WO2025166118A1

WO2025166118A1 - Dosage and administration of anti-c5 antibodies for treating iga nephropathy (igan)

Info

Publication number: WO2025166118A1
Application number: PCT/US2025/013964
Authority: WO
Inventors: Katherine Gayle Garlo; Kara Elizabeth RICE
Original assignee: Alexion Pharmaceuticals Inc
Current assignee: Alexion Pharmaceuticals Inc
Priority date: 2024-02-02
Filing date: 2025-01-31
Publication date: 2025-08-07
Anticipated expiration: 2026-08-02
Also published as: TW202545563A; AU2025214388A1

Abstract

Provided are dosages and methods for clinical treatment of C5-mediated glomerular nephritis (GN), including immunoglobulin A nephropathy (IgAN), in human 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

DOSAGE AND ADMINISTRATION OF ANTI C5 ANTIBODIES FOR TREATING IGA NEPHROPATHY (IGAN)

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/549,037 (filed February 2, 2024), U.S. Provisional Application No. 63/650,288 (filed May 21, 2024), U.S. Provisional Application No. 63/722,469 (filed November 19, 2024), and U.S. Provisional Application No. 63/743,511 (filed January 9, 2025). The entire contents of the aforementioned applications is incorporated herein by reference.

BACKGROUND

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 immunosuppressive treatments, certain types of C5-mediated glomerular nephritis (GN), such as immunoglobulin A nephropathy (IgAN) continue to respond poorly to treatment, resulting over time in CKD. No disease- specific therapies arc currently available, therefore effective treatments for managing GN, including IgAN, represent a high unmet medical need. Accordingly, it is an object of the present disclosure to provide improved methods for treating patients IgAN.

SUMMARY

Provided herein are compositions and methods for treating IgAN in a human patient (e.g., an adult 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).

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.

In embodiments, treatment of IgAN patients with an antibody of the disclosure, e.g., ravulizumab, in accordance with the present methods results in slowing of the rate of eGFR decline in adult participants with IgAN, as determined by change from baseline in eGFR over time (e.g., at Week 106) and/or via changes in annualized total eGFR slope over time, e.g., over 106 weeks of treatment. In embodiments, the treatment further improves kidney function in adult participants with IgAN, as determined, e.g., via change from baseline in proteinuria based on 24-hour urine protein to creatinine ratio (UPCR) over time, e.g., reduction in proteinuria based on 24-hour UPCR > 50% from baseline at Week 10 and/or at Week 34 of treatment. In embodiments, the treatment further improves kidney function in adult participants with IgAN, as determined, e.g., based on time to sustained > 30% eGFR decline over time, e.g., up to Week 106 and/or composite kidney failure endpoint (CKFE) over time, e.g., up to week 106 or over 106 weeks of treatment, wherein CKFE is defined as reaching at least one of the following: (a) sustained > 30% decline in eGFR relative to baseline, or (b) sustained eGFR < 15 mL/min/1.73m2, or (c) maintenance dialysis, or (d) receipt of kidney transplant, or (f) death from kidney failure.

In some embodiments, treatment of IgAN patients with an antibody of the disclosure, e.g., ravulizumab, in accordance with the present methods results in change (e.g., reduction) from baseline in proteinuria based on 24-hour UPCR over time, e.g., at Week 10, 26, 34, 50, and 106 of treatment. In some embodiments, treatment results in change (e.g., reduction) from baseline in proteinuria based on 24-hour UPCR, e.g., at Week 10, 34, and 26 of treatment. In some embodiments, treatment results in a change (e.g., improvement) from baseline in eGFR, e.g., at Week 34 of treatment. In some embodiments, treatment results in a reduction in 24-hour UPCR > 50% from baseline, e.g., at Weeks 10, 26 and 34 of treatment. In some embodiments, treatment results in a partial remission, e.g., at Week 34 of treatment. In some embodiments, treatment results in a change from baseline in albuminuria based on 24-hour UACR, e.g., at Weeks 10, 26, and 34 of treatment. In some embodiments, treatment results in improvement in annualized total eGFR slope. In some embodiments, treatment results in a change from Baseline in FACIT-Fatigue, e.g., at Week 34, 50, and 106 of treatment.

In some embodiments, treatment of IgAN patients with an antibody of the disclosure, e.g., ravulizumab, in accordance with the present methods results in change (e.g., improvement) in (a) time to UPCR < 1 g/g, e.g., as measured by urinalysis (i.e., spot urine) samples; (b) time to UPCR < 0.5 g/g; (c) time to UPCR < 0.3 g/g, e.g., as measured by urinalysis; (d) time to UPCR reduction > 50% as measured by urinalysis; (e) absence of hematuria, e.g., at Weeks 10, 26, and 34 of treatment; (f) IgAN composite endpoint over time (e.g., at Week 34 and 106) as defined herein; (g) time to sustained eGFR decline > 57% over time, e.g., up to Week 106; (h) kidney hierarchal composite endpoint(as defined herein) over time, e.g., up to Week 106; and/or (i) rate of eGFR decline < 1 mL/min/1.73 m2 over time (e.g., over 50 and 106 weeks). In further embodiments, treatment of IgAN patients with an antibody of the disclosure, e.g., ravulizumab, results in a change e.g., improvement) in quality of life outcome of the patient, as determined by one or more of: (a) change, from baseline, in EQ-5D-5L score, e.g., at Week 34, 50 and 106 of treatment; (b) change, from baseline, in KDQOL-36 score, e.g., at Week 34, 50, and 106 of treatment; (c) change, from baseline, in PGI-S score, e.g., at Week 34, 50, and 106 of treatment; (d) PGI-C, e.g., at Week 34, 50, and 106 of treatment; and/or (e) change, from baseline, in WPAI score, e.g., at Week 34, 50, and 106 of treatment.

In other embodiments, the antibody comprises the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of ravulizumab. Accordingly, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the 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.

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.

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. 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.

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 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).

In another embodiment, the antibody binds to human C5 at pH 7.4 and 25 °C with an affinity dissociation constant (KD) that is in the range 0.1 nM < KD < 1 nM. In another embodiment, the antibody binds to human C5 at pH 7.4 and 25°C with air 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.

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, 900 mg, 1200 mg, 2700 mg, or 3000 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 30 to < 40 kg. In another embodiment, 900 mg, 2400 mg, or 3000 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 40 to < 60 kg. In another embodiment, 900 mg, 2700 mg, or 3300 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 60 to < 100 kg. In another embodiment, 900 mg, 3000 mg, or 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 100 kg. In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).

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 Days 15, 17, 127, 183, 239, 295, 351, 407, 563, 519, 575, 631, and 687). In another embodiment, administration of the anti-C5 antibody, or antigen binding fragment thereof, is optionally followed by a subsequent administration (i.e., after the conclusion of the first administration cycle of weight-based loading and maintenance dosing) of the anti-C5 antibody, or antigen binding fragment thereof, (a) on Day 743 at a dose of 900 mg across all weight cohorts and (b) at Day 757 based on the weight of the patient, e.g., the anti-C5 antibody, or antigen binding fragment thereof, is administered at 2700 mg to a patient weighing > 30 to < 40 kg, 3000 mg to a patient weighing > 40 to < 60 kg, 3300 mg to a patient weighing > 60 to < 100 kg, or 3600 mg to a patient weighing > 100 kg.

In another embodiment, a method of treating a human patient with immunoglobulin A nephropathy (IgAN), 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:

(a) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

(b) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

(c) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

(d) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

In another embodiment, a method of treating a human patient with IgAN, 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 N0s:19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ Id N0s: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:

I. (a) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

(d) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg; optionally followed by 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:

II. (a) once on Day 743 at a dose of 900 mg, followed by a dose of 2700 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

(b) once on Day 743 at a dose of 900 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

(c) once on Day 743 at a dose of 900 mg, followed by a dose of 3300 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

(d) once on Day 743 at a dose of 900 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg. In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, to a patient weighing > 30 to < 40 kg once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter.

In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, to a patient weighing > 30 to < 40 kg:

(a) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter; and

(b) once on Day 183 at a dose of 900 mg, followed by a dose of 3000 mg on Day 197 and once every eight weeks thereafter.

In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, 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 at Week 2 and once every eight weeks thereafter.

In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, to a patient weighing > 40 to < 60 kg:

In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, to a patient weighing > 60 < 100 kg once on Day 1 at a dose of 2700 mg, followed by a dose of 3900 mg at Week 2 and once every eight weeks thereafter.

In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, to a patient weighing > 60 < 100 kg:

(a) once on Day 1 at a dose of 2700 mg, followed by a dose of 3900 mg at Week 2 and once every eight weeks thereafter; and (b) once on Day 183 at a dose of 900 mg, followed by a dose of 3900 mg on Day 197 and once every eight weeks thereafter.

In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, to a patient weighing > 100 kg once on Day 1 at a dose of 3000 mg, followed by a dose of 5400 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, to a patient weighing > 100 kg:

(a) once on Day 1 at a dose of 3000 mg, followed by a dose of 5400 mg at Week 2 and once every eight weeks thereafter; and

(b) once on Day 183 at a dose of 900 mg, followed by a dose of 5400 mg on Day 197 and once every eight weeks thereafter.

In one embodiment, the patient has not previously been treated with eculizumab. In another embodiment, the patient has previously been treated with eculizumab. In another embodiment, the 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.

In another embodiment, the patient is an IgAN patient has previously been treated with or is concurrently being treated with background therapy, such as a renin-angiotensin system inhibitor (RASI), e.g., angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs), Sodium-glucose cotransporter-2 inhibitor (SGLT2I), DEARA (e.g., sparsentan), endothelin receptor antagonist (ERA), or mineralocorticoid receptor antagonist (MRA). In embodiments, the IgAN patient is a patient who has or is at risk of progressing to end stage kidney disease (ESKD). In embodiments, the IgAN patient has baseline eGFR of about 20-29 mL/min/1.73m².

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 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 ug/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.

In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain at least 50 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, 120 pg, 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.

In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the patient in an amount and with a frequency to maintain a minimum 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).

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

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 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, e.g., a change from baseline eGFR at and at week 106. 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 a reduction in proteinuria compared to baseline, e.g., change from baseline in proteinuria over time. For example, in one 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 patient has an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73m2 prior to treatment. In another embodiment, the patient has an estimated glomerular filtration rate (eGFR) 20-29 mL/min/1.73m2 prior to treatment. In another embodiment, the patient has proteinuria prior to treatment. In another embodiment, the patient has a urine protein to creatinine ratio (UPCR) > 0.75 g/g prior to treatment. In another embodiment, proteinuria for an IgAN patient is a mean protein > 1 g/24-hr from 2 valid 24-hr collections. In embodiments, the patient has IgAN based on kidney biopsy, eGFR > 20 mL/min/1.73 m², UPCR > 0.75 g/g or UP > 1 g/day, and has controlled blood pressure while receiving stable optimal doses of RASI. In embodiments, the IgAN patient has advanced kidney disease (AdKD) with eGFR 20 to 29 mL/min/1.73 m². In some embodiments, the IgAN patient is a patient who is at risk of progressing to end-stage kidney/renal disease (ESKD or ESRD), e.g., due to AdKD.

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 an IgAN patient. In another embodiment, the PR comprises mean proteinuria < 1 g/24-hours based on 2 valid 24-hour urine collections.

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

In another embodiment, the treatment results in an improvement in the patient’ s quality of life, as assessed by European Quality of Life Health 5-item questionnaire dimensions 5 level (EQ-5D-5L). In another embodiment, the treatment results in an improvement in the patient’ s quality of life, as assessed by Functional Assessment of Chronic Therapy (FACIT)-Fatigue score. In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by The Patient Global Impression of Severity (PGLS) questionnaire. In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by The Patient Global Impression of Change (PGLC) questionnaire. In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by The Work Productivity and Activity Impairment Questionnaire.

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

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

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:

(c) once on Day 1 at a dose of 2700 mg, followed by a dose of 3300 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or (d) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, comprises 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, further for administration:

(a) once on Day 743 at a dose of 900 mg, followed by a dose of 2700 mg at Day 757 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

(b) once on Day 743 at a dose of 900 mg, followed by a dose of 3000 mg at Day 757 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

(c) once on Day 743 at a dose of 900 mg, followed by a dose of 3300 mg at Day 757 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

(d) once on Day 743 at a dose of 900 mg, followed by a dose of 3600 mg at Day 757 and once every eight weeks thereafter to a patient weighing > 100 kg.

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

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, optionally together with background therapy (e.g., RASI, SGLT2I, DEARA (e.g., sparsentan), ERA, or MRA). 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.

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, optionally together with a background therapy (e.g., RASI, SGLT2I, DEARA (e.g., sparsentan), ERA, or MRA), for treating IgAN in a human patient:

(a) once on Day 1 at a dose of 1200 mg, followed by a dose of 2700 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg; (b) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

In another embodiment, the kit comprises a dose of an anti-C5 antibody or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is further administered:

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, 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 in a human patient, wherein the composition optionally comprises background therapy for treating the IgAn (e.g., RASI, SGLT2I, DEARA (e.g., sparsentan), ERA, or MRA). Specifically, provided herein are compositions comprising effective amounts of ravulizumab (ULTOM1RIS®) or the antigen-binding fragment thereof, for treatment of IgAN in a human patient. In some embodiments, the effective amount comprises use of the above dosages and scheduling of the anti-C5 antibody, e. ., ravulizumab.

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, 5 and 6, respectively, in the manufacture of a composition, e.g., pharmaceutical composition or a medicament, for treating IgAN in a human patient, wherein the composition optionally comprises background therapy for the treatment of IgAN. Specifically, provided herein are use of an effective amount of ravulizumab (ULTOMIRIS®) or the antigen-binding fragment thereof, in the manufacture of a composition, e.g., pharmaceutical composition or a medicament, for treating IgAN in a human 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. In some embodiments, the optional background therapy comprises a background therapy for treating IgAN, e.g., RASI, SGLT2I, DEARA (e.g., sparsentan), ERA, or MRA.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic depicting the overall Phase 2 study design.

FIG. 2 is a graph showing the change from Baseline in 24-hour urine protein to creatinine ratio (UPCR) in patients treated with ravulizumab versus placebo.

