Dosage and administration of Anti-c5 antibodies for treating delayed graft function (DGF)

Abstract

Provided herein are dosages and methods for treating a human kidney transplant recipient, as well as methods for reducing the severity of delayed graft function (DGF) in a human kidney transplant recipient, by administering to the recipient an anti-C5 antibody, or antigen binding fragment thereof (e.g., such as ravulizumab (ULTOMIRIS) prior to transplantation.

Description

[0001] AXJ-313PC ALXN-1002-PCT01-NP

[0002] DOSAGE AND ADMINISTRATION OF ANTI-C5 ANTIBODIES FOR TREATING DELAYED GRAFT FUNCTION (DGF)

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 748,540, filed January 23. 2025, all of which is herein incorporated by reference in its entirety.

[0005] DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0006] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: AXJ-313PC_SL.xml, date recorded January 20, 2026, file size 49.551 bytes).

[0007] BACKGROUND

[0008] Delayed graft function (DGF) is commonly defined as an acute kidney injury (AKI) that occurs in the first 7 days after transplantation and requires a dialysis treatment (see, e.g., Ponticelli C, et al., J. Pers. Med. 2022; 12(10)). This definition of DGF is shared by the Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS) (see, e.g., Cavaille-Coll M, etal.,Am. J. Transplant. 2013;13(5): 1134-1148). Most often, DGF results from ischemia reperfusion injury (IRI), a complex pathological process that is a consequence of organ donor characteristics, procurement / preservation and surgical procedures, recipient factors, and progresses during organ procurement, transport, storage, implantation, and reperfusion (see, e.g., Cavaille-Coll M, et al., 2013).

[0009] Although most kidneys with DGF regain function over time, DGF has deleterious and life threatening short- and long-term consequences. In the short term, DGF adds to the complexity of patient care and places a higher burden on the patient as additional evaluations and procedures may be required, including, but not limited to, dialysis, diagnostic tests, minor surgical procedures including biopsies, treatment of complications, and immunosuppressive drug monitoring. DGF has been associated with significantly higher odds of an acute rejection episode compared with patients who did not experience DGF and. in the long-term, poorer kidney function, decreased graft survival, and decreased quality of life (see, e.g., Li MT, et al., Transplant Direct. 2023;9(2):el433, Wu WK, et al., Kidney Int. 2015;88(4):851-858, Coemans M, Siisal C, et al., Kidney Int. 2018;94(5):964-973, Incerti D, et al.. Transplant Recipients in theAXJ-313PC ALXN-1002-PCT01-NP United States. MDM Policy Pract. 2018;3(1):2381468318781811 ; and Lopez-Hoyos M, et al., Hum. Immunol. 2005;66(4):371-377).

[0010] Currently, there are no approved therapies for the prevention of DGF or the reduction in its severity after kidney transplantation. Preventive measures consist of donor management and organ preservation solutions. The current management strategy for DGF is supportive care with dialysis and monitoring for rejection with serial biopsies (see, e.g., Lim MA, Bloom RD., Clin. J. Am. Soc. Nephrol. 2020; 15(1): 13-15). Accordingly, it is an object of the present disclosure to provide methods for treating a human kidney transplant recipient, as well as methods for reducing the severity of DGF in a human kidney transplant recipient.

[0011] SUMMARY

[0012] Provided herein are compositions and methods for treating a human kidney transplant recipient, as well as methods for reducing the severity of delayed graft function (DGF) in a human kidney transplant recipient, comprising administering to the recipient an anti-C5 antibody, or antigen binding fragment thereof, prior to transplantation, 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).

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

[0014] In one embodiment, 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.AXJ-313PC ALXN-1002-PCT01-NP In another embodiment, the antibody comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each according to the EU numbering convention.

[0015] 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.

[0016] 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.

[0017] 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

[0018] 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).

[0019] 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 an affinity dissociationAXJ-313PC ALXN-1002-PCT01-NP 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.

[0020] In one embodiment, the dose of the anti-C5 antibody, or antigen binding fragment thereof, is based on the weight of the human kidney transplant recipient. In one embodiment, for example, 2700 mg, 3000 mg, 3300 mg, or 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a recipient. In one embodiment, 2700 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to the recipient (e.g., a recipient weighing > 30 to < 40 kg). In one embodiment, 3000 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a recipient (e.g., a recipient weighing > 40 to < 60 kg). In one embodiment, 3300 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a recipient e.g., a recipient weighing > 60 to < 100 kg). In one embodiment, 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a recipient (e.g., a recipient weighing > 100 kg).

[0021] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 2700 mg to a recipient weighing > 30 to < 40 kg.

[0022] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3000 mg to a recipient weighing > 40 to < 60 kg.

[0023] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3300 mg to a recipient weighing > 60 to < 100 kg.

[0024] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3600 to a recipient weighing > 100 kg.

[0025] In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).

[0026] In one aspect a method of reducing the severity of delayed graft function (DGF) in a human kidney transplant recipient is provided, the method comprising administering to the recipient 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,AXJ-313PC ALXN-1002-PCT01-NP CDR2 and CDR3 light chain sequences as set forth in SEQ ID N0s:4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen binding fragment thereof, is administered to the recipient prior to transplantation at a dose of:

[0027] (a) 2700 mg to a recipient weighing > 30 to < 40 kg;

[0028] (b) 3000 mg to a recipient weighing > 40 to < 60 kg;

[0029] (c) 3300 mg to a recipient weighing > 60 to < 100 kg; or

[0030] (d) 3600 to a recipient weighing > 100 kg.

[0031] In another aspect, a method of treating a human kidney transplant recipient is provided, the method comprising administering to the recipient 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 to the recipient prior to transplantation at a dose of:

[0032] (a) 2700 mg to a recipient weighing > 30 to < 40 kg;

[0033] (b) 3000 mg to a recipient weighing > 40 to < 60 kg;

[0034] (c) 3300 mg to a recipient weighing > 60 to < 100 kg; or

[0035] (d) 3600 to a recipient weighing > 100 kg.

[0036] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered intravenously to the recipient prior to transplantation (e.g., via intravenous infusion). In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered intravenously to the recipient 24 hours or less prior to the start of transplantation (e.g., 1, 2, 3, 4. 5, 6, 7. 8, 9, 10. 11. 12. 13. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours prior to the start of transplantation). In one embodiment, the intravenous administration of the anti-C5 antibody, or antigen binding fragment thereof, to the recipient is complete at least 30 minutes before the start of transplantation (e.g., at least 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3, hours, 4, hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12, hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before the start of transplantation.

[0037] In one embodiment, dialysis is performed between administration of the anti-C5 antibody, or antigen binding fragment thereof, to the recipient and before the start ofAXJ-313PC ALXN-1002-PCT01-NP transplantation. Tn one embodiment, dialysis is initiated no earlier than 60 minutes after administration of the anti-C5 antibody, or antigen binding fragment thereof, to the recipient.

[0038] The methods described herein reduce the severity of DGF in a human kidney transplant recipient. In one embodiment, the recipient receives a kidney from a donor through donation after circulatory death (DCD). In one embodiment, the recipient receives a kidney from a donor through donation after brain death (DBD). In one embodiment, the recipient has dialysisdependent end-stage kidney disease (ESKD) prior to transplant. In one embodiment, the recipient is an adult recipient.

[0039] In one embodiment, the start of transplant (also referred to as transplantation) is the time of the first skin incision. In one embodiment, post-transplant refers to the time of skin closure or the last stitch.

[0040] The severity of DGF in a human kidney transplant recipient post-transplant can be assessed by any art-recognized method. In one embodiment, freedom from dialysis posttransplant is indicative of a reduction in severity of DGF. In one embodiment, freedom from dialysis at least 1 week, 2 weeks, 3, weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or one-year post-transplant is indicative of a reduction in severity of DGF.

[0041] In one embodiment a decrease in number of dialysis sessions for the recipient posttransplant compared to number of dialysis sessions for the recipient prior to transplant is indicative of a reduction in severity of DGF. In one embodiment, a decrease in number of dialysis sessions for the recipient post-transplant at 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 9 months, or one-year post-transplant compared to number of dialysis sessions for the recipient prior to transplant is indicative of a reduction in severity of DGF.

[0042] In one embodiment, a reduction in severity of DGF is achieved when the recipient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2 in the absence of dialysis posttransplant. In one embodiment, a reduction in severity of DGF is achieved when the recipient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2 in the absence of dialysis at 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 9 months, or one-year posttransplant.

[0043] In one embodiment, a reduction in severity of DGF is assessed by rejection-free graft survival post-transplant. In one embodiment, the recipient maintains rejection-free graft survivalAXJ-313PC ALXN-1002-PCT01-NP through 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 9 months, or one-year posttransplant.

[0044] In one embodiment, the methods 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 method 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.

[0045] 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 method maintains a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of 100 pg / mL or greater, 150 pg / mL or greater, 200 pg / mL or greater, 250 pg / mL or greater, or 300 pg / mL or greater. In another embodiment, the method 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 method maintains a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of about 175 pg / mL.

