Dosage and administration of Anti-c5 antibodies for treating c5-mediated glomerular nephritis (GN), including IGA nephropathy (IGAN) and / or IGA vasculitis nephritis (IGAVN) in pediatric patients

Abstract

Provided are dosages and methods for clinical treatment of C5-mediated glomerular nephritis (GN), including immunoglobulin A nephropathy (IgAN) and / or IgA vasculitis with nephritis (IgAVN) in human pediatric patients using an anti-C5 antibody, or antigen binding fragment thereof (e.g., such as ravulizumab (ULTOMIRIS®)), optionally together with background therapy for treating IgAN.

Description

[0001] AXJ-314PC ALXN-1003-PCT01-NP

[0002] DOSAGE AND ADMINISTRATION OF ANTI-C5 ANTIBODIES FOR TREATING C5- MEDIATED GLOMERULAR NEPHRITIS (GN), INCLUDING IGA NEPHROPATHY (IGAN) AND / OR IGA VASCULITIS NEPHRITIS (IGAVN) IN PEDIATRIC PATIENTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Nos. 63 / 746,039, filed January 16, 2025; and 63 / 917,316, filed November 14, 2025, all of which are herein incorporated by reference in their entireties.

[0004] DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0005] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: AXJ-314PC_SL.xml, date recorded January 7, 2026, file size 49,656 bytes).

[0006] INCORPORATION BY REFERENCE

[0007] All publications, patents, and patent applications herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference, hi the event of a conflict between a term herein and a term in an incorporated reference, the term herein controls.

[0008] BACKGROUND

[0009] Chronic kidney disease (CKD) has become a worldwide public health issue due to its high incidence, poor prognosis, and substantial economic burden. When not properly diagnosed and managed, CKD can lead to many adverse outcomes, such as end-stage renal disease (ESRD). Despite advances in treatments, certain types of C5-mediated glomerular nephritis (GN), such as Primary Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A vasculitis nephritis (IgAVN) continue to respond poorly to treatment, resulting over time in CKD.

[0010] The majority of current therapeutic options provide supportive care without addressing the underlying disease pathophysiology. Moreover, management of pediatric IgAN and IgAVN is controversial and supported by minimal quality evidence. The lack of evidence is due to multiple factors, including disease heterogeneity, its inter-ethnic variability, and the difficulty ofAXJ-314PC ALXN-1003-PCT01-NP extrapolating data from adult studies due to the unique characteristics of the condition in children. There remains a high unmet medical need for targeted, disease-modifying, therapeutics for the treatment of IgAN and IgAVN that can prevent disease progression and improve patient reported outcomes. Accordingly, it is an object of the present disclosure to provide improved methods for treating pediatric patients with C5-mediated GN, such as IgAN and IgAVN.

[0011] SUMMARY

[0012] Provided herein are compositions and methods for treating C5-mediated GN. including IgAN and / or IgAVN, in a human pediatric patient, comprising administering to the patient an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered (or is for administration) according to a particular clinical dosage regimen (e.g., at a particular dose amount and according to a specific dosing schedule). In one embodiment, the methods relate to treatment of IgAN in a pediatric patient. In another embodiment, the methods relate to treatment of IgAVN in a pediatric patient. In another embodiment, the methods relate to treatment of IgAN and IgAVN in a pediatric patient.

[0013] An exemplary anti-C5 antibody is ravulizumab (ULTOMIRIS®) comprising the heavy and light chains having the sequences shown in SEQ ID NOs:14 and 11, respectively, or antigen binding fragments and variants thereof.

[0014] In another embodiment, the antibody comprises the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of ravulizumab.

[0015] Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence shown in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence shown in SEQ ID NO:8. In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID Nos: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID Nos:4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO:8, respectively. In another embodiment, the antibody comprises a heavy chain constant region as set forth in SEQ ID NO: 13.AXJ-314PC ALXN-1003-PCT01-NP In another embodiment, the antibody comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each according to the EU numbering convention.

[0016] In another embodiment, the antibody comprises CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID Nos: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID Nos:4, 5 and 6, respectively and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each according to the EU numbering convention.

[0017] In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the BNJ421 antibody (described in WO2015134894 and US Patent No. 9,079,949). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody (see US Patent No. 9,765,135). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the REGN3918 antibody.

[0018] In another embodiment, the antibody competes for binding with, and / or binds to the same epitope on C5 as any of the above-mentioned antibodies. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity to any of the

[0019] above-mentioned antibodies (e.g., at least about 90%, 95% or 99% variable region identity with SEQ ID NO: 12 or SEQ ID NO:8).

[0020] In another embodiment, the antibody binds to human C5 at pH 7.4 and 25 °C with an affinity dissociation constant (KD) that is in the range 0.1 nM < KD < 1 nM. In anotherAXJ-314PC ALXN-1003-PCT01-NP embodiment, the antibody binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) of about 0.5 nM. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25°C with a KD > 10 nM. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25°C with a KD of about 22 nM. In yet another embodiment, the [(KD of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25°C) / (KD of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and at 25 °C)] of the antibody is greater than 20, preferably greater than 25.

[0021] In one embodiment, the dose of the anti-C5 antibody, or antigen binding fragment thereof, is based on the weight of the pediatric patient. In one embodiment, for example, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient. In one embodiment, 600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 10 to < 20 kg). In one embodiment. 900 mg and / or 2100 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 20 to < 30 kg). In one embodiment, 1200 mg and / or 2700 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 30 to < 40 kg). In one embodiment, 2400 mg and / or 3000 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 40 to < 60 kg). In one embodiment, 2700 mg and / or 3300 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 60 to < 100 kg). In one embodiment, 3000 mg and / or 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient e.g., a pediatric patient weighing > 100 kg).

[0022] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 10 to < 20 kg once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter.

[0023] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 20 to < 30 kg once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter.AXJ-314PC ALXN-1003-PCT01-NP In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 30 to < 40 kg once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter.

[0024] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 40 to < 60 kg once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter.

[0025] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 60 to < 100 kg once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter.

[0026] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 100 once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter.

[0027] In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).

[0028] In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered for one or more administration cycles. In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at an initial loading dose on Day 1. In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at maintenance dose (e.g., on Day 15 and every four our eight weeks thereafter).

[0029] In another embodiment, a method of treating a human pediatric patient with C5-mediated GN, including IgAN and / or IgAVN, is provided, the method comprising administering to the patient (e.g., during an administration cycle) an effective amount of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID Nos: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID Nos:4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen binding fragment thereof is administered:

[0030] (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a pediatric patient weighing > 10 to < 20 kg; (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 20 to < 30 kg;AXJ-314PC ALXN-1003-PCT01-NP (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 30 to < 40 kg;

[0031] (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 40 to < 60 kg;

[0032] (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 60 to < 100 kg; or

[0033] (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 100.

[0034] In another embodiment, a method of treating a human pediatric patient with C5-mediated GN, including IgAN and / or IgAVN, is provided, the method comprising administering to the patient (e.g., during an administration cycle) an effective amount of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ Id NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ Id NOs:4, 5 and 6, respectively, and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering, wherein the anti-C5 antibody or antigen binding fragment thereof is administered:

[0035] (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a pediatric patient weighing > 10 to < 20 kg; (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 20 to < 30 kg; (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 30 to < 40 kg;AXJ-314PC ALXN-1003-PCT01-NP (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 40 to < 60 kg;

[0036] (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 60 to < 100 kg; or

[0037] (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 100.

[0038] In one embodiment, the pediatric patient has not previously been treated with eculizumab. In another embodiment, the pediatric patient has previously been treated with eculizumab. In another embodiment, the pediatric patient has previously been treated with eculizumab and Day 1 (e.g., of the administration cycle) is two weeks or more from the pediatric patient’s last dose of eculizumab.

[0039] In another aspect, the treatment regimens described are sufficient to maintain particular serum trough concentrations of the anti-C5 antibody or antigen binding fragment thereof. In one embodiment, for example, the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265. 270, 280, 290, 300. 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or

[0040] 400 pg / mL or greater. In one embodiment, the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 100 pg / mL or greater, 150 pg / mL or greater, 200 pg / mL or greater, 250 pg / mL or greater, or 300 pg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of between 100 pg / mL and 200 pg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of about 175 pg / mL.

[0041] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the pediatric patient in an amount and with a frequency to maintain at least 50 pg, 55 pg, 60 pg, 65 pg. 70 pg, 75 pg, 80 pg, 85 pg, 90 pg, 95 pg, 100 pg, 105 pg, 110 pg. 115 pg,AXJ-314PC ALXN-1003-PCT01-NP 120 g, 125 pg, 130 pg, 135 pg, 140 pg, 145 pg, 150 pg, 155 pg, 160 pg, 165 pg, 170 pg, 175 pg, 180 pg, 185 pg, 190 pg, 195 pg, 200 pg, 205 pg, 210 pg, 215 pg, 220 pg, 225 pg, 230 pg. 235 pg, 240 pg, 245 pg, 250 pg, 255 pg or 260 pg of antibody per milliliter of the patient’s blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain between 50 pg and 250 pg of antibody per milliliter of the patient’s blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain between 100 pg and 200 pg of antibody per milliliter of the patient’s blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain about 175 pg of antibody per milliliter of the patient’s blood.

[0042] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the pediatric patient in an amount and with a frequency to maintain a minimum free C5 concentration. In one embodiment, for example, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain a free C5 concentration of 0.5 pg / mL or less (e.g., 0.4 pg / mL, 0.3 pg / mL, 0.2 pg / mL, or 0.1 pg / mL or less).

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

[0044] In some embodiments, the pediatric patient has previously been treated or is concurrently being treated with another therapeutic agent. For example, in one embodiment, the pediatric patient has previously been treated or is concurrently being treated with a renin-angiotensin system inhibitor (RASI). In another embodiment, the pediatric patient has previously been treated or is concurrently being treated with an angiotensin AT(l)-receptor blocker (ARB). In another embodiment, the patient has IgAVN and has previously been treated or is concurrently being treated with one or more immunosuppressive medications, such as corticosteroid, cyclophosphamide, calcineurin inhibitors, mizoribine, and / or or mycophenolate mofetil.

[0045] In another embodiment, the treatment results in a shift towards normal levels of one or more biomarkers selected from the group consisting soluble C5b-9 (sC5b-9), Factor Ba, C4d, CD68, CD88, CD163, Gd-IgAl, kidney injury molecule 1 (KIM-1), and creatinine. In some embodiments, the treatment results in a shift towards normal levels of one or more bloodAXJ-314PC ALXN-1003-PCT01-NP biomarkers selected from the group consisting of: C4d and Ba. In some embodiments, the treatment results in a shift towards normal levels of one or more urine biomarkers selected from the group consisting of: sC5b-9, CD163. and KIM-1.

[0046] In another embodiment, the treatment results in a change in Estimated glomerular filtration rate (eGFR) compared to baseline over time (z.e., a change from baseline eGFR over time). For example, the treatment results in a change from baseline eGFR at week 10. 20, 30, 40, 50, 60, 70, 80, 90, 100, 105, 106, 107, 108, 109, or 110. In another embodiment, the treatment results in a change in eGFR compared to baseline, e.g., a change from baseline in eGFR at Week 50 and / or Week 106. In another embodiment, the pediatric patient has an eGFR > 30 mL / min / 1.73m2prior to treatment.

[0047] In another embodiment, the treatment results in a change in eGFR slope compared to baseline. In another embodiment, the treatment results in an improvement in eGFR slope compared to baseline. In another embodiment, the treatment results in an improvement in eGFR slope compared to baseline by week 10, 20, 30, 40, 50. 60. 70. 80. 90, 100. 105, 106, 107, 108, 109, or 110. In another embodiment, the treatment results in an improvement eGFR slope compared to baseline, e.g., an improvement in the annualized total eGFR slope over 50 and / or 106 weeks.

[0048] In another embodiment, the treatment results in a reduction in proteinuria compared to baseline, e.g., change from baseline in proteinuria over time. In another embodiment, the treatment results in a reduction in proteinuria compared to baseline by 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In another embodiment, the treatment results in a reduction in proteinuria compared to baseline, e.g., a change from baseline in proteinuria at Week 34.

[0049] In another embodiment, the treatment results in a reduction in albuminuria compared to baseline, e.g., change from baseline in albuminuria over time. In another embodiment, the treatment results in a reduction in albuminuria compared to baseline by 30%. 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In another embodiment, the treatment results in a reduction in albuminuria compared to baseline, e.g., a change from baseline in albuminuria at Week 34.

[0050] In another embodiment, the pediatric patient has a urine protein to creatinine ratio (UPCR) of > 1 g / g prior to treatment. In another embodiment, the treatment results in a urine protein creatinine ratio (UPCR) < 0.5 g / g at Week 34. In another embodiment the treatmentAXJ-314PC ALXN-1003-PCT01-NP results in a reduction in proteinuria compared to baseline based on UPGR from 24-hour urine collections at Week 10 and Week 34 (e.g., reduction in 24-hour UPCR > 50% from baseline). In another embodiment the treatment results in a reduction in 24-hour UPCR > 30%, e.g., a reduction in 24-hour UPCR > 50% from baseline.

[0051] In another embodiment, the treatment results in an improvement in UPCR compared to baseline. In another embodiment, the treatment results in a reduction in 24-hour UPCR by at least 30% (e.g., 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%. 96%, 97%, 98%, or 99%. In another embodiment, the treatment results in a 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% improvement in UPCR compared to baseline. In another embodiment, the treatment results in a 25%, 30%, 35%. 40%, 45%, 50%, 55%, 60%. 65%, 70%, 75%, 80%, 85%. 90%, or 95% reduction in proteinuria compared to baseline. In another embodiment, the reduction in proteinuria occurs at 6 weeks, 8 weeks, 10 weeks. 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 34 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks or 106 weeks, after treatment compared to baseline. In another embodiment, proteinuria is measured by a complete 24-hour urine collection. In another embodiment, the treatment results in Partial Remission (PR) in the pediatric patient.