FIG. 3 is graph showing mean spot UPCR over 26 weeks in patients treated with ravulizumab versus placebo.

FIG. 4 is a graph showing % reduction in proteinuria at Week 26 in patients treated with ravulizumab versus placebo.

FIG. 5 shows change in proteinuria with ravulizumab versus placebo by subgroups of patients. FIG. 6 is a schematic depicting the overall Phase 3 study design.

FIG. 7 depicts the Schedule of Activities during Screening.

FIG. 8 depicts the Schedule of Activities for the Treatment Period: Day 1 Through Week 106 Visits.

FIG. 9 depicts the Schedule of Activities during the Open-label Ravulizumab Access Period. DETAILED DESCRIPTION

I. Definitions

As used herein, the term “subject” or “patient” is a human patient (e.g., a patient having IgAN).

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).

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).

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), 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).

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).

The pathophysiology of IgAN is related to the overproduction of under-glycosylated immunoglobulin Al (IgA 1) which accumulates in the kidney glomeruli. However, aberrant galactosylation alone is insufficient to induce renal injury; glycan-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) autoantibodies that recognize the under-galactosylated IgAl molecule likely also contribute. This process leads to the local inflammation and complement activation in the kidney (see, e.g., Oortwijn et al., Semin Nephrol. 2008 ;28(1 ) :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 et al., 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., Zwirner 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).

IgAN patients may have signs or symptoms of the disease based on parameters such as, e.g., kidney biopsy score, eGFR, UPCR, elevated blood pressure, or a combination thereof. In some embodiments, IgAN patients treated with the therapeutic molecules of the disclosure may have threshold severity of IgAN disease based on MEST-C score and other tissue-based biomarkers (e.g. , IgG, IgA, IgM, C3, C4d, and Clq staining), eGFR of > 20 mL/min/1.73 nr, UPCR of > 0.75 g/g and/or UP > 1 g/day, while having controlled blood pressure while receiving stable optimal doses of RASI. In embodiments, the IgAN patient has advanced kidney disease (AdKD) with eGFR 20 to 29 mL/min/1.73 m². In some embodiments, the IgAN patient is a patient who is at risk of progressing to end-stage kidney /renal disease (ESKD or ESRD), e.g., due to AdKD.

Treatments for IgAN include RAS blocking agents, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). These therapies are aimed 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.).

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 (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)).

In embodiments of the present disclosure, effective treatment of IgAN with an antibody of the disclosure, e.g., ravulizumab, results in slowing of the rate of eGFR decline in adult participants with IgAN, as determined via changes in annualized total eGFR slope, e.g., over 106 weeks. In embodiments, effective treatment improves kidney function in adult participants with IgAN, as determined, e.g., via change from baseline in proteinuria based on 24-hour UPCR, e.g., at Week 10 of treatment and/or composite kidney failure endpoint (CKFE), e.g., over 106 weeks of treatment, wherein CKFE is defined as reaching at least one of the following: (a) sustained > 30% decline in eGFR relative to baseline, or (b) sustained eGFR < 15 mL/min/1 ,73m2, or (c) maintenance dialysis, or (d) receipt of kidney transplant, or (f) death from kidney failure.

In embodiments of the present disclosure, effective treatment of IgAN with an antibody of the disclosure, e.g., ravulizumab, results in change (e.g., reduction) from baseline in proteinuria based on 24-hour UPCR, e.g., at Week 34 of treatment. In some embodiments, effective treatment further results in one or more of: (a) change (e.g., reduction) from baseline in proteinuria based on 24-hour UPCR, e.g., at Week 10 and 26 of treatment; (b) a change (e.g., improvement) from baseline in eGFR, e.g., at Week 34 of treatment; (c) a reduction in 24-hour UPCR > 50% from baseline, e.g., at Weeks 10, 26 and 34 of treatment; (d) a partial remission, e.g., at Week 34 of treatment; (e) a change from baseline in albuminuria based on 24-hour UACR, e.g., at Weeks 10, 26, and 34 of treatment; and/or (f) improvement in annualized total eGFR slope. In some embodiments, treatment results in a change from Baseline in FACIT-Fatigue, e.g., at Week 34 of treatment.

In some embodiments, effective treatment with an antibody of the disclosure, e.g., ravulizumab, results in change (e.g., improvement) in (a) time to UPCR < 1 g/g, e.g., as measured by urinalysis; (b) time to UPCR < 0.3 g/g, e.g., as measured by urinalysis; (c) time to UPCR reduction > 50% as measured by urinalysis; (d) complete remission, e.g., at Week 34 of treatment; (e) absence of hematuria, e.g., at Weeks 10, 26, and 34 of treatment; and/or (f) patient’s use of alternative IgAN therapy such as, e.g., immunosuppressive medications, over time. In further embodiments, effective treatment results in a change (e.g., improvement) in quality of life outcome of the patient, as determined by one or more of: (a) change, from baseline, in EQ-5D-5L score, e.g., at Week 34 of treatment; (b) change, from baseline, in KDQOL-36 score, e.g., at Week 34 of treatment; (c) change, from baseline, in PGI-S score, e.g., at Week 34 of treatment; (d) PGI-C, e.g., at Week 34 of treatment; and/or (e) change, from baseline, in WPAI score, e.g., at Week 34 of treatment.

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 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)).

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

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

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.

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.

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 ait 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 antibody-derived antigen binding site.

II. Anti-C5 Antibodies

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.

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, ait 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.

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.

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. 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.

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.

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). 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. et al. (Mol. Immunol., 33: 1389-401, 1996) exemplifies the identification of CDR boundaries according to Kabat and Chothia numbering schemes.

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 chain CDRs or variable regions of the 7086 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody, or antigen binding fragment thereof, comprises heavy chain CDR1 , CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:24, 25 and 26, respectively. In another embodiment, the antibody, or antigen binding fragment thereof, comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO:27, and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO:28.

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 81 10 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.

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

Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. et 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, or antigen binding fragment thereof, comprises a heavy chain comprising SEQ ID NO:45 and a light chain comprising SEQ ID NO:46.

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. 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: 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:

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

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

DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIK (SEQ ID NO : 8 ) . 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 Fc constant region to FcRn at pH 6.0, while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining pH dependence of the interaction) arc known in the art and exemplified in the working examples. See, e.g., WO2015134894 and US Patent No.9, 079949 the disclosures of each of which are incorporated herein by reference in their entirety.

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: P257I/Q3 I 1 1. P257I/N434H and D376V/N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282: 1709-17, 2007), the disclosures of each of which are incorporated herein by reference in their entirety.

In some embodiments, the variant constant region has a substitution at EU amino acid posaition 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.

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. 8,088,376.

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.

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; alanine for asparagine or serine at position 384; aspartic acid or histidine for glycine at position 385; proline for glutamine at position 386; glutamic acid for proline at position 387; alanine or serine for asparagine at position 389; alanine for serine at position 424; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine for methionine at position 428; lysine for histidine at position 433; alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine for asparagine at position 434; and histidine for tyrosine or phenylalanine at position 436, all in EU numbering.

Suitable anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence 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.

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.

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, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).

Methods for determining whether an antibody binds to a protein antigen and/or the affinity for an antibody to a protein antigen are known in the ail. 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. et al., J. Immunol. Meth,., 160: 191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51: 19-26, 1993; Jonsson, U. et al., 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.

As used herein, the term “k_a” refers to the rate constant for association of an antibody to an antigen. The term “kd” 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 = k_a/kd. 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.

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

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, 2^nd Edition,” 135-240, Springfield, IL, CC 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 arc 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 ait can also be used. Using assays of these or other suitable types, candidate agents capable of inhibiting human complement component C5 can be screened.

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.

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 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 Anorogenic 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.

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 Wicslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). BrieAy, 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 Anorogenic substrate and measuring the Auorescence 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, 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. BrieAy, to activate the classical complement pathway, undiluted serum samples (e.g., reconstituted human serum samples) are added to microassay wells containing the 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).

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.

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).

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 antigen: antibody complexes, and 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.

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” (i.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).

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. 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. Alternatively, one may isolate DNA sequences that encode a monoclonal antibody or a binding fragment thereof by screening a DNA library from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

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 (HCDR1-3 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).

III. Compositions

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 CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the 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.

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.

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.

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,” 20^th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7^th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3^rd Edition (ISBN: 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).

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, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrasternal injection and infusion.

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, 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 in a human patient, wherein the effective amount comprises administration of the anti-C5 antibody, or the antigen binding fragment thereof:

(a) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

(b) once on Day 1 at a dose of 2700 mg, followed by a dose of 3900 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

(c) once on Day 1 at a dose of 3000 mg, followed by a dose of 5400 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg; optionally followed by administering the anti-C5 antibody, or the antigen binding fragment thereof:

(d) once on Day 743 at a dose of 900 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

(e) once on Day 743 at a dose of 900 mg, followed by a dose of 3300 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

(f) once on Day 743 at a dose of 900 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

In some embodiments, the anti C5-antibody, or antigen binding fragment thereof, is further administered:

(a) once on Day 183 at a dose of 900 mg, followed by a dose of 3000 mg at Day 197 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

(b) once on Day 183 at a dose of 900 mg, followed by a dose of 3900 mg at Day 197 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

(c) once on Day 183 at a dose of 900 mg, followed by a dose of 5400 mg at Day 197 and once every eight weeks thereafter to a patient weighing > 100 kg.

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 HCDRi-a 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 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 Met429Eeu 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 a pharmaceutical composition or a medicament comprising an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof, e.g., comprising the HCDR1-3 and the ECDR1-3 of ravulizumab, for use in the treatment of IgAN, in a human patient.

IV. Methods

Provided herein are methods for treating IgAN in a human patient, comprising administering to the patient an anti-C5 antibody, or antigen binding fragment thereof, wherein the anti-C5 antibody or antigen binding fragment thereof is administered (or is for administration) according to a particular clinical dosage regimen (e.g., at a particular’ dose amount and according to a specific dosing schedule). 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, 900 mg, 1200 mg, 2700 mg, or 3000 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 30 to < 40 kg. In another embodiment, 900 mg, 2400 mg, or 3000 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 40 to < 60 kg. In another embodiment, 900 mg, 2700 mg, or 3300 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 60 to < 100 kg. In another embodiment, 900 mg, 3000 mg, or 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing > 100 kg. In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).

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 Days 15, 17, 127, 183, 239, 295, 351, 407, 563, 519, 575, 631, and 687). In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose on Day 743, Day 757, and every eight weeks (q8w). In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered for up to one, two, three, four, or five years.

In another embodiment, a method of treating a human patient with IgAN, 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:

In another embodiment, a method of treating a human patient with IgAN, is provided, the method comprising further administering to the patient the anti-C5 antibody, or antigen binding fragment thereof:

(d) once on Day 743 at a dose of 900 mg, followed by a dose of 3600 mg at Day 757 and once every eight weeks thereafter to a patient weighing > 100 kg. In another embodiment, a method of treating a human patient with IgAN is provided, the method comprising administering an anti-C5 antibody, or antigen binding fragment thereof, to a patient weighing > 30 to < 40 kg once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter.

In another embodiment, the patient is an IgAN patient who has previously been treated with a renin-angiotensin system (RAS) inhibiting medication, such as an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).

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, 5 and 6, respectively, in the manufacture of a composition, e.g., pharmaceutical composition or a medicament, for treating IgAN in a human patient, wherein the effective amount comprises administration of the anti-C5 antibody or the antigen binding fragment thereof:

(d) once on Day 1 at a dose of 3000 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg; optionally followed by administering the anti-C5 antibody, or the antigen binding fragment thereof:

(e) once on Day 743 at a dose of 900 mg, followed by a dose of 2700 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 30 to < 40 kg;

(f) once on Day 743 at a dose of 900 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 40 to < 60 kg;

(g) once on Day 743 at a dose of 900 mg, followed by a dose of 3300 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 60 to < 100 kg; or

(h) once on Day 743 at a dose of 900 mg, followed by a dose of 3600 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

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, in a human 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, in a human patient. V. Outcomes

Provided herein are methods for treating IgAN in a patient comprising administering to the patient an anti-C5 antibody.

Symptoms of IgAN 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).

In one embodiment, 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 |ig/mL or greater. In one embodiment, 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.

In one embodiment, patients treated according to the disclosed methods have a free C5 concentration of 0.5 pg/mL or less (e.g., 0.4 ug/mL. 0.3 pg/mL, 0.2 pg/mL, or 0. 1 pg/mL or less).

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.

In another embodiment, the treatment results in a change in Estimated glomerular filtration rate (eGFR) compared to baseline. 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 a reduction in proteinuria compared to baseline. In another embodiment, the patient has an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73m2 prior to treatment. In another embodiment, the patient has an estimated glomerular filtration rate (eGFR) 20-29 mL/min/1.73m2 prior to treatment. In another embodiment, the patient has proteinuria prior to treatment. In another embodiment, the patient has a urine protein to creatinine ratio (UPCR) > 0.75 g/g prior to treatment. In another embodiment, proteinuria for an IgAN patient is a mean protein > 1 g/24-hr from 2 valid 24-hr collections. In another embodiment, the treatment results in an 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% 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% 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 an IgAN patient. In another embodiment, the PR comprises mean proteinuria < 1 g/24-hours based on 2 valid 24-hour urine collections.

In another embodiment, the treatment results in an improvement in the patient’ s quality of life, as assessed by European Quality of Life Health 5-item questionnaire dimensions 5 level (EQ-5D-5L).

In another embodiment, the treatment results in an improvement in the patient’ s quality of life, as assessed by Functional Assessment of Chronic Therapy (FACIT)-Fatigue score. In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by The Patient Global Impression of Severity (PGI-S) questionnaire. In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by The Patient Global Impression of Change (PGI-C) questionnaire. In another embodiment, the treatment results in an improvement in the patient’s quality of life, as assessed by The Work Productivity and Activity Impairment Questionnaire.

In another embodiment, the treatment results in terminal complement inhibition. In another embodiment, the treatment results in a reduction in adverse events. VI. Kits and Unit Dosage Forms

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 patient having IgAN. The kit also can include a syringe.

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.