[0046] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered to the recipient 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 recipient’s blood. In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to the recipient in an amount and with a frequency to maintain between 50 pg and 250 pg of antibody, or antigen binding fragment thereof, per milliliter of the recipient’s blood. In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to the recipient in an amount and with a frequency to maintain between 100 pg and 200 pg of antibody, or antigen binding fragment thereof, per milliliter of the recipient’s blood. In another embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered to the recipient in an amount and with a frequency to maintain about 175 pg of antibody, or antigen binding fragment thereof, per milliliter of the recipient’s blood.AXJ-313PC ALXN-1002-PCT01-NP In another embodiment, to obtain an effective response, the anti-C5 antibody, or antigen binding fragment thereof, is administered to the recipient in an amount and with a frequency to maintain a minimum free C5 concentration. In one embodiment, for example, the anti-C5, or antigen binding fragment thereof, antibody is administered to the recipient 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,

[0047] 0.3 pg / mL, 0.2 pg / mL, or 0.1 pg / mL or less).

[0048] The anti-C5 antibodies, or antigen binding fragments thereof, can be administered to a recipient by any suitable means. In one embodiment. anti-C5 antibody, or antigen binding fragment thereof, is administered intravenously (e.g., via intravenous infusion).

[0049] In one embodiment, the recipient has previously been treated or is concurrently being treated with another therapeutic agent. For example, in one embodiment, the recipient has previously been treated or is concurrently being treated with induction immunosuppression (e.g., anti-thymocyte globulin). In one embodiment, the recipient has previously been treated or is concurrently being treated with maintenance immunosuppression (e.g., a calcineurin inhibitor (tacrolimus), an antimetabolite (e.g.., Mycophenolate mofetil or Mycophenolate sodium), and / or a corticosteroid (e.g., prednisone or prednisone equivalent).

[0050] In one embodiment, the methods described herein result in a change in the recipient from baseline as assessed by EuroQoL-5 Dimension-5 Levels (EQ-5D-5L) compared to 7, 14, 30, 90, 180, and 360 days post-transplant. In one embodiment, the methods result in a change in the recipient from baseline as assessed by “36-item Short Form Survey” (SF-36) compared to 7, 14, 30, 90, 180, and 360 days post-transplant. In one embodiment, the methods result in a change in the recipient from baseline as assessed by “Kidney Transplant Questionnaire - 25-items” (KTQ-25) compared to 7, 14, 30, 90, 180, and 360 days post-transplant.

[0051] In one embodiment, the methods described herein result in a shift towards normal levels of one or more biomarkers. In one embodiment, the biomarker is soluble C5b-9 (sC5b-9). In one embodiment, the biomarker is neutrophil gelatinase-associated lipocalin (NGAL). In one embodiment, the biomarker is interleukin- 18 (IL- 18).

[0052] In one embodiment, the methods described herein result in an improvement in estimated glomerular filtration rate (eGFR) in the recipient post-transplant compared to baseline over time. For example, the methods described herein result in an improvement from baseline in eGFR at 1AXJ-313PC ALXN-1002-PCT01-NP week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 9 months, or one-year post-transplant compared to baseline.

[0053] In one embodiment, the methods described herein further comprise administering a supplemental dose of the antibody when plasmapheresis and / or plasma exchange (PP / PE) is administered to the recipient as rescue therapy; particularly, wherein the recipient receives concomitant PP / PE rescue therapy within the first 5-day period post-transplant. In one embodiment, the supplemental dose of the anti-C5 antibody is started within 48 hours after a PP / PE session is completed; preferably wherein the supplemental dose of the anti-C5 antibody is administered based on the already administered scheduled single dose per Table 2. In one embodiment, the supplemental dose comprises administering a dose of 1100 mg of the anti-C5 antibody to a recipient who is > 30 to < 40 kg: 1500 mg of the anti-C5 antibody to a recipient who is > 40 to < 60 kg; 1800 mg of the anti-C5 antibody to a recipient who is > 60 to < 100 kg; and 1800 mg of the anti-C5 antibody to a recipient who is > 100 kg.

[0054] Further provided are kits that include a pharmaceutical composition containing an anti-C5 antibody, or antigen binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the methods described herein. In one aspect, provided herein is a kit for treating a human kidney transplant recipient, 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 instructions for using the anti-C5 antibody, or antigen binding fragment thereof, in any of the methods described herein.

[0055] In yet a further aspect, 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 is provided, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a human kidney transplant recipient prior to transplantation at a dose of: 2700 mg to a recipient weighing > 30 to < 40 kg; 3000 mg to a recipient weighing > 40 to < 60 kg; 3300 mg to a recipient weighing > 60 to < 100 kg; or 3600 to a recipient weighing > 100 kg. In one embodiment, the anti-C5 antibody, orAXJ-313PC ALXN-1002-PCT01-NP antigen binding fragment thereof, is determined to be safe, tolerable, efficacious and sufficiently non-immunogenic after multiple IV doses in human patients.

[0056] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic depicting the overall design of the clinical trial. Ravulizumab or placebo is given no earlier than 24 hours and at least 30 minutes before the start of transplant surgery. A) Ravulizumab weight-based dose: > 30 to < 40 kg = 2700 mg; > 40 to < 60 kg = 3000 mg; > 60 to < 100 kg = 3300 mg; > 100 kg = 3600 mg.

[0057] FIG. 2 sets forth the Schedule of Activities.

[0058] FIG. 3 sets forth the schedule of Pharmacokinetics / Pharmacodynamics (PK / PD), Immunogenicity, and Exploratory Assessments. Blood and Urine Sampling.

[0059] DETAILED DESCRIPTION

[0060] I. Definitions

[0061] As used herein, the term “subject” or “patient” is a human patient.

[0062] 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).

[0063] As used herein, “kidney transplant” refers to a surgery done to replace a diseased or injured kidney with a healthy kidney from a donor. The kidney may come from a deceased organ donor or from a living donor. In one embodiment, the start of transplant (also referred to as transplantation) is the time of the first skin incision. In one embodiment, post-transplant refers to the time of skin closure or the last stitch.

[0064] As used herein, the “The Kidney Donor Profile Index” (“KDPI”) is a numerical measure that combines ten donor factors, including clinical parameters and demographics, to summarize into a single number the quality of deceased donor kidneys relative to other recovered kidneys. The KDRI is an estimate of the relative risk of post-transplant kidney graft failure (in an average, adult recipient) from a particular deceased donor compared to a reference donor. The KDPI summarizes the risk of graft failure after transplantation, with higher scores indicating worse graftAXJ-313PC ALXN-1002-PCT01-NP survival (see, e.g., Rao PS, et al., Transplantation. 2009;88:231-236; and “Organ Procurement and Transplantation Network. A guide to calculating and interpreting the Kidney Donor Profile Index. Available at optn.transplant.hrsa.gov / media / j34dm4mv / kdpi_guide.pdf (updated October 10, 2024). Kidneys from donors with a KDPI >85% (high KDPI) are considered marginal and offer inferior long-term survival to kidneys from lower KDPI donors (see, e.g., Sampaio MS, Chopra B, Tang A, etal., Transpl. hit. 2018;31:729-738).

[0065] As used herein, “Delayed graft function” (“DGF”) following renal transplantation refers to the failure of the transplanted kidney to function immediately, necessitating renal replacement therapy (dialysis) within the first week post-transplant (see, e.g., Kurtis J., et. al., Transplantation Reviews, Volume 36, Issue 3, 2022, 100707, ISSN 0955-470X). While many definitions have been proposed, the former is the most common definition and the one used by the United Network of Organ Sharing (UNOS). DGF is one of the most frequent early complications following kidney transplantation (see, e.g., Sweet AL, et al., Prog. Transplant. 2023; 33(4): 1-19. Epub 2023 Nov 14. PMID: 37964564). The main signs of DGF are little or no urine and high creatinine levels in blood tests, post-transplant.

[0066] 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.

[0067] 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.

[0068] An effective amount can be administered in one or more administrations.

[0069] 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.

[0070] The term “antibody” describes a polypeptide comprising at least one antib ody-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 bispecificAXJ-313PC ALXN-1002-PCT01-NP antibody or a chimeric antibody. The antibody also can be a Fab, Fab’2, ScFv, SMIP, Affibody®, nanobody or a single-domain antibody. The antibody also can be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgAsec, IgD, IgE or combinations thereof. The antibody can be a naturally occurring antibody or an antibody that has been altered by a protein engineering technique (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). An antibody can include, for example, one or more variant amino acids (compared to a naturally occurring antibody) that change a property (e.g., a functional property) of the antibody. Numerous such alterations are known in the art that affect, e.g., half-life, effector function, and / or immune responses to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that comprise at least one

[0071] antibody-derived antigen binding site.

[0072] II. Anti-C5 Antibodies

[0073] 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.