[0052] In another embodiment, the treatment results in a reduction or cessation in one or more of the following symptoms in a pediatric patient compared to baseline: hematuria, dark brown or cola colored urine, edema, flank pain, hypertension, foamy urine, and / or proteinuria.

[0053] In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by Pediatric Quality of Life Inventory Generic Core Scales (PedsQL 4.0).

[0054] In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (peds FACIT-F).

[0055] In another embodiment, the treatment results in terminal complement inhibition.

[0056] In another embodiment, the treatment results in a reduction in adverse events.AXJ-314PC ALXN-1003-PCT01-NP In another aspect, an anti-C5 antibody, or antigen binding fragment thereof, is provided, comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8, for administration:

[0057] (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a pediatric patient weighing > 10 to < 20 kg: (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 20 to < 30 kg; (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 30 to < 40 kg;

[0058] (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 40 to < 60 kg;

[0059] (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 60 to < 100 kg; or

[0060] (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a pediatric patient weighing > 100.

[0061] In one embodiment, the antibody is determined to be safe, tolerable and sufficiently non-immunogenic after multiple IV doses for use in pediatric patients.

[0062] Further provided are kits that include a pharmaceutical composition containing an anti-C5 antibody, or antigen binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the methods described herein. In one embodiment, the kit comprises; (a) a dose of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8; and (b) instructions for using the anti-C5 antibody or antigen binding fragment thereof in the methods described herein.AXJ-314PC ALXN-1003-PCT01-NP In one embodiment, the kit comprises a dose of an anti-C5 antibody or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered, for treating IgAN and / or IgAVN, in a human pediatric patient:

[0063] (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a patient weighing > 10 to < 20 kg;

[0064] (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 20 to < 30 kg;

[0065] (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

[0066] (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

[0067] (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 100.

[0068] In some embodiments, the disclosure relates to a composition, e.g., pharmaceutical composition or a medicament, comprising an effective amount of an anti-C5 antibody or an antigen binding fragment thereof, comprising heavy chain complementarity determining regions (HCDRs) comprising HCDR1, HCDR2 and HCDR3 sequences as set forth in SEQ ID NOs:19.

[0069] 18 and 3, respectively, and light chain complementarity determining regions (LCDRs) comprising LCDR1, LCDR2 and LCDR3 sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, for use in the treatment of IgAN and / or IgAVN in a human pediatric patient. Specifically, provided herein are compositions comprising effective amounts of ravulizumab (ULTOMIRIS®) or the antigen-binding fragment thereof, for treatment of IgAN and / or IgAVN in a human pediatric patient. In some embodiments, the effective amount comprises use of the above dosages and scheduling of the anti-C5 antibody, e.g., ravulizumab.

[0070] In some embodiments, the disclosure relates to use of an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising heavy chain complementarity determining regions (HCDRs) comprising HCDR1, HCDR2 and HCDR3 sequences as set forth in SEQ ID NOs:19, 18 and 3, respectively, and light chain complementarity determining regionsAXJ-314PC ALXN-1003-PCT01-NP (LCDRs) comprising LCDR1, LCDR2 and LCDR3 sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, in the manufacture of a composition, e.g., pharmaceutical composition or a medicament, for treating IgAN and / or IgAVN in a human pediatric patient. Specifically, provided herein are use of an effective amount of ravulizumab (ULTOMIRIS®) or the antigenbinding fragment thereof, in the manufacture of a composition, e.g., pharmaceutical composition or a medicament, for treating IgAN and / or IgAVN in a human pediatric patient, wherein the composition comprises background therapy for the treatment of IgAN. In some embodiments, the effective amount comprises use of the above dosages and scheduling of the anti-C5 antibody, e.g., ravulizumab, optionally together with dosages and scheduling of the background therapy.

[0071] In embodiments, a pediatric patient of the disclosure is from 0- 17 years of age. In embodiments, the pediatric patient is from 2-5 years of age. In embodiments, the pediatric patient is from 12-17 years of age. In embodiments, the pediatric patient is from 6-11 years of age.

[0072] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic depicting the overall design of the clinical. All participants will be followed up for safety for 8 weeks after the last dose of ravulizumab IV. Weight-based dosing regimen will be based on the last recorded study visit body weight:aAll participants receive weight-based loading dose of ravulizumab IV on Day 1;bAll participants receive weight-based maintenance dose of ravulizumab IV on Day 15;cParticipants <20 kg receive dosing q4w and participants >20 kg receive dosing q8w;dMinimum of 18 evaluable participants with IgAN (including at least 4 participants <40 kg), and up to approximately 6 participants with IgAVN.

[0073] FIGS. 2A-2G set forth the Schedule of Activities from Screening through the end of the Primary Evaluation Period for the Week 34 Visit. All assessments are performed prior to administration of study intervention on dosing days, unless otherwise specified:aWeek 34 assessments for the Primary Evaluation Period is performed predose. Dosing on Week 34 is the start of the Extension period;bFor participants who discontinue study intervention, an ED visit is completed no later than 8 weeks (56 ± 7 days) after the last dose of study intervention, the remote safety follow-up is not required;cPK / PD serum samples falling on dosing days are collected predose (within 90 minutes prior to the dose of study intervention) and postdose (within 60 minutes after the dose of study intervention). Samples may be drawn through the venous access created forAXJ-314PC ALXN-1003-PCT01-NP the dose infusion, prior to administration of the dose. The postdose samples will be drawn from the participant’s opposite, non-infused arm;dAbbreviated PE consists of a body system relevant examination based upon Investigator, or qualified designee, judgment and participant symptoms;eBody weight is obtained at every on-site study visit and measured predose. The dosing regimen is based on the last recorded study visit body weight. If the study intervention needs to be prepared the night prior to the visit, the body weight from the previous visit is used;fVital sign measurements include systolic and diastolic BP, heart rate, respiratory rate, and temperature. On dosing days, vital signs and pulse oximetry are taken predose and after the participant has been resting for at least 5 minutes;8Participants are supine for approximately 5-10 minutes before ECG collection and remain supine but awake during ECG collection;hIn the event that a participant’s weight changes from <20 kg to >20kg on a “q4w” visit, the participant will receive the >10 to <20 kg maintenance dose (600 mg) that day and then receive the new >20 kg maintenance dose (2100mg) at the next visit in order to start the new q8w dosing schedule;1any remaining blood from Day 1 blood collection is aliquoted in the blood biomarkers tube.

[0074] FIGS. 3A-3F set forth the Schedule of Activities for the Extension Period for Week 38 through Week 106. All assessments are performed prior to administration of study intervention on dosing days, unless otherwise specified:aFor participants who discontinue study intervention, an ED visit is completed no later than 8 weeks (56 ± 7 days) after the last dose of study intervention. If the ED visit is conducted <8 weeks (56 ± 7 days) after the last dose of study intervention, safety follow up is conducted remotely to collect AEs, concomitant medications, nonpharmacologic therapies, and procedures. If the ED visit is conducted at 8 weeks (56 ± 7 days) after the last dose of study intervention, the remote safety follow-up is not required;bPK / PD serum samples falling on dosing days are collected predose (within 90 minutes prior to the dose of study intervention) and postdose (within 60 minutes after the dose of study intervention). Samples are drawn through the venous access created for the dose infusion, prior to administration of the dose. The postdose samples are drawn from the participant’s opposite, noninfused arm;cTargeted PE consists of a body system relevant examination based upon investigator or qualified designee judgment and participant symptoms;dbody weight is obtained at every on-site visit and measured predose. The dosing regimen is based on the last recorded study visit body weight. If the study intervention needs to be prepared the night prior to the visit,AXJ-314PC ALXN-1003-PCT01-NP the body weight from the previous visit is used;evital sign measurements include systolic and diastolic BP, heart rate, respiratory rate, and temperature. On dosing days, vital signs are taken predose and after the participant has been resting for at least 5 minutes; f participants should be supine for approximately 5-10 minutes before ECG collection and remain supine but awake during ECG collection;gin the event that a participant’s weight changes from <20kg maintenance dose (2100mg) at the next visit in order to start the new q8w dosing schedule.

[0075] DETAILED DESCRIPTION

[0076] I. Definitions

[0077] As used herein, the term “subject” or “patient” is a human patient.

[0078] As used herein, the term "pediatric patient" refers to an infant, child, or adolescent from birth up to the age of 18 (e.g., from 0-17 years of age). In one embodiment, the pediatric patient has GN. In one embodiment, the pediatric patient has IgAN. In one embodiment, the pediatric patient has IgAVN. In one embodiment, the pediatric patient has IgAN and IgAVN. In one embodiment, the pediatric patient has IgAN or IgAVN.

[0079] As used herein, the term “adult” patient is a human patient that has been classified by a physician or caretaker as such, e.g., one who is not a newborn, infant, child or adolescent, e.g., based on age, developmental status, physiological features, etc. Typically, adult patients are patients who are 18 years of age or older (>18 years of age).

[0080] As used herein, the term Glomerulonephritis (GN) refers to a group of renal diseases affecting the glomeruli, e.g., due to damage mediated by immunological mechanisms. A large proportion of the disease manifestations are caused by disturbances in the complement system. As used herein, C5-mediated glomerular nephritis (GN) refers to GN caused, in whole or part, due to complement component C5. C5-mediated GN includes disorders, such as immunoglobulin A nephropathy (IgAN).

[0081] As used herein, IgA nephropathy (IgAN), also known as Berger’s disease, refers to the most common global primary glomerulonephropathy that can progress to renal failure (see, e.g., Lai et al., FlOOOResearch. 2016;5 : 161). Symptoms of IgAN include, but are not limited to. hematuria (blood in the urine that can sometimes make it pink, dark brown or cola colored),AXJ-314PC ALXN-1003-PCT01-NP edema (e.g., in the hands, ankles or feet), pain on the side of the back (flank pain), high blood pressure (hypertension), and / or foamy urine (due to proteinuria, excess protein in urine).

[0082] IgAN is a type of CKD that leads to the production of autoantibodies IgA and IgG against Gd-IgAl and formation of immune complexes (see, e.g., Coppo R., Pediatr Nephrol.

[0083] 2021;36(3):491-496; and Lai, et al., Am. J. Kidney Dis. 2020;75(l):84-104). These autoantibodies and immune complexes deposit in the glomeruli, leading to local inflammation and complement activation, and resulting in renal injury (see, e.g., Paranhos RM, et al.. Nephrology (Carlton, Vic).

[0084] 2022;27(4):307-317). IgAN is a chronic progressive disease that often leads to end stage kidney disease (ESK.D) requiring dialysis or kidney transplant (see, e.g., KDIGO. Kidney Disease:

[0085] Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 ; 100(4S):S 1-S276). The pathophysiology process of IgAN disease is similar between adults and pediatrics (see, e.g., Coppo (2021) and Paranhos (2022)). However, compared to adults, pediatric IgAN has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage (see, e.g., Vivarelli M, et cd., Pediatric Nephrology, 2024 Sep 27. doi: 10.1007 / S00467-024-06502-6. Epub ahead of print. PMID: 39331079).

[0086] Risk factors for disease progression are similar in adults and pediatrics. Traditional risk factors, including increased proteinuria, persistent microscopic hematuria, hypertension, kidney biopsy characteristics and reduced eGFR, at the time of diagnosis are consistent and strong predictors of poor renal survival (see, e.g., Coppo R, et al., J. Nephrol. 2020;33(6): 1219- 1229). Lower ranges of proteinuria are clinically significant markers of disease progression at 0.5 g / g in children when compared with adults at 0.75 g / g or 1 g / d (see, e.g., Vivarelli M, et al., Pediatr. Nephrol. 2024).

[0087] There is currently no approved treatment for pediatric patients with IgAN, and in the absence of data in pediatric patients with IgAN. treatment recommendations are based mostly on adult patient data. The standard of care includes glucocorticoids, which introduce safety risk to the patients. Like adults, pediatric patients with IgAN are treated with RAS inhibition which is supported in the clinical guidelines by strong evidence (see, e.g., KDIGO (2021)). Unlike adults, the use of immunosuppressive therapies (ISTs) is more widespread in patients with elevated proteinuria despite optimized RAS inhibition. However, credible evidence from well-designedAXJ-314PC ALXN-1003-PCT01-NP trials demonstrating clinical benefit over risk is lacking. Systemic glucocorticoids are the most commonly used 1ST and dosing regimens, and duration vary between prescribers and patient characteristics.

[0088] Immunoglobulin A (IgA) nephropathy is a lifelong disease leading to CKD and progresses to ESRD in 30% to 40% of patients over the course of 20 to 30 years (Lai, 2016). Patients initially present with hematuria and hypertension and proteinuria develops as the disease progresses. Diagnosis of IgAN is made by renal biopsy demonstrating IgA immunofluorescence in the glomeruli usually co-dominant with complement 3 (C3) according to the Oxford Classification nomenclature (see, e.g., KDIGO Clinical practice guideline for glomerulonephritis. Kidney International Supplements. 2012;2(2): 140, Rizk et al., Front Immunol. 2019; 10:504; and Trimarchi et al., Kidney Int. 2017;91(5): 1014-1021).