In one embodiment, a kit for treating IgAN in a human 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.

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:

(c) once on Day 1 at a dose of 3000 mg, followed by a dose of 5400 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

In another embodiment, the kit comprises a dose of an anti-C5 antibody or antigen binding fragment thereof, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered:

(a) once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter and once on Day 183 at a dose of 900 mg, followed by a dose of 3000 mg on Day 197 and once every eight weeks thereafter, to a patient weighing > 40 to < 60 kg;

(b) once on Day 1 at a dose of 2700 mg, followed by a dose of 3900 mg at Week 2 and once every eight weeks thereafter and once on Day 183 at a dose of 900 mg, followed by a dose of 3900 mg on Day 197 and once every eight weeks thereafter, to a patient weighing > 60 to < 100 kg; or

(c) once on Day 1 at a dose of 3000 mg, followed by a dose of 5400 mg at Week 2 and once every eight weeks thereafter and once on Day 183 at a dose of 900 mg, followed by a dose of 5400 mg on Day 197 and once every eight weeks thereafter, to a patient weighing > 100 kg.

The following examples are 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.

EXAMPLES

EXAMPLE 1: Subgroup and Secondary Endpoint Evaluation of a Phase 2 Randomized, Placebo- Controlled Trial of Ravulizumab in IgA Nepropathy

A phase 2 randomized, placebo-controlled trial of ravulizumab in IgA nephropathy was conducted substantially according to the protocol described in Examples 1 and 2 of W020220609 1, as well as Barratt et al. 2023 (Poster TH-PO1127: Efficacy and Safety of Ravulizumab in a Phase 2 Randomized Controlled Trial in IgA Nephropathy (ASN Meeting, NOV 1-5, 2023)) and Barratt et al. (Abstract WCN24-1197: Efficacy and Safety of Ravulizumab in a Phase 2 Randomized Controlled Trial in IgA Nephropathy (2024)), the contents of all of which are expressly incorporated herein by reference. See also Lafayette et al. "Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial" J Am Soc Nephrol., 2024 Oct 25. doi: 10.1681/ASN.0000000534 (Phase 2 trial number NCT04564339).

A schematic of the study design is shown in FIG. 1. The trial evaluated safety and efficacy of ravulizumab (intravenous (IV); weight-based dosing every eight weeks (Q8W)) versus placebo in adults with primary IgA nephropathy. Key eligibility criteria included: (1) patient age between 18-75 years, (2) biopsy-confirmed IgA nephropathy, proteinuria > Ig/day (mean of two complete 24-hour urine collections), (3) estimated glomerular filtration rate (eGFR) >30mL/min/1.73m2, and (4) on stable maximally tolerated renin-angiotensin system inhibitor (RASi). Patients were randomized (2:1), stratified by proteinuria (1-2 versus >2 g/day).

The primary endpoint was proteinuria reduction from BL to week 26 based on 24-hour urine collections at each timepoint. The secondary endpoint at Week 26 was percentage of patients with >50% reduction in proteinuria, percentage with <lg/day proteinuria; change from Baseline in serum complement component 3 (C3) and complement component 4 (C4) levels. A further endpoint was percentage change in proteinuria at Week 26 among subgroups of sex, race, duration of disease, baseline proteinuria, and eGFR. Subgroup and secondary analyses were descriptive in nature, with no statistical testing of adjustment for multiplicity. The Post-Hoc endpoint was change in proteinuria at Week 26 by Baseline scrum C3 and C4, as well as safety data.

66 patients were included in the study, including 43 treated with ravulizumab and 23 treated with placebo. The mean age was 40.1 years. 71.2% of the patients were white. Baseline demographic and clinical characteristics are set forth in Table 1.

Table 1: Baseline Demographic and Clinical Characteristics

*A11 other categories (American Indian or Alaska Native, Black or African American, Native Hawaiian or Other Pacific Islander, Unknown, and Missing) had n=0.

**Disease duration is defined as the time from kidney biopsy used for eligibility to screening. Background RASi therapy was permitted within 3 months prior to screening and up to first dose of study intervention and is summarized in Table 2. There were no changes in background therapy during the treatment period. Concomitant SGLT2i therapy is summarized in Table 3.

Table 2: Background RASi Therapy

Table 3: Concomitant SGLT21 T lerapy At Baseline, 2 patients in the ravulizumab group had low serum C3 and 1 patient in the placebo group had low serum C3. No patients had low serum C4. Normal range for serum C3 is 0.9- 1.8 g/L and normal range for serum C4 is 0.1-0.4 g/L. As shown in Table 4, there was no change in mean serum C3 and C4 from Baseline to Week 26.

Change in proteinuria from Baseline to Week 26 by Baseline serum C3 and C4 cutoffs (lowest quartile and above lowest quartile) are shown in Table 5. Table 5: Percentage Change (95% CI) in Proteinuria (24-hr UP) From BL to week 26 by BL Serum C3 and C4 Categories

Annualized total eGFR slope computed based on data from Baseline to Week 26 is set forth in Table 6. Table 6: Annualized Total eGFR Slope At Week 26, ravulizumab-treated patients had a -41.9% (95% CI -50.2, -32.0) change from Baseline in 24-hour urine protein (UP). Placebo -treated patients had a -16.8% (95% CI, -31.8, 1.6) change from Baseline in 24-hour UP. At Week 26, ravulizumab-treated patients had a -40.4% (95% CI -48.5, -31.1) change from Baseline in 24-hour urine protein: creatinine ratio (UPCR). Placebo-treated patients had a -10.9% (95% CI, -26.6, 8.3) change from Baseline in 24-hour UPCR, as shown in FIG. 2. Mean spot UPCR over 26 weeks is depicted in FIG. 3 and the corresponding data is set forth in Table 7. 43.9% (95% CI 28.5, 60.3) and 18.2% (95% CI 5.2, 40.3) in the ravulizumab and placebo groups, respectively, had >50% reduction in proteinuria at Week 26, as shown in FIG. 4. Change in proteinuria with ravulizumab versus placebo by subgroups of patients is shown in FIG. 5. Proteinuria < lg/day was achieved in 26.8% (95% CI 14.2, 42.9) and 18.2% (95% CI 5.2, 40.3 of patients in the ravulizumab and placebo arms, respectively, at Week 26.

Table 7: Mean Sport UPCR Over 26 Weeks

In conclusion, in this Phase 2 trial of ravulizumab in IgA nephropathy, there was a statistically significant reduction in proteinuria with ravulizumab versus placebo through Week 26. A statistically significant reduction in proteinuria with ravulizumab versus placebo was seen across several subgroups of patients. There was no reduction in proteinuria by Baseline serum C3 and C4 with ravulizumab through 6 months.

EXAMPLE 2: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (Study ALXN1210-IgAN-320) to Evaluate the Efficacy and Safety of Ravulizumab in Adult Participants with Immunoglobulin A Nephropathy (IgAN)

A Phase 3, randomized, double-blind, placebo-controlled study is conducted to evaluate the efficacy and safety of ravulizumab compared with placebo in participants with primary IgAN on optimal treatment with renin-angiotensin system (RAS) blockade using angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) who are at risk of progressing to end stage kidney disease (ESKD). The study also includes an open-label, single-group, Open-Label Cohort to evaluate the efficacy and safety of ravulizumab in participants with baseline eGFR 20-29 mL/min/1.73m2 during Screening (referred to herein as the “Open-Label Cohort”). The study also includes a randomized Placebo-controlled Cohort with approximately 40 participants enrolled to improve the evidence base for treatment effect of ravulizumab compared to placebo. The placebo comparison strengthens the scientific level of evidence over the single arm design. The AdKD cohorts with eGFR 20 to 29 mL/min/1.73 m² are analyzed separately from the Main Cohort. The study design is set forth in FIG. 6.

1 . Objectives a. Interim Analysis

The primary objective of the interim analysis is to evaluate the efficacy of ravulizumab compared with placebo on UPCR reduction from baseline at Week 34.

The primary clinical question of interest is: What is the mean change in UPCR at Week 34 in participants with IgAN treated with ravulizumab versus placebo in the absence of alternative IgAN therapy use?

The primary objective of the study is to evaluate the efficacy of ravulizumab compared with placebo to reduce proteinuria in adult participants with IgAN. Primary estimands include: (1) population (adult participants with IgAN), (2) endpoint: change from baseline in proteinuria based on 24- hour UPCR at Week 34), (3) treatment conditions (ravulizumab and placebo), (4) handling of intercurrent events (data collected after use of alternative IgAN therapy is censored and imputed using copy increments from reference; data missing due to treatment discontinuation is imputed using retrieved dropouts; data missing due to renal death is imputed using 10% of worst values), and (5) population-level summary (difference in log change from baseline in UPCR between treatment groups at Week 34).

Secondary objectives include: (1) evaluating the efficacy of ravulizumab compared with placebo on measures of kidney function in adult participants with IgAN (e.g., via change from baseline in proteinuria based on 24-hour UPCR at Week 10 and 26, change from baseline in eGFR at Week 34, reduction in 24-hour UPCR > 50% from baseline at Weeks 10, 26 and 34, partial remission at Week 34, change from baseline in albuminuria based on 24-hour UACR at Weeks 10, 26, and 34, and annualized total eGFR slope over 50 weeks) and (2) assessing quality of life based on participant-reported outcomes in adult participants with IgAN based on treatment with ravulizumab compared with placebo (e.g., via change from Baseline in FACIT-Fatigue at Week 34).

The safety objective is to characterize the safety and tolerability of ravulizumab in adult participants with IgAN (e.g., via incidence of treatment-emergent adverse events (TEAEs), treatment- emergent serious adverse events (TESAEs), and adverse events of special interest (AESIs) over time.

Further objectives include assessing immunogenicity to ravulizumab in adult participants with IgAN (e.g., via antidrug antibody (ADA) incidence, response categories, and titer, as well as neutralizing antibody (Nab) incidence for the duration of the study) and characterizing the pharmacokinetics (PK) / pharmacodynamics (PD) of ravulizumab in adult participants with IgAN (e.g., via serum ravulizumab concentrations over time and serum total C5 and free C5 concentrations over time).

Exploratory objectives include evaluating the efficacy of ravulizumab compared with placebo to improve measures of kidney function in adult participants with IgAN (e.g., via 24-hour urine protein < 0.5 g/d over time, complete remission (complete remission is defined as 24hour urine protein < 0.3 g/d), time to UPGR < 1 g/g (only applies for participants with UPCR > 1 g/g at baseline), time to < 0.5 g/g, time to UPCR < 0.3 g/g , time to UPCR reduction > 50%, and absence of hematuria (absence of hematuria is defined as negative (0 or trace) blood on urine dipstick or < 5 RBCs on urinalysis) at Weeks 10, 26, and 34 and use of alternative IgAN therapy (e.g., immunosuppressive medications) over time, as well as assessing quality of life based on participant-reported outcomes in adult participants with IgAN based on treatment with ravulizumab compared with placebo (e.g., via change from baseline in EQ-5D-5L at Week 34, change from baseline in KDQOL-36 at Week 34, change from baseline in PGI-S at Week 34, PGI-C at Week 34, a change from baseline in WPAI at Week 34), and investigating parenchymal changes utilizing tissue-based biomarkers in the kidney in participants treated with ravulizumab or placebo who participate in the optional repeat kidney biopsy substudy (e.g., via change from Baseline in MEST-C parameters and other tissue-based biomarkers at Week 50. b. Final Analysis

The primary objective of the final analysis is to evaluate the efficacy of ravulizumab compared with placebo on Change from Baseline in eGFR at Week 106.

The primary clinical question of interest is: What is the mean change from Baseline in eGFR in participants with IgAN treated with ravulizumab versus placebo in the absence of alternative IgAN therapy use? The primary objective is to evaluate the efficacy of ravulizumab compared with placebo on change in eGFR in adult participants with IgAN. Primary estimands include (1) population (adult participants with IgAN), (2) endpoint: change from Baseline in eGFR at Week 106, (3) treatment conditions: Ravulizumab and placebo, (4) handling of intercurrent events (data collected after use of alternative IgAN therapy is censored and imputed using copy increments from reference; data missing due to treatment discontinuation is imputed using retrieved dropouts; and data missing due to renal death is imputed using 10% of worst values), and (5) population-level summary (difference in in eGFR change from Baseline between treatment groups at Week 106), as well as a supplement to the primary estimand which includes (1) population (adult participants with IgAN), (2) endpoint: annualized total eGFR slope over 106 weeks, (3) treatment conditions: Ravulizumab and placebo, (4) handling of intcrcurrcnt events (data collected after use of alternative IgAN therapy is censored and imputed using copy increments from reference; data missing due to treatment discontinuation is imputed using retrieved dropouts; and data missing due to renal death is imputed using 10% of worst values), and (5) population-level summary (difference in annualized total eGFR slopes between treatment groups).