[0074] Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the methods described herein can be generated using methods known in the art. Alternatively, art recognized anti-C5 antibodies can be used. Antibodies that compete for binding to C5 with any of these art recognized antibodies or antibodies described herein can also be used.

[0075] 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.AXJ-313PC ALXN-1002-PCT01-NP 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.

[0076] 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.

[0077] 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.

[0078] 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 orAXJ-313PC ALXN-1002-PCT01-NP heavy chain variable region are as defined by Chothia et al. (Nature, 342:877-83, 1989).

[0079] 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. etal. (Mol. Immunol., 33:1389-401, 1996) exemplifies the identification of CDR boundaries according to Kabat and Chothia numbering schemes.

[0080] 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.

[0081] Another exemplary anti-C5 antibody is the 8110 antibody also described in US Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody, or antigen binding fragment thereof, comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:32, 33 and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO:35, and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO:36.

[0082] Another exemplary anti-C5 antibody is the 305LO5 antibody described in US Patent No.

[0083] 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 andAXJ-313PC ALXN-1002-PCT01-NP 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.

[0084] Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. el al., Sci. Rep., 7:1080, 2017). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody, or antigen binding fragment thereof, comprises a heavy chain comprising SEQ ID NO:45 and a light chain comprising SEQ ID NO:46.

[0085] 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.

[0086] 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:

[0087] 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:

[0088] QVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA PGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED TAVYYCARYF FGSSPNWYFD VWGQGTLVTV SS (SEQ ID NO: 12).

[0089] In some embodiments, an anti-C5 antibody described herein comprises a light chain variable region comprising the following amino acid sequence:

[0090] DIQMTQSPSS LSASVGDRVT ITCGASENIY GALNWYQQKP GKAPKLLIYG ATNLADGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQN VLNTPLTFGQ GTKVEIK (SEQ ID NO:8).AXJ-313PC ALXN-1002-PCT01-NP 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.

[0091] Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining pH dependence of the interaction) are known in the art and exemplified in the working examples. See, e.g., WO2015134894 and US Patent No.9,079949 the disclosures of each of which are incorporated herein by reference in their entirety.

[0092] Substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn are known in the art and include, e.g., (1) the M252Y / S254T / T256E triple substitution (Dall’Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) the M428L or T250Q / M428L substitutions (Hinton, P. et al., J. Biol. Chem.. 279:6213-6. 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) the N434A or T307 / E380A / N434A substitutions (Petkova, S. et al., Int. Immunol., 18:1759-69, 2006). The additional substitution pairings: P257VQ311I, P257I / N434H and D376V / N434H (Datta-Mannan, A. etal., J. Biol. Chem., 282:1709-17, 2007), the disclosures of each of which are incorporated herein by reference in their entirety.

[0093] In some embodiments, the variant constant region has a substitution at EU amino acid position 255 for valine. In some embodiments, the variant constant region has a substitution at EU amino acid position 309 for asparagine. In some embodiments, the variant constant region has a substitution at EU amino acid position 312 for isoleucine. In some embodiments, the variant constant region has a substitution at EU amino acid position 386.

[0094] 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,AXJ-313PC ALXN-1002-PCT01-NP 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.

[0095] 8,088,376.

[0096] 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 435 S 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.

[0097] 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 arginineAXJ-313PC ALXN-1002-PCT01-NP 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.

[0098] 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.

[0099] 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.

[0100] 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,AXJ-313PC ALXN-1002-PCT01-NP 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).

[0101] Methods for determining whether an antibody binds to a protein antigen and / or the affinity for an antibody to a protein antigen are known in the art. The binding of an antibody to a protein antigen, for example, can be detected and / or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), or enzyme-linked immunosorbent assay (ELISA; Benny K. C. Lo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160:191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Jonsson, U. et l., 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.

[0102] As used herein, the term “ka” 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 = kakd. 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.

[0103] 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

[0104] pro-inflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) at the surface of a cell are inhibited.

[0105] 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 andAXJ-313PC ALXN-1002-PCT01-NP Mayer (eds.), “Experimental Immunochemistry, 2ndEdition,” 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 are known in the art (Evans, M. et al., Mol. Immunol., 32:1183-95, 1995). The concentration and / or physiologic activity of C5a and C5b in a body fluid can be measured, for example, by methods known in the art. For C5b, hemolytic assays or assays for soluble C5b-9 as discussed herein can be used. Other assays known in the art can also be used. Using assays of these or other suitable types, candidate agents capable of inhibiting human complement component C5 can be screened.

[0106] 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.

[0107] 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

[0108] pathway-mediated hemolysis in a serum test solution In vitro, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with anti-chicken erythrocyte antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, for example, as utilized in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody, or antigen binding fragment thereof, in the presence of a human IgM antibody. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the absorbance at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody, or antigen binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with a C5 polypeptide.AXJ-313PC ALXN-1002-PCT01-NP To determine the effect of an anti-C5 antibody, or antigen binding fragment thereof, on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes can be used as the target cells. In some embodiments, the serum test solution is a C5-deficient serum reconstituted with a C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, for example, as utilized in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody, or antigen binding fragment thereof, in the presence of lipopolysaccharide. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the fluorescence at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody, or antigen binding fragment thereof.

[0109] 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.

[0110] Briefly, to activate the classical complement pathway, undiluted serum samples (e.g., reconstituted human serum samples) are added to microassay wells containing the

[0111] antibody-sensitized erythrocytes to thereby generate TCC. Next, the activated sera are diluted in microassay wells, which are coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC). The TCC present in the activated samples bind to the monoclonal antibodies coating the surface of the microassay wells. The wells are washed and to each well is added a detection reagent that is detectably labeled and recognizes the bound TCC. The detectable label can be, e.g., a fluorescent label or an enzymatic label. The assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).AXJ-313PC ALXN-1002-PCT01-NP Inhibition, e.g., as it pertains to terminal complement activity, includes at least a 5 (e.g., at least a 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60) % decrease in the activity of terminal complement in, e.g., a hemolytic assay or CH50eq assay as compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at an equimolar concentration. Substantial inhibition, as used herein, refers to inhibition of a given activity (e.g., terminal complement activity) of at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 or greater) %. In some embodiments, an anti-C5 antibody described herein contains one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs:l-6), yet retains at least 30 (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95) % of the complement inhibitory activity of eculizumab in a hemolytic assay or CH50eq assay.

[0112] 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).

[0113] In one embodiment, the antibody competes for binding with, and / or binds to the same epitope on C5 as an antibody described herein. The term “binds to the same epitope” with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether antibodies bind to the same epitope on C5 with an antibody described herein include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigemantibody complexes, and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor theAXJ-313PC ALXN-1002-PCT01-NP 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.

[0114] 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).

[0115] 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.

[0116] 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.

[0117] 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. el al., Science, 246:1275-81, 1989).AXJ-313PC ALXN-1002-PCT01-NP In some embodiments, the anti-C5 antibody does not comprise eculizumab (SOLTRIS®) 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).

[0118] In some embodiments, 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 is provided, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a human kidney transplant recipient prior to transplantation at a dose of: 2700 mg to a recipient weighing > 30 to < 40 kg; 3000 mg to a recipient weighing > 40 to < 60 kg; 3300 mg to a recipient weighing > 60 to < 100 kg; or 3600 to a recipient weighing > 100 kg. In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is determined to be safe, tolerable, efficacious and sufficiently non-immunogenic after multiple IV doses in human patients.

[0119] III. Methods

[0120] Provided herein are methods for treating a human kidney transplant recipient, as well as methods for reducing the severity of delayed graft function (DGF) in a human kidney transplant recipient, comprising administering to the recipient an anti-C5 antibody, or antigen binding fragment thereof, prior to transplantation, 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).

[0121] In one embodiment, the dose of the anti-C5 antibody, or antigen binding fragment thereof, is based on the weight of the human kidney transplant recipient. In one embodiment, for example, 2700 mg, 3000 mg, 3300 mg, or 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a recipient. In one embodiment, 2700 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to the recipient (e.g., a recipient weighing > 30 to < 40 kg). In one embodiment, 3000 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a recipient (e.g., a recipient weighing > 40 to < 60 kg). In one embodiment, 3300 mg of the anti-C5 antibody, or antigen binding fragmentAXJ-313PC ALXN-1002-PCT01-NP thereof, is administered to a recipient (e.g., a recipient weighing > 60 to < 100 kg). In one embodiment, 3600 mg of the anti-C5 antibody, or antigen binding fragment thereof, is administered to a recipient (e.g., a recipient weighing > 100 kg).

[0122] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 2700 mg to a recipient weighing > 30 to < 40 kg.

[0123] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3000 mg to a recipient weighing > 40 to < 60 kg.

[0124] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3300 mg to a recipient weighing > 60 to < 100 kg.

[0125] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3600 to a recipient weighing > 100 kg.

[0126] In certain embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).

[0127] The anti-C5 antibodies, or antigen binding fragments thereof, can be administered to recipient by any suitable means. In one embodiment, anti C5 antibody, or antigen binding fragment thereof, is administered intravenously (e.g., via intravenous infusion).