[0089] The pathophysiology of IgAN is related to the overproduction of under-glycosylated immunoglobulin Al (IgAl) which accumulates in the kidney glomeruli. However, aberrant glycosylation alone is insufficient to induce renal injury; glycan-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) autoantibodies that recognize the under- glycosylated IgAl molecule likely also contribute. This process leads to the local inflammation and complement activation in the kidney (see, e.g., Oortwijn etal., Semin Nephrol. 2008;28(l):58-65). Both the alternative and lectin complement pathways may be activated, leading to generation of anaphylatoxins, and the membrane attack complex terminal complement (C5b-9), with subsequent promotion of inflammatory mediators (see, e.g.. Maillard etal., J Am Soc Nephrol. 2015;26(7): 1503- 1512). Complement component 4 (C4) and C3 complexes and activated C3 products are elevated in up to 30% of patients with IgAN. Activated C3 products are associated with elevated levels of proteinuria and hematuria compared to patients with IgAN who have normal levels, and correlate with deterioration of renal function (see, e.g.. Zwimer et al., Kidney Int. 1997:51(4): 1257-64). Complement activity on kidney biopsy and circulating complement proteins are associated with disease activity and progression of CKD. Together these findings suggest a role of complement in the pathophysiology and the prognostic value of complement biomarkers in IgAN (see, e.g., Rizk et al., Front Immunol. 2019; 10:504).

[0090] Treatments for IgAN include RAS blocking agents, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). These therapies are aimedAXJ-314PC ALXN-1003-PCT01-NP at controlling blood pressure, preserving kidney function through decreasing intraglomerular pressure which in turn reduces proteinuria, and suppressing the immune response. These treatments are insufficient in preserving renal function as the proportions of patients who progress to CKD and ESRD are high. Patients with baseline hypertension and proteinuria > 1 g / day are at increased risk for progression (see Reich, et al., J Am Soc Nephrol. 2007 ; 18( 12):3177-3183).

[0091] Immunoglobulin A vasculitis nephritis (IgAVN) is another type of CKD that is also a severe autoimmune disease with formation of immune complexes. IgAVN and IgAN are on continuous spectrum of disease with a common underlying pathophysiology, and unlike IgAN, IgAVN has clinical systemic manifestations (see, e.g., Pillebout E„ J. Clin. Med.

[0092] 2021 ;10(l l):2310; and Suzuki et al., Kidney Int. 2018;93(3):700-705). The systemic symptoms of IgAVN (e.g., abdominal pain, arthritis, Henoch-Schonlein purpura skin lesions) are often severe. These patients also commonly present with of rapidly progressive glomerulonephritis and nephrotic syndrome manifested by hematuria and proteinuria. Recent data across global representation indicate same distribution of Gd-IgAl immune complex deposits and similar MEST-C characteristics between IgAN and IgAVN (see, e.g., Barbour SJ, et al., Clin. J. Am. Soc. Nephrol. 2024;19(4):438-451).

[0093] As used herein, “effective treatment” refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement over baseline, e.g., an improvement over a measurement or observation made prior to initiation of therapy according to the method. Effective treatment may refer to alleviation of at least one symptom of IgAN and / or IgAVN (e.g., hematuria (blood in the urine that can sometimes make it pink, dark brown or cola colored), edema (e.g., in the hands, ankles or feet), pain on the side of the back (flank pain), high blood pressure (hypertension), and / or foamy urine (due to proteinuria, excess protein in urine)).

[0094] The term “effective amount” refers to an amount of an agent that provides the desired biological, therapeutic and / or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying and / or alleviation of one or more of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. In one example, an “effective amount” is the amount of anti-C5 antibody, or antigen binding fragment thereof, clinically proven to alleviate at least one symptom of IgAN and / or IgAVN (e.g., hematuria (blood in the urine thatAXJ-314PC ALXN-1003-PCT01-NP can sometimes make it pink, dark brown or cola colored), edema (e.g., in the hands, ankles or feet), pain on the side of the back (flank pain), high blood pressure (hypertension), and / or foamy urine (due to proteinuria, excess protein in urine)).

[0095] An effective amount can be administered in one or more administrations.

[0096] As used herein, the term “loading dose” refers to the first dose administered (e.g., during an administration cycle).

[0097] As used herein, the terms “maintenance” and “maintenance phase” are used interchangeably and refer to the second phase of treatment. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

[0098] As used herein, the term “serum trough level” refers to the lowest level that the agent (e.g., the anti-C5 antibody, or antigen binding fragment thereof) or medicine is present in the serum. In contrast, a “peak serum level,” refers to the highest level of the agent in the serum. The “average serum level,” refers to the mean level of the agent in the serum over time.

[0099] The term “antibody” describes a polypeptide comprising at least one antibody-derived antigen binding site (e.g., VH / VL region or Fv, or CDR). Antibodies include known forms of antibodies, e.g., the antibody can be a human antibody, a humanized antibody, a bispecific antibody or a chimeric antibody. The antibody also can be a Fab, Fab’2, ScFv, SMIP, Affibody®, nanobody or a single-domain antibody. The antibody also can be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgAsec, IgD, IgE or combinations thereof. The antibody can be a naturally occurring antibody or an antibody that has been altered by a protein engineering technique (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). An antibody can include, for example, one or more variant amino acids (compared to a naturally occurring antibody) that change a property (e.g., a functional property) of the antibody. Numerous such alterations are known in the art that affect, e.g., half-life, effector function, and / or immune responses to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that comprise at least one

[0100] antibody-derived antigen binding site.AXJ-314PC ALXN-1003-PCT01-NP IT. Anti-C5 Antibodies

[0101] Anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit the cleavage of C5 into fragments C5a and C5b. As described above, such antibodies also have, for example, improved pharmacokinetic properties relative to other anti-C5 antibodies (e.g., eculizumab) used for therapeutic purposes.

[0102] Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the methods described herein can be generated using methods known in the art. Alternatively, art recognized anti-C5 antibodies can be used. Antibodies that compete for binding to C5 with any of these art recognized antibodies or antibodies described herein can also be used.

[0103] An exemplary anti-C5 antibody is ravulizumab comprising 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 WO2015134894 and US Patent No: 9,079,949, the entire teachings of which are hereby incorporated by reference. The terms ravulizumab. BNJ441, and ALXN1210 may be used interchangeably throughout this document, but all refer to the same antibody. Ravulizumab selectively binds to human complement protein C5, inhibiting its cleavage to C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9 while preserving the proximal or early components of complement activation (e.g., C3 and C3b) essential for the opsonization of microorganisms and clearance of immune complexes.

[0104] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of ravulizumab having the sequence set forth in SEQ ID NO:12, and the CDR1, CDR2 and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO:8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO:8, respectively.AXJ-314PC ALXN-1003-PCT01-NP Another exemplary anti-C5 antibody is antibody BNJ421 comprising heavy and light chains 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 WO2015134894 and US Patent No.9, 079, 949, the entire teachings of which are hereby incorporated by reference.

[0105] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO:8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO:8, respectively.

[0106] The exact boundaries of CDRs are defined differently according to different methods. In some embodiments, the positions of the CDRs or framework regions within a light or heavy chain variable domain are as defined by Kabat et al. [(1991) “Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD]. In such cases, the CDRs can be referred to as “Kabat CDRs” (e.g., “Kabat LCDR2” or “Kabat HCDR1”). In some embodiments, the positions of the CDRs of a light or heavy chain variable region are as defined by Chothia et al. (Nature, 342:877-83, 1989).

[0107] Accordingly, these regions can be referred to as “Chothia CDRs” (e.g., “Chothia LCDR2” or “Chothia HCDR3”). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions can be defined by a Kabat-Chothia combined definition. In such embodiments, these regions can be referred to as “combined Kabat-Chothia CDRs.” Thomas, C. el al. (Mol. Immunol., 33:1389-401, 1996) exemplifies the identification of CDR boundaries according to Kabat and Chothia numbering schemes.

[0108] Another exemplary anti-C5 antibody is the 7086 antibody described in US Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chainAXJ-314PC ALXN-1003-PCT01-NP CDRs or variable regions of the 7086 antibody (see US Patent Nos. 8,241,628 and 8,883,158). Tn another embodiment, the antibody, or antigen binding fragment thereof, comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:24, 25 and 26, respectively. In another embodiment, the antibody, or antigen binding fragment thereof, comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO:27, and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO:28.

[0109] Another exemplary anti-C5 antibody is the 8110 antibody also described in US Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody, or antigen binding fragment thereof, comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:32, 33 and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO:35, and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO:36.

[0110] Another exemplary anti-C5 antibody is the 305LO5 antibody described in US Patent No.

[0111] 9,765,135. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody, or antigen binding fragment thereof, comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:40, 41 and 42, respectively. In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:43, and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:44.

[0112] Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. el al., Sci. Rep., 7:1080, 2017). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody, orAXJ-314PC ALXN-1003-PCT01-NP antigen binding fragment thereof, comprises a heavy chain comprising SEQ TD NO:45 and a light chain comprising SEQ ID NO:46.

[0113] In some embodiments, the anti-C5 antibody comprises the heavy and light chain variable regions or heavy and light chains of the REGN3918 antibody (see US Patent No. 10,633,434). In some embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region sequence set forth in SEQ ID NO: 47 and a light chain variable region comprising the sequence set forth in SEQ ID NO: 48. In some embodiments, the anti-C5 antibody, or antigen-binding fragment thereof, comprises a heavy chain sequence set forth in SEQ ID NO: 49 and a light chain sequence set forth in SEQ ID NO: 50.

[0114] In some 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 some embodiments, an anti-C5 antibody described herein comprises a heavy chain CDR2 comprising, or consisting of, the following amino acid sequence:

[0115] EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, an anti-C5 antibody described herein comprises a heavy chain variable region comprising the following amino acid sequence:

[0116] QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SS (SEQ ID NO: 12) .

[0117] In some embodiments, an anti-C5 antibody described herein comprises a light chain variable region comprising the following amino acid sequence:

[0118] DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIK (SEQ ID NO : 8 ) .

[0119] An anti-C5 antibody described herein can, in some embodiments, comprise a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn) with greater affinity than that of the native human Fc constant region from which the variant human Fc constant region was derived. The Fc constant region can, for example, comprise one or more (e.g., two. three, four, five, six, seven, or eight or more) amino acid substitutions relative to the native human Fc constant region from which the variant human Fc constant region was derived. The substitutions can increase the binding affinity of an IgG antibody containing the variant FcAXJ-314PC ALXN-1003-PCT01-NP constant region to FcRn at pH 6.0, while maintaining the pH dependence of the interaction.

[0120] Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining pH dependence of the interaction) are known in the art and exemplified in the working examples. See, e.g., WO2015134894 and US Patent No. 9,079,949 the disclosures of each of which are incorporated herein by reference in their entirety.

[0121] Substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn are known in the art and include, e.g., (1) the M252Y / S254T / T256E triple substitution (Dall’Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) the M428L or T250Q / M428L substitutions (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) the N434A or T307 / E380A / N434A substitutions (Petkova, S. et al.. Int. Immunol., 18:1759-69, 2006). The additional substitution pairings: P257VQ311I, P257EN434H and D376V / N434H (Datta-Mannan, A. etal., J. Biol. Chem., 282:1709-17, 2007), the disclosures of each of which are incorporated herein by reference in their entirety.

[0122] In some embodiments, the variant constant region has a substitution at EU amino acid position 255 for valine. In some embodiments, the variant constant region has a substitution at EU amino acid position 309 for asparagine. In some embodiments, the variant constant region has a substitution at EU amino acid position 312 for isoleucine. In some embodiments, the variant constant region has a substitution at EU amino acid position 386.

[0123] In some embodiments, the variant Fc constant region comprises no more than 30 e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2) amino acid substitutions, insertions, or deletions relative to the native constant region from which it was derived. In some embodiments, the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of: M252Y, S254T. T256E, N434S. M428L, V259I. T250I and V308F. In some embodiments, the variant human Fc constant region comprises a methionine at position 428 and an asparagine at position 434 of a native human IgG Fc constant region, each in EU numbering. In some embodiments, the variant Fc constant region comprises a 428L / 434S double substitution as described in, e.g., U.S. Patent No.

[0124] 8,088,376.AXJ-314PC ALXN-1003-PCT01-NP In some embodiments the precise location of these mutations may be shifted from the native human Fc constant region position due to antibody engineering. For example, the 428L / 434S double substitution when used in a IgG2 / 4 chimeric Fc may correspond to 429L and 435S as in the M429L and N435S variants found in ravulizumab and described in US Patent Number 9,079,949 the disclosure of which is incorporated herein by reference in its entirety.

[0125] In some embodiments, the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360. 376, 380, 382, 384. 385, 386, 387, 389, 424, 428, 433, 434 or 436 (EU numbering) relative to the 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;AXJ-314PC ALXN-1003-PCT01-NP 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.

[0126] Suitable anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO:11. Alternatively, the anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO:20 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0127] In one embodiment, the antibody binds to C5 at pH 7.4 and 25 °C (and, otherwise, under physiologic conditions) with an affinity dissociation constant (KD) that is 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 one embodiment, the antibody binds to C5 at pH 7.4 and 25°C (and, otherwise, under physiologic conditions) with an affinity dissociation constant (KD) that is about 0.5 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 some embodiments, the antibody binds to C5 at pH 6.0 and 25°C (and, otherwise, under physiologic conditions) with a KD that is about 22 nM.

[0128] In other embodiments, the [(KD of the antibody for C5 at pH 6.0 at 25°C) / (KD of the antibody for C5 at pH 7.4 at 25C)] 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,AXJ-314PC ALXN-1003-PCT01-NP 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

[0129] Methods for determining whether an antibody binds to a protein antigen and / or the affinity for an antibody to a protein antigen are known in the art. The binding of an antibody to a protein antigen, for example, can be detected and / or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), or enzyme-linked immunosorbent assay (ELISA; Benny K. C. Lo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921); Johne, B. etal., J. Immunol. Meth., 160:191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Jonsson, U. etal., Biotechniques, 11:620-7, 1991). In addition, methods for measuring the affinity (e.g., dissociation and association constants) are set forth in the working examples.

