—Continuous Monitoring^ Randomization ^p X Introduction ALXN1210 ⁴ X X X X Eculizumab administration X X X X X X X X X X X X X

Abbreviations: ADA=antibody against drug; ECG=electrocardiogram; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-30 Scale; ET=early termination; FACIT-Fatigue=Functional Evaluation of Chronic Disease Therapy - Fatigue; HIV=human immunodeficiency virus; LDH=lactate dehydrogenase; N/A=not applicable; PD=pharmacodynamics PK=pharmacokinetics; PNH=paroxysmal nocturnal hemoglobinuria.

^a All patients were vaccinated against meningococcal infections within 3 years prior to or at the time of initiation of Investigational Medicinal Product. Patients initiating study drug treatment less than 2 weeks after meningococcal vaccine administration were treated with appropriate prophylactic antibiotics up to 2 weeks after vaccination.

^b Clone size of leukocytes (WBC; granulocytes and monocytes) and erythrocytes (RBC) measured by high sensitivity flow cytometry at screening and day 1; only RBC clone size at day 71 and day 183.

^c For female patients of childbearing potential only. Serum pregnancy test at screening and day 183; urine pregnancy test at all other necessary time points. A negative urine test result was required prior to administration of ALXN1210 or eculizumab for female patients of reproductive potential at these examinations.

^d Transfusions given during and between visits were recorded.

^e Prior to randomization and within 5 days prior to study drug administration on Day 1, each patient's hemoglobin was assessed either by a local or central laboratory. If at that time the patient's hemoglobin was within the protocol transfusion guidelines, the patient was transfused with pRBC to a hemoglobin level above the protocol's transfusion limit to be eligible for randomization. Either the local or central laboratory confirmed that the patient's hemoglobin level after the transfusion exceeded the transfusion limit specified in the protocol.

^f Investigator or designee assessment of the following events: fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.

^g Therapist-reported and patient-reported scores were obtained prior to administration of study drug.

^h The abbreviated physical examination consisted of a meaningful body system examination based on the judgment of the investigator (or designee) and the patient's symptoms. At least 1 body system was checked for an abbreviated physical examination.

¹ Vital signs measurements were taken after the patient rested for at least 5 minutes and included systolic and diastolic blood pressure (millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate ( breaths/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On the day of dosing, vital signs were determined prior to study drug administration.

¹ A single 12-lead ECG was performed at screening and pre-dose on day 57 and day 183. Patients were supine for approximately 5-10 minutes prior to ECG and remained supine, but awake, during ECG.

^k Clinical laboratory measurements were performed before dosing on the day of dosing. FSH levels were measured only during screening to confirm postmenopausal status.

¹ Serum samples for PK/PD analyzes were collected before dosing (within 0.5 h before the start of the infusion) and at the end of the infusion (within 0.5 h after the end of the infusion). To minimize needle sticks to the patient, a pre-dose sample may be taken through the venous access obtained for dose infusion prior to dosing. Samples at the end of the infusion were taken from the opposite, non-infused arm of the patient. It should be noted that the sample at the end of the infusion on day 183 was considered as an assessment in the expansion period (see tables. 31 and 32). All collection times were recorded in eCRF. At an abrupt hemolysis event, a serum sample was collected for PK/PD analysis.

^m Serum samples for PK/PD analyzes were collected before dosing (within 0.5 h prior to infusion) for patients treated with eculizumab and at any time for patients treated with ALXN1210. All collection times were recorded in eCRF. At an abrupt hemolysis event, a serum sample was collected for PK/PD analysis.

ⁿ Samples for ADA were collected before dosing.

⁰ If the predicted event of acute hemolysis occurred, the parameters LDH, PK and PD were analyzed in the central laboratory. If the predicted event of acute hemolysis did not occur at the time of the scheduled visit, an off-schedule visit was performed to assess the patient's condition and collect the necessary LDH, PK, and PD parameters.

^p Patients were randomly enrolled for treatment using an interactive system allowing access by phone call or via the Internet (IxRS).

^q The dose of ALXN1210 is based on the patient's last recorded body weight during the study visit.

^r Primary efficacy endpoints were assessed prior to dosing on day 183. Dosing on day 183 was the start of the expansion period. Additional procedures on day 183 after dosing, see table. 31 and 32.

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Table 31

Study Schedule and Evaluations: Extension Period - Patients Transferred from Group ALXN1210

Period Expand period union Research days 183 ^a 239 295 351 407 463 519 575 631 687 743 799 855 911 EOS/E T Window (day) ±2 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 clone size PNH ^b X X X X X X X X X X X X X Weight X X X X X X X X X X X X X Pregnancy test ⁰ X X X X X X X X X X X X X Registration of transfusions and transfusion parameters ⁰ X X X X X X X X X X X X X Symptoms of PNH ^e X X X X X X X X X X X X X FACIT- ^Fatigue X X X X EORTC QLQ-C30 ¹ X X X X £ Symptom Questionnaire PNH X X X X X X X X X X X X X Questionnaire for patients on the use of ^resources X X X X X X X X X X X X X Abbreviated physical examination ⁸ X X X X X X X Vital Signs ¹¹ X X X X X X X X X X X X X Safety, 12-lead ECG ¹ X Chemical analysis including LDH ^j X X X X X X X X X X X X X Hematology, including free hemoglobin and blood coagulation ¹ X X X X X X X X X X X X X Urinalysis and urinalysis ^] X X X X X X X X X X X X X sampling for PK/PD ^k X X X X X Immunogenicity (ADA) ¹ X X X X X X X Safety Checklist Overview X X X X X X X X X X X X X

- 84 043233

Acute hemolysis ¹¹¹ <—Continuous monitoring—”· Concomitant medicines <—Continuous monitoring—” Adverse Events <—Continuous monitoring—” Introduction ALXN1210 ¹¹ X xxxxxxxxxxxxxxxx

Abbreviations: ADA=antibody against drug; ECG=electrocardiogram; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-30 Scale; EOS=end of study; ET=early termination; FACI Fatigue = Chronic Disease Therapy Functional Evaluation Scale - Fatigue; LDH=lactate dehydrogenase; PD=pharmacodynamics; PK=pharmacokinetics; PNH=paroxysmal nocturnal hemoglobinuria.

^a All patients registered for the expansion period were administered ALXN1210 on day 183 after all evaluations.

^b Clone size of granulocytes and erythrocytes (RBC) measured by high sensitivity flow cytometry on days 351 and 743; only the size of the RBC clone at other examinations.

^c For female patients of childbearing potential only. Serum pregnancy test only for ET; urine pregnancy test at all other time points. A negative urine test was required prior to administration of ALXN1210 to female patients of reproductive potential on the day of dosing.

^d Transfusions given during and between visits were recorded.

^e Investigator or designee assessment of the following events: fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.

^f Therapist-reported and patient-reported scores were obtained prior to administration of study drug.

^g The abbreviated physical examination consisted of a meaningful body system examination based on the judgment of the investigator (or designee) and the patient's symptoms. At least one body system was tested for a reduced physical examination.

h Vital signs measurements were taken after the patient rested for at least 5 minutes and included systolic and diastolic blood pressure (millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate ( breaths/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). Vital signs were determined prior to the administration of each study drug.

¹ A single 12-lead ECG was performed on day 911 or ET. Patients were supine for approximately 5-10 minutes prior to the ECG and remained supine, but awake, during the ECG.

j Clinical laboratory measurements were taken before dosing on the day of dosing.

^k Serum samples for PK/PD analyzes were collected at the end of the infusion on day 183; before dosing (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) on days 351, 575 and 743; and at any time on the day 911 or ET. To minimize needle sticks to the patient, a pre-dose sample was taken through the venous access obtained for dose infusion prior to dosing. Samples at the end of the infusion were taken from the opposite, non-infused arm of the patient. All collection times were recorded in eCRF. At an abrupt hemolysis event, a serum sample was collected for PK/PD analysis.

¹ Samples for ADA were collected before dosing.

^m If the predicted event of acute hemolysis occurred, the parameters LDH, PK and PD were analyzed in the central laboratory. If the predicted event of acute hemolysis did not occur at the time of the scheduled visit, an off-schedule visit was performed to assess the patient's condition and collect the necessary LDH, PK, and PD parameters.

ⁿ The dose of ALXN1210 is based on the patient's last recorded body weight during the study visit.

- 85 043233

Table 32

Schedule of examinations and assessments during the study: expansion period - patients,

translated from eculizumab groups Period Expansion period Research days 183 ^a 197 225 253 309 365 421 477 533 589 645 701 757 813 869 925 EOS/E T Window (day) ±2 ±3 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 clone size PNH ^b X X X X X X X X X X X X X X Weight X X X X X X X X X X X X X X X Pregnancy test ⁰ X X X X X X X X X X X X X X Registration of transfusions and transfusion parameters ⁰ X X X X X X X X X X X X X X X Symptomatology PNH ^e X X X X X X X X X X X X X X X FACIT- ^Fatigue X X X X EORTC QLQC30 ^f X X X X PNH symptom questionnaire ^f X X X X X X X X X X X X X X Questionnaire for patients on the use of ^resources X X X X X X X X X X X X X X Abbreviated physical examination ⁸ X X X X X X X X X Vital Signs ¹¹ X X X X X X X X X X X X X X X Safety, 12-lead ECG ¹ X Chemical analysis including LDH ^J X X X X X X X X X X X X X X X Hematology, including free hemoglobin and blood coagulation ³ X X X X X X X X X X X X X X X Urinalysis and urinalysis ³ X X X X X X X X X X X X X X X Sampling for PK/PD ^k X X X X X X X Immunogenicity (ADA) ¹ X X X X X X X Safety Checklist Overview X X X X X X X X X X X X X X X Acute hemolysis ¹¹¹ •«—Continuous Monitoring^ Concomitant medicines "—Continuous Monitoring—"· Adverse Events "—Continuous Monitoring—" Introduction ALXN1210 ¹¹ X X X X X X X X X X X X X X

Abbreviations: ADA=antibody against drug; ECG=electrocardiogram; EORTC

QLQ-C30=European Organization for Research and Development Quality of Life Core Questionnaire-30 Scale

- 86 043233 treatment of malignant tumors; EOS=oKOH4aHue research; ET=early termination; FACI Fatigue = Chronic Disease Therapy Functional Evaluation Scale - Fatigue;

LDH=lactate dehydrogenase; PD=pharmacodynamics; PK=pharmacokinetics; PNH=paroxysmal nocturnal hemoglobinuria.

a All patients enrolled for the expansion period received ALXN1210 on day 183, after all evaluations.

^b Clone size of granulocytes and erythrocytes (RBC) measured by high sensitivity flow cytometry on days 365 and 757; only the size of the RBC clone at other examinations.

^c For female patients of childbearing potential only. Serum pregnancy test only for ET; urine pregnancy test at all other time points. A negative urine test was required prior to administration of ALXN1210 to female patients of reproductive potential on the day of dosing.

^d Transfusions given during and between visits were recorded.

^e Investigator's or designee's evaluation of the following events: fatigue, abdominal pain, dyspnea, dysphagia, chest pain, and erectile dysfunction.

f Therapist-reported and patient-reported scores were obtained prior to administration of study drug.

^g The abbreviated physical examination consisted of a meaningful examination of the body system based on the judge's (or designee's) judgment and the patient's symptoms. At least one body system was tested for a reduced physical examination.

^h Vital signs measurements were taken after the patient rested for at least 5 minutes and included systolic and diastolic blood pressure (millimeters of mercury [mmHg]), heart rate (beats/minute), respiratory rate ( breaths/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). Vital signs were determined prior to administration of each study drug.

¹ A single 12-lead ECG was performed on day 925 or ET. Patients were supine for approximately 5-10 minutes prior to the ECG and remained supine, but awake, during the ECG.

- ¹ Clinical laboratory measurements were performed before dosing on the day of dosing.

^k Serum samples for PK/PD analyzes were collected before dosing (within 0.5 h before the start of the infusion) and at the end of the infusion (within 0.5 h after the end of the infusion) on days 197, 365, 589, and 757; at the end of the infusion on day 183; and at any time on the day 225 and 925 or ET. To minimize needle sticks to the patient, a pre-dose sample was taken through the venous access obtained for dose infusion prior to dosing. Samples at the end of the infusion were taken from the opposite, non-infused arm of the patient. All collection times were recorded in eCRF. At an abrupt hemolysis event, a serum sample was collected for PK/PD analysis. ¹ Samples for ADA were collected before dosing.

^m If the predicted event of acute hemolysis occurred, the parameters LDH, PK and PD were analyzed in the central laboratory. If the predicted event of acute hemolysis did not occur at the time of the scheduled visit, an off-schedule visit was performed to assess the patient's condition and collect the necessary LDH, PK, and PD parameters.

ⁿ The dose of ALXN1210 is based on the patient's last recorded body weight during the study visit.