[0128] In one aspect a method of reducing the severity of delayed graft function (DGF) in a human kidney transplant recipient is provided, the method comprising administering to the recipient 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 to the recipient prior to transplantation at a dose of:

[0129] (a) 2700 mg to a recipient weighing > 30 to < 40 kg;

[0130] (b) 3000 mg to a recipient weighing > 40 to < 60 kg;

[0131] (c) 3300 mg to a recipient weighing > 60 to < 100 kg; or

[0132] (d) 3600 to a recipient weighing > 100 kg.

[0133] In another aspect, a method of treating a human kidney transplant recipient is provided, the method comprising administering to the recipient 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 asAXJ-313PC ALXN-1002-PCT01-NP set forth in SEQ ID N0s:4, 5 and 6, respectively, wherein the anti-C5 antibody or antigen binding fragment thereof, is administered to the recipient prior to transplantation at a dose of:

[0134] (a) 2700 mg to a recipient weighing > 30 to < 40 kg;

[0135] (b) 3000 mg to a recipient weighing > 40 to < 60 kg;

[0136] (c) 3300 mg to a recipient weighing > 60 to < 100 kg; or

[0137] (d) 3600 to a recipient weighing > 100 kg.

[0138] In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered intravenously to the recipient prior to transplantation (e.g., via intravenous infusion). In one embodiment, the anti-C5 antibody, or antigen binding fragment thereof, is administered intravenously to the recipient 24 hours or less prior to the start of transplantation (e.g., 1, 2, 3, 4. 5, 6, 7, 8, 9, 10, 11. 12. 13. 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours prior to the start of transplantation). In one embodiment, the intravenous administration of the anti-C5 antibody, or antigen binding fragment thereof, to the recipient is complete at least 30 minutes before the start of transplantation (e.g., at least 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3, hours, 4, hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12, hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before the start of transplantation.

[0139] In certain embodiments, the methods described herein further include administering a supplemental dose of an antibody, such as an anti-C5 antibody, to a recipient when plasmapheresis and / or plasma exchange (PP / PE) is administered as rescue therapy. In particular embodiments, the recipient receives concomitant PP / PE rescue therapy within the first five-day period following transplantation, and a supplemental dose of the antibody is administered to compensate for antibody removal associated with PP / PE.

[0140] In some embodiments, the supplemental dose of the anti-C5 antibody is initiated within 48 hours after completion of a PP / PE session. In particular embodiments, the amount of the supplemental dose is determined based on an already administered scheduled single dose, for example, a scheduled dose as set forth in Table 2, such that therapeutic antibody exposure is maintained despite PP / PE treatment.

[0141] In further embodiments, the supplemental dose comprises administering a weight-based amount of the anti-C5 antibody. By way of non-limiting example, the supplemental dose may comprise administering about 1100 mg of the anti-C5 antibody to a recipient weighing at least 30AXJ-313PC ALXN-1002-PCT01-NP kg and less than 40 kg; about 1500 mg to a recipient weighing at least 40 kg and less than 60 kg; about 1800 mg to a recipient weighing at least 60 kg and less than 100 kg; and about 1800 mg to a recipient weighing at least 100 kg. Such dosing regimens may be used to restore or maintain effective circulating levels of the anti-C5 antibody following PP / PE rescue therapy.

[0142] In one embodiment, dialysis is performed between administration of the anti-C5 antibody, or antigen binding fragment thereof, to the recipient and before the start of transplantation. In one embodiment, dialysis is initiated no earlier than 60 minutes after administration of the anti-C5 antibody, or antigen binding fragment thereof, to the recipient.

[0143] The methods described herein reduce the severity of DGF in a human kidney transplant recipient. In one embodiment, the recipient receives a kidney from a donor through donation after circulatory death (DCD). In one embodiment, the recipient receives a kidney from a donor through donation after brain death (DBD). In one embodiment, the recipient has dialysisdependent end-stage kidney disease (ESKD) prior to transplant. In one embodiment, the recipient is an adult recipient.

[0144] The severity of DGF in a human kidney transplant recipient post-transplant can be assessed by any art-recognized method. In one embodiment, freedom from dialysis posttransplant is indicative of a reduction in severity of DGF. In one embodiment, freedom from dialysis at least 1 week, 2 weeks, 3, weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or one-year post-transplant is indicative of a reduction in severity of DGF.

[0145] In one embodiment a decrease in number of dialysis sessions for the recipient posttransplant compared to number of dialysis sessions for the recipient prior to transplant is indicative of a reduction in severity of DGF. In one embodiment, a decrease in number of dialysis sessions for the recipient post-transplant at 1 week, 2 weeks, 3 weeks, 1 month, 2 months. 3 months, 9 months, or one-year post-transplant compared to number of dialysis sessions for the recipient prior to transplant is indicative of a reduction in severity of DGF.

[0146] In one embodiment, a reduction in severity of DGF is achieved when the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2 in the absence of dialysis posttransplant. In one embodiment, a reduction in severity of DGF is achieved when the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2 in the absence of dialysis at 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months. 9 months, or one-year post-transplant.AXJ-313PC ALXN-1002-PCT01-NP In one embodiment, a reduction in severity of DGF is assessed by rejection -free graft survival post-transplant. In one embodiment, the patient maintains rejection-free graft survival through 1 week, 2 weeks, 3 weeks, 2 months, 3 months, 9 months, or one-year post-transplant.

[0147] IV. Optional Background Therapies

[0148] In one embodiment, the recipient has previously been treated or is concurrently being treated with another therapeutic agent. For example, in one embodiment, the recipient has previously been treated or is concurrently being treated with induction immunosuppression {e.g., anti- thymocyte globulin). In one embodiment, the recipient has previously been treated or is concurrently being treated with maintenance immunosuppression {e.g., a calcineurin inhibitor (tacrolimus), an antimetabolite {e.g.., Mycophenolate mofetil or Mycophenolate sodium), and / or a corticosteroid {e.g., prednisone or prednisone equivalent).

[0149] V. Outcomes

[0150] In one embodiment, the methods 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 method 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 method maintains a serum trough concentration of the anti C5 antibody, or antigen binding fragment thereof, of 100 pg / mL or greater, 150 pg / mL or greater, 200 pg / mL or greater, 250 pg / mL or greater, or 300 pg / mL or greater. In another embodiment, the method 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 method maintains a serum trough concentration of the anti C5 antibody, or antigen binding fragment thereof, of about 175 pg / mL.

[0151] In another embodiment, to obtain an effective response, the anti C5 antibody is administered to the recipient 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,AXJ-313PC ALXN-1002-PCT01-NP 240 g, 245 pg, 250 pg, 255 pg or 260 pg of antibody per milliliter of the recipient’s blood. In another embodiment, the anti C5 antibody, or antigen binding fragment thereof, is administered to the recipient in an amount and with a frequency to maintain between 50 pg and 250 pg of antibody, or antigen binding fragment thereof, per milliliter of the recipient’s blood. In another embodiment, the anti C5 antibody, or antigen binding fragment thereof, is administered to the recipient in an amount and with a frequency to maintain between 100 pg and 200 pg of antibody, or antigen binding fragment thereof, per milliliter of the recipient’s blood. In another embodiment, the anti C5 antibody, or antigen binding fragment thereof, is administered to the recipient in an amount and with a frequency to maintain about 175 pg of antibody, or antigen binding fragment thereof, per milliliter of the recipient’s blood.

[0152] In another embodiment, to obtain an effective response, the anti C5 antibody, or antigen binding fragment thereof, is administered to the recipient in an amount and with a frequency to maintain a minimum free C5 concentration. In one embodiment, for example, the anti C5, or antigen binding fragment thereof, antibody is administered to the recipient 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).

[0153] In one embodiment, the methods described herein result in a change in the recipient from baseline as assessed by EuroQoL-5 Dimension-5 Levels (EQ-5D-5L) compared to 7, 14, 30, 90, 180, and 360 days post-transplant. In one embodiment, the methods result in a change in the recipient from baseline as assessed by “36-item Short Form Survey” (SF-36) compared to 7, 14, 30, 90, 180, and 360 days post-transplant. In one embodiment, the methods result in a change in the recipient from baseline as assessed by “Kidney Transplant Questionnaire - 25-items” (KTQ-25) compared to 7, 14, 30, 90, 180, and 360 days post-transplant.

[0154] In one embodiment, the methods described herein result in a shift towards normal levels of one or more biomarkers. In one embodiment, the biomarker is soluble C5b-9 (sC5b-9). In one embodiment, the biomarker is neutrophil gelatinase-associated lipocalin (NGAL). In one embodiment, the biomarker is interleukin- 18 (IL- 18).

[0155] In one embodiment, the methods described herein result in an improvement in estimated glomerular filtration rate (eGFR) in the recipient post-transplant compared to baseline over time. For example, the methods described herein result in an improvement from baseline in eGFR at 1AXJ-313PC ALXN-1002-PCT01-NP week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 9 months, or one-year post-transplant compared to baseline.