[0130] As used herein, the term “ka” refers to the rate constant for association of an antibody to an antigen. The term “ka” refers to the rate constant for dissociation of an antibody from the antibody / antigen complex. And the term “KD” refers to the equilibrium dissociation constant of an antibody-antigen interaction. The equilibrium dissociation constant is deduced from the ratio of the kinetic rate constants, KD = ka / ka. Such determinations can be measured, for example, at 25C or 37C (see the working examples). The kinetics of antibody binding to human C5 can be determined, for example, at pH 8.0, 7.4, 7.0. 6.5 and 6.0 via SPR on a BIAcore 3000 instrument using an anti-Fc capture method to immobilize the antibody.

[0131] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, blocks the cleavage of C5 into C5a and C5b. Through this blocking effect, for example, the

[0132] pro-inflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) at the surface of a cell are inhibited.

[0133] Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cell-lysing ability of complement in a subject’s body fluids. Such reductions of the cell-lysing ability of complement present in the body fluid(s) can be measured by methods known in the art such as, for example, by a conventional hemolytic assay such as the hemolysis assay (Kabat and Mayer (eds.), “Experimental Immunochemistry, 2ndEdition,” 135-240, Springfield, IL, CCAXJ-314PC ALXN-1003-PCT01-NP Thomas (1961), pages 135-139), or a conventional variation of that assay such as the chicken erythrocyte hemolysis method (Hillmen, P. et al.,N. Engl. J. Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into forms C5a and C5b are known in the art (Evans, M. et al., Mol. Immunol., 32: 1183-95, 1995). The concentration and / or physiologic activity of C5a and C5b in a body fluid can be measured, for example, by methods known in the art. For C5b, hemolytic assays or assays for soluble C5b-9 as discussed herein can be used. Other assays known in the art can also be used. Using assays of these or other suitable types, candidate agents capable of inhibiting human complement component C5 can be screened.

[0134] Immunological techniques such as, but not limited to, ELISA can be used to measure the protein concentration of C5 and / or its split products to determine the ability of an anti-C5 antibody, or antigen binding fragment thereof, to inhibit conversion of C5 into biologically active products. In some embodiments, C5a generation is measured. In some embodiments, C5b-9 neoepitope-specific antibodies are used to detect MAC formation.

[0135] Hemolytic assays can be used to determine the inhibitory activity of an anti-C5 antibody, or antigen binding fragment thereof, on complement activation. To determine the effect of an anti-C5 antibody, or antigen binding fragment thereof, on classical complement

[0136] pathway-mediated hemolysis in a serum test solution in vitro, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with anti-chicken erythrocyte antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, for example, as utilized in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody, or antigen binding fragment thereof, in the presence of a human IgM antibody. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the absorbance at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody, or antigen binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with a C5 polypeptide.AXJ-314PC ALXN-1003-PCT01-NP To determine the effect of an anti-C5 antibody, or antigen binding fragment thereof, on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes can be used as the target cells. In some embodiments, the serum test solution is a C5-deficient serum reconstituted with a C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, for example, as utilized in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody, or antigen binding fragment thereof, in the presence of lipopolysaccharide. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the fluorescence at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody, or antigen binding fragment thereof.

[0137] In some embodiments, C5 activity, or inhibition thereof, is quantified using a CH50eq assay. The CH50eq assay is a method for measuring the total classical complement activity in serum. This test is a lytic assay, which uses antibody- sensitized erythrocytes as the activator of the classical complement pathway and various dilutions of the test serum to determine the amount required to give 50% lysis (CH50). The percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, since the TCC themselves are directly responsible for the hemolysis that is measured. The assay is known and commonly practiced by those of skill in the art.

[0138] Briefly, to activate the classical complement pathway, undiluted serum samples (e.g., reconstituted human serum samples) are added to microassay wells containing the

[0139] antibody-sensitized erythrocytes to thereby generate TCC. Next, the activated sera are diluted in microassay wells, which are coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC). The TCC present in the activated samples bind to the monoclonal antibodies coating the surface of the microassay wells. The wells are washed and to each well is added a detection reagent that is detectably labeled and recognizes the bound TCC. The detectable label can be, e.g., a fluorescent label or an enzymatic label. The assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).AXJ-314PC ALXN-1003-PCT01-NP Inhibition, e.g., as it pertains to terminal complement activity, includes at least a 5 (e.g., at least a 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60) % decrease in the activity of terminal complement in, e.g., a hemolytic assay or CH50eq assay as compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at an equimolar concentration. Substantial inhibition, as used herein, refers to inhibition of a given activity (e.g., terminal complement activity) of at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 or greater) %. In some embodiments, an anti-C5 antibody described herein contains one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs:l-6), yet retains at least 30 (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95) % of the complement inhibitory activity of eculizumab in a hemolytic assay or CH50eq assay.

[0140] An anti-C5 antibody described herein has a serum half-life in humans that is at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50. 51. 52. 53. 54 or 55) days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is at least 40 days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is approximately 43 days. In another embodiment, the anti-C5 antibody described herein has a serum half-life in humans that is between 39-48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, an anti-C5 antibody, or antigen binding fragment thereof, described herein has a serum half-life that is at least 20 (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400 or 500) % greater than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the working examples (e.g., the C5-deficient / NOD / scid mouse or hFcRn transgenic mouse model system).

[0141] In one embodiment, the antibody competes for binding with, and / or binds to the same epitope on C5 as an antibody described herein. The term “binds to the same epitope” with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether antibodies bind to the same epitope on C5 with an antibody described herein include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigemantibody complexes, andAXJ-314PC ALXN-1003-PCT01-NP hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of the antibody to peptide antigen fragments or mutated variations of the antigen where loss of binding due to a modification of an amino acid residue within the antigen sequence is often considered an indication of an epitope component. In addition, computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies having the same VH and VL or the same CDR1, CDR2 and CDR3 sequences are expected to bind to the same epitope.

[0142] Antibodies that “compete with another antibody for binding to a target” refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, may be determined using known competition experiments. In certain embodiments, an antibody competes with, and inhibits binding of another antibody to a target by at least 10%. 20%, 30%, 40%, 50%, 60%. 70%, 80%, 90% or 100%. The level of inhibition or competition may be different depending on which antibody is the “blocking antibody” (z.e., the antibody that is incubated first with the target). Competing antibodies can bind to, for example, the same epitope, an overlapping epitope or to adjacent epitopes (e.g., as evidenced by steric hindrance).

[0143] Anti-C5 antibodies, or antigen-binding fragments thereof described herein, used in the methods described herein can be generated using a variety of art-recognized techniques.

[0144] Monoclonal antibodies can be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell (Kohler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976)). Methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses or other methods known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host.

[0145] Alternatively, one may isolate DNA sequences that encode a monoclonal antibody or a bindingAXJ-314PC ALXN-1003-PCT01-NP fragment thereof by screening a DNA library from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0146] In some embodiments, the anti-C5 antibody does not comprise eculizumab (SOLIRIS®) or an antigen-binding fragment thereof (e.g., comprising heavy and light chain complementarity determining regions (HCDR13 and LCDR1-3, respectively) of eculizumab). In some embodiments, the anti-C5 antibody is not a biosimilar of eculizumab (SOLIRIS®), e.g., ABP 959 antibody (manufactured by Amgen Inc., USA), ELIZARIA® (manufactured by Generium JNC, Russia), or SB 12 (manufactured by Samsung Bioepis, Incheon, South Korea).

[0147] III. Compositions

[0148] Also provided herein are compositions comprising an anti-C5 antibody, or antigen binding fragment thereof. In one embodiment, the composition comprises an anti-C5 antibody comprising the CDRL CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO:8. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences shown in SEQ ID NOs: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.

[0149] The compositions can be formulated as a pharmaceutical solution, e.g., for administration to a subject for the treatment of IgAN. The pharmaceutical compositions generally include a pharmaceutically acceptable carrier. As used herein, a “pharmaceutically acceptable carrier” refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The compositions can include a pharmaceutically acceptable salt, e.g., an acid addition salt or a base addition salt, sugars, carbohydrates, polyols and / or tonicity modifiers.

[0150] Preferably, the pharmaceutical composition of the disclosure comprises ravulizumab which has been formulated at pH 7.4 and supplied in 11 mL single-use vials, wherein each vial of ravulizumab contains 1100 mg of ravulizumab (100 mg / mL) in 50 mM sodium phosphate, 25mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection. Compositions of ravulizumab can be provided at 1,100 mg / 1 ImL concentrate for solution for infusion.

[0151] Compositions of ravulizumab can also be provided at 300 mg / 3 mL concentrate for solution forAXJ-314PC ALXN-1003-PCT01-NP infusion. In embodiments, the concentration of a diluted solution for infusion of ravulizumab is about 50 mg and the actual dose administered to a patient is based on body weight and / or conditions treated.

[0152] The compositions can be formulated according to standard methods. Pharmaceutical formulation is an established art (see, for example, Gennaro (2000) “Remington: The Science and Practice of Pharmacy.” 20thEdition, Lippincott. Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7thEdition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3rdEdition (ISBN:

[0153] 091733096X)). In some embodiments, a composition can be formulated, for example, as a buffered solution at a suitable concentration and suitable for storage at 2-8C {e.g., 4 °C). In some embodiments, a composition can be formulated for storage at a temperature below 0C {e.g., -20°C or -80°C). In some embodiments, the composition can be formulated for storage for up to 2 years {e.g., 1 month, 2 months, 3 months, 4 months, 5 months. 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, P / 2 years or 2 years) at 2-8°C e.g., 4°C). Thus, in some embodiments, the compositions described herein are stable in storage for at least 1 year at 2-8°C e.g., 4°C).

[0154] The pharmaceutical compositions can be in a variety of forms. These forms include, e.g., liquid, semi-solid and solid dosage forms, such as liquid solutions {e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. Compositions containing a composition intended for systemic or local delivery, for example, can be in the form of injectable or infusible solutions. Accordingly, the compositions can be formulated for administration by a parenteral mode {e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). “Parenteral administration,” “administered parenterally” 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,AXJ-314PC ALXN-1003-PCT01-NP transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrastemal injection and infusion.

[0155] In some embodiments, the disclosure relates to a composition, e.g., pharmaceutical composition or a medicament, comprising an effective amount of an anti-C5 antibody or an antigen binding fragment thereof, comprising heavy chain complementarity determining regions (HCDRs) comprising HCDR1, HCDR2 and HCDR3 sequences as set forth in SEQ ID NOs:19.

[0156] 18 and 3, respectively, and light chain complementarity determining regions (LCDRs) comprising LCDR1, LCDR2 and LCDR3 sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, for use in the treatment IgAN and / or IgAVN in a human pediatric patient, wherein the effective amount comprises administration of the anti-C5 antibody, or the antigen binding fragment thereof:

[0157] (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a patient weighing > 10 to < 20 kg;

[0158] (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 20 to < 30 kg;

[0159] (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

[0160] (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

[0161] (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 100.

[0162] In some embodiments, the disclosure relates to a composition, e.g., pharmaceutical composition or a medicament, comprising an effective amount of an anti-C5 antibody or antigen binding fragment thereof, comprising HCDR1-3 comprising SEQ ID NOs:19, 18 and 3 and LCDR1.3 comprising SEQ ID NOs: 4, 5 and 6, for use in the treatment of IgAN, in a human pediatric patient, wherein the anti-C5 antibody further comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding toAXJ-314PC ALXN-1003-PCT01-NP methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering. Particularly, the disclosure relates to a pharmaceutical composition or a medicament comprising an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof, e.g., comprising the HCDRi 3 and the LCDRi 3 of ravulizumab, for use in the treatment of IgAN and / or IgAVN, in a human pediatric patient.

[0163] IV. Methods

[0164] Provided herein are methods for treating IgAN and / or IgAVN in a human pediatric patient, comprising administering to the patient an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody or antigen binding fragment thereof is administered (or is for administration) according to a particular clinical dosage regimen (e.g., at a particular dose amount and according to a specific dosing schedule). In one embodiment, the methods relate to treatment of IgAN in a pediatric patient. In another embodiment, the methods relate to treatment of IgAVN in a pediatric patient. In another embodiment, the methods relate to treatment of IgAN and IgAVN in a pediatric patient.

[0165] A pediatric patient of the disclosure can be from 0-18 years of age. In embodiments, the pediatric patient is from 2-5 years of age. In embodiments, the pediatric patient is from 12-17 years of age. In embodiments, the pediatric patient is from 6-11 years of age. A pediatric patient can be of any age from 0 up to 18 years of age. A pediatric patient can be a newborn, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 yr„ 2 yrs.. 3 yrs., 4 yrs., 5 yrs., 6 yrs.. 7 yrs., 8 yrs., 9 yrs., 10 yrs., 11 yrs.. 12 yrs., 13 yrs., 14 yrs., 15 yrs., 16 yrs., 17 yrs., or up to 18 yrs of age.

[0166] In one embodiment, the dose of the anti-C5 antibody, or antigen binding fragment thereof, is based on the weight of the patient. In one embodiment, for example, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient. In one embodiment, 600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 10 to < 20 kg). In one embodiment, 900 mg and / or 2100 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 20 to < 30 kg). In one embodiment, 1200 mg and / or 2700 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administeredAXJ-314PC ALXN-1003-PCT01-NP to a pediatric patient (e.g., a pediatric patient weighing > 30 to < 40 kg). In one embodiment, 2400 mg and / or 3000 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 40 to < 60 kg). In one embodiment, 2700 mg and / or 3300 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 60 to < 100 kg). In one embodiment, 3000 mg and / or 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient (e.g., a pediatric patient weighing > 100 kg).

[0167] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 20 to < 30 kg once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter.

[0168] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 30 to < 40 kg once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter.

[0169] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 40 to < 60 kg once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter.

[0170] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 60 to < 100 kg once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter.

[0171] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to a pediatric patient weighing > 100 once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter.

[0172] In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).