3. Study population.

A total of 195 patients with documented PNH are enrolled and randomly assigned to treatment with either ALXN1210 (ravulizumab) or eculizumab at approximately 50 study sites worldwide. Individuals who were not eligible for this study (not screened) may be rescreened. Prospective approval of protocol deviations based on invitation and registration criteria, also known as permissions for protocol deviations or exemptions from protocol restrictions, was not allowed.

Patients were eligible for study enrollment 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. Treatment with eculizumab, in accordance with the stated PNH dosing recommendations, for at least 6 months up to Day 1.

3. Lactate dehydrogenase (LDH) < 1.5 x ULN at screening. The sample must be obtained on the scheduled pre-dose eculizumab dosing day (i.e. at the lowest eculizumab level) and analyzed at the central laboratory.

4. Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry (Borowitz MJ et al., Cytometry Part B, 78B:211-230, 2010) RBC and leukocyte (WBC) evaluation, with >5% granulocyte or monocyte clone size.

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5. To reduce the risk of meningococcal infections (Neisseria meningitidis), all patients should be vaccinated against meningococcal infections within 3 years before or at the start of study drug administration. Patients initiating study drug treatment less than 2 weeks after meningococcal vaccine administration were treated with appropriate prophylactic antibiotics up to 2 weeks after vaccination.

6. Female patients of reproductive potential and male patients with female partners of reproductive potential should follow protocol guidance to prevent pregnancy during treatment and for 8 months after the last dose of study drug.

7. Patients must be willing and able to give informed consent and adhere to the schedule of all exam examinations and procedures, including the use of any data collection device(s) for direct recording of patient data.

Patients were excluded from enrollment in the study if they met any of the following criteria:

1. LDH level > 2 x ULN within 6 months to day 1.

2. MAVE within 6 months to day 1.

3. Platelet count < 30,000/mm ³ (30 x 109/L) at screening.

4. Absolute neutrophil count < 500/µl (0.5 x 10 ⁹ /l) at screening.

5. Bone marrow transplantation in history.

6. Body weight < 40 kg at screening.

7. History of N. meningitides infection.

8. Unspecified, recurrent infection history.

9. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug administration on day 1.

10. Presence of fever > 38°C (100.4°F) within 7 days prior to study drug administration on day 1.

11. Human immunodeficiency virus (HIV) infection (as proven by anti-HIV-1 or anti-HIV-2 antibody titer).

12. Immunization with live attenuated vaccine 1 month prior to study drug administration on day 1.

13. History of malignancy within 5 years of screening, excluding treated non-melanoma skin cancer or carcinoma in situ of the cervix, with no evidence of recurrence.

14. A history of or current underlying heart, lung, kidney, endocrine, or hepatic disease (eg, active hepatitis) that, in the opinion of the investigator or sponsor, prevents the patient from participating in exploratory clinical trials.

15. Unstable medical conditions (eg, myocardial ischemia, active gastrointestinal bleeding, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, concomitant chronic non-PNH anemia) that make them less likely to tolerate protocol requirements (eg transfusion guidelines).

16. Concomitant use of anticoagulants is prohibited unless administered on a stable regimen for at least 2 weeks prior to Day 1.

17. History of hypersensitivity to any ingredient contained in the investigational medicinal product, including hypersensitivity to mouse proteins.

18. Women who are planning a pregnancy, or are currently pregnant or breastfeeding.

19. Women who have a positive pregnancy test at screening or on day 1.

20. Participation in another interventional treatment study or use of any experimental therapy within 30 days prior to the start of study drug administration on Day 1 in that study or within 5 half-lives of that study product, whichever is greater.

21. Known or suspected history of drug or alcohol addiction or dependence within 1 year prior to screening.

22. Known medical or psychological condition(s) or risk factor that, in the opinion of the Investigator, may preclude the patient's full participation in the study, pose any additional risk to the patient, or misrepresent the patient's assessment or study outcome.

The patient had the right to withdraw from the study at any time. If the patient withdrew consent, the scores indicated for the early termination (ET) review were performed. Patients who dropped out of the study were not replaced.

Patients were permanently discontinued treatment with ALXN1210 if any of the following occurred during the course of the study:

1. Serious infusion reaction (such as bronchospasm with wheezing or need for ventilator support, or symptomatic hypotension) or serum sickness reactions occurring 1-14 days after drug administration;

2. Severe uncontrolled infection;

3. Pregnancy or pregnancy planning; or

4. If it was in the best interests of the patient.

If the study drug was discontinued for a patient, the patient was encouraged to return to the remaining examinations in his or her schedule prior to initiation of excellent complement-targeted therapy.

If the study was terminated for a patient with a current adverse event or laboratory result that was considered by the Investigator to be significantly outside the reference range and clinically significant, the Investigator made efforts to ensure follow-up until satisfactory clinical resolution of the laboratory result or adverse event was achieved. If a female patient permanently discontinued ALXN1210 treatment due to pregnancy, the investigator made efforts to follow up to the outcome of the pregnancy.

The sponsor or public health authority may terminate the study for reasonable cause. The end of the study was defined as the date of the last examination of the last patient in the expansion period.

6. Investigational drug.

The study drugs in this study were ALXN1210 (ravulizumab) and eculizumab (active control). Both ALXN1210 and eculizumab are humanized anti-C5 monoclonal antibodies.

ALXN1210 and eculizumab formulations were supplied for clinical trials as sterile preservative-free solutions of 10 mg/ml in disposable vials and developed for infusion by dilution in commercially available saline (0.9% sodium chloride for injection; country-specific pharmacopeia) for administration by IV infusion (see Table 33).

Table 33

Investigational drug

Investigational drug Product name ALXN1210 Eculizumab Dosage form Concentrated solution (10 mg/ml) for infusion Concentrated solution (10 mg/ml) for infusion Method of administration IV infusion IV infusion Physical Description Clear to translucent, whitish, practically free of particles Clear, colorless solution, practically free of particles Manufacturer Alexion Pharmaceuticals Inc. or an organization that manufactures under a contract Alexion Pharmaceuticals Inc. or an organization that manufactures under a contract

ALXN1210 and eculizumab were packaged in USP/EPS Type 1 borosilicate glass vials and sealed with butyl rubber stoppers with an aluminum crimp cap and flip cap. Study drug was supplied in kits. Investigational drug orders were distributed to each center upon receipt of all required required documents based on current regulations.

Upon arrival of the investigational drug kits at the study site, the pharmacist or authorized person immediately removed the investigational drug kits from the transport refrigerator and stored them in their original boxes under refrigerated conditions at 2-8°C (35-47°F) and protected from Sveta. ALXN1210 and eculizumab were not designed for freezing. Investigational drug was stored in secure, restricted storage and temperature was monitored daily.

Eculizumab or ALXN1210 was not administered as an IV bolus or bolus injection. Study drug infusions were prepared using an aseptic technique. The required patient dose of ALXN1210 or eculizumab was further diluted in commercially available saline (0.9% sodium chloride; country-specific Pharmacopoeia) in the volume shown in Table 1. 34 for ALXN1210 or tab. 35 for eculizumab (see also approved local labeling or

- 89 043233 current IB for eculizumab). A mixture of ALXN1210 or eculizumab was administered to the patient using an IV tubing set via an infusion pump. It was necessary to use a 0.2 micron filter during ALXN1210 infusion.

Table 34

Reference map. dosing for dose preparation ALXN1210

Dose type Body weight (kg) ^a Dose (mg) Volume ALXN1210 (ml) Salt solution volume (ml) Total volume (ml) Minimum long-term infusion, minutes (hour) Maximum infusion rate (ml/hour) load > 40 - < 60 2400 240 240 480 114(1.9) 253 > 60 - < 100 2700 270 270 540 102 (1.7) 318 > 100 3000 300 300 600 108 (1.8) 333 Supportive > 40 - < 60 3000 300 300 600 140 (2.4) 250 > 60 - < 100 3300 330 330 660 120 (2.0) 330 > 100 3600 360 360 720 132 (2.2) 328

Note: See the Pharmaceutical Manual for additional instructions for dose preparation.

^a Body weight, as recorded at the last examination in the study.

Table 35 _____Dosing reference chart for eculizumab dose preparation_____

Dose type Dose (mg) Eculizumab volume (ml) Salt solution volume (ml) Total volume (ml) Long term infusion (minutes) Approximate infusion rate (ml/hour) Supportive 900 90 90 180 35 300

Only a pharmacist or qualified healthcare professional prepared and dispensed study drug doses. Investigational drug was distributed only to enrolled patients confirmed to be eligible for this study. After preparation of the investigational medicinal product for a patient, it was administered only to that patient. The study drug vials are for single use only and no drug remaining in the vial has been used on another patient. No drug remaining in the infusion tubing or infusion bag was used on another patient.

Patients were randomly enrolled in a 1:1 ratio to either continue eculizumab or switch to ALXN1210 for 26 weeks. Study drug was administered as a slow IV infusion (see Tables 34 and 35). Day 1 of study drug administration occurred 2 weeks after the last dose of eculizumab was administered to the patient.

The dosing regimen for ALXN1210 was a loading dose on day 1 followed by maintenance doses on day 15 and every 8 weeks (q8w) thereafter. The dose of ALXN1210 is based on the patient's last recorded body weight during the study visit, as shown in Table 1. 36.

Table 36

ALXN1210 doses based on weight

ALXN1210 treatment group, body weight Loading dose maintenance dose > 40 - < 60 kg 2400 mg 3000 mg > 60 - < 100 kg 2700 mg 3300 mg > 100 kg 3000 mg 3600 mg

Patients randomly enrolled to continue eculizumab continued to receive maintenance doses of eculizumab, according to the approved PNH dosing regimen, which was 900 mg q2w.

After the randomized treatment period, all patients entered the expansion period and were and continued to be treated with ALXN1210 until the product became registered or approved (according to country-specific guidelines), or for up to 2 years, whichever will come earlier. Beginning on day 183, patients randomized to the ALXN1210 treatment arm received a weight-based maintenance dose of ALXN1210 every 8 weeks (q8w), and patients randomized to the eculizumab arm received a weight-based loading dose of ALXN1210 followed by 2 weeks and every 8 weeks (q8w) thereafter, weight-based maintenance dose of ALXN1210 (Table 36; Fig. 26). The actual time of administration of all doses was recorded in the patient's electronic clinical trial participant card (eCRF).

- 90 043233

Patients meeting all enrollment criteria were randomly enrolled for study treatment with ALXN1210 or eculizumab at baseline (Day 1). Assignment to a treatment group was determined by a computer-generated random sequence using an interactive system allowing access by phone call or via the Internet (IxRS). Randomization was a stratified randomization. Patients were stratified into 1 of 2 groups based on history of transfusions (undergoing pRBC transfusion within 12 months to day 1, yes or no). Patients within both groups were then randomly enrolled in a 1:1 ratio to either continue eculizumab or switch to ALXN1210 during a 26-week randomized treatment period.

The weight-based doses of ALXN1210 in this study (Table 36) were based on PK/PD data from early development studies in healthy adult volunteers, as well as available data for patients with PNH in the current phase 1b dose-finding study (ALXN1210 -PNH-103) and in the current phase 2 proof-of-concept study (ALXN1210-PNH-201). The choice of ALXN1210 dosing regimen was based on targeted immediate, complete, and long-term inhibition of the terminal complement complex in patients with PNH.

The dose of eculizumab was the approved dose for the treatment of patients with PNH (U.S. Prescribing Information [USPI] and Summary of Product Characteristics [SmPC] for Soliris®).

Infusion of other monoclonal antibodies has been associated with infusion reactions, usually onset during or shortly after completion of the infusion. Prior medicinal products (including vitamins and herbal preparations) - including those discussed in the exclusion criteria and procedures section (any therapeutic intervention such as surgery/biopsy or physical therapy) that the patient is administered or administered within 28 days (or 3 years for documentation of meningococcal vaccination) prior to screening, up to the first dose of investigational medicinal product, were recorded on the patient's electronic clinical trial participant (eCRF) record.

Transfusions of pRBCs within 1 year prior to the first study drug administration were recorded in the patient's eCRF.

All drug use and procedures performed during the study were recorded on the clinical trial participant registration form/medical record and the patient's eCRF. This registration included all prescription drugs, herbal products, vitamins, minerals, over-the-counter drugs, and current PNH drugs. Concomitant medicinal products were registered from the first infusion of investigational medicinal product until 56 days after the last dose of investigational medicinal product administered to the patient. Any changes to concomitant medications were also recorded on the clinical trial participant registration form/medical record and the patient's eCRF. Any concomitant drug deemed necessary for the patient's standard of care during the course of the study, or for the treatment of any adverse event (AE), together with the eligible drugs described below, was administered at the discretion of the investigator.