A key secondary objective is to evaluate the efficacy of ravulizumab compared with placebo on measures of kidney function in adult participants with IgAN. Key secondary estimands include (a) endpoint: reduction in 24-hour UPCR > 50% from Baseline at Week 34 e.g., with population: adult participants with IgAN; treatment conditions: Ravulizumab and placebo; handling of intercurrent events (UPCR data collected after use of alternative IgAN therapy is censored and imputed using copy increments from reference prior to derivation of response status, UPCR data collected after treatment discontinuation is included as observed prior to derivation of response status, and UPCR data following death, kidney transplant, or dialysis is imputed using 10% of worst change values prior to derivation of response status); and population-level summary: Difference in proportion of participants achieving > 50% reduction from Baseline in UPCR between treatment groups at Week 34), (b) endpoint: change from Baseline in proteinuria based on 24-hour UPCR at Week 10 (e.g., with population: adult participants with IgAN; treatment conditions: Ravulizumab and placebo; handling of intercurrent events (data collected after use of alternative IgAN therapy is censored and imputed using copy increments from reference; data missing due to treatment discontinuation is imputed using retrieved dropouts; and data missing due to renal death is imputed using 10% of worst values); and population-level summary: Difference in 24-hour UPCR change from Baseline between treatment groups at Week 10, (c) endpoint: time to sustained > 30% eGFR decline up to Week 106 (confirmed by a second scrum creatinine measurement after at least 28 days) (e.g., with population: adult participants with IgAN; treatment conditions: Ravulizumab and placebo; handling of intercurrent events (eGFR data collected after use of alternative IgAN therapy is censored and imputed using copy increments from reference prior to derivation of response status; eGFR data collected after treatment discontinuation is included as observed prior to derivation of response status; and eGFR data following death, kidney transplant, or dialysis is imputed using 10% of worst change values prior to derivation of response status), and population-level summary: Hazard ratio for achieving sustained > 30% eGFR decline between treatment groups up to Week 106, and (d) endpoint: time to first occurrence of composite kidney event endpoint up to Week 106 (defined as reaching at least 1 of the following: (i) sustained > 30% decline in eGFR relative to Baseline, or (ii) sustained eGFR < 15 mL/min/1 .73 m², or (iii) maintenance dialysis, or (iv) receipt of kidney transplant, or (v) death from kidney failure) (e.g., with population: adult participants with IgAN; treatment conditions: Ravulizumab and placebo; handling of intercurrent events (eGFR data collected after use of alternative IgAN therapy is censored and imputed using copy increments from reference prior to derivation of composite endpoint; eGFR data collected after treatment discontinuation is included as observed prior to derivation of composite endpoint), and population-level summary: hazard ratio for achieving the composite kidney event endpoint between treatment groups up to Week 106.A further objective is to evaluate the efficacy of ravulizumab compared with placebo on measures of kidney function in adult participants with IgAN (e.g., via change from baseline in proteinuria based on 24-hour UPCR at Weeks 26, 34, 50 and 106, change from baseline in eGFR at Weeks 34 and 50, change from baseline in albuminuria at Weeks 10, 26, 34, 50, and 106, reduction in 24-hour UPCR > 50% from baseline at Weeks 10, 26, 34, 50, and 106, time to individual components of composite kidney event endpoint up to Week 106, time to sustained eGFR decline > 40% up to Week 106, partial remission (partial remission is defined as UPCR < 1 g/d based on 24-hour urine collection(s) and at least 25% reduction from baseline (only applies for participants with UPCR > 1 g/d at Baseline) at Weeks 34, 50, and 106, time to sustained eGFR decline (confirmed by a second serum creatinine measurement after at least 28 days), and use of alternative IgAN therapy).

A further objective is to assess quality of life based on participant-reported outcomes in adult participants with IgAN based on treatment with ravulizumab compared with placebo (e.g., via change from baseline in FACIT-Fatigue at Weeks 34, 50, and 106).

The safety objective is to characterize the safety and tolerability of ravulizumab in adult participants with IgAN (e.g., via incidence of TEAEs, TESAEs, and AESIs over time). Another objective is to assess immunogenicity to ravulizumab in adult participants with IgAN (e.g., via ADA incidence, response categories, and titers, as well as NAb incidence for the duration for the study).

Yet another objective is to characterize the PK/PD of ravulizumab in adult participants with IgAN (e.g., via senrm ravulizumab concentrations over time and serum total C5 and free C5 concentrations over time).

Exploratory objectives include:

(1) evaluating the efficacy of ravulizumab compared with placebo to improve measures of kidney function in adult participants with IgAN (e.g., via 24-hour urine protein < 0.5 g/d over time, complete remission (complete remission is defined as UPCR < 0.3 g/d based on a 24-hour urine collection) at Weeks 34, 50, and 106, time to UPCR < 1 g/g(only applies for participants with UPCR > 1 g/g at baseline), time to UPCR < 0.5 g/g, time to UPCR < 0.3 g/g, time to UPCR reduction > 50%, absence of hematuria (absence of hematuria is defined as negative (0 or trace) blood on urine dipstick or < 5 RBCs/high-poer field in the urine sediment (only applies for participants with positive hematuria at Baseline)), IgAN composite endpoint at Week 34 and Week 106 (defined as achieving both partial remission (partial remission is defined as 24-hour urine protein < 1 g/d and at least 25% reduction from Baseline (only applies for participants with 24-hour urine protein > 1 g/d at Baseline)) and absence of hematuria), time to sustained eGFR decline > 57% up to Week 106, kidney hierarchial composite endpoint (the kidney hierarchical composite endpoint is defined as the most severe outcome of a participant according to the following severity of outcomes: death from kidney failure, kidney transplant, maintenance dialysis, sustained eGFR < 15 mL/min/1.73 m², sustained eGFR decline from Baseline > 57%, sustained eGFR decline from Baseline > 40%, sustained eGFR decline from Baseline > 30% and change from Baseline in eGFR) up to Week 106, and rate of eGFR decline < 1 mL/min/1.73 m² over 50 and 106 weeks);

(2) assessing quality of life based on participant-reported outcomes in adult participants with IgAN based on treatment with ravulizumab compared with placebo (e.g., via change from baseline in EQ-5D-5L at Weeks 34, 50, and 106, change from baseline in KDQOL-36 at Weeks 34, 50, and 106, change from baseline in PGLS at Weeks 34, 50, and 106, PGI-C at Week 34, 50, and 106, and change from baseline in WPAI at Weeks 34, 50, and 106;

(3) assessing biomarkers of disease, inflammation, renal damage and complement activation (e.g., via change from baseline in biomarker levels of IgAN disease, inflammation, renal damage and complement activation over time);

(4) evaluating health resource utilization in adult participants with IgAN based on treatment with ravulizumab compared with placebo;

(5) exploring how genetic variations may affect clinical parameters, risk and prognosis of disease and the response to medications (e.g., by exploratory endpoints related to the data generated from the genetic analysis of pat or all of the participant’s genetic information); and

(6) investigating parenchymal changes utilizing tissue-based biomarkers in the kidney in participants treated with ravulizumab or placebo who participate in the optional repeat kidney biopsy substudy (e.g., via change from Baseline in MEST-C parameters and other tissue-based biomarkers at Week 50. c. Open-Label Cohort

The Open-Label cohort assesses the efficacy, safety, and PK/PD of open-label ravulizumab treatment in adult participants with IgAN and baseline eGFR 20-29 mL/min/1.73m2 using the same endpoints as described above. However, there is no comparison to placebo.

2. Overall Design

A Phase 3, randomized, double-blind, placebo-controlled study is conducted to evaluate the efficacy and safety of ravulizumab compared with placebo in participants with primary IgAN on optimal treatment with renin-angiotensin system (RAS) blockade using angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) who arc at risk of progressing to end stage kidney disease (ESKD). The study also includes an open-label, single-group, Open-Label Cohort to evaluate the efficacy and safety of ravulizumab in participants with baseline eGFR 20-29 mL/min/1.73m2 during Screening.

The primary objectives of Study ALXN1210-IgAN-320 are to demonstrate the superiority of ravulizumab versus placebo administered IV every 8 weeks on proteinuria reduction at Week 34 (interim analysis) and the change in eGFR at Week 106 (final analysis).

All participants in the study must have a diagnosis of IgAN based on kidney biopsy, eGFR > 20 mL/min/1.73 m², urine protein to creatinine ratio (UPCR) > 0.75 g/g or urine protein (UP) > 1 g/day based on the mean of two 24-hour urine collections during the Screening Period, controlled blood pressure. The Main Cohort includes approximately 450 participants with eGFR > 30 mL/min/1.73 m² and the additional AdKD cohorts includes approximately 60 participants with eGFR 20 to 29 mL/min/1.73 nr. Participants with eGFR 20 to 29 mL/min/1.73 m² are analyzed separately from the Main Cohort.

The study consists of a Screening Period of up to approximately 6-weeks, a 106-week Treatment Period, and a 98-week Ravulizumab Access Period (Open-label Ravulizumab Access Period).

The aim of the Screening Period is to confirm eligibility and ensure adherence to stable concomitant IgAN therapy (RASI). Participants must be on a stable and maximally allowed or tolerated dose of concomitant IgAN therapy for at least 3 months prior to Screening. Concomitant IgAN therapy includes at minimum RASI (ACEI and/or ARB). SGLT2I, DEARA (e.g., sparsentan), MRA, and ERA therapies are not required but must be continued for participants on a stable and maximally allowed or tolerated dose for at least 3 months prior to Screening and adherence is monitored during the Screening Period on the participant home IgAN medication log. During the Screening Period, all participants are advised by the Investigator which medications are considered concomitant IgAN medications. All participants record adherence to concomitant IgAN therapy in the IgAN medication log. This log must be completed daily during the Screening Period up to Day 1.

Changes to the current concomitant IgAN therapy with RASI (ACEI or ARB) and, when applicable, SGLT2I, DEARA (e.g., sparsentan), MRA, or ERA are prohibited during the Screening Period and through Week 106.

Two 24-hour urine collections are obtained during the Screening Period beginning approximately 4 weeks after signing the ICF. Eligibility and stratification are based on the mean of the 2 collections. If eligibility criteria are met, participants proceed to the Treatment Period.

Approximately 450 eligible participants with eGFR > 30 mL/min/1.73 m² are randomized for the Main Cohort in a 1: 1 allocation ratio to receive a weight-based IV infusion of either ravulizumab or placebo. In addition, participants are expected to be on stable concomitant IgAN treatment consistent with care for patients with IgAN.

Approximately 60 participants with eGFR 20 to 29 mL/min/1.73 m² also are enrolled in the AdKD cohorts. Inclusion of these participants is intended to expand the evidence of ravulizumab in participants with IgAN and advanced kidney impairment at high risk for ESKD progression. Approximately 20 participants are enrolled into the Open-label Cohort (previously named Exploratory Cohort) where participants receive open-label ravulizumab and 40 participants are enrolled into the randomized Placebo-controlled Cohort where the participants are randomized in a 1: 1 ratio to either receive ravulizumab or placebo. Participants with eGFR 20 to 29 mL/min/1.73 nr are analyzed separately from the Main Cohort.

Changes to the current concomitant IgAN therapy with RASI (ACEI or ARB) and when applicable SGLT2I, ERA, or MRA, are prohibited during the Treatment Period (Day 1 through Week 106), consistent with the eligibility requirement of a stable and maximally allowed or tolerated dose of concomitant IgAN therapy. Alternative IgAN therapies are also prohibited during the Treatment Period (Day 1 through Week 106) except for participants who meet the criteria for sustained worsening of kidney function after Week 34.

An interim analysis for the Main Cohort can be conducted. The final analysis for the Main Cohort is conducted to evaluate the eGFR e endpoint when approximately 450 participants complete the Week 106 Visit. After Week 106, participants have the option to enter thcOpcn-labcl Ravulizumab Access Period and receive open-label ravulizumab. Upon completion of the Treatment Period, participants can opt to transition to the Open-label Ravulizumab Access Period. During this time, all participants receive IV ravulizumab at the weight-based dose administered during the Treatment Period. Safety data is collected on AEs, ADAs, concomitant medications, and non-pharmacological therapies/procedures. Very limited efficacy data is collected,

After the 106-week Treatment Period and assessments, participants in the placebo group receive a blinded weight-based loading dose of ravulizumab and participants in the ravulizumab group receive a blinded ravulizumab dose of 900 mg. The 900 mg dose was chosen to ensure maintenance of complete C5 inhibition until the next scheduled maintenance dose at Week 108. Stalling at Week 108, all participants begin receiving open-label weight-based ravulizumab maintenance doses every 8 weeks.

A participant is considered to have completed the Treatment Period (i.e., a “completer”) when they have completed the last visit at Week 106. A participant is considered to have completed the study if they have completed the last visit of the Ravulizumab Access Period wherein the participant is followed for safety and minimal efficacy data.

3. Study Population

The study population is patents with IgAN. The eligibility criteria are designed to identify participants with primary IgAN who are at high risk of progression to kidney failure while receiving optimized IgAN therapy (including ACEI/ARB, SGLT2I, DEARA (e.g., sparsentan), ERA, or MRA). Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

Approximately 510 participants are assigned; 450 to study intervention as the Main Cohort and 60 in the AdKD cohorts (including 20 in the Open-label Cohort and 40 in the randomized Placebo- controlled Cohort). “Enrolled” means participants’ agreement to participate in a clinical study following completion of the informed consent process, excluding screen failures. Participants who are screened for the purpose of determining eligibility for the study, but do not participate in the study, are considered screen failures, unless otherwise specified by the protocol. A participant is considered enrolled if the informed consent is not withdrawn prior to participating in any study activity after Screening, unless otherwise specified by the protocol.

For all participants the duration of participation is up to 112 weeks. The duration of participation with the Ravulizumab Access Period (Open-label Ravulizumab Access Period) is up to 210 weeks. TheMScreening Period is 6 weeks, the Treatment Period is 106 weeks, and the Ravulizumab Access Period is 98 weeks.

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

1. Participant must be > 18 years of age at the time of signing the informed consent.

2. Documentation of IgAN diagnosis established on kidney biopsy obtained any time prior to or during the Screening Period.

3. UPCR > 0.75 g/g or UP >1 g/day from the mean of two 24-hour urine collections during Screening.

4. Estimated GFR > 30 mL/min/1.73 m2 at Screening as calculated by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI). Open-Label Cohort: eGFR 20-29 mL/min/1.73 m2 at Screening. A kidney biopsy is required within 6 months prior to Screening or during the Screening Period. Kidney biopsy report must demonstrate < 75% each of interstitial fibrosis, tubular atrophy, and glomerular sclerosis.

5. Body weight > 30 kg at Screening

6. Male or female

7. Agree to follow protocol- specified contraception guidance

8. Capable of giving signed informed consent as described herein which includes compliance with the requirements and restrictions listed in the informed consent form (ICE) and in this protocol. 9. Adherence to and compliance with stable and maximum allowed or tolerated RASI (ACEI and/or ARB) dose for > 3 months prior to Screening with no planned change during Screening through Week 106. Participants with intolerance to RASI medications may be included.

10. Participants who are on an SGLT2I, DEARA (e.g., sparsentan), ERA, or MRA must be on a stable and maximum allowed or tolerated dose for > 3 months prior to Screening with no planned change through Week 106.