[0156] VI. Kits

[0157] 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 earner, in a therapeutically effective amount adapted for use in the methods described herein. 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 the recipient. The kit also can include a syringe.

[0158] 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.

[0159] In one embodiment, the kit includes a pharmaceutical composition containing an anti-C5 antibody, or antigen binding fragment thereof, such as ravulizumab, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the methods described herein. In one aspect, provided herein is a kit for treating a human kidney transplant recipient, 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 instructions for using the anti-C5 antibody, or antigen binding fragment thereof, in any of the methods described herein. In one embodiment, the anti-C5 antibody or antigen binding fragment thereof, is administered to the recipient prior to transplantation at a dose of: 2700 mg to a recipient weighing > 30 to < 40 kg; 3000 mg to a recipient weighing > 40 to < 60 kg; 3300 mg to a recipient weighing > 60 to < 100 kg; or 3600 to a recipient weighing > 100 kg.AXJ-313PC ALXN-1002-PCT01-NP The following example is merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0160] Example: Phase 3 Clinical Study

[0161] A Phase 3, double-blind, randomized, placebo-controlled, multicenter study is conducted to evaluate the efficacy and safety of Ravulizumab administered intravenously in adult participants at high risk of delayed graft function after kidney transplantation.

[0162] I. Objectives

[0163] The primary objective of the study is to assess the efficacy of ravulizumab versus placebo in reducing the severity of delayed graft function (DGF) as measured by time to freedom from dialysis in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney. Time to freedom from dialysis through 90 days post-transplant as defined as the time from the transplant procedure to the last day of the last dialysis session (inclusive) through 90 days post-transplant.

[0164] Key secondary objectives include: (1) assessing the effect of ravulizumab versus placebo on DGF incidence in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (DGF incidence: Requirement of at least 1 dialysis session within the first 7 days post-transplant), (2) assessing the effect of ravulizumab versus placebo on dialysis utilization in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (number of dialysis sessions through 90 days post- transplant), and (3) assessing graft function in renal transplant recipients treated with ravulizumab versus placebo in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (time to first occurrence of eGFR > 30 mL / min / 1.73 m2 through 90 days post-transplant). Key secondary efficacy endpoints are tested in a hierarchical approach (numbers included for rank order of analyses).

[0165] Another secondary objective includes assessing the effect of ravulizumab versus placebo on eGFR and dialysis requirement in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (e.g., eGFR level measured through allAXJ-313PC ALXN-1002-PCT01-NP scheduled timepoints post-transplant, achieving eGFR > 30 mL / min / 1.73 m2 in the absence of dialysis in the last 24 hours at all scheduled visits post-transplant, and requirement of dialysis treatment initiated beyond 7 days post-transplant through 90 days post-transplant).

[0166] A further secondary objective to assess the effect of ravulizumab versus placebo on graft survival, graft rejection, and mortality in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (e.g., graft rejection measured through 30, 90, 180, and 360 days post- transplant, rejection-free graft survival through 30, 90, 180, and 360 days post- transplant, and all-cause mortality measured through 30, 90, 180, and 360 days posttransplant). Graft rejection is defined based on Banff criteria and confirmed by biopsy performed at the discretion of the Investigator in line with local standard of care clinical practice (see Coemans M, Tran TH, Dohler B, Massie AB, Verbeke G, Segev DL, Gentry SE, Naesens M. A competing risks model to estimate the risk of graft failure and patient death after kidney transplantation using continuous donor-recipient age combinations. Am J Transplant. 2025 Feb:25(2):355-367. Graft loss is defined as irreversible loss of kidney function necessitating dialysis, allograft nephrectomy or retransplantation up to 1-year post-transplant surgery.

[0167] Another secondary objective is to assess the effect of ravulizumab versus placebo on kidney allograft dysfunction in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (e.g., incidence of slow graft function (SGF) (SGF is defined as sCr > 3 mg / dL at 5 days post-transplant and no need for dialysis within the first 5 days post-transplant); incidence of functional delayed graft function (fDGF) (fDGF is defined as failure of sCr to decrease from baseline by at least 10% daily on 3 consecutive days during the first 7 days post-transplant irrespective of dialysis), and incidence of primary nonfunction (PNF) (as assessed by the Investigator) at 90 days post-transplant. PNF is a condition in which kidney does not recover its function and the participant continues to require dialysis).

[0168] A safety objective is to characterize the overall safety and tolerability of ravulizumab vs placebo in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (e.g., via incidence of adverse events (AEs) and serious adverse events (SAEs) over time, and change from baseline in vital signs and laboratory assessments).

[0169] A further objective is to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ravulizumab in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (e.g., via (1) serum concentrations of ravulizumab over timeAXJ-313PC ALXN-1002-PCT01-NP through 360 days post-transplant, (2) absolute values, change from baseline and percent change from baseline in serum free C5 concentrations through 360 days post-transplant, and (3) absolute values, change from baseline and percent change from baseline in serum total C5 concentrations through 360 days post-transplant).

[0170] The immunogenicity objective is to assess immunogenicity to ravulizumab in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (e.g., via antidrug antibody (ADA) incidence, ADA response categories, and titer, as well as neutralizing antibody (Nab) incidence, for the duration of the study).

[0171] Exploratory objectives include: (1) assessing the effect of ravulizumab versus placebo on healthcare resource utilization in adult participants who are at increased risk of DGF after undergoing transplant of deceased donor kidney (e.g., via duration of index hospitalization stay, number of hospitalizations and duration of stay through 30, 90, 180, and 360 days posttransplant, rate of hospital readmission through 30, 90, 180, and 360 days post- transplant, and number of ICU admissions and ICU duration of stay through 30, 90, 180. and 360 days posttransplant), (2) evaluating the effect of ravulizumab versus placebo on quality of life (QoL) in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney (e.g., change from baseline in EQ-5D-5L measured at 7, 14, 30, 90, 180, and 360 days post-transplant, change from baseline in SF-36 v2 measured at 14, 30, 90, 180, and 360 days post-transplant, and change from baseline in KTQ-25 measured at 14, 30, 90, 180, and 360 days post-transplant), and (3) assessing biomarkers at baseline and change in response to treatment (e.g., assessment of biomarkers can include, but is not limited to, complement pathway activation (e.g., plasma, urine sC5b9), renal injury (e.g., urine NGAL), and immune inflammatory response (e.g., urine IL- 18).

[0172] An optional objective is to explore how genetic variations may affect clinical parameters, risk and prognosis of diseases, and the response to medications (e.g., exploratory endpoints are related to the data generated from the genetic analysis of part or all of the participant’s genetic information). The sample is taken from consented participants for DNA isolation and storage.

[0173] Primary Estimands

[0174] The primary clinical question of interest for the primary objective is: What is the treatment effect of ravulizumab compared with placebo in reducing the severity of DGF in adults who are at high risk of DGF after undergoing transplant of deceased donor kidney? The primaryAXJ-313PC ALXN-1002-PCT01-NP estimand is described by the following attributes: (1) Population: all adult participants who are at high risk of DGF after kidney transplant surgery; (2) Endpoint: Time to freedom from dialysis through 90-days post-transplant; (3) Treatment of interest: Randomized treatment (ravulizumab or placebo); (4) ICE handling: Composite strategy for graft loss and death; treatment policy for use of protocol prohibited therapy after study intervention is administered; and (5) Summary measure: hazard ratio between treatment groups.

[0175] Supplemental Estimands

[0176] The clinical question is the same as for the primary estimand. The supplementary estimand shares the same attributes for population, endpoint, and treatment of interest. The summary measure used is the difference in the restricted mean time to freedom from dialysis between treatment groups. The treatment effect is estimated as the difference in the restricted mean survival time (RMST) for time to freedom from dialysis through 90-day post-transplant between ravulizumab and placebo. The handling of ICEs and missing data from early discontinuation are the same as for the primary estimand.

[0177] Secondary Estimands

[0178] A. Analysis of DGF Incidence

[0179] The first key secondary clinical question of interest is: what is the treatment effect of ravulizumab compared with placebo in preventing DGF development in the targeted patient population after kidney transplant surgery? The secondary estimand is described by the following attributes: (1) Population: all adult participants who are at high risk of DGF after kidney transplant surgery; (2) Endpoint: DGF incidence, defined as the requirement of at least 1 dialysis session within the first 7 days post-transplant; (3) Treatment of interest: randomized treatment (ravulizumab or placebo); (4) ICE handling: composite strategy for graft loss and death; treatment policy for use of protocol prohibited therapy after study intervention is administered; (5) Summary measure: absolute difference in DGF incidence between treatment groups.