Concomitant use of anticoagulants was prohibited unless administered on a stable dosing regimen for at least 2 weeks prior to Day 1. The use of complement inhibitors other than the study drug assigned to the patient was prohibited.

Due to their mechanism of action, the use of eculizumab or ALXN1210 increases the patient's susceptibility to N. meningitidis infections. To reduce the risk of meningococcal infections, all patients were vaccinated against meningococcal infections within 3 years before or at the start of study drug administration. Patients initiating study drug treatment less than 2 weeks after meningococcal vaccine administration were treated with appropriate prophylactic antibiotics up to 2 weeks after vaccination. Vaccines against serotypes A, C, Y, W135 and B, when available, are recommended to prevent infection with common pathogenic meningococcal serotypes. Patients were vaccinated or revaccinated according to current national vaccination guidelines or local practice for the use of vaccination with complement inhibitors (eg, eculizumab).

Vaccination may not be sufficient to prevent meningococcal infection. Official guidance and local practice for the appropriate use of antibacterial agents may be taken into account. All patients can be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics as needed.

7. Performance evaluations.

Red cell transfusion (pRBC) was performed when the patient had:

hemoglobin level of 9 g/dl or less with signs or symptoms of sufficient severity to

- 91 043233 justify the transfusion;

hemoglobin level of 7 g/dl or less, regardless of the presence of clinical signs or symptoms.

Signs or symptoms typically associated with or provoking a patient's need for transfusion were documented in the eCRF for each individual patient. Typical anemia-related symptoms warranting transfusions included angina pectoris, altered mental status (eg, syncope, dizziness, confusion, stroke, transient ischemic attack), severe or worsening difficulty breathing, and severe or worsening fatigue. Other symptoms that provoke a potential need for a transfusion can be discussed with a medical supervisor before the transfusion is performed.

If a patient met any of the transfusion criteria during the course of the study, the investigator determined the appropriate number of pRBC units to be administered via transfusion. It was recommended that the transfusion be performed within 48 hours of determining the hemoglobin level leading to the transfusion. The conduct of the transfusion, including the hemoglobin result and symptoms triggering the transfusion, and the number of units administered by transfusion, were documented in the eCRF.

Prior to randomization and within 5 days prior to study drug administration on day 1, each patient's hemoglobin was assessed either by a local or central laboratory. If the patient's hemoglobin level met this transfusion guideline at that time, the patient was transfused with pRBC to a hemoglobin level above the transfusion limit to be eligible for randomization. Either the local or central laboratory confirmed that the patient's hemoglobin level after transfusion exceeded the transfusion limit.

E. LDH and other disease-related laboratory parameters.

Blood and urine samples were collected. The following disease-related laboratory parameters were measured during the study: LDH, free hemoglobin, occult blood, urinalysis, total C5, haptoglobin, reticulocyte count, RBC clone size at PNH estimated by high sensitivity flow cytometry, D-dimer concentration, estimated rate glomerular filtration rate (calculated using the kidney failure diet modification formula), urine albumin:creatinine ratio, and C-reactive protein.

F. Questionnaires for quality of life, additional signs and symptoms of PNH, and resource use.

Two validated QoL scales were offered to patients prior to study drug administration. The FACIT Fatigue Scale, version 4.0, is a collection of QoL questionnaires related to the management of symptoms of fatigue due to chronic disease. FACI Fatigue is a 13-item questionnaire assessing patient-reported fatigue and its impact on daily activities and functions during the previous 7 days. Patients rated each item on a 5-point scale: 0 (not at all) - 4 (very strongly). The overall score ranged from 0 to 52, with a higher score indicating a better QoL score.

The European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire-30 Scale (QLQ-C30), version 3.0, is a questionnaire designed to assess the QoL of patients with malignant tumors. The questionnaire includes the following subscales: general health, functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social activity), symptom scales (fatigue, nausea and vomiting, and pain), and individual items (dyspnea, insomnia, loss of appetite, constipation, diarrhea and financial difficulties). Thirty questions were related to QoL, where the first 28 questions were rated on a 4-point scale (1=not at all - 4=very bad) and the last 2 questions, analyzing the patient's general health and QoL, were rated on a scale of 1 (very bad) - 7 (Great). Each subscale had a range of 0-100%, where a high score represented a higher response rate. Thus, a high score on the functional scale represented a high level of functioning, but a high score on the symptom scale represented a high level of symptomatology/problem.

Patients completed two additional questionnaires to assess disease burden. These questionnaires were administered to patients prior to study drug infusion. The PNH symptom questionnaire lists the following symptoms: yellowing of the eyes, discoloration of urine, chest pain, difficulty breathing, headache, fatigue, abdominal pain, confusion, erectile dysfunction, difficulty swallowing, and others. Patients indicated whether they had experienced each of the symptoms in the past week, and if so, they rated frequency (on a 4-point scale ranging from rare to almost always), severity (on a 4-point scale ranging from mild to very severe) and associated with this degree of stress/anxiety (on a 5-point scale ranging from not at all to very severe).

The Resource Utilization Questionnaire asked patients to report the number of times during the last month they had to: visit their healthcare provider primarily for PNH treatment (excluding protocoled study visits), arrive at emergency room primarily for PNH, admitted to hospital primarily for PNH, had dark urine, and/or missed a day of work as a result of PNH symptoms.

a) Major adverse vascular events.

Major adverse vascular events (MAVE) were assessed as part of a routine assessment of adverse events (AE). A description of the MAVE, including diagnostic method and resolution date (or current), was collected in the eCRF as part of the patient's medical history (before baseline).

MAVE was defined as follows: thrombophlebitis/deep vein thrombosis, pulmonary embolism, myocardial infarction, transient ischemic attack, unstable angina, renal vein thrombosis, acute peripheral vascular occlusion, thrombosis or infarction of mesenteric/visceral veins, thrombosis or infarction of mesenteric/visceral arteries, thrombosis hepatic/portal vein (Budd-Chiari syndrome), cerebral artery occlusion/acute cerebrovascular accident, cerebral vein occlusion, renal artery thrombosis, gangrene (non-traumatic; non-diabetic), amputation (non-traumatic; non-diabetic) and dermal thrombosis, other.

G. Safety ratings.

The investigator or his/her designee met with patients to discuss the potential safety risks of ALXN1210 (ravulizumab) and eculizumab, and to give the investigator an opportunity to address any patient concerns regarding the study. The investigators tracked any AEs to their completion (resolution or stabilization). The timing of clinical and laboratory evaluations is indicated in the evaluation schedule. Any clinically significant abnormal findings were monitored until resolution or stabilization.

Demographic parameters were reviewed, including age, gender, race and ethnicity. A complete medical history was collected and documented. Weight and height were recorded. Growth was measured only at screening.

The medical history of the patient with PNH, including the onset of the first symptom of PNH, date of diagnosis, PNH clone size, pRBC transfusions, and any history of MAVE, was documented at the screening examination.

The patient's medical history, including prior and comorbid conditions/disorders and history of transfusions, was recorded at the screening examination. Drug use (prescription or non-prescription, including vitamins and/or herbal supplements) within 28 days prior to screening and meningococcal vaccination within 3 years prior to the first dose of study drug were also recorded.

The physical examination included the following assessments: general appearance; skin; head, ears, eyes, nose and throat; neck; lymph nodes; chest; hearts; abdominal cavity; limbs; central nervous system; and the musculoskeletal system. The abbreviated physical examination consisted of a meaningful body system examination based on the investigator's judgment and the patient's symptoms.

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

Samples were collected for a serum pregnancy test, hematology analysis, chemical analysis, blood coagulation analysis, and urinalysis. Samples for laboratory evaluations were collected prior to the administration of each study drug. If the predicted event of abrupt hemolysis occurred, an off-schedule inspection was performed in which a sample was collected for LDH and PK/PD analysis at a central laboratory.

It is understood that some laboratory values may be outside the normal range due to comorbidity. The investigators used physician judgment in assessing the clinical significance of these values. Clinical significance was defined as any deviation in laboratory measurements that was of medical significance and that resulted in a change in medical care. If there were clinically significant laboratory changes from baseline, the changes were documented as AE in AE eCRF. The investigator also assessed association with study treatment for all clinically relevant values outside the range. The Investigator continued to monitor the patient through additional laboratory evaluations until (1) values returned to the normal range or baseline, or (2) the Investigator expressed the opinion that values outside the normal range are not related to study drug administration or other protocol-specific procedures .

For women of reproductive potential, a serum or urine pregnancy test was performed

- 93 043233 (i.e. beta-human chorionic gonadotropin [β-hCG]).

Blood samples were analyzed for serum chemistry. Indirect bilirubin was calculated from the levels of total and direct bilirubin; thus, results for indirect bilirubin were not available if direct bilirubin was below the limit of quantitation. Serum FSH levels were measured during screening for postmenopausal female patients to confirm their postmenopausal status. Conducted chemical evaluations. Estimated glomerular filtration rate was calculated using the Renal Failure Diet Modification formula at all examinations at which serum chemistries were performed. Blood samples were analyzed for blood coagulation parameters.

Urine samples were analyzed. Microscopic examination of urine samples was performed if the results of macroscopic analysis were abnormal. Urine samples were also analyzed to measure the level of proteins and creatinine to calculate the ratio of protein:creatinine in the urine.

HIV testing for human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2) was required for all patients prior to enrollment. No known HIV-positive patients were registered.

A single digital 12-lead ECG was performed for each patient. Patients were supine for approximately 5-10 minutes prior to the ECG and remained supine, but awake, during the ECG.

Blood samples were collected to test for the presence and titer of anti-ALXN1210 ADA or eculizumab in serum prior to study drug administration. Additional characterization of antibody responses was performed as needed, including binding and neutralizing antibodies, PK/PD, safety and potency of ALXN1210 or eculizumab.

An adverse event (AE) was any adverse medical event in a patient who was administered a pharmaceutical product and was not necessarily causally related to that treatment. AE could thus be any adverse or unintended sign (eg, abnormal laboratory finding), symptom, or disease associated in time with drug use, whether or not thought to be drug-related.

Situations in which an adverse medical event did not occur (eg, hospitalization for elective surgery if scheduled prior to study entry, hospitalization for social or convenience reasons), and envisaged daily fluctuations in preexisting disease(s) or condition(s) ) present or detected at the start of the study that did not worsen were not AEs.

No drug effect was not an AE in clinical trials because the purpose of the clinical trial was to determine drug effect.

A medication error (including intentional misuse, product abuse and overdose) or use other than that specified in the protocol was not considered an AE unless an adverse medical event was present as a result of the medication error.

Pregnancies occurring during maternal or paternal exposure to study product were recorded within 24 hours of notification to the investigator/centre. Data on fetal outcome and breastfeeding were collected for reporting to regulatory authorities and safety assessments.

Adverse events were recorded from the time the consent was signed. AE recorded after informed consent but before study drug administration was considered as pre-treatment AE.

C5 inhibition is known to increase susceptibility to infections caused by encapsulated bacteria, in particular N. meningitidis. The following events were important identified risks in this study: meningococcal infections, sepsis, serious infections, aspergillus infection, infusion reactions. Additional events of interest in this study included the following: serious skin adverse reactions, cardiac events (including ventricular fibrillation), and angioedema.

The severity of adverse events (AE) was ranked using the Common Criteria for Adverse Events Terminology (CTCAE) version 4.03 or higher. A ranking (severity) scale is provided for each AE term. Each CTCAE term was a Low Level Term (LLT) according to the Medical Dictionary for Regulatory Activities (MedDRA®). Each LLT was coded with a MedDRA Preferred Term (PT).

The grade referred to the severity of the AE. CTCAE assigned grades 1-5, with unique clinical descriptions of severity for each AE (Table 37).

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Table 37

Ranking scale for the severity of adverse events _______

Degree Description Degree 1 soft; asymptomatic or mild symptoms; only clinical or diagnostic observations; no intervention shown. Degree 2 moderate; minimal, local or non-invasive intervention is indicated; restriction of age-appropriate instrumental activity in activities of daily living (ADL) ^a Degree 3 Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization is indicated; disabling; limiting self-service ADL ¹³ Degree 4 Life-threatening consequences; urgent intervention is indicated. Degree 5 AE-related death.

Abbreviations: ADL=activity in daily activities; AE=adverse event.

^and Instrumental ADL refers to cooking, shopping for groceries or clothes, using the phone, managing money, etc.

^b Self care ADL refers to washing, dressing and undressing, eating, using the toilet, taking medication, and not being bedridden.

Any change in AE severity was documented based on specific guidance in the eCRF completion instructions. Severity and severity were distinguished: severity described the intensity of the AE, while the term severity referred to an AE that met specific SAE criteria.

The investigator should provide an estimate of causation (no association, unlikely, possible, probable, or certain) for all AEs (both serious and non-serious), based on the investigator's judgment and observed symptoms associated with the event (Table 38). This score was recorded on the eCRF and any additional forms as needed.