11. Controlled blood pressure of < 140/90 mmHg at Screening.

12. To reduce the risk of meningococcal infection (N meningitidis), all participants must be vaccinated against meningococcal infection from serogroups A, C, W, Y (and B where available) within 3 years prior to study intervention on Day 1. If vaccination occurs

< 2 weeks from Day 1, the participant receives prophylactic antibiotics for at least 2 weeks after initial meningococcal vaccination.

Participants are excluded from the study if any of the following criteria apply:

1. Diagnosis of rapid progressive glomerulonephritis as measured by eGFR loss > 50% over a period of 3 months prior to Screening.

2. Secondary IgAN (e.g., due to systemic lupus erythematosus (SLE), cirrhosis, or celiac disease; IgAV-N may be eligible).

3. Concomitant clinically significant renal disease other than IgAN.

4. Uncontrolled diabetes mellitus with glycosylated hemoglobin (HbAlc) > 8.5%.

5. Clinically active Henoch-Schonlein purpura (IgA vasculitis) requiring ongoing systemic immunosuppressive therapy at Screening.

6. History of kidney transplant or planned kidney transplant during the Treatment Period.

7. History of other solid organ (heart, lung, small bowel, pancreas, or liver) or bone marrow transplant; or planned transplant during the Treatment Period or open-label Open-Label Cohort, except for corneal transplant.

8. Body mass index > 38 kg/m2.

9. Splenectomy or functional asplenia.

10. History of Neisseria meningitidis infection.

11. Known history of human immunodeficiency virus (HIV) infection as documented by HIV-l/HIV-2 testing or positive HIV-l/HIV-2 antibody titer at Screening. 12. Evidence of hepatitis B (positive hepatitis surface antigen [HBsAg] or positive core antibody (anti-HBc) with negative surface antibody [anti-HBs]) or hepatitis C viral infection (HCV antibody positive, except for participants with documented successful treatment. If locally available, sustained virologic response is documented or established at Screening).

13. Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization.

14. Drug or alcohol abuse or dependence within 1 year prior to Screening that interferes with ability to participate in the clinical study.

15. 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.

16. Hypersensitivity to any ingredient contained in the study intervention, including to murine proteins.

17. Systemic corticosteroid therapy > 10 mg/day or any other systemic immunosuppression for the treatment of IgAN > three months duration of systemic immunosuppression therapy of Screening (except short course steroids [approximately 14 days] for non-IgAN treatment).

18. Ongoing budesonide therapy or budesonide therapy within 6 months prior to Screening.

19. Biologic(s) for the treatment of IgAN < 6 months prior to Screening.

20. Traditional Chinese medicines and Chinese proprietary medicines with systemic immunosuppressive properties including but not limited to Tripterygium Wilfordii for the treatment of IgAN within 6 months prior to Screening.

21. Currently receiving or previously received a complement inhibitor within 30 days or 5 half-lives, whichever is longer, prior to Screening.

22. Participation in another investigational drug or investigational device study within 30 days before Screening or within 5 half-lives of that investigational product, whichever is greater.

23. Pregnant, breastfeeding, or intending to conceive during the study.

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

25. Participant is imprisoned or lawfully retained at an institution via administrative or judicial order.

26. Participant is an employee or directly related to an employee of the sponsor or the institution/investigational site. A screen failure occurs during the Screening Period when a participant who has consented to participate in the clinical study does not meet the criteria for participation. Some individuals who do not meet the criteria for participation in this study (screen failure) are rescreened up to a maximum of 3 times based on discussion and agreement between the Investigator and the Medical Monitor. If a potential participant is rescreened during the initial 6-week Screening Period, potential participants have another 6 weeks to repeat the assessment or procedure that led to screen failure without signing a new consent, unless a new version of consent became available or due to local regulations. If a participant is rescreened outside the initial 6-week Screening Period, all assessments need to be repeated, including consent.

Documentation of diagnosis with IgAN based on a kidney biopsy anytime in the patient’s life is required for eligibility. The kidney biopsy can be obtained prior to or during the Screening Period. Eligibility is determined using the local pathologist documentation before randomization (Day 1). If available, the MEST-C score and degree of IgG, IgA, IgM, C3, C4d, and Clq staining are obtained from the local pathology report and documented in the CRF along with other characteristics of the biopsy.

Report of kidney biopsy within 6 months of Screening or during Screening is required to confirm < 75% each of interstitial fibrosis, tubular atrophy, and glomerular sclerosis for participants in the Open-Label Cohort with eGFR 20-29 mL/min/1.73 m2 (approximately 20 participants).

During the Study, a repeat biopsy at Week 106 is optional. If available, the MEST-C score and degree of IgG, IgA, IgM, C3, C4d, and Clq staining are obtained from the local pathology report and documented in the CRF along with other characteristics of the biopsy. To investigate parenchymal changes utilizing tissue-based biomarkers in the kidney in participants treated with ravulizumab or placebo who participate in the optional repeat kidney biopsy substudy, a change from Baseline in MEST-C parameters and other tissue-based biomarkers at Week 50 is obtained.

Due to its mechanism of action, the use of ravulizumab increases a participant’ s susceptibility to meningococcal infection due to N meningitidis. To reduce the risk of meningococcal infection, all participants must be vaccinated against N meningitidis serogroups A, C, W135, Y, (and serogroup B where available) at least 14 days prior to but no more than 3 years prior to Day 1. Participants who do not meet this requirement are vaccinated against these N meningitidis serogroups before receiving the first dose of study intervention. If Day 1 occurs < 2 weeks after the initial vaccination, participants receive prophylactic antibiotics for at least 2 weeks after the meningococcal vaccination. Revaccination or booster during the study is administered according to national/local guidelines.

Vaccination may not be sufficient to prevent meningococcal infection. All participants are monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics, if necessary. Participants are vaccinated or revaccinated against other pathogens according to current national vaccination guidelines or local practice for vaccination use as part of standard of care.

4. Schedule of Activities

The assessments are conducted in the following order. Electrocardiograms (ECGs), vital sign measurements, and participant-reported questionnaires (e.g., EuroQoL 5-dimension 5-level [EQ-5D- 5L] ) before blood sampling. Blood samples for safety laboratory tests drawn before pharmacokinetics (PK) samples (provided that the PK sampling times are not affected)._Assessments and/or blood samples that coincide with a dose of study intervention are completed before study intervention administration. Peak (postdose) PK samples are obtained after study intervention administration. The same order of assessments is applied consistently across the study. Study procedures and their timing are summarized in FIGs 7-9. Specifically, FIG. 7 depicts the Schedule of Activities during Screening. FIG. 8 depicts the Schedule of Activities for the Treatment Period: Day 1 Through Week 106 Visits. FIG. 9 depicts the Schedule of Activities for the Open-label Ravulizumab Access Period.

5. Study Intervention, Dosage, and Mode of Administration

Ravulizumab is formulated at pH 7.4 and is supplied in 11 mL single-use vials. 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. The comparator product (placebo) is formulated as a matching sterile, colorless to yellow solution with the same buffer components, but without active ingredient. Additional details are presented in Table 8.

Table 8: Study Intervention(s) Administered

Abbreviations: AxMP = auxiliary medicinal product; IMP = investigational medicinal product; IV = intravenous; q8w = every 8 weeks

The dosage regimen consists of a loading dose followed by maintenance dosing administered every 8 weeks (q8w) (Table 9). The loading dose is administered on Day 1 and maintenance dosing is initiated on Day 15. For the first dose in the Ravulizumab Access Period, participants in the placebo group switch to receive a blinded loading dose of ravulizumab and participants in the ravulizumab group receive a blinded ravulizumab dose of 900 mg at Week 106. Blinding during the switch is achieved by matching the number of kits and the volume used for the 2 groups.

Table 9: Weight-based Doses of Ravulizumab ^a Dose is based on the last recorded study visit body weight. If the study drug is prepared the night before a visit, the weight from the most recent study visit is used. The first maintenance dose is administered on Day 15. Abbreviation: q8w = every 8 weeks

6. Prior and Concomitant Therapy

Any medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, vitamins, and/or herbal supplements) that the participant receives is recorded at the time of enrollment or receives during the study.

All participants must be compliant and adherent to a stable and maximally tolerated or allowed dose of RAS blocking agent(s) (ACE inhibitor and/or ARB) for at least 3 months prior to Screening unless an intolerance is documented. Record the date of first administration of RASI medications (including all start/stop dates) and confirm adherence/compliance on the CRF. Caution is advised if participants are on dual therapy with both ACEI and ARB as the risk of side effects may be higher. The dose of RASI does not change and new RASI therapies are not added through Week 106. SGLT2 inhibitor, DEARA (e.g., sparsentan), MRA, and ERA are not required, but are allowed for participants on a stable and maximally tolerated or allowed dose for > 3 months prior to Screening. The dose of SGLT2I, DEARA (e.g., sparsentan), ERA, or MRA does not change and new medications are added through Week 106.

If a participant is receiving < 10 mg/day of systemic corticosteroid therapy (e.g., prednisone or prednisone equivalent) the dose must not change through Day 106.

If a participant is receiving a stable dose of HCQ for at least 3 months prior to Screening, HCQ must be continued, and the dose must not change through Week 106.

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) are avoided when clinically possible during Screening through Week 106. New or changes to glucagon-like peptide (GLP)- 1 receptor agonists are avoided when clinically possible during Screening through Week 106. If, in rare circumstances, modifications to concomitant IgAN therapy are required (e.g., drug recall), they are discussed. The circumstance and participant characteristics are reviewed. If a modification is determined necessary, participants continue to receive the study intervention and continue in the study.

Initiation of new use of nonsteroidal anti-inflammatory drugs (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.

Premedication for administration of study intervention (including but not limited to IV fluids, corticosteroids, antihistamines) is allowed but not required per the clinical judgement of the Investigator.

Any medication or therapy deemed necessary for the participant’ s care or for the treatment of AE, can be given with discretion, other than those listed as disallowed medications.

Participants are prohibited from receiving any of the following medications and therapies during the study: systemic immunosuppressive therapies (includes Tripterygium Wilfordii) for the treatment of IgAN through Week 106, other complement inhibitor through Week 106, experimental interventions or therapies through the end of the study; systemic corticosteroid, budesonide (for treatment of IgAN), or any other systemic immunosuppression therapy within 3 months of Screening (except short course steroids [approximately 14 days] for non-IgAN therapy) through Week 106 per Exclusion Criteria with the exception if conditions are met as specified above. The end of the study is defined as the date of the last participants’ Week 204 Visit or ED/ET from the Open-label Ravulizumab Access Period in the study globally.

Withdrawal from the study intervention and/or the study compromises the results and diminishes the public health value of the study. Therefore, efforts are made to ensure participant retention in the study. If a participant discontinues the study intervention, the participant is strongly encouraged to continue in the study for the remainder of the study visits to complete all assessments and procedures. Changes to concomitant IgAN therapy are not reasons for discontinuation of study intervention or the study.

7. Efficacy Assessments

For the determination of UPCR/UP, 24-hour urine collections are analyzed by a central laboratory. Two 24-hour UPCR/UP measurements are collected within approximately 2 weeks prior to Day 1. Collection #2 is > 5 days before the planned randomization date to allow for central laboratory shipping, processing, and resulting. Eligibility is based on the mean of the two 24- hour collection measurements and must be UPCR > 0.75 g/g or UP > Ig/day. During the study, the 24- hour urine collections are obtained before dosing and within 2 weeks prior to the clinic visit at Weeks 10, 26, 34, 50, and 106. In addition to protein, albumin, sodium, and creatinine are also quantified in each of the 24-hour urine collections. Both UPCR, as well as urine albumin to creatinine ratio (UACR), are calculated. The last 24-hour urine collection should occur no later than 7 days before the planned date of randomization (Day 1).

Rigorous exercise and significant change in dietary salt intake is avoided within 48 hours before collection of 24-hour urine samples, whenever possible. The 24-hour urine collection is not recommended while a participant is febrile cither in response to illness or vaccination or within 48 hours of fever. The 24-hour urine collections are obtained at the participant’ s home and collected by a mobile nurse. If the data from the 24-hour urine collection is not able to be analyzed or reported or the results are not interpretable or do not fit the clinical scenario of the patient, the collection is repeated.

In summary, there are a total of seven 24-hour urine collections during the study. Two during the Screening Period; within approximately 2 weeks prior to Day 1. Collection #2 is 5 days before the planned randomization date to allow for central laboratory shipping, processing, and resulting. Five during the Study Treatment Period; within 2 weeks before the clinic visit at: Week 10, Week 26, Week 34, Week 50, and Week 106. Two additional aliquots from the 24-hour urine collection are obtained for exploratory biomarker analyses at the following timepoints: Screening (Collection #2), Week 26, and Week 50.

Urinary protein, albumin, and creatinine levels from urinalysisprior to dosing are also measured to assess the effect of ravulizumab on UPCR and UACR.

During the Treatment Period, the urinalysisis obtained prior to administration of study intervention. The urinalysisdoes not need to be captured from the first morning void.

Changes in renal function are monitored using measurements of eGFR (mL/min/1.73m2) and creatinine clearance on a 24-hour urine collection. The eGFR calculation is based on the CKD-EPI formula for all participants using serum creatinine collected prior to administration of study intervention, if applicable using the revised 2021 equation (see Inker LA, et al., N. Engl. J. Med. 2021a;385:1737-1749). eGFR are calculated using cystatin C according to the CKD-EPI formula for exploratory purposes and may be used as confirmation of eGFR based on serum creatinine. A complete physical examination includes, at a minimum, assessments of the following organs/body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, chest, heart, abdomen, extremities, musculoskeletal, and neurological state (with emphasis on presence/degree of edema). An abbreviated physical examination includes a body system-relevant examination based upon Investigator’s (or qualified designee) judgment and participant symptoms. At least 1 body system must be checked for an abbreviated examination.

Height and weight are measured and recorded. Temperature (°C or °F), heart rate (beats per minute), respiratory rate (breaths per minute), and blood pressure (mmHg) is assessed. Blood pressure and pulse measurements are assessed with the participant in a seated position using a completely automated device. Manual techniques (with an appropriately sized cuff) are used only if an automated device is not available. Blood pressure and pulse measurements arc preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). Ideally, the same arm for each participant is used for measurements. Pulse oximetry is assessed. All vital signs measurements are obtained before blood collection for laboratory tests. Single 12-lead electrocardiograms (ECGs) are conducted locally to obtain heart rate, PR, QRS, interval between the start of the Q wave and the end of the T wave in an ECG (QT), and corrected QT interval (QTc) (QT interval corrected for heart rate using Fridericia’s formula [QTcF]). Participants must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.