[0180] B. Analysis of Number of Dialysis Sessions

[0181] The second key secondary clinical question of interest is: what is the treatment effect of ravulizumab compared with placebo in reducing the total number of dialysis sessions through 90AXJ-313PC ALXN-1002-PCT01-NP days post-transplant in the target patient population? The secondary estimand is described by the following attributes: (1) Population: all adult participants who are at high risk of DGF after kidney transplant surgery; (2) Endpoint: Number of dialysis sessions through 90 days posttransplant. The derivation of the number of dialysis sessions is based on all dialyses that occur after transplant surgery through 90 days post-transplant, regardless of when the first dialysis occurs, or whether there is any period of > 10 consecutive days with no dialysis. Dialysis sessions that are ongoing at 90 days post-transplant is included; (3) Treatment of interest: randomized treatment (ravulizumab or placebo); (4) ICE handling: composite strategy for graft loss, death; treatment policy for use of protocol prohibited therapy after study intervention is administered; and (5) Summary measure: relative rate reduction.

[0182] C. Analysis for time to first occurrence of eGFR reaching 30 mL / min / 1.73 m2

[0183] The third key secondary clinical question of interest is: what is the treatment effect of ravulizumab compared with placebo in improving graft function in terms of time to the first occurrence of eGFR reaching 30 mL / min / 1.73 m2in the targeted patient population after kidney transplant surgery. The secondary estimand is described by the following attributes: (1) Population: all adult participants who are at high risk of DGF after kidney transplant surgery. (2) Endpoint: Time to first occurrence of eGFR > 30 / mL / min / 1.73 m2through 90 days posttransplant (assessed as the number of days between transplant and the date when eGFR reaches 30 mL / min / 1.73 m2for the first time. It is calculated as: the earliest date when eGFR > 30 mL / min / 1.73 m2- date of transplant + 1). (3) Treatment of interest: randomized treatment (ravulizumab or placebo). (4) ICE handling: composite strategy for graft loss, death and dialysis within 24 hours prior to eGFR assessment; treatment policy for use of protocol prohibited therapy after study intervention is administered. (5) Summary measure: hazard ratio between treatment groups.

[0184] 2. Overall Design Synopsis

[0185] This is a multicenter, prospective, double-blind, randomized, placebo-controlled study to assess the efficacy of a single dose of ravulizumab administered IV in reducing the severity of DGF in adult participants with dialysis-dependent ESK.D undergoing kidney transplant from DCD and DBD kidney donors. The study also assesses the safety and tolerability of ravulizumab in this population. The study population is adult participants with dialysis-dependent ESKDAXJ-313PC ALXN-1002-PCT01-NP undergoing kidney transplant from donation after circulatory death (DCD) and donation after brain death (DBD) kidney donors.

[0186] FIG. 1 provides a schematic of the overall study. Home visits (excluding home dialysis) are allowed after discharge, where available and in accordance with all national, state, and local laws or regulations of the pertinent regulatory authorities. Phone or telemedicine visits can occur in conjunction with home visits. A) Assessments on Visits 6 and 7 are performed if participant has not been discharged from the hospital. Assessments are performed on the discharge day if coinciding with a study visit day. B) Assessments done for Screening within 1 day prior to dosing (VI) do not need to be repeated at VI. C) Sample at ED only required if participant discontinues prior to Day 270. D) Body weight-based dosage regimen is based on the last recorded study visit body weight. This is commonly the current visit as body weight is measured prior to dose preparation on the day of the visit. If the study intervention is prepared before a visit, the body weight from the most recent prior study visit is used.

[0187] FIG. 2 set forth the Schedule of Activities. FIG. 3 shows the PK / PD, Immunogenicity, and Exploratory Assessments, Blood and Urine Sampling schedule. Within the schedule: A) Collection of additional PK / PD samples on all unscheduled visits where ADA sample is collected; and B) Urine samples are only required for participants producing urine.

[0188] The study consists of the following 3 study periods: (A) Screening Period: up to 7 days prior to transplant, (2) Primary Evaluation Period: From transplant to 90 days post-transplant, and (3) LTFU Period: From 91 days post-transplant to up to 360 days post-transplant.

[0189] The study enrolls and doses approximately 450 participants randomized in a 1:1 ratio to ravulizumab or placebo stratified by donor type (DCD or DBD). The proportion of DCD donor kidneys is capped to enroll approximately 20% of the total randomized population. “Enrolled” means participants’ agreement to participate in a clinical study following completion of the informed consent process excluding screen failures. Potential 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.

[0190] Consenting participants are screened for study eligibility up to 7 days prior to transplant surgery. Participants who satisfy the eligibility criteria are enrolled into the study.AXJ-313PC ALXN-1002-PCT01-NP Participants receive a single intravenous (IV) dose of weight-based ravulizumab or placebo prior to the transplant surgery. The IV infusion must be completed no earlier than 24 hours and at least 30 minutes before the start of transplant surgery (defined as the timing of first skin incision). In case of dialysis between study intervention infusion and transplant procedure, dialysis is initiated no earlier than 60 minutes after the infusion is complete.

[0191] During the Primary Evaluation and Long-term Follow-up Period, participants receive background therapy consistent with the standard of care for participants with kidney transplant and are monitored for safety, clinical events of interest, and kidney function.

[0192] Two non-binding interim analyses are planned. An interim analysis for futility is planned no later than when approximately 180 participants have completed the 90-day Primary Evaluation Period. The futility is assessed using the predictive probability of final study success. A second interim analysis is conducted when 338 participants have completed the 90-day Primary Evaluation Period, aiming to assess futility and efficacy for early stopping for regulatory submission.

[0193] 3. Inclusion Criteria

[0194] Participants (z.e.. transplant recipients) are eligible to participate in the study only if all of the following criteria apply:

[0195] 1. > 18 years of age at the time of signing the informed consent.

[0196] 2. Diagnosed with dialysis-dependent end-stage kidney disease (ESKD).

[0197] 3. A candidate for kidney transplant from 1 of the following:

[0198] a. Donation after circulatory death (DCD) donor;

[0199] b. Donation after brain death (DBD) donor with Kidney Donor Profile Index (KDPI) score of > 60% (by Organ Procurement and Transplantation Network “OPTN” calculator); or c. If OPTN calculator is not available, DBD donor fulfilling the following criteria: (A) 41 to 50 years of age with at least 2 of the following conditions: history of diabetes mellitus (DM), hypertension (HTN), or cerebrovascular accident (CVA) as cause of death, (B) 51 to 60 years of age with at least a history of one of the following conditions: DM or HTN, or CVA as cause of death, and (C) Any DBD donor > 60 years of age.

[0200] 4. Has undergone at least 1 year of dialysis (hemodialysis or peritoneal) treatment prior to enrollment.

[0201] 5. Body weight of > 30 kg.AXJ-313PC ALXN-1002-PCT01-NP 6. Male or female assigned at birth, inclusive of all gender identities.

[0202] 7. Agrees to follow protocol- specified contraception guidance.

[0203] 8. Provides signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and this protocol.

[0204] 9. Willing to be vaccinated against N. meningitidis and willing to receive prophylactic treatment with appropriate antibiotics, if needed.

[0205] 10. Willing to receive hemodialysis for the first 90 days post-transplant. Participants receiving peritoneal dialysis prior to transplant must be willing to switch to hemodialysis for the first 90 days post-transplant.

[0206] 11. Participants with a known history of past HBV or HCV infection or positive serology indicating inactive or past infection, provided the infection occurred > 3 months prior to screening.

[0207] Participants (i.e., transplant recipients) are excluded from the study if any of the following criteria apply:

[0208] 1. Is to receive a kidney from a donor after circulatory death (DCD) with the following Maastricht classification

[0209] (see, e.g., Sanchez-Fructuoso, et al., J. Am. Soc. Nephrol. 2000;ll(2):350-358):

[0210] a. Category I: Dead on arrival at hospital.

[0211] b. Category II: Unsuccessful resuscitation.

[0212] c. Category IV: Unexpected cardiac arrest after brain death.

[0213] d. Category V: Unexpected cardiac arrest in intensive care.

[0214] 2. Is to receive a kidney from a donor known of having had either of the following:

[0215] a. acute kidney injury (AKI) Kidney Disease Improving Global Outcomes (KDIGO) Stage 3 (defined as creatinine 3.0 times baseline OR increase in sCr to > 4.0 mg / dL [> 353.6 pmol / L])

[0216] b. Urine output < 0.3 mL / kg / hour for > 24 hours OR anuria for > 12 hours) 3. Recent use of systemic immunosuppressants (e.g„ calcineurin, CD38 mAb, CD20, IL-6 / IL-6R, mTOR inhibitors) < 3 months prior to Screening Visit.

[0217] 4. Is to receive a kidney from donors supported by extracorporeal membrane oxygenation.AXJ-313PC ALXN-1002-PCT01-NP 5. Is to receive a machine perfused donor kidney.

[0218] 6. Multiorgan transplant recipient (except for previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient.

[0219] 7. Is to receive kidney(s) from donors < 6 years of age.

[0220] 8. Is to receive a dual kidney transplant (from same donor, including en bloc).

[0221] 9. Is to receive a living donor kidney.

[0222] 10. Is to receive a kidney with estimated (at time of randomization) > 24 hours of cold ischemia time.