Table 38

Descriptions of causality assessment

Grade Description Not connected/no connection Assumes no causal relationship between the product under investigation and the reported event. unlikely to be associated Assumes that the clinical picture is highly consistent with a cause other than the investigational product, but the correlation cannot be made with absolute certainty, and an association between the investigational product and AE cannot be ruled out with absolute certainty. Possibly related Suggests that treatment with the investigational product may cause or contribute to AE (i.e., the event follows a reasonable time sequence from the time of drug administration and/or follows a known pattern of response to the investigational product, but may also be caused by other factors) . Probably related Assumes that there is a reasonable temporal sequence of the event with the introduction of the investigational product, and a probable causal relationship of the event to the investigational product. This is based on the known pharmacological activity of the investigational product, known or previously reported adverse reactions to the investigational product or drug class, or an opinion based on the investigator's clinical experience. Definitely related Temporal association with study product, other conditions (comorbid illness, reaction to concomitant drug, or progression/manifestation of a disease state) do not appear to explain the event, consistent with known pharmaceutical profile, improvement on discontinuation, recurrence on re-exposure.

A serious adverse event (SAE) was any adverse medical event that:

1. Lead to death.

2. Was life-threatening (i.e. the patient was at risk of death at the time of the event).

3. Required hospitalization of the patient or extension of an existing hospitalization.

4. Led to permanent or significant disability/incapacity.

5. Was a congenital malformation of the fetus / pathology of childbirth.

Significant medical events that may not have been fatal, not directly life-threatening, or not requiring hospitalization could be considered a serious adverse event when, based on the appropriate medical opinion, they put the patient at risk or required intervention to prevent one of the outcomes listed above.

Suspected unexpected serious adverse reactions (SUSAR) were serious events that were not listed in the IB and identified by the investigator.

- 95 043233 as related to the investigational product or method.

All AEs (serious and non-serious) were collected from signing the ICF up to 56 days after the last dose of study drug for patients with ET, or up to 56 days after the last dose of study drug for patients who completed the study.

(i) Pharmacokinetics and pharmacodynamics.

Blood samples for determination of serum drug concentrations and PD estimates were collected before and after study drug administration. The actual date and time (24 hour clock) of each sampling was recorded. The number of PK sampling time points for any given patient did not exceed the currently planned number of time points. In an acute hemolysis event, an additional sample for PK/PD was necessary.

Blood samples for PK and PD assessment at the end of the infusion were taken from the arm opposite the arm used for drug infusion.

PK/PD scores were as follows: change in serum concentration of ALXN1210 and eculizumab over time, change in hemolytic activity in cRBC over time (exploratory), and change in free C5 and total C5 over time.

(ii) Statistical Methods and Scheduled Analyzes.

All collected data were presented in tabular summaries. All data, as well as any outcomes inferred from the data, are presented in detailed data sheets. Graphical representations are also provided where appropriate. All analyzes were performed using SAS® Release 9.4 or later (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. Continuous variables were summarized using descriptive statistics, including number of observations and mean, standard deviation, median, minimum and maximum values. Categorical variables were summarized by frequency and percentage of patients. All statistical tests performed were based on a 2-tailed 5% significance level unless otherwise noted. Exceptions, without exception, were documented in the patient lists.

The details of the statistical analyzes described below were specified in a separate Statistical Analysis Plan (SAP) prior to the database being closed and analyzed. Any change to the data analysis methods described in the protocol required improvement only if it changed the primary or key secondary objectives, or the conduct of the study. Any other change to the data analysis methods described in the protocol or SAP, and the rationale for making the change, is described in the Clinical Study Report (CSR). Additional exploratory data analyzes were performed as deemed necessary.

CSR was generated based on efficacy, safety, PK and PD, and immunogenicity data when all patients remaining in the study completed the 26 week randomized treatment period. The final CSR to summarize data on long-term efficacy, safety, PK and PD, and immunogenicity was obtained at the end of the study.

195 patients were randomly enrolled in a 1:1 ratio to continue eculizumab (N=98) or to switch to ALXN1210 (N=97) to ensure at least 172 eligible patients (assuming a dropout rate of no more than 10%). The sample size estimate was based on a non-inferiority design comparing ALXN1210-treated patients with eculizumab-treated patients.

The primary endpoint of hemolysis, as measured directly by LDH-PCHG from baseline to day 183, was used to assess non-inferiority.

Table 39

Generalization of the parameters used to determine the sample size

Options Percent change in LDH level Power 90% Type I error 1-sided 0.025 Limit of no less efficiency 0.15 distribution ratio 1:1 Standard deviation for eculizumab/ALXM!210 response 0.30/0.30 Alleged difference in treatments 0 Estimated Sample Size (SS) 172 Adjusted SS for 10% dropout 192

Note: Software package: Hintze, J. (2011). PASS 11. NCSS, LLC. Kaysville, Utah, US. www.ncss.com.

Efficacy analyzes were performed on the complete analysis population (FAS). Primary efficacy endpoint analyzes, as well as key secondary endpoint analyzes, were performed on the per-protocol (PP) analysis population. FAS was the primary population for all efficacy analyses. FAS included all patients who received at least 1 dose

- 96 043233

ALXN1210 or eculizumab.

The RR population finalized prior to database closure consisted of FAS patients who met all of the following criteria:

Missed no doses of ALXN1210 or missed no more than 1 dose of eculizumab during the 26-week randomized treatment period.

Met inclusion criteria #2, 3 and 4.

Did not meet exclusion criteria #1, 2, 3, 4, or 5.

Never subjected to incorrect randomized treatment.

The transfusion guidelines specified in the protocol were followed.

Safety analyzes were performed on a safety population defined as all patients who received at least 1 dose of ALXN1210 or eculizumab. Pharmacokinetic and PD analyzes were performed on all patients treated with at least 1 dose of study drug and who had measurable PK and PD data. Patient demographics and baseline characteristics, including medical and transfusion history, were summarized by treatment group and pooled for FAS and safety populations. The number of infusions administered to a patient was tabulated by treatment group for FAS and safety populations.

The primary efficacy endpoint was the difference between treatment groups in LDHPCHG from baseline to day 183. Baseline was defined as the mean of all scores analyzed in the central laboratory prior to the first administration of study drug.

Percent change in LDH was analyzed using a repeated measures mixed-effects model (MMRM) with fixed, categorical treatment effects, study visit, and study visit interaction with treatment group, as well as a continuous, fixed covariance of baseline LDH, and a stratification score. history of randomization for pRBC transfusions (yes/no within 12 months to day 1). The Kenward-Roger approximation was used to estimate the degrees of freedom of the denominator. The difference in LDHPCHG between the ALXN1210 and eculizumab treatment groups was calculated, along with a two-sided 95% CI.

If the upper limit of the 95% CI for difference (ALXN1210-eculizumab) was less than 15% NIM, then ALXN1210 treatment was concluded to be non-inferior to eculizumab. If no less efficacy was obtained and a greater effect was observed for ALXN1210, then superiority was assessed using a two-tailed 5% test.

The key secondary efficacy endpoints were the proportion of patients with acute hemolysis, change from baseline in FACIT-Fatigue, the proportion of patients not requiring transfusion, and the proportion of patients with stabilized hemoglobin, summarized by treatment group. The percentage of patients with acute hemolysis was calculated for both ALXN1210 and eculizumab treatment groups. The difference in the percentage of patients with acute hemolysis in the 2 treatment groups was calculated, together with a 95% CI for the difference. The 95% CI for the difference between the ALXN1210 and eculizumab treatment groups was calculated using the Newcomb CI method. The same method was used to exclude transfusions and stabilized hemoglobin. Transfusion exclusions were granted only for those patients who were not transfused and who did not comply with the transfusion guidelines specified in the protocol. For change from baseline on the FACIT-Fatigue scale, the same method was used for the primary endpoint.

These key secondary endpoints were tested in a hierarchical order, provided no lesser performance was claimed for the primary endpoint. If non-inferiority was obtained for the key secondary endpoint and a greater effect was observed for ALXN1210, then superiority was assessed using a 2-tailed test of 0.05 for each parameter.

When conducting analyzes of key secondary efficacy endpoints, a closed-loop testing method was used; the lack of test significance prevented analysis of subsequent tests. Scores and CIs were calculated for all key secondary efficacy endpoints, regardless of whether the lack of test significance prevented analysis of subsequent tests.

1. If the upper limit of 95% CI for the difference between ALXN1210 and eculizumab treatment groups in the proportion of patients with acute hemolysis was less than NIM 20%, then ALXN1210 was declared non-inferior in this parameter, and the next parameter was tested.

2. If the lower limit of 95% CI for the difference between ALXN1210 and eculizumab treatment groups in change from baseline on the FACIT-Fatigue scale was greater than NIM -3, then ALXN1210 was declared non-inferior in this parameter and the next parameter was tested.

3. If the lower limit of 95% CI for the difference between ALXN1210 and eculizumab treatment groups for TA was above NIM -20%, then ALXN1210 was declared non-inferior to eculizumab and the next parameter was tested.

4. If the lower limit of 95% CI for the difference between the ALXN1210 and eculizumab treatment groups in the proportion of patients with stabilized hemoglobin exceeded the NIM of -20%, then ALXN1210 was said to be non-inferior in this parameter.

The total number of pRBC units administered by transfusion during treatment and the number (%) of LDH patients within the normal range at each study visit were calculated for both ALXN1210 and eculizumab treatment arms. Changes from baseline in EORTC-QLQ-C30 were summarized by treatment group at baseline and at the study visits where these scores were collected. Changes from baseline in the clinical manifestations of PNH were summarized by treatment group and at the study visits where these scores were collected. The number of any treatment-induced MAVE (n) and the number of patients with events (n, %) were displayed by treatment group.

All safety analyzes were performed on the safety population, defined as all patients who received at least 1 dose of ALXN1210 or eculizumab. Safety results were recorded by treatment group.

The following definitions were used for AE:

Pre-Treatment Adverse Events: Any AE that began after informed consent was given but before the first infusion of study drug.

Treatment-induced adverse event (TEAE): Any AE that began during or after the first infusion of study drug.

The incidence of TEAE, TEAE leading to study discontinuation, TEAE leading to study drug discontinuation, drug-related TEAE, TEAE during study drug administration, severe TEAE, and SAE were summarized. All AEs were coded using MedDRA version 18 or higher and summarized by organ system class (SOC) and PT.

Adverse changes from baseline in physical examination findings were classified as AEs and analyzed accordingly. Vital signs were summarized descriptively at baseline and time points after baseline, and by change from baseline across the treatment group.

Observed values and changes from baseline for clinical chemistry, hematology, and urinalysis were summarized descriptively at baseline and at each time point after baseline. For laboratory results that can be classified as normal, low, or high, based on the normal range of values, shifts from baseline in classification were summed for all examinations within the study.

Received data lists for ECG parameters by patient. Changes from baseline in electrocardiogram intervals (PR, RR, QT and QTcF) were presented by treatment group. The QT interval was corrected for heart rate using the Friederick formula (QTcF).

Abnormal immunogenicity findings, including incidence and titers of ADA against ALXN1210 or eculizumab, were summarized in a tabular format by treatment group. One can analyze the proportion of patients ever positive and the proportion of patients always negative.

Individual serum concentration data for all patients treated with at least 1 dose of study drug (i.e., ALXN1210 or eculizumab) and who had measurable PK data were used to derive PK parameters for ALXN1210 and eculizumab.

Build graphs of profiles of the average concentration in serum depending on time. Serum concentration profiles versus time for individual patients can also be plotted. The actual timing of dosing and sampling was used for all calculations. Descriptive statistics were calculated for serum concentration data at each sampling time point, as appropriate. Population PK estimates can be considered using data from this study or in combination with data from other studies.

Descriptive statistics were presented for all ALXN1210 and eculizumab PD endpoints at each sampling time point. The effects of PD of ALXN1210 and IV eculizumab were assessed by evaluating absolute values and changes, and percent change from baseline for total serum C5 and free C5 serum concentrations, and cRBC hemolysis over time, as appropriate. PK/PD association estimates of ALXN1210 can be explored using data from this study or in combination with data from other studies.

If there was no score on day 1, the screening score was used as the baseline score. Manipulations with missing data for the QoL tools were performed as indicated in the instructions for each tool.

Example 5

Results of a randomized, open-label, phase 3, active drug-controlled study of ALXN1210 versus eculizumab in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) previously treated with eculizumab.

The following is a summary of the data obtained from the current phase 3 open label clinical trial conducted according to the protocol described in Example 4 above. A summary of the results for efficacy and safety is presented below.