All laboratory tests with values considered clinically significantly abnormal during participation in the study are repeated until the values return to normal or baseline or are no longer considered clinically significant. If clinically significant values do not return to normal/baseline within a period of time judged, the etiology is identified. If laboratory values from non-protocol-specified laboratory tests performed at the institution’s local laboratory require a change in participant management or are considered clinically significant by the Investigator (e.g., SAE or AE or dose modification), then the results are documented.

HIV-1, HIV-2, hepatitis B, and hepatitis C virus testing is required for all participants prior to enrollment. Participants who are HIV antibody positive are not be enrolled.

Similarly, participants who are positive at the Screening Visit for HBsAg, anti-HBc with negative anti- HBs, or HCV antibody positive (except for participants with documented successful treatment and documented sustained viral response) are not enrolled. Pregnancy testing (serum or urine) is performed on all women of childbearing potential (WOCBP). A negative pregnancy test is required for WOCBP before administration of study intervention. Any female participant who becomes pregnant while participating in the study is discontinued from the study intervention.

8. Pharmacokinetics (PK) & Pharmacodynamics

Blood samples are collected for measurement of serum concentrations of ravulizumab. Additional samples may be collected at additional timepoints during the study if warranted. The timing of sampling can be altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. Predose PK blood samples are collected within 90 minutes before administering study intervention. The predose blood samples can be drawn through the venous access created for the dose infusion, prior to administration of the dose. Postdose PK blood samples are collected within 60 minutes after completing the infusion. The postdose blood samples are drawn from the participant’s opposite, non-infused arm.

With respect to pharmacodynamics, blood samples collected for measurement of total C5 and free C5. Additional samples can collected at additional time points during the study if warranted. Samples are used to evaluate the PD of ravulizumab. S amples collected for analyses of ravulizumab concentration can be used for research purposes or to evaluate safety or efficacy aspects during or after the study. PD results that would unblind the study are not reported to investigational sites or blinded personnel until the study has been unblinded.

9. Genetics & Biomarkers

Collection of optional samples for Genomics Initiative research is also a part of Study ALXN1210-IgAN-320.

Blood and urine samples for biomarker research (e.g., exploratory) are collected from all participants in this study. Biomarker samples can be analyzed after study completion for absolute values, change from baseline, and for association with observed clinical responses. Blood (scrum and plasma) samples for biomarker research are collected for testing that can include, but are not limited to, assessments of the following: (1) markers of complement pathway activation (e.g., C4d, Ba), (2) markers of localized inflammation (e.g., CD68, CD88), and (3) Markers of disease (e.g., Gd-IgAl and kidney injury molecule- 1 (KIM-1)). Urine samples for biomarker research are collected for testing that includes, but is not limited to, assessments of the following: (1) markers of complement pathway activation (e.g., sC5b-9 [soluble C5b-9]), (2) markers of localized inflammation (e.g., CD163), and (3) Creatinine.

Serum samples for ADA and neutralizing antibody (NAb) analysis are collected. All efforts are made to obtain the immunogenicity samples at the exact nominal time relative to dosing. The detection and characterization of ADA to ravulizumab is performed using a validated assay method. Antibodies to ravulizumab are evaluated in serum samples collected from all participants. ADA positive samples are further characterized for antibody titer and presence of neutralizing antibodies. ADA results that may unblind the study are not reported to investigational sites or blinded personnel until the study has been unblinded.

10. Participant-Reported Outcomes Measures

Quality of life scales are administered prior to other study procedures at specified visits.

The Kidney Disease Quality of Life-36 items (KDQOL-36TM), a 36-item kidney-specific health-related QoL measure includes the 12-item Short Form Health Survey (SF-12) as generic core plus the burden, symptoms, and effects of kidney disease scales (see Hays RD, et al., Qual. Life Res. 1994;3(5):329-338).

The EuroQoL 5dimension, 5-level (EQ-5D-5L) questionnaire is a self-assessed, standardized instrument to assess the participant’s health status at the time of administration. The questionnaire contains 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each of which includes 5 levels of response (no problems, slight problems, moderate problems, severe problems, and extreme problems) (see EQ-5D. EQ-5D-5L User Guide. Basic information on how to use the EQ-5D-5L instrument. Available from: euroqol.org/publications/user-guides. EuroQoL Research Foundation [Internet]. 2019 September, 2019).

The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, Version 4.0, is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days (Celia D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: A new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol. 1997;34(3): 13-19).

The Patient Global Impression of Severity (PGI-S) is a l -item questionnaire that is used to assess a participant’s overall perception of the severity of their IgAN symptoms during the week before the clinic visit (see Guy W. ECDEU assessment manual for psychopharmacology. 1976. Available from world- wide- web: searchworks.stanford.edu/view/2520902).

The Patient Global Impression of Change (PGI-C) is a 1-item questionnaire that is used to assess a participant’s overall perception of the change in their IgAN symptoms since the start of the study (Day 1) (see Guy W. ECDEU assessment manual for psychopharmacology. 1976. Available from worldwide-web: searchworks, stanford.edu/view/2520902).

The Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (Work Productivity and Activity Index [WPAI]: General Health [GH] 2.0) is a 6-item questionnaire that is used to assess the effect of general health and symptom severity on work productivity and regular activities during the preceding 7 days (see Reilly M. Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH 2.0). 2013. Available from: cprovidc.mapi-trust.org/instrumcnts/work- productivity-and-activity-impairment-questionnaire-general-health-v2.0).

11. Statistical Considerations

The Statistical Analysis Plan (SAP) is finalized prior to database lock. The primary objective at the interim analysis is to evaluate whether treatment with ravulizumab decreases proteinuria at Week 34 relative to placebo. The following hypothesis is tested:

H_o : A= 0 versus H_a : A _f 0 where A represents the difference (ravulizumab - placebo) in log change in proteinuria at Week 34.

The primary objective at the final analysis is to evaluate the change from Baseline in eGFR at Week 106 compared to placebo. The following hypothesis is tested:

H_o : 0 = 0 versus H_a : 0 0 where 0 represents the difference in annualized total eGFR slope between placebo and ravulizumab.

For the Open-Label Cohort, analyses is descriptive in nature and no formal hypothesis is tested.

The overall Type I error for primary and key secondary endpoints is controlled at a 1 -sided significance level of 0.025 using a parallel gatekeeping procedure.

The UPCR endpoint is tested first at a one-sided significance level of 0.005 at the interim analysis. If the UPCR comparison is statistically significant at the interim analysis, the eGFR slope endpoint at the final analysis is tested at a one-sided significance level of 0.025. If the UPCR comparison is not statistically significant at the interim analysis, then it is re-tested at the final analysis at a one-sided significance level of 0.005 and the eGFR slope endpoint is tested at a one-sided significance level of 0.02.

If the comparison of the eGFR slope endpoint at the final analysis is statistically significant, the key secondary endpoints are tested at the same significance level as the eGFR slope endpoint in the following hierarchical manner until a nonsignificant test is observed, at which point only nominal p- values are reported for all subsequent endpoints. (1) Change from baseline in UPCR at Week 10. (2) Composite kidney failure endpoint over 106 weeks.

The following participant analysis sets are defined below in Table 10:

Table 10: Analysis Sets

An interim analysis can be performed. The final analysis is performed when approximately 450 participants have completed the Week 106 Visit. An interim analysis for the Main Cohort may be conducted to evaluate the proteinuria endpoint. Limited data is collected during the Ravulizumab Access Period and is summarized descriptively as applicable. All analyses for the Open-Label Cohort are summarized separately and are descriptive in nature with no formal statistical testing. Summary statistics are computed and displayed by treatment group and by visit, where applicable. Descriptive statistics for continuous variables minimally include the number of participants, mean, standard deviation (SD), minimum, median, and maximum. For categorical variables, frequencies, and percentages are presented. Ninety-five percent Cis are provided for all treatment effect estimates. Additionally, Cis reflecting the final 1-sided significance level resulting from the parallel gatekeeping procedure are provided for the primary and key secondary efficacy endpoints. For the UPCR endpoint, a final one-sided significance level of 0.005 leads to construction of a 2-sided 99% CI. For the eGFR endpoint and key secondary endpoints, a final 1 -sided significance level of either 0.025 (if the interim primary endpoint is significant) or 0.02 (if the interim primary endpoint is not significant) leads to construction of a 2-sidcd 95% or 96% CI, respectively. Graphical displays arc provided as appropriate. Analyses are performed using the SAS® software Version 9.4 or higher.

The primary efficacy analysis for the interim analysis and final analysis of the Main Cohort is based on the Full Analysis Set (FAS). The primary endpoint for the interim analysis is change from baseline in UPCR at Week 34. Proteinuria is measured by 24-hour UPCR in g/g. Baseline proteinuria is defined as the mean of the 2 collections taken during the Screening Period. To reduce skewness, the natural logarithm is used to transform UPCR values before analysis.

A mixed-effect model for repeated measures (MMRM) is used for the primary efficacy endpoint using all available longitudinal data measurements up to Week 34. The model includes change from baseline in log-transformed UPCR as the response variable and fixed, categorical effects of treatment group, stratification factors, visit, and treatment group- by- visit interaction, as well as a fixed, continuous effect of baseline log UPCR as a covariate. An unstructured covariance matrix is used to model the correlations among repeated measurements within each participant. If this analysis model fails to converge, a first-order autoregressive covariance matrix is used. The Kenward— Roger approximation is used to estimate denominator degrees of freedom. The treatment effect is evaluated using a contrast for treatment group-by-visit term at Week 34.

Use of alternative IgAN therapy, treatment discontinuations, and renal deaths are considered intercurrent events for the primary endpoint for the interim analysis. Data collected after treatment discontinuation are included as observed. Data following death, kidney transplant, or dialysis are imputed using 10% of worst change values. Missing data due to study withdrawal are imputed using retrieved dropouts; intermittent missing data are considered MAR. The primary endpoint for the final analysis is change from baseline in eGFR at Week 106. Total annualized eGFR slope is evaluated as a supplementary analysis to the primary endpoint. Kidney function evaluated by eGFR is calculated based on the 2021 Kidney Disease - Improving Global Outcomes (KDIGO) CKD-EPI formula. Baseline eGFR is defined as the mean of the Screening and Day 1 measurements.

Change from Baseline in eGFR at Week 106 is analyzed using an MMRM including all available longitudinal data. The model includes change from Baseline in eGFR as the response variable and fixed, categorical effects of treatment group, stratification factors, visit, and treatment group by visit interaction, as well as a fixed, continuous effect of Baseline eGFR as a covariate. An unstructured covariance matrix is used to model the correlations among repeated measurements within each participant. If this model fails to converge, a first-order autoregressive covariance matrix is used. The Kenward-Roger approximation is used to estimate denominator degrees of freedom. The treatment effect is evaluated using a contrast between treatment groups at Week 106. The point estimate, 2-sided 95% CI, and p- value for the LS mean treatment difference is presented.

As a supplementary analysis, the annualized total eGFR slope, which is defined as the mean rate of decline from Baseline to Week 106 expressed as an annual rate, is estimated using a linear mixed effects model including data through 106 weeks. The model includes eGFR as the response variable, random participants effects for intercepts and slopes, fixed categorical effects for treatment groups and randomization stratification factors, fixed continuous effect of time, and treatment group-by-time interaction. The total slope effect (i.e., slope difference between treatment groups) is evaluated using the contrast between treatment groups. The total slope effect over 106 weeks is annualized for ease of interpretation. The point estimate, 2-sided 95% CI, and p-value for the mean difference of total annualized slopes is presented.

Use of alternative IgAN therapy, treatment discontinuation, and renal death are considered intercurrent events for the primary endpoint for the final analysis. Data collected after use of alternative IgAN therapy is censored and imputed using copy increments from reference. Data collected after treatment discontinuation is included as observed. Data following death, kidney transplant, or dialysis is imputed using 10% of worst change values. Missing data due to study withdrawal is imputed using retrieved dropouts; intermittent missing data is considered MAR. Sensitivity analyses considering alternative assumptions for handling of missing data and intercurrent events for the primary and/or key secondary endpoints are fully specified in the SAP. Briefly, these analyses include:

(a) MAR analysis: Data after receipt of alternative IgAN therapy, or treatment discontinuation, is excluded and handled in the MMRM under MAR assumption.

(b) Treatment policy analysis: The primary endpoint is analyzed in the same manner as the primary analysis, except all observed data are included, regardless of experiencing an intercurrent event.

(c) Tipping point analysis: Participants who experience an intercurrent event, withdraw early or die are assumed to have outcomes that are worse than otherwise similar participants who remain in the study or did not experience an intcrcurrcnt event. Based on the delta-adjusted stress testing method (tipping point analysis), this approach assumes that participants who discontinue from study treatment or who receive alternative IgAN therapy experience worsening, defined by a prespecified adjustment (delta) in the primary efficacy endpoint compared with the observed efficacy score of participants that continue the study to next visit. For each value of delta, the treatment effect is determined, and the value of delta for which the nominal 1-sided p-value crosses 0.005, is considered as the ‘tipping point’ in the sense that the conclusion drawn from the primary analysis is reversed when participants who drop out or who receive alternative IgAN therapy are assumed to experience this fixed adjustment after the discontinuation visit or receipt of alternative IgAN therapy. After such a tipping point is determined, clinical judgment is applied as to the plausibility of the assumptions underlying this tipping point. This methodology is expected to inform what it would take to overturn study conclusions based on varying assumptions about missing data (Ratitch and O'Kelly, 2014; Ratitch, 2013).

The secondary efficacy analyses are based on the FAS. The overall Type I error for the primary and key secondary endpoints is controlled at a 1-sided significance level of 0.025.

Other secondary endpoints are not adjusted for multiple comparisons, and the nominal p-value is reported.