[0223] 11. Highly sensitized (defined as having a calculated panel reactive antibody (cPRA > 90%, or an equivalent measure of sensitization using a locally validated PRA methodology). Participants with preformed DSA are excluded).

[0224] 12. To be the recipient of an ABO incompatible kidney (A2 donors to B and O recipients are allowed if the site has the ability to confirm A2 subtype).

[0225] 13. Is to receive a kidney from donors with a known history or positive serology of HBV or HCV infection (including successfully treated participants with positive HCV antibody and negative HCV RNA test).

[0226] 14. Known or suspected complement-mediated disease (including, but not limited to, aHUS or PNH, C3 glomerulopathies [including dense deposit disease and C3 glomerulonephritis], immune complex-mediated membrano-proliferative glomerulonephritis [IC-MPGN], cold agglutinin disease).

[0227] 15. Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization.

[0228] 16. Known history of HIV who are not on anti-retroviral therapy or if on therapy have a known detectable viral load within 1 year of Screening.

[0229] 17. Participants with a known history of HBV or HCV infection (past infection) or positive serology indicating inactive or past infection within 3 months prior to Screening are excluded. Successfully treated participants with positive HCV antibody and negative HCV RNA test are also excluded.

[0230] 18. Congenital immunodeficiency.

[0231] 19. History of unexplained, recurrent infection.AXJ-313PC ALXN-1002-PCT01-NP 20. Known medical or psychological condition(s), including substance abuse, or risk factor that, in the opinion of the Investigator, might interfere with the participant’s full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study.

[0232] 21. History of, or unresolved, N. meningitidis infection.

[0233] 22. Hypersensitivity to any ingredient contained in the study intervention, including hypersensitivity to murine proteins.

[0234] 23. Current malignancy or receiving treatment for malignancy except for nonmelanoma skin cancer.

[0235] 24. Prior use of any complement inhibitors within 5 half-lives (if known) or 6 months before initiation of the study intervention, whichever is longer, or planned use during the course of the study.

[0236] 25. Participation in another investigational drug study within 5 half-lives (if known) or 30 days before initiation of the study intervention, whichever is longer, or planned participation during the course of the study.

[0237] 26. Pregnant, breastfeeding, or intending to conceive within 8 months after the dose of the study intervention.

[0238] 27. Planning to receive home hemodialysis post-transplant.

[0239] 28. Plasmapheresis (PP) and / or Plasma Exchange (PE) prior to transplant (i.e., at screening prior to visit 2).

[0240] 4. Study Intervention Administered

[0241] Study intervention is defined as any investigational intervention(s), marketed product(s), or placebo intended to be administered to a study participant according to the study protocol. The study intervention administered is described in Table 1.

[0242] Table 1: Study Intervention Administered

[0243]

[0244] AXJ-313PC ALXN-1002-PCT01-NP

[0245] > <

[0246] > <

[0247] > <

[0248] >

[0249]

[0250] After Screening, all eligible participants are randomly assigned to study intervention (either ravulizumab or placebo group) under a 1:1 allocation ratio using an IRT system. Before the study is initiated, IRT information (log-in and support telephone number) is provided to each site.

[0251] To reduce the effects of potential confounding factors for treatment effect, randomization is stratified by donor type (DCD or DBD; the proportion of DCD donor kidneys is capped to enroll approximately 20% of the total randomized population).

[0252] Study intervention is dispensed at the study visit as summarized in the Schedule of Activities. Once a randomization number has been assigned, it must not be reassigned.

[0253] Ravulizumab 100 mg / mL drug product is distinguishable from placebo based on color. To mitigate the risk of unblinding when ravulizumab admixtures at 50 mg / mL are prepared, an independent preparer is required to prepare doses for administration and to mask the delivery containers (e.g., IV bags). Independent preparers or unblinded personnel during dose preparation should apply IV bag covers (or equivalent) and / or yellow colored tape on syringes to mask for color differences (note: masking of infusion sets / lines is not required).AXJ-313PC ALXN-1002-PCT01-NP Consistent with approved ravulizumab labeling for treating adult and pediatric patients with aHUS and PNH, and adult patients with gMG, supplemental dosing of study drug (or placebo) at PI discretion is recommended in the setting of concomitant PP / PE rescue therapy within the first 5-day period post-transplant. For participants receiving PP / PE, supplemental dose administration is started within 48 hours after a PP / PE session is completed. The supplemental dose amount that is administered is based on the already administered scheduled single dose per Table 2.

[0254] Table 2: Supplemental Dose for When Plasmapheresis and / or Plasma Exchange is Administered as Rescue Therapy

[0255] > <

[0256] > <

[0257] > <

[0258] >

[0259]

[0260] 5. Prior and Concomitant Therapy

[0261] Any medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, vitamins, and herbal supplements) that the participant is receiving at the time of enrollment or receives during the study are recorded along with the reason for use, dates of administration including start and end dates, and dosage information including dose and frequency.

[0262] Only the following medications are considered standard of care immunosuppressive therapy which are allowed and should be taken during the entire study duration at the doses based on Investigator judgment. The recommended drug blood concentrations and doses are reported below.

[0263] A. Induction immunosuppression (e.g., anti-thymocyte globulin (rabbit;

[0264] Thymoglobulin®): total cumulative dose of 3 to 6 mg / kg. Dosing should begin prior to the transplant and may be given in divided doses over several days per study center’s standard practice).

[0265] B. Maintenance immunosuppression

[0266] - Calcineurin inhibitor (tacrolimus) (trough levels based on local laboratory assessment). Tacrolimus trough level 6 to 12 ng / mL: from time of transplantAXJ-313PC ALXN-1002-PCT01-NP through Day 30, then per center practice. Calcineurin inhibitor cessation / interruption is allowed in case of thrombotic microangiopathy

[0267] - Antimetabolite (choice of agent per center practice), e.g., Mycophenolate mofetil or Mycophenolate sodium.

[0268] - Corticosteroids: Prednisone or prednisone equivalent of < 10 mg per day are achieved via a tapered approach by 30 days post-transplant.

[0269] Prophylactic medications or pre-emptive monitoring approaches to infectious disease(s) are performed according to the standard institutional protocol and applied uniformly to all enrolled participants regardless of treatment group.

[0270] Previous kidney transplants are not contraindicated. However, participant must meet all inclusion / exclusion criteria.

[0271] Use of PE / PP (acute use only) is allowed for participants post-transplant at the discretion of the Investigator. Every effort should be made to notify the Sponsor within 24 hours should a participant require rescue therapy.

[0272] Participants are prohibited from receiving any of the following medications and therapies during study participation through the end of study (EOS):

[0273] A. Eculizumab, ravulizumab (other than protocol-specified study intervention), or other agents that act on the complement pathway.

[0274] B. Use of any pharmacologic agent specifically for prevention or treatment of DGF; these therapies can be used for their approved indications.

[0275] C. Use of any other complement inhibitors.

[0276] D. Experimental interventions or therapies through the EOS.

[0277] E. Use of a prohibited medication and / or therapy must be documented in the CRF.

[0278] Although the protocol's disallowed medications section may not explicitly list all therapeutic agents, there are currently no approved or investigational treatments against DGF that would be considered allowable within the framework of this study. F. Use of PP and PE are prohibited prior to transplant.

[0279] G. ECMO use is altogether excluded from the DGF study, whether it is used when the donor is alive, or at any point after the donor’s death during the kidney procurement process. NRP (Normothermic [regional] machine perfusion) is a modified ECMO circuit and therefore is excluded from the study as well.AXJ-313PC ALXN-1002-PCT01-NP

[0280] 6. Vaccination and Antibiotic Prophylaxis

[0281] Due to its mechanism of action, the use of ravulizumab increases the participant’s susceptibility to infection due to N. meningitidis. To reduce the risk of meningococcal infection (A. meningitidis), all participants must be vaccinated against meningococcal infection from serogroups A, C. W, and Y (and. where available, serogroup B). If a participant has not been vaccinated or is not up-to-date with their meningococcal vaccines within the window of 14 days to 3 years prior to transplant, the participant must receive prophylactic antibiotics for protection against N. meningitidis starting from Visit 1 prior to dosing until at least 14 days after vaccination. When the participant can clinically mount an immune response (as determined by the Investigator), vaccines must be administered while under C5 inhibition during the study until Day 270, in accordance with national guidelines for persons receiving a complement inhibitor and recommendations for vaccination post-transplant. In the event that immune competence is not restored, and vaccination is not feasible post-transplant, the participant continues on antibiotics until Day 270. If a participant has been randomized and dosed but has not received the transplant, the PI should make every effort to ensure that participants receive prophylactic antibiotics and / or vaccination as indicated. These prophylactic measures are also required, in case a participant is dosed, but does not receive the transplant or receives a partial dose of the study intervention.

[0282] Antibiotic prophylaxis with penicillin (e.g., oral penicillin V 500 mg twice-daily) is the preferred choice. If participants cannot tolerate penicillin, other antibiotic options can include ciprofloxacin (e.g., 500 mg daily) or azithromycin (e.g. 250 mg daily). The choice of the prophylactic antibiotics and dosing regimen is at the Investigator’s discretion depending on local / national guidelines as well as participant factors.