1. Generalization of the study.

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This Phase 3 human clinical trial was an open-label, randomised, multicentre, active drug-controlled study designed to evaluate the safety and efficacy of ALXN1210 (also known as Ultomiris™, BNJ441 antibody, or ravulizumab) versus eculizumab (Soliris®) administered via intravenous (IV) infusion to adult patients with PNH who have been treated with eculizumab for at least 6 months. The study enrolled a total of 195 patients. A total of 191 patients completed the study, and 186 of these patients are included in this per-protocol analysis. Only 4 subjects discontinued the study during the course of the study (1 from the ALXN1210 group and 3 from the eculizumab group).

This Phase 3 study achieved its primary goal of showing that ALXN1210 (ravulizumab) was non-inferior to eculizumab. Specifically, the study achieved the pre-assigned limits of non-inferiority (NIM) for percent change in LDH (LDH-PCHG) from baseline, with values better than the 15% limits required by the FDA and as specified in the protocol, but not well achieved. advantage in this study (p<0.0583). In addition, all 4 key secondary endpoints were shown to be superior to ALXN1210 and showed non-inferiority compared to eculizumab. For abrupt hemolysis (STH), a quantitative trend towards the advantage of ALXN1210, compared with eculizumab, was also shown, with 0% vs. 5.1%, respectively. In fact, no patients treated with ALXN1210 experienced VTN, compared with 5 for eculizumab (1 eculizumab patient had 3 VTN events). Importantly, the sensitivity analysis showed reliable results for all efficacy endpoints. The data are presented in the accompanying figures and tables and are discussed more fully below.

The non-inferiority study design comparing ALXN1210 and eculizumab is shown in FIG. 25. The study compared an individualized weight-based dosing regimen for ALXN1210 with an existing approved dosing regimen for eculizumab for PNH in an attempt to demonstrate non-inferiority in patients with PNH who had been administered eculizumab for at least 6 months prior to the start of this study. The dose selected for ALXN1210 was based on weight and included a loading dose (2400 mg for patients >40 kg - <60 kg, 2700 mg for patients >60 kg - <100 kg, 3000 mg for patients >100 kg) on Day 1 , followed by maintenance doses of ALXN1210 (3000 mg for patients >40 kg - <60 kg, 3300 mg for patients >60 - <100 kg, 3600 mg for patients >100 kg) on Day 15 and every 8 weeks thereafter. See fig. 25. In contrast, the dose of eculizumab includes a maintenance dose of 900 mg given IV on day 1 and every 2 weeks thereafter. See fig. 25. After completion of the study, subjects in both the ALXN1210 and eculizumab groups entered an expansion period as described in Example 4. During the expansion period, the ALXN1210 group continued to receive ALXN1210 every 8 weeks. In the eculizumab group, a loading dose of ALXN1210 (2400 mg for patients >40 kg - <60 kg, 2700 mg for patients >60 kg - <100 kg, 3000 mg for patients >100 kg) was administered on day 183, followed by maintenance doses of ALXN1210 ( 3000 mg for patients >40 kg - <60 kg, 3300 mg for patients >60 - <100 kg, 3600 mg for patients >100 kg) on Day 197 and every 8 weeks thereafter. The complete dosing regimen for both ALXN1210 and eculizumab groups is shown in FIG. 26.

The study enrolled more patients than originally planned. Specifically, 195 patients were enrolled in the study and randomized to either ALXN1210 or eculizumab (see FIG. 27). A total of 13 subjects were not screened. Of the 195 patients to be included in the 26-week treatment period and completed, 191 were transferred to the current expansion study (see Fig. 27). Baseline characteristics and demographics for the study population are shown in FIG. 28. Baseline disease characteristics are shown in FIG. 29.

Of the 197 randomized patients, 195 treated patients (97 patients in the ALXN1210 arm and 98 patients in the eculizumab arm) were included in the FAS and safety populations, as shown in Table 1 below. 40.

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Table 40

Populations for data analysis (all randomized patients)

ALXN1210, η (%) Eculizumab, n(%) Total, η (%) Number of randomized patients 98(100) 99 (100) 197 (100) Number of patients in FAS 97 (99.0) 98 (99.0) 195 (99.0) Number of patients excluded from FAS 1 (1.0) 1 (1.0) 2(1.0) Number of patients in the RR population 93 (94.9) 93 (93.9) 186 (94.4) Number of patients excluded from the RR population 5(5.1) 6(6.1) And (5,6) Number of patients in the safety population 97 (99.0) 98 (99.0) 195 (99.0) Number of patients excluded from the safety population 1 (1.0) 1 (1.0) 2(1.0) Number of patients in the population for PK analysis 97 (99.0) 98 (99.0) 195 (99.0) Number of patients excluded from the population for PK analysis 1 (1.0) 1 (1.0) 2(1.0)

Abbreviations: PA8=complete population for analysis; PP = according to the protocol.

Eleven patients were excluded from the RR population (ALXN1210: n=5, eculizumab, n=6). Below are the reasons for the exception. Two patients were randomized but not treated due to patient exclusions prior to the first dose (see Table 41). Two patients in the ALXN1210 arm were determined not to have met eculizumab treatment criteria as stated in the PNH dosing recommendation (eculizumab every 14±2 days) within 6 months to day 1 because some of the eculizumab doses were administered outside the ±2 window days. Two patients in the eculizumab arm were determined to have an LDH level >2 x ULN within 6 months to day 1. Five patients (ALXN1210: n=2, eculizumab: n=3) met the protocol-specified criteria for pRBC transfusion (hemoglobin < 7 g/dl), but they were not transfused at this time or at any other time during the initial evaluation period. Although other patients were eligible for transfusion at a particular examination but did not receive a transfusion, these patients are included in the PP population because they received at least 1 transfusion according to the criteria for transfusion.

Three differences in actual stratification at time of randomization, compared with observed stratification, for history of transfusions, were present in this study, as indicated in Table 1. 41. Of 24 patients stratified by transfusion history Yes, 1 patient was determined to have no history of transfusion. Of 173 patients stratified by history of transfusion No, 2 patients had a history of previous transfusions.

Table 41

Stratification groups at randomization and observation (all randomized patients)

Stratification groups for randomization Observed stratification groups ALXN1210 (Ν=98) Eculizumab (N=99) Total (Ν=197) History of transfusions, η (%) Yes Yes 12 (12.2) 11(11.1) 23(11.7) Yes No 0 I (1.0) 1 (0.5) No Yes I(1.0) I (1.0) 2(1.0) No No 85 (86.7) 86 (86.9) 171 (86.8)

Note: Baseline was defined as the last non-missing value prior to the first dose of study drug. The ULN for LDH is 246 U/L.

In the study population of patients with stable disease, only 12.8% had a history of pRBC transfusions within a year prior to the first dose of study drug, as shown in Table 1. 42. The mean number of transfusions within 1 year of the first dose was higher in the ALXN1210 group than in the eculizumab group, as was the mean number of units administered via transfusion.

This difference can be attributed to 2 ALXN1210 patients with severe transfusion dependence.

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Table 42

RBC transfusions within 12 months prior to first dose (total, analysis population)

Variable category ALXN1210 (Ν=97) Eculizumab (N=98) Total (Ν=195) Number of patients with pRBC/whole blood transfusions within 1 year prior to first dose, η (%) 13 (13.4) 12(12.2) 25 (12.8) pRBC/whole blood transfusions within 1 year prior to first dose Total 64 thirty 94 Average (SD) 4.9 (5.51) 2.5 (2.32) 3.8 (4.38) Median 3.0 1.5 2.0 Min, max 1, 17 1.8 1, 17 Units of pRBC/whole blood administered via transfusion within 1 year prior to first dose Total 103 50 153 Average (SD) 7.9 (8.78) 4.2 (3.83) 6.1 (7.00) Median 4.0 2.5 3.0 Min, max 1.32 2, 15 1.32

Abbreviations: max=maximum; min=minimum; pRBC=erythrocyte mass; SD=standard deviation.

The types of PNH symptoms that patients experienced prior to informed consent were similar between treatment groups, with the most common (>20% of all patients) being fatigue or asthenia (general weakness), red or dark urine, abdominal pain, difficulty breathing ( dyspnea), bile effusion, CNS-related symptoms such as headache, dizziness or difficulty concentrating, biliary effusion (yellowing of the skin or eyes), and dysphagia.

In the general population, 95.4% of patients had documented PNH-associated conditions diagnosed prior to informed consent, as indicated in Table 1. 43. It should be noted that 37.4% of patients had a history of aplastic anemia, 9.2% of patients had a history of renal failure, and 4.6% of patients had myelodysplastic syndrome.

Table 43

PNH-associated conditions diagnosed at any time prior to informed consent (full population for analysis)

ΡΝΗ-associated states, n(%) ALXN1210 (Ν=97) Eculizumab (N=98) Total (Ν=195) Patients with any ΡΝΗ conditions prior to informed consent 90 (92.8) 96 (98.0) 186 (95.4) Anemia 64 (66.0) 67 (68.4) 131 (67.2) Hematuria or hemoglobinuria 47 (48.5) 48 (49.0) 95 (48.7) aplastic anemia 34 (35.1) 39 (39.8) 73 (37.4) kidney failure I (P,3) 7 (7.1) 18 (9.2) Complication during pregnancy 4 (4.1) 9 (9.2) 13 (6.7) myelodysplastic syndrome 3(3,1) 6(6.1) 9 (4.6) Other* 14(14.4) 14(14.3) 28 (14.4)

Note: Conditions as documented in the patient's medical record. Patients can be counted in more than one category.

a Another category included neutropenia (n=3), proteinuria, renal dysfunction (n=3), lymphoid hyperplasia, pancytopenia (n=2), thrombopenia (n=3), iron deficiency anemia (n=2), non-severe aplasia, splenomegaly, grade 1 liver cytolysis (n=2), hemolytic anemia, severe haptoglobin drop, pulmonary hypertension, monosomy 7, mild bone marrow hypocellularity, reduced trilinear hematopoiesis, medullary hypoplasia, haptoglobin deficiency and hyperreticulocytosis, leukopenia, dysgranulopoiesis, dyserythropoiesis, dysplastic dyserythropoiesis, recurrence of idiopathic medullary aplasia, thrombocytosis, thrombocytopenia, leukocytosis, muscle aches and pains, and gallstones.

Abbreviation: PNH=paroxysmal nocturnal hemoglobinuria.

A history of one or more MAVEs was recorded in only 25.6% of patients, as indicated in Table 1 below. 44.

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Table 44

History of major adverse vascular events (complete population for analysis)

Category MAVE ALXN1210 (N=97) Eculizumab (N=98) Total (N=195) Patients with a history of MAVE 28 (28.9) 22 (22.4) 50 (25.6) Thrombophlebitis / deep vein thrombosis I (I, 3) 5(5.1) 16 (8.2) Thrombosis of the hepatic/portal veins (syndrome 8 (8.2) 6(6.1) 14 (7.2) Badda-Chiari) Cerebral artery occlusion/acute 5 (5.2) 6(6.1) And (5,6) cerebrovascular accident Cerebral vein occlusion 3(3,1) 2 (2.0) 5 (2.6) thrombosis or infarction 2(2,1) 3 (3.1) 5 (2.6) mesenteric/visceral arteries thrombosis or infarction 1 (1.0) 4 (4.1) 5 (2.6) mesenteric/visceral veins Pulmonary embolism 5 (5.2) 0 (0.0) 5 (2.6) Dermal thrombosis 2(2,1) 0 (0.0) 2(1.0) Transient ischemic attack 1 (1.0) I(1.0) 2(1.0) myocardial infarction 1 (1.0) o(0,0) 1 (0.5) Acute peripheral vascular occlusion 0 (0.0) 0 (0.0) 0 (0.0) Amputation (non-traumatic; 0 (0.0) 0 (0.0) 0 (0.0) non-diabetic) Gangrene (non-traumatic; 0 (0.0) 0 (0.0) 0 (0.0) non-diabetic) Thrombosis of the renal arteries 0 (0.0) 0 (0.0) 0 (0.0) Thrombosis of the renal veins 0 (0.0) 0 (0.0) 0 (0.0) Unstable angina 0 (0.0) 0 (0.0) 0 (0.0) Another ^a 2(2,1) 3(3,1) 5 (2.6)

Note: Patients can be counted in more than one category.

^a Another category included recurrent transjugular intrahepatic portosystemic shunt thrombosis, inferior vena cava thrombosis, retinal vein thrombosis, left atrial thrombosis, superficial thrombosis of the left lower limb, ischemic enteritis.

Abbreviation: MAVE=major adverse vascular event As required, all 195 patients had a history of eculizumab use. Two patients in the ALXN1210 arm were not vaccinated against meningococcal infection within 3 years before or at the time of initiation of study drug administration. All other patients received the meningococcal vaccine no later than day 1.