At the final analysis, the proportion of participants achieving > 50% reduction from Baseline without receiving alternative IgAN therapy in UPCR at Week 34 based on 24-hour urine collections is summarized by treatment group. The point estimate, 95% Cis, and p-value for the treatment difference in proportions are estimated after accounting for stratification factors with the Cochran-Mantel-Haenszel weights. Intercurrent events of alternative IgAN therapy, treatment discontinuation, death, kidney transplant, and dialysis are handled using the same approach as the primary endpoints. Proteinuria data missing due to study withdrawal are imputed using retrieved dropouts; intermittent missing data are considered MAR. Proteinuria values are imputed according to the intercurrent event or missing data strategy prior to deriving a status of achieving > 50% reduction from Baseline in UPCR.

At the final analysis, the change from Baseline in 24-hour UPCR at Week 10 is analyzed using the same MMRM method as the primary endpoint at the interim analysis. The model includes change from Baseline in log-transformed UPCR as the response variable and fixed, categorical effects of treatment group, randomization stratification factors, visit and treatment group by visit interaction, as well as a fixed, continuous effect of Baseline log UPCR as a covariate. The treatment effect is estimated using the contrast between treatment groups at Week 10. Intercurrent events of alternative IgAN therapy, treatment discontinuation, death, kidney transplant, and dialysis are handled using the same approach as the primary endpoints. Data missing due to study withdrawal are imputed using retrieved dropouts; intermittent missing data are considered MAR.

At the final analysis, time from randomization to first occurrence of sustained > 30% eGFR decline relative to Baseline (confirmed by a second semm creatinine after at least 28 days) is evaluated by treatment group. The treatment groups are compared using a stratified Cox proportional hazards model with strata defined by the randomization factors, a factor for treatment group, and adjusting for Baseline eGFR. Participants who do not achieve sustained > 30% eGFR decline from Baseline to Week 106 are censored at their last contact date. The p-value, HR, and 95% CI are provided. Intercurrent events of alternative IgAN therapy, treatment discontinuation, death, kidney transplant, and dialysis are handled using the same approach as the primary endpoints. eGFR data missing due to study withdrawal are imputed using retrieved dropouts; intermittent missing data are considered MAR. eGFR values are imputed according to the intercurrent event or missing data strategy prior to deriving status of achieving sustained > 30% eGFR decline from Baseline.

Time to first occurrence of the composite kidney event endpoint is defined as reaching at least one of the following:

1. Sustained > 30% decline in eGFR relative to baseline (confirmed by a second serum creatinine after at least 28 days); 2. Sustained eGFR <15 mL/min/1.73 m² (confirmed by a second serum creatinine after at least 28 days);

3. Maintenance dialysis for at least 28 days;

4. Receipt of kidney transplant; and/or

5. Death from kidney failure.

For the analysis of composite kidney event endpoint at the final analysis, time from randomization to first event is evaluated by treatment group and analyzed similarly as the key secondary endpoint for sustained > 30% eGFR decline described previously. Participants who do not reach the composite kidney event endpoint are censored at their last contact date. The p-value, HR, and 95% CI arc provided.

Intercurrent events of alternative IgAN therapy and treatment discontinuation are handled using the same approach as the primary endpoints. eGFR data missing due study withdrawal are imputed using retrieved dropouts; intermittent missing data are considered MAR. eGFR values are imputed according to the intercurrent event or missing data strategy prior to deriving status of composite kidney event.

In addition, each individual component of the composite kidney event endpoint is examined as other secondary endpoints. Methods similar to those described for the composite kidney event endpoint are used to separately analyze the time from randomization to the first occurrence of each component of the composite kidney event endpoint. Participants who do not reach the endpoint of interest are censored at their last contact date. The p-value, HR, and 95% CI are provided.

Kaplan-Meier estimates of the cumulative incidence to the first occurrence of any event are calculated and plotted for the composite kidney event endpoint and for the individual components.

The change from baseline in 24-hour UPCR at Weeks 26, 34, 50, and 106 is analyzed using the same MMRM method as the primary endpoint at the interim analysis. The model includes change from baseline in log — transformed UPCR as the response variable and fixed, categorical effects of treatment group, randomization stratification factors, visit and treatment group by visit interaction, as well as a fixed, continuous effect of Baseline log UPCR as a covariate. The treatment effect is estimated using the contrast between treatment groups at each scheduled visit. The point estimate and 2-sided 95% CI for the LS mean treatment difference of log-transformed UPCR are back-transformed (via exponentiation) to obtain the GMR and corresponding 2-sided 95% CI. The values also are expressed as percentage change (expressed as percentage change (e.g., [GMR - 1] x 100%) from Baseline in UPCR at each visit.

The change from Baseline in eGFR at Weeks 34 and 50 is analyzed using the same MMRM method as the primary endpoint at the final analysis. The model includes change from Baseline in eGFR as the response variable and fixed, categorical effects of treatment group, randomization stratification factors, visit and treatment group by visit interaction as well as a fixed, continuous effect of Baseline eGFR as a covariate. The treatment effect is estimated using the contrast between treatment groups at each scheduled visit. The point estimate and 2- sided 95% CI for the LS mean treatment difference is presented.

The proportion of participants achieving > 50% reduction from Baseline in UPCR at Weeks 10, 26, 50, and 106 based on 24-hour urine collections is summarized by treatment group. The point estimate, 95% Cis, and p-value for the treatment difference in proportions is estimated using the Cochran-Mantel-Haenszel weights, adjusting for stratification factors. In addition, the proportion of participants achieving > 50% reduction from Baseline in UPCR at both Week 34 and Week 106 based on 24-hour urine collections is summarized by treatment group in a similar manner.

Partial remission is defined as UPCR < 1 g/g based on 24-hour urine collection(s) and at least 25% reduction from Baseline. The proportion of participants achieving par tial remission at Weeks 34, 50, and 106 are summarized by treatment group.

The change from baseline in 24-hour UACR at Weeks 10, 26, 34, 50, and 106 is analyzed using the same MMRM method as the primary endpoint at the interim analysis. The model includes change from baseline in UACR as the response variable and fixed, categorical effects of treatment group, randomization stratification factors, visit and treatment group by visit interaction, as well as a fixed, continuous effect of baseline UACR as a covariate. The treatment effect is estimated using the contrast between treatment groups at each scheduled visit. The point estimate and 2-sided 95% CI for the LS mean treatment difference are presented.

The change from baseline in FACIT-Fatigue score at Weeks 34, 50, and 106 is analyzed using the same MMRM method as the primary endpoint at the interim analysis. The model includes change from baseline in FACIT-Fatigue score as the response variable and fixed, categorical effects of treatment group, randomization stratification factors, visit and treatment group by visit interaction, as well as a fixed, continuous effect of baseline FACIT-Fatigue score as a covariate. The treatment effect at each visit is estimated using the contrast between treatment groups at each scheduled visit. The point estimate and 2-sided 95% CI for the LS mean treatment difference are presented.

The annualized total eGFR slope over 50 weeks is analyzed using the same linear’ mixed effects model as the primary endpoint at the final analysis. The model includes eGFR as the response variable, random participants effects for intercepts and slopes, fixed categorical effects for treatment groups and randomization stratification factors, fixed continuous effect of time, and treatment group-by-time interaction (total slope effect). The total slope effect (i.e., slope difference between treatment groups) is evaluated using the contrast between treatment groups. The total slope effect over 50 weeks is annualized for ease of interpretation. The point estimate and 2-sided 95% CI for the mean difference of total annualized slopes is presented.

Sustained eGFR < 15 mL/min/1.73 m² is confirmed by a second scrum creatinine after at least 28 days. Time from randomization to first occurrence of sustained eGFR < 15 mL/min/1.73 m² is analyzed similarly as the key secondary endpoint for sustained > 30% eGFR decline described previously. Participants who do not achieve sustained eGFR < 15 mL/min/1.73 m² over 106 weeks are censored at their last contact date. The p-value, HR, and 95% CI are provided.

Time to first maintenance dialysis for at least 28 days over 106 weeks is analyzed similarly as the key secondary endpoint for sustained > 30% eGFR decline described previously. Participants who do not maintain dialysis for at least 28 days over 106 weeks are censored at their last contact date. The p-value, HR, and 95% CI are provided.

Time to first receipt of a kidney transplant over 106 weeks is analyzed similarly as the key secondary endpoint for sustained > 30% eGFR decline described previously. Participants who do not receive a kidney transplant over 106 weeks are censored at their last contact date. The p-value, HR, and 95% CI are provided.

Time to death from kidney failure over 106 weeks is analyzed similarly as the key secondary endpoint for sustained > 30% eGFR decline described previously. Participants who do not experience a death from kidney failure over 106 weeks are censored at their last contact date. The p-value, HR and 95% CI are provided.

Time from randomization to first occurrence of sustained > 40% eGFR decline from Baseline to Week 106 is analyzed similarly as the key secondary endpoint for sustained > 30% eGFR decline described previously. Participants who do not achieve sustained > 40% eGFR decline from Baseline to Week 106 are censored at their last contact date. The p-value, HR, and 95% CI are provided. At the final analysis, the proportion of participants with at least one use of alternative IgAN therapy through Week 106 are summarized by treatment group and overall. In addition, the proportion of participants who meet the criteria for sustained worsening of kidney function, as specified previously, through Week 106 is summarized by treatment group and overall.

The point estimate, 95% Cis, and p- value for the treatment difference in proportions are estimated after accounting for stratification factors with the Cochran- Mantel-Haenszel weights. Exploratory endpoints include additional measures of kidney function, participant-reported outcomes, health resource utilization, and genetics. The exploratory analyses are descriptive in nature and based on the FAS.

In general, the analysis methods used for the secondary endpoints are applied to the exploratory endpoints.

(a) For continuous endpoints, the MMRM method used for the continuous secondary endpoints is applied. The point estimate and 95% CI for treatment difference is presented.

(b) For binary endpoints, the Cochran-Mantel-Haenszel weights used for the binary secondary endpoints is applied. The point estimate and 95% CI for the treatment difference is presented.

(c) For time to event endpoints, the stratified Cox proportional hazards model used for the time- to-event secondary endpoints is applied. The hazard ratio and 95% CI are presented.

Full details of the exploratory analyses are presented in the main SAP or in a separate, exploratory SAP, if needed.

All safety analyses are made on the Safety Set based on the actual treatment received. The safety and tolerability of ravulizumab is assessed based on treatment-emergent adverse events (TEAEs), clinical laboratory findings, vital sign findings, ECG abnormalities, and physical examination. The incidence of TEAEs, TEAEs leading to treatment discontinuation, and treatment- emergent serious adverse events (TESAEs) arc summarized by treatment group. All TEAEs are coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 23 or higher and are summarized by System Organ Class (SOC) and Preferred Term overall, by severity, and by relationship to treatment. Detailed by-participant listings of TEAEs, TESAEs, related TEAEs, and TEAEs leading to treatment di continuation is provided. Adverse changes from baseline in physical examination findings are classified as TEAEs and analyzed accordingly. Vital signs are summarized descriptively by treatment group at baseline and postbaseline timepoints and for changes from baseline. Observed values and changes from baseline in clinical chemistry, hematology, and urinalysis are summarized descriptively by treatment group at baseline and 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 is summarized for all study visits.

Electrocardiograms 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 is be corrected for heart rate (QTcF). QT is the interval between the start of the Q wave and the end of the T wave in an ECG. Qtc is the QT interval corrected for heart rate.

Graphs of mean scrum ravulizumab conccntration-timc profiles arc constructed. Graphs of serum concentration-time profiles for individual participants can also be provided. Actual dose administration and sampling times are used for all calculations. Descriptive statistics are calculated for serum concentration data at each sampling time, as appropriate. The PD effects of ravulizumab are evaluated by assessing the serum free C5 and total C5 concentrations over time, as appropriate. Additionally, box and whisker plots of free C5 concentrations over time are generated.

All immunogenicity analyses are performed on the Immunogenicity Analysis Set. Immunogenicity variables include ADA status, ADA response category, ADA incidence and titer and NAb incidence over the duration of the study. Definitions of the ADA status and ADA response categories are provided in the SAP. ADA status and ADA response categories are summarized as absolute occurrence (n) and percentage of all participants:

1. ADA status categories (ADA negative or ADA positive)

2. Participants who are ADA positive are further categorized into ADA response categories as follows: (a) Pre-existing immunoreactivity, (b) Treatment-emergent ADA responses, and (3) Treatment-boosted ADA responses

3. Participants with treatment-emergent or treatment-boosted ADA responses are further categorized as: (a) Persistent responses, (b) Indeterminate responses, and (c) Transient responses.

4. ADA positive samples are further characterized for neutralizing activity in the NAb assay. NAb status categories are as follows: NAb positive or NAb negative.

5. NAb status is summarized as absolute occurrence (n) and percentage of all participants. Summaries of the primary efficacy endpoints at interim and final analysis are presented by the following subgroups, but not limited to:

• Age at screening

• Gender

• Race

• Geographic region

• Duration of disease

• Baseline eGFR

• Baseline 24-hour UPCR

• Baseline SGLT2I use

• Baseline DEARA or ERA use

• Baseline HCQ use

• IgA vasculitis

• Baseline C3 and C4 quartiles

• Baseline hematuria

• Baseline tonsillectomy

Full details of the subgroup analyses are presented in the SAP.

An interim analysis for the Main Cohort is conducted to evaluate the proteinuria endpoint. The interim analysis assesses the primary endpoint of change from Baseline in proteinuria based on 24-hour UPCR at Week 34. Data support proteinuria reduction as a reasonably likely surrogate endpoint for a treatment’s effect on the loss of kidney function and progression to ESKD (Thompson, 2019). The interim analysis supports potential early regulatory submission where pathways allow for a conditional or accelerated approval based on a reasonably likely surrogate endpoint. Confirmatory evidence is provided at the final analysis of the study. An independent statistical center conducts the interim analysis, and participants, investigative site personnel, and sponsor personnel or designees involved in study conduct remains blinded to individual treatment assignments until the end of the Treatment Period (Week 106).