[0173] In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered for one or more administration cycles. In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at an initial loading dose on Day 1. In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at maintenance dose (e.g., on Day 15 and every four our eight weeks thereafter).AXJ-314PC ALXN-1003-PCT01-NP In another embodiment, a method of treating a human pediatric patient with IgAN and / or IgAVN, is provided, the method comprising administering to the patient (e.g., during an administration cycle) an effective amount of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID Nos: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID Nos:4, 5 and 6. respectively, wherein the anti-C5 antibody or antigen binding fragment thereof is administered:

[0174] (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a patient weighing > 10 to < 20 kg;

[0175] (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 20 to < 30 kg;

[0176] (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg; (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg; (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 100.

[0177] In another embodiment, a method of treating a human pediatric patient with IgAN and / or IgAVN, is provided, the method comprising administering to the patient (e.g., during an administration cycle) an effective amount of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ Id NOs:19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ Id NOs:4, 5 and 6, respectively, and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering, wherein the anti-C5 antibody or antigen binding fragment thereof is administered:AXJ-314PC ALXN-1003-PCT01-NP (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a patient weighing > 10 to < 20 kg;

[0178] (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 20 to < 30 kg;

[0179] (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

[0180] (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

[0181] (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 100.

[0182] In one embodiment, the pediatric patient has not previously been treated with eculizumab. In another embodiment, the pediatric patient has previously been treated with eculizumab. In another embodiment, the pediatric patient has previously been treated with eculizumab and Day 1 (e.g., of the administration cycle) is two weeks or more from the patient’s last dose of eculizumab.

[0183] In some embodiments, the pediatric patient has previously been treated or is concurrently being treated with another therapeutic agent. For example, in one embodiment, the pediatric patient has previously been treated or is concurrently being treated with a renin-angiotensin system inhibitor (RASI). In another embodiment, the pediatric patient has previously been treated or is concurrently being treated with an angiotensin AT(l)-receptor blocker (ARB). In another embodiment, the patient has IgAVN and has previously been treated or is concurrently being treated with one or more immunosuppressive medications, such as corticosteroid, cyclophosphamide, calcineurin inhibitors, mizoribine, and / or or mycophenolate mofetil.

[0184] In some embodiments, the disclosure relates to use of an effective amount of an anti-C5 antibody or antigen binding fragment thereof, comprising heavy chain complementarity determining regions (HCDRs) comprising HCDR1, HCDR2 and HCDR3 sequences as set forth in SEQ ID NOs:19, 18 and 3, respectively, and light chain complementarity determining regions (LCDRs) comprising LCDR1, LCDR2 and LCDR3 sequences as set forth in SEQ ID NOs:4, 5AXJ-314PC ALXN-1003-PCT01-NP and 6, respectively, in the manufacture of a composition, e.g., pharmaceutical composition or a medicament, for treating IgAN and / or IgAVN in a human pediatric patient, wherein the effective amount comprises administration of the anti-C5 antibody or the antigen binding fragment thereof:

[0185] (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a patient weighing > 10 to < 20 kg;

[0186] (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 20 to < 30 kg;

[0187] (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

[0188] (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

[0189] (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 100.

[0190] In some embodiments, the disclosure relates to use of an effective amount of an anti-C5 antibody or antigen binding fragment thereof comprising HCDR1-3 comprising SEQ ID NOs:19, 18 and 3 and LCDR1-3 comprising SEQ ID NOs: 4, 5 and 6, in the manufacture of a composition, e.g., pharmaceutical composition or a medicament, for treating IgAN and / or IgAVN, in a human pediatric patient, wherein the anti-C5 antibody further comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering. Particularly, the disclosure relates to use of an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof, e.g., comprising the HCDR1-3 and the LCDRI-3 of ravulizumab, in the manufacture of a composition, e.g., pharmaceutical composition or a medicament, for IgAN and / or IgAVN, in a human pediatric patient.

[0191] V. Outcomes

[0192] Provided herein are methods for treating IgAN and / or IgAVN in a pediatric patient comprising administering to the patient an anti-C5 antibody.AXJ-314PC ALXN-1003-PCT01-NP Symptoms of IgAN and TgAVN include, but are not limited to, e.g., hematuria (blood in the urine that can sometimes make it pink, dark brown or cola colored), edema (e.g., in the hands, ankles or feet), pain on the side of the back (flank pain), high blood pressure (hypertension), and / or foamy urine (due to proteinuria, excess protein in urine).

[0193] In one embodiment, pediatric patients treated according to the disclosed methods maintain a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of at least 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325. 330, 335, 340, 345. 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 pg / mL or greater. In one embodiment, pediatric patients treated according to the disclosed methods maintain a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of at least 175 pg / mL or greater.

[0194] In one embodiment, pediatric patients treated according to the disclosed methods have a free C5 concentration of 0.5 pg / mL or less (e.g., 0.4 pg / mL, 0.3 pg / mL, 0.2 pg / mL, or 0.1 pg / mL or less).

[0195] In another embodiment, the treatment results in a shift towards normal levels of one or more biomarkers selected from the group consisting of soluble C5b-9 (sC5b-9), Factor Ba, C4d, CD68, CD88, CD163, Gd-IgAl, KIM-1, and creatinine.

[0196] In another embodiment, the treatment results in a change in Estimated glomerular filtration rate (eGFR) compared to baseline over time (i.e., a change from baseline eGFR over time). For example, the treatment results in a change from baseline eGFR at week 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 105, 106, 107, 108, 109, or 110. In another embodiment, the treatment results in a change in eGFR compared to baseline, e.g., a change from baseline in eGFR at Week 50 and / or Week 106. In another embodiment, the pediatric patient has an eGFR > 30 mL / min / 1.73m2 prior to treatment.

[0197] In another embodiment, the treatment results in a change in eGFR slope compared to baseline. In another embodiment, the treatment results in an improvement in eGFR slope compared to baseline. In another embodiment, the treatment results in an improvement in eGFR slope compared to baseline by week 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 105, 106, 107, 108, 109, or 110. In another embodiment, the treatment results in an improvement eGFR slopeAXJ-314PC ALXN-1003-PCT01-NP compared to baseline, e.g., an improvement in the annualized total eGFR slope over 50 and / or 106 weeks.

[0198] In another embodiment, the treatment results in a reduction in proteinuria compared to baseline, e.g., change from baseline in proteinuria over time. In another embodiment, the treatment results in a reduction in proteinuria compared to baseline by 30%, 40%, 50%, 60%, 70%, 80%. 90%. or 95%. In another embodiment, the treatment results in a reduction in proteinuria compared to baseline, e.g., a change from baseline in proteinuria at Week 34.

[0199] In another embodiment, the treatment results in a reduction in albuminuria compared to baseline, e.g., change from baseline in albuminuria over time. In another embodiment, the treatment results in a reduction in albuminuria compared to baseline by 30%, 40%, 50%, 60%, 70%, 80%, 90%. or 95%. In another embodiment, the treatment results in a reduction in albuminuria compared to baseline, e.g., a change from baseline in albuminuria at Week 34.

[0200] In another embodiment, the pediatric patient has a urine protein to creatinine ratio (UPCR) of > 1 g / g prior to treatment. In another embodiment, the treatment results in a UPCR < 0.5 g / g at Week 34. In another embodiment the treatment results in a reduction in proteinuria compared to baseline based on UPCR from 24-hour urine collections at Week 10 and Week 34 (e.g., reduction in 24-hour UPCR > 50% from baseline). In another embodiment the treatment results in a reduction in 24-hour UPCR > 30%, e.g., a reduction in 24-hour UPCR > 50% from baseline.

[0201] In another embodiment, the treatment results in an improvement in UPCR compared to baseline. In another embodiment, the treatment results in a reduction in 24-hour UPCR by at least 30% (e.g., 31%, 32%, 33%, 34%. 35%, 36%, 37%, 38%, 39%. 40%, 41%, 42%, 43%, 44%.

[0202] 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%. 79%. 80%, 81%, 82%, 83%. 84%. 85%, 86%, 87%, 88%. 89%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In another embodiment, the treatment results in a 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% improvement in UPCR compared to baseline. In another embodiment, the treatment results in a 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% reduction in proteinuria compared to baseline. In another embodiment, the reduction inAXJ-314PC ALXN-1003-PCT01-NP proteinuria occurs at 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 34 weeks, 50 weeks, 60 weeks, 70 weeks, 80 weeks, 90 weeks, 100 weeks or 106 weeks, after treatment compared to baseline. In another embodiment, proteinuria is measured by a complete 24-hour urine collection. In another embodiment, the treatment results in Partial Remission (PR) in the pediatric patient.

[0203] In another embodiment, the treatment results in a reduction or cessation in one or more of the following symptoms in an IgAN and / or IgAVN patient compared to baseline: hematuria, dark brown or cola colored urine, edema, flank pain, hypertension, foamy urine, and / or proteinuria.

[0204] In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by Pediatric Quality of Life Inventory Generic Core Scales (PedsQL, e.g., PedsQL 4.0). The PedsQL Measurement Model is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It is a brief, standardized, generic assessment instrument that systematically assesses patients' and parents' perceptions of HRQOL in pediatric patients with chronic health conditions using pediatric cancer as an exemplary model (see, e.g., Vami JW, et al., Med Care. 1999 Feb;37(2): 126-39). The PedsQL is based on a modular approach to measuring HRQOL and consists of a 15 -item core measure of global HRQOL and eight supplemental modules assessing specific symptom or treatment domains. Each item of the assessment is scored on a 5-point scale from 0- 4 for ages 8-18 as follows: 0 = never a problem, 1 = almost never a problem, 2 = sometimes a problem, 3 = often a problem, 4 = almost always a problem. Each item of the assessment is scored on a 3-point scale for a young child selfreporting (ages 5- 7) as follows: 0 = not at all a problem, 2 = sometimes a problem, 4 = a lot of a problem. A large score means worst symptoms. Scores are linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50. 3 = 25, 4 = 0), in which high score means better condition. Different forms are available for different ages.

[0205] In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (peds FACIT-F). The peds FACIT-F is a 13-item self-report measure of pediatric cancer-related fatigue and is part of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system, peds FACIT-F was derived from the 51-item pediatric fatigue item bankAXJ-314PC ALXN-1003-PCT01-NP (pedsFIB) (see, e.g., Lai JS, et al., J. Pediatr. Hematol. Oncol. 2007 Jul;29(7):471-9. Each item is rated on a 0 to 4 scale: "None of the time", "A little bit of the time", "Some of the time", “Most of the time”, “All of the time”. It measures fatigue in the past seven days. Scores on the peds FACIT-F discriminate between patients with and without anemia and among patients with different functional status. As with all FACIT questionnaires, a high score is good. Therefore, a score of “0” indicates a severely symptomatic patient, and the highest possible score (varies per scale and subscale) indicates an asymptomatic patient.

[0206] In another embodiment, the treatment results in terminal complement inhibition.

[0207] In another embodiment, the treatment results in a reduction in adverse events.

[0208] VI. Kits and Unit Dosage Forms

[0209] Also provided herein are kits that include a pharmaceutical composition containing an anti-C5 antibody or antigen binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods. The kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a pediatric patient having IgAN. The kit also can include a syringe.

[0210] Optionally, the kits include multiple packages of the single-dose pharmaceutical compositions each containing an effective amount of the anti-C5 antibody, or antigen binding fragment thereof, for a single administration in accordance with the methods provided above. Instruments or devices necessary for administering the pharmaceutical composition(s) also may be included in the kits. For instance, a kit may provide one or more pre-filled syringes containing an amount of the anti-C5 antibody or antigen binding fragment thereof.

[0211] In one embodiment, a kit for treating IgAN and / or IgAVN in a human pediatric patient comprises: (a) a dose of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8; and (b) instructions for using the anti-C5 antibody, or antigen binding fragment thereof, according to any of the methods described herein.AXJ-314PC ALXN-1003-PCT01-NP In one embodiment, the kit comprises a dose of an anti-C5 antibody or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered:

[0212] (a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a patient weighing > 10 to < 20 kg;

[0213] (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 20 to < 30 kg;

[0214] (c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg; (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg; (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 100.

[0215] The following example is merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, GenBank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0216] EXAMPLE EXAMPLE: Phase 3 Study in Pediatric Patients

[0217] A phase 3, open-label, multicenter study is conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of ravulizumab in pediatric participants (2 to < 18 years of age; e.g., 2-5 years, 12-17 years, and / or 6-11 years) with primary immunoglobulin A nephropathy (IgAN).AXJ-314PC ALXN-1003-PCT01-NP 1. Objectives and Endpoints

[0218] The main objective of this study is to assess the efficacy of ravulizumab administered intravenously (IV) in pediatric patients by evaluating change from Baseline in proteinuria based on urine protein-to-creatinine ratio (UPGR) at Week 34. Secondarily to characterize the PK and PD of treatment with ravulizumab IV dosing in pediatric participants (2 to < 18 years of age; e.g., 2-5 years. 12-17 years, and / or 6-11 years) with IgAN or immunoglobulin A vasculitis associated nephritis (IgAVN) who are at risk of progressing to end stage kidney disease (ESKD) to support the extrapolation of efficacy from the adult population. Given the same diagnostic criteria, similar pathophysiology and overall clinical characteristics in adult and pediatric patients with IgAN, data obtained from adult participants with primary IgAN are extrapolated to the pediatric population to support the PK / PD, safety, and efficacy of ravulizumab in the pediatric population. The study is also intended to evaluate the efficacy, safety, and tolerability of ravulizumab IV in pediatric participants.

[0219] The primary objective for the IgAN and IgAVN cohorts is to characterize proteinuria reduction in pediatric patients. The secondary objective is characterization of the PK and PD of treatment with ravulizumab IV in pediatric participants to support the extrapolation of efficacy from the adult population. Change from baseline in proteinuria based on UPCR at week 34 in pediatric patients with IgAN or IgAVN is evaluated as a primary objective.

[0220] PK / PD parameters (at trough and peak) are evaluated at Baseline and at different timepoints through Week 34 as follows: (1) PK: Cmax and Ctrough (measured at end of dosing interval) and (2) PD: change in serum free C5 concentrations over time.