The most commonly reported (>10% of patients) prior drug groups other than meningococcal vaccine were vitamin B12 and folic acid (59.5%), beta-lactam antibacterials (penicillins) (43.1%), antithrombotics ( 19.0%), drugs for peptic ulcer and gastroesophageal reflux disease (15.4%), and other analgesics and antipyretics (12.8%). In total, 97.9% of patients (97.9% in the ALXN1210 group and 98.0% in the eculizumab group) were treated with at least one concomitant drug. The most commonly reported (>10% of patients) antecedent groups were vitamin B12 and folic acid (62.1%), beta-lactam antibacterials (penicillins) (52.8%), other analgesics and antipyretics (36.9 %), antibacterial vaccines (29.2%), antithrombotic agents (22.6%), antiviral vaccines (19.5%), drugs for peptic ulcer and gastroesophageal reflux disease (19.0%), quinolone antibacterial drugs (16.4%), anti-inflammatory and antirheumatic drugs, nonsteroidal drugs (13.3%) and opioids (10.3%). During the study, only 30.3% were subjected to a non-pharmacological medical procedure.

2. Primary/secondary endpoints and disease-related parameters.

ALXN1210 achieved a statistically significant non-inferiority compared to eculizumab for the primary endpoint, percent change in LDH level (LDH-PCHG) from baseline to day 183, for FAS. Specifically, the primary efficacy endpoint percent change in LDH (LDH-PCHG) had a very clear match and superiority, as shown in FIG. 30. The red triangle in FIG. 30 denotes the non-inferiority limit required by the FDA and specified in the protocol. For the LDH-PCHG endpoint, the 15% non-inferiority limits are well exceeded and the non-inferiority limit of better than 1% is reached. See fig. thirty.

Key secondary endpoints abrupt hemolysis (HTH), FACIT fatigue score change, transfusion exclusion (TA) and hemoglobin stabilization (HGB-S) were also positive and showed an advantage of ALXN1210 compared to eculizumab (see Fig. 30). Moreover, all of the secondary endpoints not only showed the benefit of ALXN1210, but they all significantly exceeded the limits of non-inferiority shown by the red triangles in the graph (see Fig. 30).

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Key primary and secondary endpoints are presented in tabular form in FIG. 31. The benefit of the treatment effect for each endpoint for ALXN1210 was also shown over the effect for eculizumab. For example, the first row shows that the treatment effect for percentage change in LDH (LDH-PCHG) for ALXN1210, compared to eculizumab, was -9.2%, much greater than the required non-inferiority limit of 15%, and clearly represents the detection less effective drug. Similarly, all primary and secondary endpoints led to the same conclusion of non-inferiority of ALXN1210 compared to eculizumab. In other words, ALXN1210 was found to be better than eculizumab; reaching a statistical conclusion of superiority was impossible, probably due to the sample size (see Fig. 31).

The efficacy data for this LDH-PCHG study were subjected to a variety of different sensitivity analyses. The results are shown in FIG. 32. For example, the treatment effect (point estimate) for 1210 was -9.2% better than for eculizumab, with a 95% confidence interval (CI) of -18.8%0.42%. The 0.42% number is significantly better than the predetermined 15% non-inferiority limit. This table shows a variety of sensitivity assays that all support robust primary assay detections. It is worth noting that this consistency is unusual for clinical studies of this type and supports the idea that this study was of very high quality.

The efficacy results for the primary endpoint of LDH-PCHG were analyzed in the form of subgroups of the patient population and are shown in FIG. 33. LDH-PCHG (percent change in lactate dehydrogenase level) refers to the percentage change in LDH level from baseline to day 183. Subgroup analyzes for LDH-PCHG found that stronger evidence showed a benefit of ALXN1210. Gray lines are 95% confidence intervals and blue squares are point estimates. The evaluation was based on the General Estimating Equations (GEE) method. The model included the following terms: treatment group, history of transfusions, and baseline LDH levels. The scores to the right of 1 show the benefit of ALXN1210 and the scores to the left show the benefit of eculizumab. All point estimates were to the right of the predefined limit of non-inferiority (red triangle) (15%). None of the endpoints clearly showed a benefit of eculizumab. In conclusion, the benefit of ALXN1210 compared to eculizumab was shown for all subgroups (see Fig. 33).

In FIG. 34 shows mean values for percent change from baseline (upper panel) and overall level (lower panel) of LDH over time. As shown in FIG. 34, mean values for LDH levels were within the normal range for the patient population at baseline and remained below the upper limit of normal (1 x ULN LDH) throughout the study for the ALXN1210 treatment group. In contrast, mean LDH levels exceeded this upper limit of normal in the eculizumab treatment group on days 29, 113, and 127. The dotted line in FIG. 34 shows the value of the upper limit of normal for LDH or 1x ULN LDH. The box below the graph shows the number of patients in each group, which contributes to that day's average. In conclusion, it is clear that the mean LDH in patients treated with ALXN1210 remained below the critical level of 1.5x ULN (see FIG. 34). The percentage of patients maintaining LDH normalization at various time points during the course of the study is shown in FIG. 35. Over 50% of patients treated with both ALXN1210 and eculizumab remained within the normal range throughout the study (see FIG. 35). In FIG. 36 shows the mean change from baseline in quality of life, as measured by the Functional Assessment of Chronic Disease Therapy (FACIT) - Fatigue, version 4, over time. In FIG. 37 shows the mean score for FACIT fatigue over time. As shown in FIG. 36, for mean change from baseline, improvement was shown for the ALXN1210 treatment group over the course of the study, and for most time points showed a trend towards higher improvement than the improvement seen with the eculizumab treatment group. However, despite improvements in FACIT fatigue scores from baseline, neither group showed a mean increase of more than 3 points (>3 points), as indicated by the dotted line. The box below the graph shows the number of patients in each group, which contributes to that day's average. As shown in FIG. 37, showing the mean assessed FACIT fatigue scores (0-52, where a higher score indicates less fatigue), the ALXN1210 treatment group shows higher mean FACIT fatigue scores than the eculizumab treatment group at all time points.

In addition to the primary and secondary endpoints, the following disease-related laboratory parameters were measured during the study: free hemoglobin, urinary occult blood, total C5, haptoglobin, reticulocyte count, RBC clone size at PNH, D-dimer concentration, eGFR, albumin:creatinine ratio in a single portion of urine and C-reactive protein. Overall RBC clone size in PNH was similar between treatment groups at baseline, with no noticeable change in each group over the course of the study. There was no apparent trend towards a change in the mean free hemoglobin level from baseline over time.

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Mean D-dimer levels decreased from baseline at most post-baseline visits within the study in each treatment group. Mean haptoglobin was low (reference range: 0.4-2.4 g/L) at baseline and throughout the 26-week treatment period in both treatment groups (ALXN1210: 0.283-0.298 g/L; eculizumab: 0.255-0.257 g/l from the starting point to the day 183). Urinary occult blood test was negative in the majority of patients in both ALXN1210 and eculizumab treatment groups, and remained negative during the treatment period. The ratio of reticulocytes/erythrocytes was stable and constant in both groups throughout the 26-week treatment period (ALXN1210: 5.70-6.54%; eculizumab: 5.54-5.87% from baseline to day 183). No marked change from baseline was observed in the mean urinary microalbumin:creatinine ratio over time in both treatment groups. Mean CRP levels were similar between treatment groups at baseline, with little change noted over time in each treatment group.

3. Safety.

Fig. 38 is a tabular presentation of the key safety results in the ALXN1210-PNH-301 phase III clinical study. In general, safety differences in terms of adverse events (AEs) were observed generally at similar rates between ALXN1210 and eculizumab, and there were no discontinuations due to AEs or deaths observed during the initial evaluation period (see FIG. 38). Serious adverse events (SAEs) were less frequent for ALXN1210 compared to eculizumab (4% vs 8%), as shown in FIG. 39. The most common AEs were headache (27% vs. 17%) and nasopharyngitis (22% vs. 20%), as shown in FIG. 40 and 41. In addition, no meningococcal infections were present during the initial evaluation period (see FIG. 42).

There were no observed treatment-induced cases of anti-drug antibody (ADA) formation for ALXN1210, and there was 1 case observed for eculizumab. There was no formation of neutralizing antibodies, and there was no clear effect on PK/PD, efficacy or safety.

Patient compliance with the drug regimen was perfect for this clinical study, showing 100% patient compliance with the drug regimen throughout the 6-month treatment period (see Fig. 43).

2. Pharmacokinetic results.

Pharmacokinetic parameters for ALXN1210 are summarized in Table 1 below. 45 and 46 for the first (induction) and last (maintenance) doses, respectively. Geometric mean (geometric CV%) C _max and C _min of ALXN1210 after the first dose in all patients were 822.3 (22.03) and 390.9 (26.78) µg/mL, respectively. After the last dose of ALXN1210, the geometric mean (%CV) of _Cmax and Cmin in all patients was 1359.3 (19.50) and 479.8 (30.68) µg/mL, respectively.

Table 45 Pharmacokinetic parameters of ALXN1210 ( _Cmax and _Cmin ) after the first (loading) dose of ALXN1210 (PK assay population)

Parameter Statistics All patients (N=96) > 40 - < 60 kg (N=26) > 60 - < 100 kg (N=63) > 100 kg (N=7) S _Max η 95 26 62 7 (µg/ml) Average 842.9 903.2 823.1 794.7 SD 203.47 150.42 216.00 239.70 cv% 24.14 16.65 26.24 30.16 Median 811.0 893.0 779.5 802.0 Minimum 511 656 536 511 Maximum 1750 1450 1750 1240 Geometric mean 822.3 892.6 801.0 765.1 Geometric eCV% 22.03 15.41 22.77 30.39 Smin η 96 26 63 7 (µg/ml) Average 405.4 448.2 394.5 344.3 SD 121.24 151.41 108.28 50.29 cv% 29.91 33.78 27.45 14.61 Median 384.0 440.5 373.0 352.0 Minimum 197 219 197 294 Maximum 1040 1040 896 421 Geometric mean 390.9 428.6 382.1 341.2 Geometric eCV% 26.78 30.34 25.37 14.61

Abbreviations: C _max = maximum serum concentration; C _min =minimum serum concentration; CV=coefficient of variation; SD=standard deviation.

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Table 46

Pharmacokinetic parameters of ALXN1210 ( _Cmax and _Cmin ) after the last ________ maintenance dose of ALXN1210 (PK assay population)________

Parameter Statistics All patients (N=96) > 40 - < 60 kg (N=27) > 60 - < 100 kg (N=61) > 100 kg (N=8) With _mac s η 96 27 61 8 (µg/ml) Average 1384.5 1561.1 1347.4 1071.1 SD 267.61 261.30 231.75 115.87 cv% 19.33 16.74 17.20 10.82 Median 1395.0 1520.0 1360.0 1040.0 Minimum 902 1040 902 924 Maximum 2320 2320 1850 1240 Geometric mean 1359.3 1540.8 1327.6 1065.8 Geometric CV% 19.50 16.57 17.60 10.68 s ^min η 95 27 60 8 (µg/ml) Average 500.8 560.7 484.1 423.5 SD 143.17 135.18 143.05 108.74 cv% 28.59 24.11 29.55 25.68 Median 508.0 542.0 472.5 472.5 Minimum 232 340 240 232 Maximum 854 854 853 520 Geometric mean 479.8 544.9 462.9 408.9 Geometric CV% 30.68 25.00 31.38 30.43

Abbreviations: C _max = maximum serum concentration; C _min =minimum serum concentration; CV=coefficient of variation; SD=standard deviation.

Non-compartmental PK parameters after the last maintenance dose of ALXN1210 are presented in Table. 47. PK ALXN1210 at equilibrium was obtained after administration of multiple doses, for all maintenance doses on a weight basis (Table 48).

Table 47 Summary of non-compartmental analysis of pharmacokinetic parameters of ALXN1210 after the last maintenance dose of ALXN1210 (PK assay population)

PK parameter (units) 1max (hour) Smake (mcg/ml) Smin (mcg/ml) All patients (N=96) Mean±8P (%CV) 2.42 (2.0, 307.0) 1384.5±267.6 (19.3) 500.8±143.2 (28.6) > 40 - < 60 kg (N=27) Mean±8P (%CV) 2.58 (2.3, 3.5) 1561.1±261.3 (16.7) 560.7±135.2 (24.1) > 60 - < 100 kg (N=61) Mean±8P (%CV) 2.32 (2.0, 307.0) 1347.4±231.8 (17.2) 484.1±143.1 (29.6) > 100 kg (N=8) Mean±8P (%CV) 2.43 (2.3, 2.8) 1071.1±115.9 (10.8) 423.5±108.7 (25.7) AUC _T (hour mcg/m l) 1043617.0±205648.0(19.7) 1178769.2±185661, 1 (29.8) 1004866.7±192953.0 (19.2) 895000.0±137834.3 (15.4) CL (l/h) 0.0015±0.0006 (35.8) 0.0019±0.0004 (29.0) 0.002±0.0007 (34.5) 0.0022±0.0007 (33.1) Vz(n) 3.0± 0.7 (22.7) 2.4±0.4 (18.2) 3.2±0.5 (17.3) 3.8±0.9 (23.7)

Note: Mean elimination half-life cannot be reliably estimated due to continuous therapeutic maintenance dosing.

a t _max values are presented as median (minimum, maximum). Abbreviations: AUC _τ = area under the serum concentration-time curve over the dosing interval; C _max = maximum observed serum concentration; C _min = concentration at end of dosing interval; CL=total clearance; CV=coefficient of variation; SD=standard deviation; 1 _max = time to maximum observed serum concentration; V _z =volume of distribution at equilibrium.