This study plans to enroll approximately 450 participants in the Main Cohort in a 1:1 ratio to receive either weight-based IV infusion of ravulizumab or placebo. The required to evaluate the primary endpoint at the final analysis is 450 participants. The primary objective of the interim analysis is to evaluate the efficacy of ravulizumab compared with placebo to reduce proteinuria at Week 34. Sample size calculations are based on a 1- sided, 2-sample t-test of log-transformed proteinuria values and were performed in PASS software. In early stages of CKD, a 30% reduction in the geometric mean of albuminuria/proteinuria was associated with a significant treatment effect on the clinical outcome (Levey, 2020). A Phase 2 study of ravulizumab in IgAN patients reported an 11% reduction (GMR = 0.89) in proteinuria for the placebo group (Barratt, 2023).

The primary objective of the final analysis is to evaluate the efficacy of ravulizumab compared with placebo on change from Baseline in eGFR at Week 106. The final analysis is performed when approximately 450 participants in the Main Cohort have completed the Week 106 Visit or have discontinued early. Sample size calculations arc based on a 1-sidcd, 2-samplc t-test and were performed in PASS software.

In addition, approximately 60 participants with Baseline eGFR 20 to 29 mL/min/1.73 m² are enrolled in AdKD cohorts. The sample sizes for the AdKD cohorts are not based on statistical considerations. Results are descriptive in nature and not statistically powered for hypothesis testing.

12. Clinical Laboratory Tests

The tests detailed in Table 11 are performed by a central laboratory unless otherwise noted. Local laboratory results are only required in the event that the central laboratory results are not available in time for either study intervention administration and/or response evaluation. If a local sample is required, it is important that the sample for central analysis is obtained at the same time.

Pregnancy testing: WOCBPs are only enrolled after a negative serum pregnancy test result at Screening. Additional urine pregnancy testing is standard for the protocol unless serum testing is required by site policies, local regulation, or IRB/IEC and is performed per specified time points. Laboratory/analyte results that could unblind the study are not reported to investigative sites or other blinded personnel until the study has been unblinded.

Table 11: Laboratory Assessments ^a Eligibility for hematuria can be determined via the local or central laboratory. ^b Serum/local urine pregnancy test as specified.

Abbreviations: ADA = antidrug antibody; ALP = alkaline phosphatase; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antigen antibody; AST = aspartate aminotransferase; Ba = Factor B fragment; C = complement component; CD = cluster of differentiation; CKD-EPI = Chronic Kidney Disease-Epidemiology Collaboration; eGFR = estimated glomerular filtration rate; Gd-IgAl = galactose deficient immunoglobulin Al; GGT = gamma- glutamyl transferase; HbAlC = glycosylated hemoglobin; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCHC = MCH content; MCV = mean corpuscular volume; NAb = neutralizing antibody; PCR = polymerase chain reaction; PD = pharmacodynamic; PK = pharmacokinetic; PT = prothrombin time; RBC = red blood cell; sC5b-9 = soluble membrane attack complex; WOCBP = women of childbearing potential

13. Adverse Events (AEs) and Serious Adverse Events (SAEs)

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 and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention.

Events that meet the AE definition arc as follows:

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).

2. Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.

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

4. Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

5. 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. Lack of efficacy or failure of expected pharmacological action per se are not reported as an AE or SAE. Such instances are captured in the efficacy assessments. However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy are reported as AE or SAE if they fulfill the definition of an AE or SAE.

Events that do not meet the AE Definition are as follows: 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. 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. Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the AE. 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). 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. 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. 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. 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. “Lack of efficacy” or “failure of expected pharmacological action” per sc is not reported as an AE or SAE. Such instances arecaptured in the efficacy assessments. However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy are reported as AE or SAE if they fulfill the definition of an AE or SAE. 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).

An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed:

1. Results in death.

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.

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. 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. Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline is not considered an AE.

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.

5. Is a congenital anomaly /birth defect.

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 jeopardize 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.

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

The Investigator assesses intensity for each AE and SAE 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, published 27 Nov 2017:

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

2. Grade 2: Moderate (discomfort sufficient to cause interference with normal activities)

3. Grade 3: Severe (incapacitating, with inability to perform normal activities)

4. Grade 4: Life-threatening

5. Grade 5: Fatal

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

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.

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.”

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.

Alternative causes, such as underlying discasc(s), concomitant therapy, and other risk factors, as well as the temporal relationship of the event to study intervention administration, is considered and investigated.

For causality assessment, the Investigator’s Brochure and/or product information is also consulted, for marketed products. The Investigator must review and provide an assessment of causality for each AE/SAE and document this in the medical notes. There may be situations in which an SAE has occurred and the Investigator has minimal information. The Investigator may change their opinion of causality in light of follow-up information and send an SAE follow-up report with the updated causality assessment.

EXAMPLE 3: Spot and 24-hour Assessments of Proteinuria and Albuminuria in IgA Nephropathy (IgAN)

Proteinuria is essential for diagnosing, guiding intervention, and monitoring patients with IgAN. 24-hour (24h) urine protein measurement is used in clinical trials because of the circadian variability in protein excretion, but is challenging to operationalize, requires complete collection, and contributes to patient burden in clinical trials. Accordingly, this prespecified sensitivity analysis explored the efficacy of ravulizumab in adults with IgAN using spot urine protei creatinine ratio (UPCR) and urine albumin:creatinine ratio (UACR) in comparison with 24h measurements.

A randomized, double-blind, placebo-controlled trial (as described in Example 1) evaluated efficacy and safety of ravulizumab in adults with biopsy confirmed IgAN, eGFR >30 mL/min/1.73 m², on stable and optimal renin-angiotensin blockade, and mean urine protein (UP) >1 g/d from 2 valid 24h collections. Participants were randomized 2:1 to ravulizumab (IV every 8 weeks) or placebo for 26 weeks; all patients received ravulizumab weeks 26-50. The primary endpoint was % change from baseline to week 26 in 24h proteinuria. As part of the prespecified schedule of activities, UP, albumin, and creatinine from morning spot urine samples were measured. In a post hoc analysis, the correlation between spot UPCR and UACR and 24h UPCR, UP, and UACR was studied.

43 participants were randomized to ravulizumab and 23 to placebo. As shown in Table 12, spot UPCR and 24h UPCR and UP yielded similar estimates of proteinuria in patients with IgAN. Post hoc correlation analysis indicated moderate to strong correlation among measurements (Table 13).

Table 12. Percentage Change from Baseline Through Week 26 in Proteinuria

Table 13; Correlation Between Spot and 24hr Assessments, Baseline through Week 50

* Represents the number of patient assessments where both clinical measures were collected and used to calculate the Spearman Correlation

EXAMPLE 4: Baseline Biopsy Characteristics in an IgA Nephropathy Clinical Trial of Ravulizumab

Diagnosis of IgA nephropathy (IgAN) is based on kidney biopsy that provides histopathologic prognostic information. This study characterized the biopsy features of patients enrolled in a phase 2 trial of the complement C5 inhibitor, ravulizumab, in patients with IgAN (as described in Example 1). Agreement of local versus central pathology scoring was also assessed.

The phase 2, randomized placebo-controlled trial evaluated ravulizumab in patients with biopsy-confirmed IgAN, proteinuria >1 g/day, and on stable/optimal renin-angiotensin blockade. Eligibility was determined using local pathology. A central pathology lab reviewed biopsies performed within 1 year prior to randomization. MEST-C (mesangial [M] and endocapillary [E] hypercellularity, segmental sclerosis [S], interstitial fibrosis/tubular atrophy [T], and crescents) scores were reported, as well as % agreement between central and local pathology scores. Complement C3 glomerular staining was assessed and a post hoc analysis of baseline proteinuria by biopsy characteristics was included. Thirty of 66 patients (45.5%) in the study had a biopsy within a year prior to randomization.

Nine were within the prior 3 months, 9 within the prior 3-6 months, and 12 within the prior 6-12 months. Of the 19 patients with available/non-missing MEST-C central pathology assessment and biopsy within a year prior to randomization, 47% had Ml lesions, 37% had El lesions, all had SI, 84% had T1 and 5% had T2 lesions; 37% had Cl and no patients had C2 lesions (Table 14). Glomerular C3 staining of 2+/3+ was seen in 55% of biopsies.

Both central and local pathology MEST-C scores were available for 24 of 66 patients (regardless of age of biopsy). There was strong agreement between central and local pathology on E (87.5%), S (91.7%), and C (90.9%) scoring (kappa statistic 0.75, 0.62, and 0.81, respectively); percent agreement for M and T scoring was 75.0% and 66.7%, respectively. Baseline mean proteinuria was similar across MEST-C scores and C3 staining categories (Table 15).

Table 14: MEST-C Scores and Glomerular C3 Staining (central pathology) for Patients with

Biopsy w ithin a Year of Randomization

Table 15: Post hoc analysis of baseline 24-hour UPCR by MEST-C score and glomerular C3 staining (central pathology) for patients with biopsy within a year of randomization [data shown for categories with n = 5 or more] IQR=interquartile range; SD=standard deviation; UPCR=urine protein:creatinine ratio.

SEQUENCE SUMMARY

Claims

CLAIMS What is claimed is:

1. A method of treating a human patient with immunoglobulin A nephropathy (IgAN), 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:

2. The method of claim 1, further comprising administering the anti C5 antibody, or antigen binding fragment thereof:

3. The method of any one of the preceding claims, 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.

4. The method of any one of the preceding claims, 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.

5. 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.

6. 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.

7. 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).

8. 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).

9. The method of any one of the preceding claims, wherein the anti-C5 antibody is administered to a patient weighing > 30 to < 40 kg once on Day 1 at a dose of 2400 mg, followed by a dose of 3000 mg at Week 2 and once every eight weeks thereafter.

10. The method of any one of claims 1-8, 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 at Week 2 and once every eight weeks thereafter.

11. The method of any one of claims 1-8, wherein the anti-C5 antibody is administered to a patient weighing > 60 < 100 kg once on Day 1 at a dose of 2700 mg, followed by a dose of 3900 mg at Week 2 and once every eight weeks thereafter.

12. The method of any one of claims 1-8, 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 5400 mg at Week 2 and once every eight weeks thereafter to a patient weighing > 100 kg.

13. The method of any one of claims 1-8, wherein the anti-C5 antibody is administered to a patient weighing > 30 to < 40 kg:

(a) 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; and

(b) once on Day 743 at a dose of 900 mg, followed by a dose of 2700 mg on Day 757 and once every eight weeks thereafter.

14. The method of any one of claims 1-8, wherein the anti-C5 antibody is administered to a patient weighing > 40 to < 60 kg:

(a) 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; and

(b) once on Day 743 at a dose of 900 mg, followed by a dose of 3000 mg on Day 757 and once every eight weeks thereafter.

15. The method of any one of claims 1-8, wherein the anti-C5 antibody is administered to a patient weighing > 60 < 100 kg:

(a) 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; and (b) once on Day 743 at a dose of 900 mg, followed by a dose of 3300 mg on Day 757 and once every eight weeks thereafter.

16. The method of any one of claims 1-8, wherein the anti-C5 antibody is administered to a patient weighing > 100 kg:

(a) 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; and

(b) once on Day 743 at a dose of 900 mg, followed by a dose of 3600 mg on Day 757 and once every eight weeks thereafter.

17. 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.

18. 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.

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

20. The method of any one of the preceding claims, wherein the patient has previously been treated or is concurrently being treated with a renin-angiotensin system inhibitor (RASI), Sodiumglucose cotransporter-2 inhibitor (SGLT2I), DEARA (e.g., sparsentan), endothelin receptor antagonist (ERA), or mineralocorticoid receptor antagonist (MRA).

21. 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 of soluble C5b-9 (sC5b-9), Factor Ba, C4d, CD68, CD88, CD163, Gd-IgAl, kidney injury molecule- 1 (KIM-1), and creatinine.

22. 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 106.

23. 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 106 weeks.

24. The method of any one of the preceding claims, wherein the patient has an estimated glomerular filtration rate of: (a) eGFR > 20 mL/min/1.73 m2; (b) eGFR > 30 mL/min/1.73 m2; or (c) eGFR 20 to 29 mL/min/1.73 m2.

25. The method of any one of claims 1-23, wherein the patient has an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73m2 prior to treatment.

26. The method of any one of the preceding claims, wherein the patient has a urine protein to creatinine ratio (UPCR) of > 0.75 g/g prior to treatment.

27. The method of any one of the preceding claims, wherein proteinuria is a urine protein to creatinine ratio (UPCR) > 1 g/g from one 24-hr urine collection.

28. The method of claim 27, wherein proteinuria is a mean protein > 1 g/24-hr from 2 valid 24-hr collections.

29. The method of claim 28, wherein proteinuria is measured by a complete 24-hour urine collection.

30. The method of any one of the preceding claims, wherein the treatment results in a reduction in proteinuria compared to baseline.

31. The method of claim 30, wherein there is a 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% reduction in proteinuria after treatment compared to baseline.

32. The method of any one of the preceding claims, wherein the treatment results in a reduction in 24-hour UPCR > 30%, e.g., a reduction in 24-hour UPCR > 50% from baseline.

33. The method of any one of the preceding claims, wherein the treatment results in Partial Remission (PR).

34. The method of claim 33, wherein PR comprises mean proteinuria < 1 g/24-hours based on 2 valid 24-hour urine collections.

35. 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.

36. 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 European Quality of Life Health 5-item questionnaire dimensions 5 level (EQ-5D-5L).

37. 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 Functional Assessment of Chronic Therapy (FACIT)-Fatigue score.

38. 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 The Patient Global Impression of Severity (PGI-S) questionnaire.

39. 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 The Patient Global Impression of Change (PGI-C) Questionnaire.

40. 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 The Work Productivity and Activity Impairment Questionnaire.

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

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

43. The method of any one of the preceding claims, wherein the human patient is an adult patient, specifically wherein the patient is human adult patient with immunoglobulin A nephropathy (IgAN) with advanced kidney disease (AdKD).

44. A kit for treating immunoglobulin A nephropathy (IgAN) in a human 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.

45. 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:

46. The anti-C5 antibody, or antigen binding fragment thereof of claim 45, further comprising administration:

47. The antibody of claim 45 or 46, wherein the antibody is determined to be safe, tolerable, efficacious and sufficiently non-immunogenic after multiple IV doses in human patients.