[0221] A secondary objective for the IgAN and IgAVN cohorts is to assess the efficacy of ravulizumab IV in pediatric participants (e.g., via Change from Baseline in proteinuria based on UPCR at Week 34 and change from Baseline in albuminuria based on UACR at Week 34).

[0222] Additional objectives include (1) a reduction in proteinuria > 50% from Baseline at Week 34 based on UPCR from 24-hour urine collections, (2) annualized total eGFR slope over 106 weeks, (3) change from Baseline in eGFR at Weeks 50 and 106, and (4) UPCR < 0.5 g / g at Week 34. These endpoints are established surrogates of kidney disease progression (Heerspink, 2019) and are utilized in Phase 3 studies of IgAN (see, e.g., Heerspink HJL, et al., Lancet Diabetes Endocrinol. 2019;7(2): 128-139). They are also supported by modern pediatric clinicalAXJ-314PC ALXN-1003-PCT01-NP practice guidelines (see e.g., Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Ini.

[0223] 2021;100(4S):Sl-S276).

[0224] A further objective is to evaluate the safety and tolerability of ravulizumab in pediatric participants (e.g., (1) via incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs). and adverse events of special interest (AESIs) over time and (2) change from Baseline in vital signs, and laboratory assessments).

[0225] Yet another objective is to assess the immunogenicity of ravulizumab IV in pediatric participants (e.g., via anti-drug antibody (ADA) incidence, ADA response categories, and titer, as well as neutralizing anti-drug antibody (Nab) incidence for the duration of the study).

[0226] Exploratory objectives for the IgAN and IgAVN cohorts include assessing the efficacy of ravulizumab to improve measures of kidney function in pediatric participants (e.g., UPGR < 0.2 g / g at each scheduled visit, time to UPCR < 0.2 g / g up to Week 106, time to UPCR reduction > 50% up to Week 106, time to UPCR < 0.5 g / g up to Week 106, and absence of hematuria at each scheduled visit). Absence of hematuria is defined as negative (0 or trace) blood or urine dipstick or < 5 RBCs / high-power field (hpf) on urine sediment analysis (only applies for participants with positive hematuria at Baseline).

[0227] Final exploratory objectives include: (1) assessing quality of life (QoL) based on participant reported outcomes in pediatric participants based on treatment with ravulizumab (e.g., via change from Baseline in PedsQL 4.0 Generic Core Scales at each scheduled visit, and change from Baseline in peds FACIT-F at each scheduled visit), (2) assessing health resource utilization in pediatric participants based on treatment with ravulizumab (e.g., via number of inpatient admissions by Week 106, duration of hospitalizations by Week 106, and number of medical encounters (excluding study visits) by Week 106), (3) assessing blood and urine biomarkers of disease, inflammation, renal damage, and complement activation (e.g., via change from Baseline in selected biomarker levels of IgAN disease, inflammation, renal damage, and complement activation in blood and urine at each scheduled visit), and (4) exploring how genetic variations may affect clinical parameters, risk and prognosis of diseases and the response to medications (e.g., exploratory endpoints are related to the data generated from the genetic analysis of part or all of the participant’s genetic information).AXJ-314PC ALXN-1003-PCT01-NP The primary estimand or clinical question of interest for the primary objective is to determine the mean change in UPCR at Week 34 in pediatric participants treated with ravulizumab. regardless of the use of alternative IgAN therapy, newly initiated concomitant IgAN therapy, or treatment discontinuation. The primary estimand is defined by the following attributes: the population includes pediatric participants with IgAN; the endpoint is the change from baseline in proteinuria based on UPCR at Week 34; the treatment condition is ravulizumab; and the handling of intercurrent events, including the use of alternative IgAN therapy, newly initiated concomitant IgAN therapy, and treatment discontinuation, is addressed using the treatment policy strategy. The population-level summary measure is the mean change from baseline in UPCR at Week 34.

[0228] A supplementary estimand is also defined to include pediatric participants with either IgAN or IgAVN. The endpoint for this estimand is the change from baseline in proteinuria based on UPCR at Week 34, with the treatment condition being ravulizumab. Intercurrent events, such as the use of alternative or newly initiated concomitant IgAN / IgAVN therapy and treatment discontinuation, are handled using the treatment policy strategy. The population-level summary for the supplementary estimand is the mean change from baseline in UPCR at Week 34.

[0229] 2. Overall Design Synopsis

[0230] This is a Phase 3, two-cohort, open-label, single-arm, multicenter study to evaluate the PK, PD, safety, and efficacy of ravulizumab in children and adolescent participants 2 to < 18 (e.g., 2-5 years, 12-17 years, and / or 6-11 years) years of age with primary IgAN (Cohort 1) or IgAVN (Cohort 2) receiving optimal treatment with renin-angiotensin system (RAS) blockade using angiotensin-converting enzyme inhibitors (ACEIs) and / or angiotensin AT(l)-receptor blockers (ARBs) for at least 3 months prior to Screening who are at risk of progressing to endstage kidney disease (ESKD). Approximately 24 eligible participants are enrolled in the study.

[0231] FIG. 1 sets forth a schematic of the overall study design. FIGS. 2A-2G set forth the Schedule of Activities from Screening through the end of the Primary Evaluation Period for the Week 34 Visit. FIGS.3A-3F set forth the Schedule of Activities for the Extension Period for Week 38 through Week 106.AXJ-314PC ALXN-1003-PCT01-NP Cohort 1 : a minimum of 18 participants with IgAN evaluable for the primary analysis are enrolled, including at least 4 participants with IgAN < 40 kg.

[0232] Cohort 2: Up to approximately 6 eligible participants with IgAVN are enrolled in a separate cohort.

[0233] All study elements are the same across both cohorts except selected eligibility criteria (see 3. Study Population). The study consists of a Screening Period of up to 6 weeks, a 34-week Primary Evaluation Period, and a 72-week Extension Period (up to Week 106). Participants have a Follow-up Visit 8 weeks following the last dose of ravulizumab. The dose of ravulizumab is given according to a weight-based dosing regimen and is administered IV. The primary objective is to characterize change from baseline in proteinuria based on UPCR at Week 34. The secondary objective is to characterize PK / PD parameters at Baseline through Week 34. Cohort 1 and Cohort 2 are analyzed separately. This study design includes no masking / blinding.

[0234] All participants receive a weight-based loading dose of ravulizumab on Day 1, followed by weight-based maintenance treatment with ravulizumab on Day 15 and every eight weeks (q8w) thereafter for participants weighing > 20 kg, or every four weeks (q4w) for participants weighing < 20 kg. Participants receive ravulizumab for up to 106 weeks.

[0235] The initial Screening Period minimizes variability in proteinuria through ensuring adherence to RAS inhibition (ACEI and / or ARB) and blood pressure (BP) control prior to enrollment in the Primary Evaluation Period. It also ensures enrollment of the target participant population with persistent UPCR > 1 g / g and eGFR > 30 mL / min / 1.73 m2 on optimal care. Participants complete a urinalysis during the initial screening period.

[0236] The Primary Evaluation Period duration is appropriate to adequately assess the change from baseline in proteinuria on UPCR, and safety endpoints for ravulizumab in the pediatric IgAN patient populations. A 34-week Primary Evaluation Period is considered appropriate to characterize the PK / PD and proteinuria reduction to the extrapolation of efficacy from the adult population.

[0237] The Extension Period of up to Week 106 of treatment with ravulizumab enables evaluation of the long-term safety and eGFR of ravulizumab treatment.

[0238] 3. Study PopulationAXJ-314PC ALXN-1003-PCT01-NP The eligibility criteria are designed to identify participants with primary IgAN or IgAVN who are at high risk of progression to kidney failure while receiving optimized IgAN or IgAVN therapy (including ACEI and / or ARB). Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

[0239] Participants are eligible to be included in the study only if all of the following criteria apply:

[0240] 1. Participant must be > 2 to < 18 years of age inclusive, at the time of signing the informed consent or assent.

[0241] 2. UPCR > 1 g / g from the mean of 3 first morning voids (FMVs) collected within 1 week during the Screening Period (may be collected at home).

[0242] 3. eGFR > 30 mL / min / 1.73 m2 during Screening as calculated by the CKiD U25 equation (cystatin C equation) (see Pierce CB, Kidney Int. 2021;99(4):948-956).

[0243] 4. Presence of hematuria as defined by a positive result on urine dipstick for blood or > 5 RBCs / hpf microscopy on urine sediment during or within 3 months of Screening.

[0244] 5. Adherence to and compliance with stable (weight-adjusted per Pi's discretion) and maximum allowed or tolerated RASI (ACEI and / or ARB) dose for > 3 months prior to Screening with no planned change in dose (weight-adjusted per Pi's discretion) during Screening through Week 106. Participants with intolerance to RASI medications may be included.

[0245] 6. Body weight > 10 kg at Screening.

[0246] 7. Male or female (according to their reproductive organs and functions assigned by chromosomal complement) assigned at birth, inclusive of all gender identities.

[0247] 8. Contraceptive and barrier use as well as pregnancy testing as appropriate for the age and sexual activity of pediatric participants and / or as required by local regulations as outlined in the protocol.

[0248] 9. To reduce the risk of meningococcal infection (Neisseria meningitidis), all participants must be vaccinated against meningococcal infection from serogroups A, C, W135, and Y (and serogroup B, where available e.g. in the United States and Europe and participantsAXJ-314PC ALXN-1003-PCT01-NP who have received their vaccination more than 3 years before initiating ravulizumab are allowed to receive a booster dose, as applicable) within 3 years and at least 2 weeks prior to the first dose of study intervention. If vaccination occurs < 2 weeks from the first dose of study intervention, the participant receives prophylactic antibiotics for at least 2 weeks after initial vaccination. Vaccinations must follow national / local guidelines.

[0249] 10. Must have received vaccination against Haemophilus influenzae type b and Streptococcus pneumoniae unless previously vaccinated according to current national and local vaccination guidelines.

[0250] 11. The Investigator, or a person designated by the Investigator, obtains written informed consent from each study participant’s legal guardian and the participant’s assent, when applicable, before any study-specific activity is performed. All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand.

[0251] 12. Legal guardian or primary caregiver must be able to accurately maintain the child’s take home record, including items of general health.

[0252] 13. Provision of signed and dated written Optional Genetic Research Information informed consent from each study participant’s legal guardian and the participant’s assent, when applicable, prior to collection of samples for optional genetic research that supports the Genomic Initiative.

[0253] 14. Established diagnosis of primary IgAN diagnosis with < 50% tubulointerstitial fibrosis, < 50% glomerular sclerosis, and within 3 years prior to Screening or during the Screening Period.

[0254] 15. Established diagnosis of IgAVN with < 50% tubulointerstitial fibrosis, < 50% glomerular sclerosis, and within 3 years prior to Screening or during the Screening Period.

[0255] 16. If receiving immunosuppressive medications (e.g., corticosteroid, cyclophosphamide, calcineurin inhibitors, mizoribine, or mycophenolate mofetil) for the treatment of the renal manifestations of IgAVN, the medication must be stable for > 1 month prior to Screening.AXJ-314PC ALXN-1003-PCT01-NP Participants are excluded from the study if any of the following criteria apply:

[0256] Diagnosis of rapidly progressive glomerulonephritis (RPGN) as measured by eGFR loss > 50% over a period of 3 months prior to Screening and / or have > 50% crescentic glomerulonephritis on the kidney biopsy or eGFR decline of >50% within 3 months.

[0257] 2. Secondary forms of IgAN not in the context of primary IgAN or IgAV (e.g., due to systemic lupus erythematosus, cirrhosis, or celiac disease).

[0258] 3. Concomitant clinically significant renal disease other than IgAN or IgAVN.

[0259] 4. Clinical remission of IgAN / IgAVN or clinically significant improvement in proteinuria within the last 6 months.

[0260] 5. Uncontrolled diabetes mellitus with HbAlc > 8.5%.

[0261] 6. History of kidney transplant or planned kidney transplant during the Primary Evaluation Period.

[0262] 7. History of other solid organ (heart, lung, small bowel, pancreas, or liver) or bone marrow transplant; or planned transplant during the Primary Evaluation Period or Extension Period, except for corneal transplant.

[0263] 8. Splenectomy or functional asplenia.

[0264] 9. Participants with nephrotic syndrome receiving albumin infusions or with acute kidney injury requiring dialysis within the last 6 months prior to Screening.

[0265] 10. Systemic BP > 95th percentile for sex and height. If <13 years of age: Systemic BP >95th percentile + 12 mmHg for sex and height or >140 / 90 mmHg, whichever is lower. If >13 years of age: Systemic BP > 140 / 90 mm Hg.

[0266] 11. Hemolytic uremic syndrome diagnosed any time prior to Screening.

[0267] 12. Planned urological surgery expected to influence kidney function within the study time frame.

[0268] 13. Congenital immunodeficiency.

[0269] 14. History of unexplained, recurrent infection.

[0270] 15. Known medical or psychological condition(s), including substance abuse, or risk factor that, in the opinion of the Investigator, might interfere with the participant’s full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study.AXJ-314PC ALXN-1003-PCT01-NP History of or unresolved N meningitidis infection.

[0271] wn history of HIV, active hepatitis B infection, or active hepatitis C infection.

[0272] Active systemic bacterial, viral, or fungal infection within 14 days prior to enrollment. Drug or alcohol abuse or dependence within 1 year prior to Screening that interferes with ability to participate in the clinical study.

[0273] History of malignancy within 5 years of Screening, except for nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence. Hypersensitivity to any ingredient contained in the study intervention, including murine proteins.

[0274] Received biologies for the treatment of IgAN or IgAVN < 6 months prior to Screening. Traditional Chinese medicines and Chinese proprietary medicines with systemic immunosuppressive properties including, but not limited to Tripterygium wilfordii or Tripterygium wilfordii -containing medicines for the treatment of IgAN or IgAVN < 6 months prior to Screening.