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Table 48

ALXN1210 PK Equilibrium Assessment ___________ (population of pharmacokinetic assays) __________

Achieving a state of equilibrium Maintenance dose in mg (body weight group) Tilt angle Lower 95%C1 Upper 95%C1 Has a state of equilibrium been reached? Days 15, 71, 127, 183 3000 (> 40 - < 60 kg) -0.00001448 -0.00019039 0.00016143 Yes Days 15, 71, 127, 183 3300 (> 60 - < 100 kg) 0.00003648 -0.00006497 0.00013793 Yes Days 15, 71, 127.183 3600 (> 100 kg) -0.00001702 -0.00021949 0.00018545 Yes Days 15, 71, 127, 183 All patients 0.00001648 -0.00007798 0.00011093 Yes

Abbreviations: C1=confidence interval.

In FIG. 44 shows the mean serum concentration of each study drug, ALXN1210 and eculizumab, over the course of the study. Dosing on a weight basis every 8 weeks resulted in maximum exposure at equilibrium and minimum exposure, as shown in FIG. 44. In addition, serum concentrations of ALXN1210 were consistently higher than the corresponding eculizumab concentrations at each time point (see FIG. 44).

4. Pharmacodynamics.

Treatment with ALXN1210 resulted in sustained and complete inhibition of complement component C5 throughout the study and each dosing interval, compared to the large fluctuations observed for the eculizumab treatment group, as shown in FIG. 45. In the table. 49 summarizes mean serum free C5 and number (%) of patients with serum free C5 > 0.5 µg/mL over time after treatment with ALXN1210 (dose based on q8w weight) or eculizumab (900 mg q2w). Mean free C5 levels were more than 99% inhibited by the end of the first ALXN1210 infusion and remained more than 99% inhibited throughout the treatment period in the study (see FIG. 45, upper panel). In contrast, free C5 did not remain more than 99% inhibited at all time points in the eculizumab group (see Fig. 45, bottom panel).

Table 49

Mean free C5 serum concentration and number (percentage) of patients with free C5 serum concentration > 0.5 µg/mL over time (complete analysis population)

Inspection Initial Day 1, EOI Day 8 Day 15, before dosing η 96 97 95 96 ALXN12H Average CONC, free C5 in serum, mcg/ml 0.02 0.01 0.02 0.02 1 (N=97) (%) patients with CONC, serum free C5 > 0.5 µg/ml 0 0 0 0 η 97 98 98 96 Eculizuma! Average CONC, free C5 in serum, mcg/ml 0.05 0.02 0.03 0.06 δ (Ν=98) η (%) patients with CONC, serum free C5 > 0.5 µg/ml 0 0 0 1 (1.0) Day 15, EOI 93 0.01 0 94 0.02 0 Day 22 95 0.02 0 96 0.03 0 Day 29 95 0.02 0 96 0.55 2(2,1) Day 43 96 0.04 0 97 0.20 3 (3.1) Day 57 96 0.05 0 97 0.33 2(2,1) Day 71, before dosing 96 0.06 0 96 0.52 2(2,1) Day 71, EOI 94 0.02 0 92 0.02 0 Day 85 95 0.04 0 97 0.12 2(2,1) Day 99 93 0.05 0 96 0.26 3 (3.1) Day 113 94 0.06 0 96 0.06 1 (1.0) Day 127, before dosing 96 0.08 0 95 0.44 1(1,1) Day 127, EOI 95 0.02 0 91 0.02 0 Day 141 96 0.05 0 95 0.07 1(1,1) Day 155 95 0.06 0 95 0.06 1(1,1) Day 169 95 0.07 0 94 0.49 1(1,1) Day 183 95 0.08 0 94 0.36 3 (3.2)

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Note: One baseline sample of free C5 on day 1 from each treatment group was excluded because the data was considered biologically implausible. Exclusions were confirmed using paired PK data, as samples for PK and free C5 were collected at the same blood draw.

Note: Days 29, 43, 57, 85, 99, 113, 141, 155 and 169 are any time for ALXN1210 and before dosing for eculizumab. For free C5, BLOQ/2=0.00915 µg/ml was used for results which were BLOQ. Percentages were calculated using n as the denominator.

Free C5 data for ALXN1210 and eculizumab are from various bioanalytical assays.

Abbreviations: BLOQ=below the limit of quantitation; C5=complement component 5; EO1=end of infusion.

The mean (±95% CI) change from baseline for the profile of total serum C5 concentration versus time is shown in FIG. 46. Total serum C5 values were similar at baseline between treatments and remained relatively stable throughout the treatment period, with transient decreases in total C5 concentrations observed for ALXN1210 in EOI after all infusions.

Example 6

Descriptive statistics of the pharmacokinetic parameters of ravulizumab from ALXN-PNH-301 and ALXN-PNH-302 phase 3 described above are listed below in table. 50.

Table 50

Generalization of population parameters of the PK model for ravulizumab in phase 3 studies ________________(ALXN-PNH-30I and ALXN-PNH-302)____________

Dosing group Arithmetic mean (SD), median [ ^2.5th - ^97.5th percentile] CL (l/h) Q (l/h) Vc (l) Vp (l) Vss (l) tl/2/? (days) 2400/3000 mg (N=68) 0.00266 (0.000544) 0.00260 [0.00172- 0.0131 (0.000803) 0.0133 [0.01140.0141] 2.87 (0.401) 2.86 [2.183.76] 1.55 (0.121) 1.58 [1.28- 1.78] 4.42 (0.475) 4.47 [3.525.34] 50.6 (8.38) 50.9 [38.0 - 64.3] 2700/3300 mg (N=141) 0.00354 (0.000897) 0.00341 [0.00220- 0.0165 (0.00140) 0.0162 [0.01440.0196] 3.65 (0.529) 3.61 [2.634.71] 2.02 (0.216) 1.98 [1.68- 2.45] 5.67 (0.668) 5.69 [4.446.92] 49.5 (9.25) 48.9 [33.5 - 69.2] 3000/3600 mg (N=13) 0.00441 (0.000964) 0.00440 [0.00334- 0.0208 (0.00108) 0.0202 [0.01990.0231] 4.28 (0.709) 4.08 [3.305.58] 2.48 (0.221) 2.42 [2.202.94] 6.77 (0.830) 6.53 [5.718.34] 47.1 (8.29) 50.3 [34.5 - 58.2] All Phase 3 patients (N=222) 0.00332 (0.000941) 0.00320 [0.00190- 0.0157 (0.00236) 0.0155 [0.01180.0203] 3.45 (0.652) 3.44 [2.414.75] 1.91 (0.321) 1.88 [1.38- 2.50] 5.35 (0.916) 5.35 [3.747.06] 49.7 (8.94) 49.5 [34.2 - 66.1]

Abbreviations: CL=elimination; CV=coefficient of variation; PK=pharmacokinetics;

Q=intercompartment excretion; SD=standard deviation; t1/2β=terminal half-life; Vc=volume of distribution in the central compartment; Vp = volume of distribution in the peripheral compartment.

The median clearance estimate (CL) for ravulizumab was 0.00332 L/hour (standard deviation (SD), 0.00094). The mean SD elimination was 0.00266 L/hr (0.00054) for patients weighing >40-<60 kg, 0.00354 L/hr (0.00090) for patients weighing >60-<100 kg, and 0.00441 l/h (0.00096) for patients weighing > 100 kg. The mean (SD) terminal half-life of ravulizumab in 222 patients with PNH from phase 3 was 1193 h or 49.7 (8.94) days. The mean (SD) Vss of ravulizumab was 5.35 (0.916) L.

A summary of the individual Bayesian scores for the phase 3 study using eculizumab (ECU-MG-301) is shown in Table 1 below. 51.

- 107 043233

Table 51

Generalization of Individual Bayesian Estimates of the Final Population PK Model (Run 72) for Study ECU-MG-301

CL (l/h) VI (l) V2 (l) Q (l/h) Observed Smake (µg/ml) SS Smake (mcg/ml) SS Cmin (mcg/ml) Term. hatching (hour) AUC SS (µg*h/mL) Average SD Median a Min 0.0106 0.00783 0.00785 0.00362 2.54 0.758 2.44 1.32 2.73 0.554 2.61 1.76 0.251 0.107 0.218 0.0956 939 353 912 265 845 295 878 253 348 180 348 29.6 436 152 453 136 154000 68600 153000 26800 Max 0.0448 5.25 4.26 0.605 1640 1580 831 952 331000

SS=equilibrium state; SD=standard deviation; AUCss was calculated as: DOSE/CLi where DOSE is the study-specific maintenance dose (1200 mg for ECUMG-301) and CLi is individual retrospective elimination.

For eculizumab, the mean terminal half-life for the Phase 3 ECU-MG-301 study was 436 hours or 18.1 days.

A patient having a complement-associated disorder (eg, PNH or aHUS) is treated with a first anti-C5 antibody and then switched to treatment with a second distinct anti-C5 antibody. In a preferred embodiment, the second anti-C5 antibody binds to a different epitope than the epitope for the first anti-C5 antibody. To ensure that the first anti-C5 antibody is cleared (e.g., washed out) from the patient prior to administration of the second (different) anti-C5 antibody (e.g., to avoid problems associated with aggregation, immune complex formation, etc.), the half-life of the first anti-C5 antibodies are taken into account. In one embodiment, the second (different) anti-C5 antibody is not administered until the duration corresponding to 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6, 5, 7 or 7.5 times the half-life of the first anti-C5 antibody after the last administration of the first anti-C5 antibody.

In one case, a patient was previously treated with eculizumab and then switched to treatment with a different anti-C5 antibody (eg, ravulizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody). When eculizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, for example, until at least 36, 45, 54, 63, 72, 81, 90, 99, 108, 117, or 126 days have passed since the last administration of eculizumab.

In another case, the patient was previously treated with ravulizumab and then switched to treatment with a different anti-C5 antibody (eg, eculizumab, 7086 antibody, 8110 antibody, 305LO5 antibody, SKY59 antibody, or REGN3918 antibody). When ravulizumab is the first antibody administered, the second (different) anti-C5 antibody is not administered, e.g., until at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 375, or 400 days have passed after the last injection of ravulizumab.

Additionally or alternatively, methods are used to eliminate or enhance the elimination of the first anti-C5 antibody before switching to treatment with a second (different) anti-C5 antibody. Illustrative methods include, but are not limited to, plasmapheresis, blood transfusions, or administration of an antibody against the first anti-C5 antibody (e.g., anti-eculizumab, anti-ravulizumab, anti-7086, anti-8110, anti-305LO5, anti-SKY59). or anti-REGN3918 antibody) to eliminate or enhance the elimination of the first anti-C5 antibody before introducing a second (different) anti-C5 antibody.

- 108 043233 _______________Generalization of sequences______

SEQID NO:1

GYIFSNYWIQ___________________________________________

SEQ ID NO:2

EILPGSGSTEYTENFKD____________________________________

SEQ ID NO:3

YFFGSSPNWYFDV___________________________________________

SEQ ID NO:4

GASENIYGALN_______________________________________________

SEQ ID NO:5

GATNLAD________________________________________________

SEQ ID NO:6

QNVLNTPLT_________________________________________________

SEQ ID NO:7

QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWM GEILPGSGSTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARY FFGSSPNWYFDVWGQGTLVTVSS

SEQ ID NO:8

DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYGA TNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQGTK

VEIK____________________________________________________________

SEQ ID NO:9

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKC SEQ ID NO:10

QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWM GEILPGSGSTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR YFFGSSPNWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFG TQTYT CNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

- 109 043233

SEQ ID NO:11

DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIYG ATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTFGQ GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPV TKSFNRGEC

SEQ ID NO:12

SEQ ID NO:13

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVER KCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQ DWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVLHEALHSHYTQKSLSLSLGK____________________________ SEQ ID NO:14

QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWM GEILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR YFFGSSPNWYFDVWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFG TQTYT CNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLGK__________________ SEQ ID NO:15

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKC CVECPPCPAPPVAGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVQF NWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQD SEQ ID NO:16

QVQLVQSGAEVKKPGASVKVSCKASGYIFSNYWIQWVRQAPGQGLEWM GEILPGSGSTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR YFFGSSPNWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNF GT QTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKP KDTLYITREPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQ FNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTP PMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK__________________________________________________ SEQ ID NO:17

GASENIYHALN_________________________________________________

SEQ ID NO:18

EILPGSGHTEYTENFKD

- 110 043233

SEQ ID NO:19

GHIFSNYWIQ___________________________________________________

SEQ ID NO:20

ARYFFGSSPNWYFDVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFG TQT YTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK_____________________

SEQ ID NO:21

SYAIS_________________________________________________________________

SEQ ID NO:22

GIGPFFGTANYAQKFQG_____________________________________________

SEQ ID NO:23

DTPYFDY__________________________________________________________

SEQ ID NO:24

SGDSIPNYYVY________________________________________________

SEQ ID NO:25

DDSNRPS____________________________________________________________

SEQ ID NO:26

QSFDSSLNAEV________________________________________________

SEQ ID NO:27

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISVWRQAPGQGLEWMGGIGPFFGT ANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDTPYFD

YWGQGTLVTVSS____________________________________________

SEQ ID NO:28

DIELTQPPSVSVAPGQTARISCSGDSIPNYYVYWYQQKPGQAPVLVIYDDSNRPSGIPER FSGSNSGNTATLTISGTQAEDEADYYCQSFDSSLNAEVFGGGTKLTVL__________ SEQ ID NO:29

NYIS________________________________________________________________

SEQ ID NO:30

IIDPDDSYTEYSPSFQG____________________________________________

SEQ ID NO:31

YEYGGFDI__________________________________________________________

SEQ ID NO:32

SGDNIGNSYVH________________________________________________

SEQ ID NO:33

KDNDRPS__________________________________________________________

SEQ ID NO:34

GTYDIESYV__________________________________________________________

SEQ ID NO:35

EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYISWVRQMPGKGLEWMGIIDPDDSYTE YSPSFQGQVTI SADKSISTAYLQWSSLKASDTAMYYCARYEYGGFDI

WGQGTLVTVSS______________________________________________

SEQ ID NO:36

SYELTQPPSVSVAPGQTARISCSGDNIGNSYVHWYQQKPGQAPVLVIYKDNDRPSGIPE RFSGSNSGNT ATLTISGTQAEDEADYYCGTYDIESYVFGGGTKLTV L___________

SEQ ID NO:37

SSYYVA

- 111 043233

SEQ ID NO:38

AIYTGSGATYKASWAKG_______________________________________

SEQ ID NO:39

DGGYDYPTHAMHY_____________________________________________

SEQ ID NO:40

QASQNIGSSLA__________________________________________________

SEQ ID NO:41

GASKTHS___________________________________________________________

SEQ ID NO:42

QSTKVGSSYGNH______________________________________________

SEQ ID NO:43

SEQ ID NO:44

DVVMTQSPSSLSASVGDRVTITCQASQNIGSSLAWYQQKPGQAPRLLIYGASKTHSGV PSRFSGSGSGTDFTLTISSLQPEDVATYYCQSTKVGSSYGNHFGGGTKVEIK________ SEQ ID NO:45

QVQLVESGGGLVQPGRSLRLSCAASGFTVHSSYYMAWVRQAPGKGLEWVGAIFTGS GAEYKAEWAKGRVTISKDTSKNQVVLTMTNMDPVDTATYYCASDAGYDYPTHAMH YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELRRGPKVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHAHYTRKELSLSP________

SEQ ID NO:46

DIQMTQSPSSLSASVGDRVTITCRASQGISSSLAWYQQKPGKAPKLLIYGASETESGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQNTKVGSSYGNTFGGGTKVEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC__________________ SEQ ID NO:47

QVQLQESGPGLVKPSETLSLTTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNY NPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVT VSS_________________________________________________________________ SEQ ID NO:48

AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVP SRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIK___________ SEQ ID NO:49

QVQLQESGPGLVKPSETLSLTCTVSGDSVSSSYWTWIRQPPGKGLEWIGYIYYSGSSNY NPSLKSRATISVDTSKNQFSLKLSSVTAADTAVYYCAREGNVDTTMIFDYWGQGTLVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSL GTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYS RLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK_________________

SEQ ID NO:50

AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVP SRFAGRGSGTDFTLTISSLQPEDFATYYCLQDFNYPWTFGQGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC

Claims (44)

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 complement antibody (anti-C5 antibody) or an antigen-binding fragment thereof containing CDR1 sequences , CDR2 and CDR3 of the heavy chain as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and the sequences of light chain CDR1, CDR2 and CDR3 as set forth in SEQ ID NOs: 4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen-binding snippet enter: (a) once daily for 1 cycle of administration at a dose of: 2400 mg for a patient weighing >40-<60 kg, 2700 mg for a patient weighing >60-<100 kg, or 3000 mg for a patient weighing >100 kg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing >40-<60 kg, 3300 mg for a patient weighing >60-<100 kg, or 3600 mg for a patient weighing >100 kg. 2. 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 complement antibody (anti-C5 antibody) or an antigen-binding fragment thereof containing CDR1 sequences , CDR2 and CDR3 of the heavy chain indicated in SEQ ID NOs: 19, 18 and 3, respectively, the sequences of CDR1, CDR2 and CDR3 of the light chain, - 112 043233 indicated in SEQ ID NOs: 4, 5 and 6, respectively, and a human Fc constant region variant that binds the neonatal human Fc receptor (FcRn), wherein the CH3 human Fc constant region variant contains the substitutions Met-429-Leu and Asn- 435-Ser in residues corresponding to methionine 428 and asparagine 434 native human IgG Fc constant regions, each according to EU numbering, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered: (a) once daily for 1 cycle of administration at a dose of: 2400 mg for a patient weighing >40-<60 kg, 2700 mg for a patient weighing >60-<100 kg, or 3000 mg for a patient weighing >100 kg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing >40-<60 kg, 3300 mg for a patient weighing >60-<100 kg, or 3600 mg for a patient weighing >100 kg. 3. The method of claim 1 or 2, wherein the patient has previously been treated with eculizumab. 4. The method of any one of the preceding claims, wherein the administration cycle begins at least two weeks after the last dose of eculizumab administered to the patient. 5. The method of any one of the preceding claims, wherein the patient has been treated with eculizumab for at least 6 months prior to day 1 of the administration cycle. 6. The method according to any one of the preceding claims, wherein the patient has previously been treated with eculizumab at a dose of 900 mg every 2 weeks. 7. The method of any one of the preceding claims, wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises the heavy chain variable region shown in SEQ ID NO: 12 and the light chain variable region shown in SEQ ID NO: 8. 8. The method of any one of the preceding claims, wherein the anti-C5 antibody, or antigen-binding fragment thereof, further comprises the heavy chain constant region shown in SEQ ID NO: 13. 9. The method according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11. 10. The method of any one of the preceding claims, wherein the anti-C5 antibody, or antigen-binding fragment thereof, binds human C5 at pH 7.4 and 25° C. with an affinity dissociation constant (KD) in the range 0.1 nM < KD < 1 nM. 11. The method of any one of the preceding claims, wherein the anti-C5 antibody, or antigen-binding fragment thereof, binds human C5 at pH 6.0 and 25° C. with a KD > 10 nM. 12. The method of any one of the preceding claims, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing >40-<60 kg: (a) once a day for 1 cycle of administration at a dose of 2400 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg. 13. The method according to any one of claims 1 to 11, wherein the anti-C5 antibody or antigen-binding fragment is administered to a patient weighing >60-<100 kg: (a) once a day 1 cycle of administration at a dose of 2700 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3300 mg. 14. The method of any one of claims 1-11, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing > 100 kg: (a) once a day 1 cycle of administration at a dose of 3000 mg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3600 mg. 15. The method of any one of the preceding claims, wherein the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment thereof of 100 μg/ml or more during the administration cycle. 16. The method of any one of the preceding claims, wherein the treatment maintains a minimum serum concentration of anti-C5 antibody or antigen-binding fragment thereof of 200 μg/ml or more during the administration cycle. 17. The method of any one of the preceding claims, wherein the treatment maintains a free C5 concentration of 0.309-0.5 μg/ml or lower. 18. The method of any one of the preceding claims, wherein the treatment reduces the concentration of free C5 by more than 99% over the course of the treatment. 19. The method of any one of the preceding claims, wherein the treatment reduces the concentration of free C5 by more than 99.5% over the course of the treatment. 20. The method of any one of the preceding claims, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg, 3300 mg or 3600 mg every eight weeks after the administration cycle for up to two years. 21. The method of any one of the preceding claims, wherein the anti-C5 antibody or antigen-binding fragment thereof is formulated for intravenous administration. - 113 043233 22. The method according to any one of the preceding claims, wherein the administration cycle is only 26 weeks of treatment. 23. The method of any one of the preceding claims, wherein the treatment results in inhibition of the terminal complement complex. 24. The method of any one of the preceding claims, wherein the treatment results in a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels. 25. The method of any one of the preceding claims, wherein the treatment results in normalization of LDH levels. 26. The method of any one of the preceding claims, wherein the treatment results in normalization of LDH levels by at least day 24 of treatment. 27. The method of any one of the preceding claims, wherein the treatment results in a percentage change in LDH levels (LDH-PCHG) of less than 15% compared to treatment with eculizumab. 28. The method of any one of the preceding claims, wherein the treatment results in a reduction in acute hemolysis compared to treatment with eculizumab. 29. The method according to any one of the preceding claims, wherein the treatment results in the elimination of abrupt hemolysis during the treatment period. 30. The method of any one of the preceding claims, wherein the treatment results in a reduction in acute hemolysis compared to the baseline level of acute hemolysis prior to treatment. 31. The method according to any one of the preceding claims, wherein the treatment has at least one therapeutic effect selected from the group consisting of reduction or cessation of abdominal pain, dyspnea, dysphagia, chest pain, erectile dysfunction. 32. The method of any one of the preceding claims, wherein the treatment provides a shift towards normal levels of a hemolysis-associated hematological biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, erythrocyte PNH clone (RBC), and D-dimer. 33. The method according to any one of the preceding claims, wherein the treatment has at least one therapeutic effect selected from the group consisting of reduction or cessation of severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and impaired renal function . 34. The method of any one of the preceding claims, wherein the treatment provides a shift towards normal levels of factor Ba, soluble tumor necrosis factor receptor 1 [sTNFR1]), soluble vascular endothelial adhesion molecule 1 [sVCAM1], thrombomodulin, D-dimer, and cystatin C . 35. The method of any one of the preceding claims, wherein the treatment results in an increase in hemoglobin stabilization from baseline to treatment. 36. The method of any one of the preceding claims, wherein the treatment results in a reduction in the need for blood transfusions. 37. The method of any one of the preceding claims, wherein the treatment results in greater than a 70% increase in transfusion avoidance. 38. The method of any one of the preceding claims, wherein the treatment results in a reduction in major adverse vascular events (MAVE). 39. The method of any one of the preceding claims, wherein the treatment provides a shift towards normal levels of a chronic disease-associated biomarker selected from the group consisting of estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio and natriuretic peptide brain (BNP) in plasma. 40. The method of any one of the preceding claims, wherein the treatment results in a change from baseline in quality of life as measured by the Functional Evaluation of Chronic Disease Therapy Therapy (FACIT) Fatigue Scale Version 4 and the European Organization for Quality of Life Core Questionnaire-30 research and treatment of malignant tumors. 41. The method of any one of the preceding claims, wherein the treatment results in a change from baseline in quality of life as measured by the Functional Evaluation of Chronic Disease Therapy (FACIT)-Fatigue Version 4 and the European Organization's Core Quality of Life Questionnaire-30 on research and treatment of malignant tumors, at least 7 points, compared with the baseline score for patients without treatment. 42. The use of an anti-C5 complement antibody (anti-C5 antibody) or an antigen-binding fragment thereof in a method of treating a human patient with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), wherein said antibody or antigen-binding fragment thereof contains the sequences CDR1, Heavy chain CDR2 and CDR3 as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein said method comprises administering to a patient during a cycle of administering an effective amount of an anti-C5 antibody or antigen-binding fragment thereof: - 114 043233 (a) once a day 1 cycle of administration at a dose of: 2400 mg for a patient weighing >40 - <60 kg, 2700 mg for a patient weighing >60 - <100 kg or 3000 mg for a patient weighing > 100 kg; and (b) on day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg for a patient weighing >40-<60 kg, 3300 mg for a patient weighing >60-<100 kg, or 3600 mg for a patient weighing >100 kg. 43. Use according to claim 42, wherein the patient has previously been treated with eculizumab. 44. Use according to claim 42 or 43, wherein the antibody is determined to be safe, tolerable, and sufficiently non-immunogenic after multiple IV doses for use in patients with PNH.