[0275] Received a complement inhibitor < 30 days or 5 half-lives, whichever is longer, prior to Screening.

[0276] Current enrollment or past participation in any other clinical study in which an investigational intervention (e.g., drug, vaccine, invasive device) was administered within 5 half-lives (if known) days before signing of consent in this clinical study.

[0277] Pregnant, breastfeeding, or intending to conceive during the study and within 8 months after the last dose of the study intervention.

[0278] Inability to travel to the clinic for specified visits during the study or fulfill the logistical requirements of study intervention administration.

[0279] Participant, parent, or legal guardian is involved in the planning and / or conduct of the study (applies to both Sponsor personnel and / or site personnel).

[0280] Received systemic immunosuppression (e.g., corticosteroid, cyclophosphamide, calcineurin inhibitors, mizoribine, or mycophenolate mofetil) within 3 months prior to screening, or budesonide within 6 months prior to screening for the treatment of IgAN. Systemic immunosuppression within 3 months prior to Screening or for extrarenal manifestations of IgAV will exclude participation in the study. Participants with IgAVNAXJ-314PC ALXN-1003-PCT01-NP that were stable on systemic corticosteroid or any other systemic immunosuppression 1 month prior to screening are allowed to continue receiving these treatments.

[0281] 30. Received systemic immunosuppression within 3 months prior to Screening for extrarenal manifestations of IgAV.

[0282] 31. History of severe IgAV symptoms (e.g., including but not limited to orchitis, cerebral vasculitis, pulmonary hemorrhage, gastrointestinal bleeding) within 1 year before Screening.

[0283] 4. Study Interventions and Concomitant Therapy

[0284] Study interventions are all prespecified, investigational and non-investigational medicinal products, medical devices and other interventions e.g.. surgical and behavioral) intended to be administered to the study participants during the study conduct.

[0285] In this study, participants receive open-label ravulizumab IV during the entire treatment period as set forth in Table 1. Ravulizumab is formulated at pH 7.4 and is supplied in 11 mL single-use vials. Each vial of ravulizumab contains 1,100 mg of ravulizumab (100 mg / mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection. Vials of ravulizumab can also be formulated at 300 mg / 3mL (100 mg / mL).

[0286] Table 1: Study Intervention(s) Administered

[0287]

[0288] AXJ-314PC ALXN-1003-PCT01-NP

[0289]

[0290] The weight-based ravulizumab dosing regimen is set forth in Table 2. All participants receive a weight-based loading dose of ravulizumab on Day 1, followed by weight-based maintenance treatment with ravulizumab on Day 15 and q8w thereafter for participants weighing > 20 kg, or q4w for participants weighing < 20 kg. Dosages are based on the participant’s body weight recorded on the day of the dosing visit or the last recorded study visit body weight. Body weight cohort is expected to change during this pediatric study; therefore, a participant’s weight cohort may change during the study.AXJ-314PC ALXN-1003-PCT01-NP Table 2: Weight-based Ravulizumab Dosing Regimen

[0291] > <

[0292] > <

[0293] > <

[0294] > <

[0295] > <

[0296]

[0297] >

[0298] The weight-based dose regimen is based on the last recorded study visit body weight. This is because the current visit as weight is measured prior to dose preparation on the day of the visit. If the study intervention is prepared before a visit, the weight from the most recent prior study visit is used. Maintenance dosing starts 2 weeks after loading dose administration. In the event that a participant’s weight changes from < 20 kg to > 20 kg on a “q4w” visit, the participant receives the > 10 to < 20 kg maintenance dose (600 mg) that day and then receive the new > 20 kg maintenance dose (2100 mg) at the next visit in order to start the new q8w dosing schedule. At dosing visits, ravulizumab is administered after all other tests and procedures have been completed, excluding the postdose blood sample collections (PK / PD).

[0299] Participants are expected to be on stable concomitant IgAN treatment consistent with care for pediatric patients with IgAN. Changes to the current concomitant IgAN therapy with RASI (ACEI or ARB) are prohibited during the Primary Evaluation Period, consistent with the eligibility requirement of a stable and maximally allowed or tolerated dose of concomitant IgAN therapy. When participant's weight increases, dose of RASI are increased, so the participant is still receiving the maximum allowed or tolerated RASI. For IgAVN participants only, participants taking immunosuppressive medications (e.g., corticosteroid, cyclophosphamide, calcineurin inhibitors, mizoribine, or mycophenolate mofetil) for the treatment of IgAVN on a stable dose for >1 month before screening must continue their treatment during the trial.

[0300] Corticosteroids can be tapered, as need. All other immunosuppressive medications must remain stable up to at least Week 34.

[0301] Patients taking Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i), Dual endothelin angiotensin receptor antagonist (DEARA) (e.g., Sparsentan), Mineralocorticoid ReceptorAXJ-314PC ALXN-1003-PCT01-NP Antagonist (MRA), endothelin receptor antagonist (ERA) or glucagon-like peptide 1 (GLP-1) agonists can continue their treatment if participants are on stable and maximum allowed or tolerated dose for > 3 months prior to Screening with no planned change in dose through Week 34. The date of first administration of these medications (including all start / stop dates) and confirm adherence / compliance on the CRF is recorded. The dose of SGLT2i, DEARA (e.g., Sparsentan), MRA, ERA, and GLP-1 agonists must be continued, and new medications are not be added through Week 34. All participants must be compliant and adherent to a stable and maximally allowed or tolerated dose of RAS blocking agent(s) (ACE inhibitor and / or ARB) for at least 3 months prior to Screening unless an intolerance is documented. The dose of RASI does not change and new RASI therapies are not added through Week 106. When a participant's weight increases, the dose of RASI is increased, so the participant is still receiving the maximum allowed or tolerated RASI.

[0302] If blood pressure is uncontrolled after Screening, participants can receive additional antihypertensive agents (e.g., beta-blockers). Changes in antihypertensives that impact proteinuria (e.g.. diuretics, vasodilators) should be avoided when clinically possible during Screening through Week 106. New or changes to GLP-1 receptor agonists are avoided when clinically possible during Screening through Week 106.

[0303] Initiation of new use of NSAIDs is not recommended during Screening through Week 106 due to the possibility of adverse effects on renal function unless unavoidable for the management of comorbid conditions. Topical or non-systemic immunosuppressive medications for IgAV are allowed. Premedication for administration of study intervention (including but not limited to IV fluids, corticosteroids, antihistamines) is allowed, but not required.

[0304] Participants are prohibited from receiving any of the following medications and therapies during the study: (1) Systemic corticosteroid, budesonide (for treatment of IgAN or IgAVN), or any other systemic immunosuppression therapy within 3 months of Screening (except short course steroids [approximately 14 days] for non-IgAN therapy) is excluded through Week 106, (2) NSAID use (except short course [approximately 14 consecutive days] for extrarenal manifestations of IgAV), (3) traditional Chinese medicines and Chinese proprietary medicines with systemic immunosuppressive properties including but not limited to Tripterygium wilfordiiAXJ-314PC ALXN-1003-PCT01-NP or T. wilfordii containing medicines are not allowed < 6 months prior to Screening and are excluded through Week 106, and (4) other complement inhibitor through Week 106. Alternative therapies for the treatment of IgAN / IgAVN can be considered after Week 34 for participants who meet the following criteria for sustained worsening of kidney function attributed to IgAN / IgAVN that is not due to acute kidney injury:

[0305] i. Doubling of serum creatinine or 57% worsening of eGFR compared to baseline based on 2 measurements at least 4 weeks apart reported at the central laboratory; or ii. Doubling of proteinuria compared to baseline with results in the nephrotic range (> 3g / g) confirmed on 2 measurements at least 4 weeks apart reported at the central laboratory.

[0306] Causes of acute kidney injury must be evaluated and ruled out. The choice of alternative IgAN / IgAVN therapy (e.g.. other immunomodulatory agents) is at the discretion of the PI based on the participant’s clinical circumstances and laboratory assessments, and after discussion between the PI and the Medical Monitor. Participants who receive alternative IgAN / IgAVN therapies are allowed to continue the study intervention and are strongly encouraged to remain in the study for the remainder of all study visits.

[0307] 5. Adverse Events (AEs) and Serious Adverse Events (SAEs)

[0308] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable medical occurrence in a clinical study [investigation] participant that was administered study intervention, whether or not considered related to the study intervention.

[0309] Events that meet the AE definition are as follows:

[0310] 1. Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant (i.e., not related to progression of underlying disease, or more severe than expected for the participant’s condition).AXJ-314PC ALXN-1003-PCT01-NP Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and / or intensity of the condition.

[0311] New condition detected or diagnosed after study intervention administration even though it may have been present before the start of the study.

[0312] Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

[0313] Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant medication. Overdose per se is not reported as an AE / SAE unless it is an intentional overdose taken with possible suicidal / self-harming intent. Such overdoses are reported regardless of sequelae.

[0314] Events that do not meet the AE Definition are as follows:

[0315] Any abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged to be more severe than expected for the participant’s condition.

[0316] The disease / disorder being studied or expected progression, signs, or symptoms of the disease / disorder being studied, unless more severe than expected for the participant’s condition.

[0317] Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the AE.

[0318] Situations in which an untoward medical occurrence did not occur (e.g., hospitalization for elective surgery if planned before the signing the ICF, admissions for social reasons or for convenience).

[0319] A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result of a medication error.

[0320] Pregnancy itself is not an AE; however, any pregnancy complications, abnormal pregnancy outcomes, or elective termination for medical reasons are reported as an AE or SAE.

[0321] Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the participant’s condition.AXJ-314PC ALXN-1003-PCT01-NP 13. Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

[0322] If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are met (e.g., hospitalization for signs / symptoms of the disease under study, death due to progression of disease).

[0323] An SAE is any unfavorable medical occurrence that, at any dose, meets one or more of the criteria listed:

[0324] 1. Results in death.

[0325] 2. Is life threatening. The term life-threatening in the definition of serious refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

[0326] 3. Requires inpatient hospitalization or prolongation of existing hospitalization. In general, hospitalization signifies that the participant has been admitted (usually involving at least an overnight stay) at the hospital or emergency ward for observation and / or treatment that would not have been appropriate in the physician’s office or outpatient setting.

[0327] Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE is considered serious.

[0328] Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

[0329] 4. Results in persistent or significant disability / incapacity. The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial disruption.

[0330] 5. Is a congenital anomaly / birth defect.

[0331] 6. Other situations: Medical or scientific judgment is exercised in deciding whether SAE reporting is appropriate in other situations such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardizeAXJ-314PC ALXN-1003-PCT01-NP the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These events are usually be considered serious. Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions not resulting in hospitalization, or development of drug dependency or drug abuse.

[0332] A Suspected Unexpected Serious Adverse Reaction (SUS AR) is defined as an event that is serious, that has at least a reasonable possibility as being related to the investigational medicinal product (IMP).

[0333] The Investigator assesses intensity for each AE and S AE reported during the study and assign it to one of the 5 categories from National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 or higher:

[0334] 1. Grade 1: Mild (awareness of sign or symptom, but easily tolerated)

[0335] 2. Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 3. Grade 3: Severe (incapacitating, with inability to perform normal activities)

[0336] 4. Grade 4: Life-threatening

[0337] 5. Grade 5: Fatal

[0338] The Investigator is obligated to assess the relationship between study intervention and each occurrence of each AE / S AE. The Investigator uses clinical judgment to determine the relationship as either “related” or “not related.”

[0339] Causality of “related” is made if following a review of the relevant data, there is evidence for a “reasonable possibility” of a causal relationship for the individual case. The expression ‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts (evidence) or arguments to suggest a causal relationship.

[0340] The causality assessment is performed based on the available data including enough information to make an informed judgment. With no available facts or arguments to suggest a causal relationship, the event(s) is assessed as “not related.”

[0341] A reasonable possibility of a relationship conveys that there are facts, evidence, and / or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.AXJ-314PC ALXN-1003-PCT01-NP Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the temporal relationship of the event to study intervention administration, is considered and investigated.

[0342] 6. Efficacy Assessments

[0343] Urinalysis sample (otherwise known as a spot urine sample) are collected prior to dosing, to assess at minimum the effect of ravulizumab on protein excretion, albumin excretion, and hematuria. A positive result for hematuria on urine dipstick or > 5 RBCs / high power field microscopy qualifies and the result can be reported from the local or central laboratory.

[0344] Hematuria is documented during a urinary tract infection, while female participants are menstruating, or within 2 days of strenuous exercise.

[0345] During screening and within 14 days before the Week 10, Week 26, Week 34, Week 50, and Week 106 visits, 3 FMVs are collected at home_for the assessment of proteinuria. Samples are collected within a 7-day period and must be the first morning void. The average of the 3 FMV is used for the urinalysis assessment. An additional urinalysis sample is collected at each clinic visit (this does not have to be a FMV).

[0346] During the Treatment Period and the Extension Period, the urinalysis sample is obtained prior to administration of study intervention. A morning void of the urine sample is preferred for urinalysis when possible.

[0347] Changes in renal function are monitored using measurements of eGFR

[0348] (mL / min / 1.73 m2). The eGFR calculation is based on the CKiD U25 equation for all participants using serum cystatin C collected prior to administration of study intervention, if applicable (see, e.g., Pierce CB, et al., Kidney Int. 2021;99(4):948-956).

[0349] 7. Vaccine and Antibiotic Prophylaxis

[0350] As with any complement inhibition, study intervention] increases the participant’s susceptibility to meningococcal infection (N meningitidis). To reduce the risk of meningococcal infection, all participants are vaccinated against meningococcal infection within 3 years before initiating study intervention.AXJ-314PC ALXN-1003-PCT01-NP Participants receive a vaccination at least 2 weeks before first study intervention. If vaccination occurs < 2 weeks from first dose of study intervention, participants receive antibiotic prophylaxis for at least 2 weeks after the initial day of vaccination against serogroups A, C, W, Y (and sero group B where available).

[0351] Vaccines against serogroups A, C. W, and Y (and serogroup B where available) are recommended to prevent common pathogenic meningococcal serogroups.

[0352] Revaccination is followed according to current national vaccination guidelines or local practice for vaccination use with complement inhibitors (e.g., [study intervention]).

[0353] Vaccination may not be sufficient to prevent meningococcal infection.

[0354] <S’. Statistical Analyses

[0355] The primary PK / PD analysis is performed at the end of the 34-week Primary Evaluation Period. This analysis allows for evaluation of the primary endpoint and has no impact on the progression of this study. The final analysis is performed at the end of the Extension Period after all participants have completed the Safety Follow-up Visit or withdrawn from the study. Interim analyses can be performed to provide descriptive analyses for planning purposes with no impact on the progression of the study.

[0356] The primary PK and PD analyses are based on the PK Analysis Set and the PD Analysis Set, respectively. Analyses are performed at the end of the 34-week Primary Evaluation Period (i.e., after all participants have completed the Day 239 Visit or discontinued study intervention prior to completing the 34-week Primary Evaluation Period).

[0357] Individual serum concentration data for all participants in the PK Analysis Set is used to generate descriptive statistics to summarize the serum concentration data (i.e. Cmax and Ctrough) at each sampling time point. Missing data is not imputed. Graphs of mean serum concentrationtime profiles and graphs of serum concentration-time profiles for individual participants can be provided, as appropriate.

[0358] The PD effects of ravulizumab are evaluated by assessing the absolute values and changes and percentage changes from Baseline in serum free C5 concentrations over time, as appropriate using the PD Analysis Set. Descriptive statistics are calculated for the PD data at each sampling time point, as appropriate. Missing data is not imputed.AXJ-314PC ALXN-1003-PCT01-NP The secondary efficacy analyses are descriptive in nature and will be based on the FAS. For the following continuous efficacy endpoints, descriptive statistics are provided:

[0359] • Percentage change from Baseline in proteinuria based on UPCR from FMV collections at Week 34

[0360] • Percentage change from Baseline in albuminuria based on UACR at Week 34

[0361] • Change from Baseline in eGFR at Weeks 50 and 106

[0362] A mixed model for repeated measures can be used to analyze change from baseline in continuous efficacy endpoints with change from baseline as the response variable and fixed, categorical effect of visit as well as a fixed, continuous effect of baseline value as covariates. For the following categorical efficacy endpoints, frequencies and percentage of participants meeting the endpoint are provided:

[0363] • Reduction in proteinuria >50% from Baseline at Week 34

[0364] • UPCR < 0.5 g / g at Week 34

[0365] In addition, the annualized total eGFR slope through Week 106 is estimated using a linear mixed effects model including eGFR as the response variable, random participants effects for intercepts and slopes, and a fixed continuous effect of time. The total slope effect over 106 weeks is annualized for ease of interpretation. The point estimate and 2- sided 95% CI for the total annualized slope is presented.

[0366] Analyses based on participant reported outcome measures will be descriptive in nature and is based on the FAS.

[0367] For PedsQL 4.0 Generic Core Scales, the scales (Physical Functioning, Emotional Functioning, Social Functioning and School Functioning), summary scores (Psychosocial Health and Physical Health) and Total Scale Score is calculated based on the instrument instruction. Treatment of missing items also follows the instructions: when more than half of the items from any scale are missing, the scale score is not computed.

[0368] PedsQL 4.0 Generic Core Scales and peds FACIT-F score re summarized at Baseline and each postbaseline assessment using descriptive statistics for continuous variables for the observed and change from Baseline.AXJ-314PC ALXN-1003-PCT01-NP All safety analyses are performed on the Safety Set. The safety and tolerability of ravulizumab IV is assessed based on TEAEs, clinical laboratory findings, physical examination, vital sign findings, and ECG abnormalities.

[0369] All TEAEs from the first dose of ravulizumab are summarized for participants in the Safety Set. The incidence of TEAEs, TEAEs leading to study treatment discontinuation, and TESAEs is summarized. All AEs are coded using MedDRA version 24 or higher.

[0370] Adverse changes from Baseline in physical examination findings are classified as TEAEs and analyzed accordingly. Vital signs are summarized descriptively at Baseline and postbaseline timepoints and for changes from Baseline.

[0371] Observed values and changes from Baseline in clinical chemistry, hematology, and urinalysis are summarized descriptively at Baseline and at each postbaseline timepoint. For laboratory results that can be classified as normal, low, or high based on normal range values, shifts from Baseline in classification will be summarized for all study visits.

[0372] ECGs are evaluated and summarized as normal, abnormal not clinically significant, or abnormal clinically significant. A shift from Baseline to worst on-study ECG table is presented for ECG results. Observed values and change from Baseline in ECG intervals (PR, RR, QT, and QTc) are summarized descriptively at Baseline and each postbaseline timepoint. QT interval will be corrected for heart rate using Fridericia’ s formula (QTcF).

[0373] All immunogenicity analyses are performed on the Immunogenicity Analysis Set.

[0374] Immunogenicity variables including ADA status, ADA response category, ADA titer and NAb incidence, are summarized over the duration of the study. ADA status and ADA response categories are summarized as absolute occurrence (n) and percentage of all participants. ADA status categories include ADA negative and ADA positive.

[0375] Participants who are ADA positive are further categorized into ADA response categories as follows: Pre-existing immunoreactivity. Treatment-emergent ADA responses, and Treatment-boosted ADA responses. Participants with treatment-emergent or treatment-boosted ADA responses are further categorized as: Persistent responses, Indeterminate responses, or Transient responses. ADA positive samples are further characterized for neutralizing activity in the NAb assay. NAb status categories are as follows: NAb positive or NAb negative.AXJ-314PC ALXN-1003-PCT01-NP Exploratory endpoints include additional measures of kidney function,

[0376] participant-reported outcomes, health resource utilization, blood and urine biomarkers, and genetics. The exploratory analyses is descriptive in nature and is based on the FAS. In general, the analysis methods used for the secondary endpoints are applied to the Exploratory continuous and binary endpoints. For time to event endpoints, the Cox proportional hazards model is used.

[0377] The sample size for this study is not based on statistical considerations. This study is descriptive in nature and not statistically powered for hypothesis testing. The number of participants has been chosen based on feasibility and is considered adequate to meet the primary objective.

[0378] This study enrolls approximately 24 eligible participants with a minimum of 18 evaluable participants with IgAN, i.e.. who have received at least 1 dose of ravulizumab and at least 1 measurable PK / PD value for the PK / PD primary analysis. Amongst those, the study includes at least 4 participants with IgAN who weigh < 40 kg at Day 1. Up to approximately 6 eligible participants with IgAVN are enrolled in a separate cohort.

[0379] SEQUENCE SUMMARY

[0380]

[0381] AXJ-314PC ALXN-1003-PCT01-NP

[0382]

[0383] AXJ-314PC ALXN-1003-PCT01-NP

[0384]

[0385] AXJ-314PC ALXN-1003-PCT01-NP

[0386]

[0387] AXJ-314PC ALXN-1003-PCT01-NP

[0388]

Claims

AXJ-314PC ALXN-1003-PCT01-NPCLAIMSWhat is claimed is:

1. A method of treating a human pediatric patient with immunoglobulin A nephropathy (IgAN) and / or immunoglobulin A vasculitis nephritis (IgAVN), the method comprising administering to the patient an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen binding fragment thereof, is administered:(a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a patient weighing > 10 to < 20 kg;(b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 20 to < 30 kg;(c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg; (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg; (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 100.

2. The method of claim 1, wherein the anti-C5 antibody, or antigen binding fragment thereof, further comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering.AXJ-314PC ALXN-1003-PCT01-NP3. The method of claim 1 or 2, wherein the anti-C5 antibody comprises a heavy chain variable region set forth in SEQ ID NO: 12 and a light chain variable region set forth in SEQ ID NO:8.

4. The method of any one of the preceding claims, wherein the anti-C5 antibody further comprises a heavy chain constant region set forth in SEQ ID NO: 13.

5. The method of any one of the preceding claims, wherein the antibody comprises a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

6. The method of any one of the preceding claims, wherein the anti-C5 antibody binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) that is in the range 0.1 nM < KD < 1 nM (e.g., about 0.5 nM).

7. The method of any one of the preceding claims, wherein the anti-C5 antibody binds to human C5 at pH 6.0 and 25°C with a KD > 10 nM (e.g., about 22 nM).

8. The method of any one of the preceding claims, wherein the anti-C5 antibody is administered to a patient weighing > 10 to < 20 kg, once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter.

9. The method of any one of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing > 20 to < 30 kg, once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter.

10. The method of any one of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing > 30 to < 40 kg, once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter.AXJ-314PC ALXN-1003-PCT01-NP11. The method of any one of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing > 40 to < 60 kg, once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter.

12. The method of any one of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing > 60 to < 100 kg, once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter.

13. The method of any one of claims 1-7, wherein the anti-C5 antibody is administered to a patient weighing > 100 kg, once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter.

14. The method of any one of the preceding claims, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 100 pg / mL or greater.

15. The method of any one of the preceding claims, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 200 pg / mL or greater.

16. The method of any one of the preceding claims, wherein the anti-C5 antibody is formulated for intravenous administration.

17. The method of any one of the preceding claims, wherein the patient has IgAVN and has previously been treated or is concurrently being treated with one or more immunosuppressive medications, such as corticosteroid, cyclophosphamide, calcineurin inhibitors, mizoribine, and / or or mycophenolate mofetil.

18. The method of any one of the preceding claims, wherein the treatment results in a shift towards normal levels of one or more biomarkers selected from the group consisting ofAXJ-314PC ALXN-1003-PCT01-NP soluble C5b-9 (sC5b-9), Factor Ba, C4d, CD68, CD88, CD163, Gd-IgAl, kidney injury molecule- 1 (KIM-1), and creatinine.

19. The method of any one of the preceding claims, wherein the treatment results in a change in estimated glomerular filtration rate (eGFR) compared to baseline, e.g., a change from baseline in eGFR at Week 50 and / or Week 106.

20. The method of any one of the preceding claims, wherein the treatment results in an improvement eGFR slope compared to baseline, e.g.. an improvement in the annualized total eGFR slope over 50 and / or 106 weeks.

21. The method of any one of the preceding claims, wherein the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73m2 prior to treatment.

22. The method of any one of the preceding claims, wherein the patient has a urine protein to creatinine ratio (UPGR) of > 1 g / g prior to treatment.

23. The method of any one of the preceding claims, wherein the treatment results in a reduction in proteinuria compared to baseline, e.g., a change from baseline in proteinuria at Week 34.

24. The method of any one of the preceding claims, wherein the treatment results in a change in albuminuria compared to baseline, e.g.. a change from baseline in albuminuria at Week 34.

25. The method of claim 24, wherein there is a 30%, 40%. 50%. 60%, 70%, 80%, 90%. or 95% reduction in proteinuria after treatment compared to baseline.AXJ-314PC ALXN-1003-PCT01-NP 26. The method of any one of the preceding claims, wherein the treatment results in a reduction in 24-hour urine protein creatinine ratio (UPGR) > 30%, e.g., a reduction in 24- hour UPCR > 50% from baseline.

27. The method of any one of the preceding claims, wherein the treatment results in a UPCR < 0.5 g / g at Week 34.

28. The method of any one of the preceding claims, wherein the treatment results in a reduction or cessation in one or more of the following symptoms compared to baseline: hematuria, dark brown or cola colored urine, edema, flank pain, hypertension, foamy urine, and / or proteinuria.

29. The method of any one of the preceding claims, wherein the treatment results in an improvement in the patient’s quality of life, as assessed by Pediatric Quality of Life Inventory Generic Core Scales (PedsQL 4.0).

30. The method of any one of the preceding claims, wherein the treatment results in an improvement in the patient’s quality of life, as assessed by Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (peds FACIT-F).

31. The method of any one of the preceding claims, wherein the treatment results in terminal complement inhibition.

32. The method of any one of the preceding claims, wherein the treatment results in a reduction in adverse events.

33. The method of any one of the preceding claims, wherein the pediatric patient is under 18 years of age.

34. The method of claim 33, wherein the pediatric patient is from 2-5 years of age.AXJ-314PC ALXN-1003-PCT01-NP35. The method of claim 33, wherein the pediatric patient is from 12-17 years of age.

36. The method of claim 33, wherein the pediatric patient is from 6-11 years of age.

37. The method of any one of the preceding claims, wherein the treatment results in a shift towards normal levels of one or more blood biomarkers selected from the group consisting of: C4d and Ba.

38. The method of any one of the preceding claims, wherein the treatment results in a shift towards normal levels of one or more urine biomarkers selected from the group consisting of: sC5b-9, CD163, and KIM-1.

39. A kit for treating immunoglobulin A nephropathy (IgAN) and / or Immunoglobulin A vasculitis nephritis (IgAVN) in a human pediatric patient, the kit comprising:(a) a dose of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8; and (b) instructions for using the anti-C5 antibody, or antigen binding fragment thereof, in the method of any one of the preceding claims.

40. An anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered:(a) once on Day 1 at a dose of 600 mg, followed by a dose of 600 mg on Day 15 and once every four weeks thereafter to a patient weighing > 10 to < 20 kg;AXJ-314PC ALXN-1003-PCT01-NP (b) once on Day 1 at a dose of 900 mg, followed by a dose of 2100 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 20 to < 30 kg;(c) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg; (d) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg; (e) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (f) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg on Day 15 and once every eight weeks thereafter to a patient weighing > 100.

41. The antibody of claim 38, wherein the antibody is determined to be safe, tolerable, efficacious and sufficiently non-immunogenic after multiple IV doses in human patients.

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