[0283] Vaccination may not be sufficient to prevent meningococcal infection. All participants should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics, if necessary.

[0284] Participants are provided a Participant Safety Card to increase risk awareness and promote quick disclosure of any potential signs or symptoms of meningococcal infection experienced during the course of the study.

[0285] 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.AXJ-313PC ALXN-1002-PCT01-NP Vaccination status and antibiotic prophylaxis for N. meningitidis, as well as administration of any other vaccines, is recorded.

[0286] 7. Pharmacokinetics and Pharmacodynamics

[0287] Blood samples are collected for PK / PD and are assessed at the visit / timepoints specified in the Schedule of Activities. The Visit 1 pre-dose blood sample can be drawn through the venous access created for the dose infusion, prior to administration of the drug. Subsequent samples are not collected through the dosing line. Additional samples can be collected at additional timepoints during the study if warranted.

[0288] All efforts are made to obtain the PK / PD samples at the timepoints specified in the Schedule of Activities and within specified time- windows (relevant for some of these timepoints). Any deviation from the Schedule of Activities-prescribed timepoints is captured as a protocol deviation. A protocol deviation also results when the exact date and time of PK / PD sample collection is not recorded.

[0289] Instructions for the collection and handling of biological samples, along with additional information on sample collection (including blood volume requirements) are provided. The actual date and time (24-hour clock time) of each sample is recorded.

[0290] 8. Biomarkers

[0291] Sample collection for biomarker research (e.g., exploratory) is also part of this study at the time points specified. Biomarkers include, but are not limited to blood (plasma) samples e.g., Terminal complement pathway activation e.g., sC5b-9), complement pathway anaphylatoxins products as mediators of activation {e.g., complement pathway activation products [C3a, C5a]), Inducers of immune proinflammatory cytokine (e.g., IL- 18)), Urine samples {e.g., Complement pathway activation {e.g., sC5b-9), renal injury {e.g., NGAL), and Inducers of immune proinflammatory cytokine {e.g., IL- 18).

[0292] 9. Immunogenicity Assessments

[0293] Serum samples for ADA and NAb analysis are collected at specified timepoints. All efforts re made to obtain the immunogenicity samples at the exact nominal time relative to dosing. Out-of-window protocol deviations captured for immunogenicity samples follow the same approach as specified for PK sample collection.AXJ-313PC ALXN-1002-PCT01-NP The detection and characterization of ADA to study intervention is performed using a validated assay method. Antibodies to study intervention are evaluated in serum samples collected from all participants according to the Schedule of Activities.

[0294] ADA positive samples are further characterized for antibody titer and presence of NAbs. Additional analyses can be performed on collected ADA samples for further analysis or characterization.

[0295] 10. Patient-Reported Outcomes

[0296] EQ-5D-5L is a self-assessed, standardized instrument to measure health-related QoL, and has been used in a wide range of health conditions (see, e.g., Schrag A, et al., Journal of Neurology, Neurosurgery, and Psychiatry. 2000;69(l):67-73). The EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the VAS (EQ-VAS). If a participant is not able to attend the scheduled onsite visit or is unable to read or write, the EQ-5D-5L can be assessed via interview.

[0297] SF-36 v2 (Acute Version) is a 36-item self-report of health-related QoL (see, e.g.. Ware JE, Jr., Sherboume CD., Med Care. 1992;30(6):473-483). It contains 8 subscales measuring different domains of health-related QoL: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health.

[0298] KTQ-25 is a disease-specific questionnaire assessing QoL in kidney transplant participants (see, e.g., Laupacis A, et al., Nephron. 1993;64(2):226-231). It consists of 25 items grouped in 5 dimensions: (1) Physical symptoms (6 items); (2) Fatigue (4 items); (3) Uncertain ty / fear (5 items); (4) Appearance (4 items); and (5) Emotions (6 items). Each item is scored on a 7-point Likert scale. All scores in each domain are added and divided by the number of items in that dimension. For the total score of each domain, score 7 is the highest score of QoL and score 1 is the lowest. The KTQ-25 is administered via interviews during time points specified in the Schedule of Activities.

[0299] 11. Statistical Considerations

[0300] This section is a summary of the planned statistical analyses of the most important endpoints including primary and key secondary endpoints. The study unblinding occurs once the last enrolled participant completes the Day 180 Visit or ED Visit.AXJ-313PC ALXN-1002-PCT01-NP 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, SD, minimum, median, and maximum. For categorical variables, frequencies, and percentages are presented. Graphical displays are provided as appropriate. Analyses are performed using the SAS® software Version 9.4 or higher.

[0301] All statistical tests are performed at a one-sided significance level of 0.025 and 95% CI is generated unless otherwise specified.

[0302] The primary objective is to demonstrate that ravulizumab is superior to placebo in reducing the severity of DGF in adult participants who are at high risk of DGF after undergoing transplant of deceased donor kidney. The following hypothesis is tested:

[0303] HO: HR =< 1 vs Ha: HR > 1,

[0304] where HR is the ratio of instantaneous rate of reaching freedom from dialysis through 90 days post-transplant.

[0305] The overall type I error for the primary and key secondary endpoints is controlled by a closed sequential testing procedure at a one-sided significance level of 0.025.

[0306] The primary endpoint of time to freedom from dialysis is tested at the one-sided significance level of 0.0096 at the interim analysis when 338 participants (75% of the planned 450 participants) have completed the 90-day Primary Evaluation Period. If the statistical significance is not reached, no other testing is performed, and the primary endpoint is re-tested at the one-sided significant level of 0.0221 at the final analysis when all 450 participants have completed the 90-day Primary Evaluation Period. The Lan & DeMets a- spending approximation to the O’Brien & Fleming boundaries is used to determine the significance levels.

[0307] The Lan & DeMets a-spending approximation to the Pocock boundaries for the key secondary endpoints is used to control the overall type I error at one-sided 0.025 significance level. If the statistical significance for the primary endpoint analysis is reached at the interim analysis, the key secondary endpoints are tested at the one-sided significance level of 0.0207. If the statistical significance for the primary endpoint is not reached at interim but reached at the final analysis, the key secondary endpoints are tested at the one-sided significant level of 0.0120. Due to the nature of the hierarchical testing procedure, the family- wise type I error rate is controlled at one-sided 0.025 level across the primary and key secondary endpoints. The keyAXJ-313PC ALXN-1002-PCT01-NP secondary endpoints are tested until a non-significance is observed, at which point only nominal p-values are reported.

[0308] Table 3: Defined Participant Analysis Sets

[0309]

[0310] The primary endpoint for this study is time to freedom from dialysis through 90 days post-transplant. The primary analysis is performed on the ITT set. Additionally, summary statistics for the primary endpoint are presented based on the participants who develop DGF in the ITT set.

[0311] DGF incidence is defined as the requirement of having at least 1 dialysis session within the first 7 days post-transplant.AXJ-313PC ALXN-1002-PCT01-NP Time from transplant to freedom from dialysis is assessed as the number of days between transplant surgery and the last day of the last dialysis session (inclusive) through 90 days post- transplant if the first dialysis is received within 7 days post-transplant (i.e., developing DGF). It is calculated as date of freedom from dialysis - date of transplant + 1, where the date of freedom from dialysis is the last day of the last dialysis through 90 days post-transplant.

[0312] If a participant does not develop DGF. the time to freedom from dialysis is set to zero. Participants still on dialysis 90 days post-transplant are censored at Day 90.

[0313] If there is an observed period of > 10 consecutive days with no dialysis or graft loss or death, then the time to freedom of dialysis is derived using the last date of the last dialysis prior to this period and such participants are not censored. If a participant has > 1 such period, the dialysis sessions prior to the first dialysis-free period are used.

[0314] The > 10-day dialysis-free period is chosen as a sufficient period to assess the independence from dialysis based on the feedback from a steering committee. This approach is also in line with recommendations from the ADQI Consensus Report that defines kidney recovery from AKI as sustained independence from KRT for a minimum of 14 (see, e.g., Chawla LS, Nature Reviews Nephrology. 2017;13(4):241-257). A slightly shorter period of 10 days is justified by overall shorter duration and higher rates of clinical recovery of DGF compared to dialysis-dependent AKI of other etiology.

[0315] Intercurrent event (ICEs) are events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question of interest (ICH E9 Rl). Table 4 describes the ICEs in this study affecting the measurement of time to freedom from dialysis, along with the corresponding handling strategies and the censoring rules.

[0316] Table 4: Intercurrent Events

[0317]

[0318] AXJ-313PC ALXN-1002-PCT01-NP

[0319]

[0320] In addition, participants who discontinue from the study within 7 days post-transplant (not due to graft loss or death) are censored at the ED Visit date. DGF participants who discontinue from the study within 10 days from the last dialysis, are censored at the ED Visit date. In all cases, if the early discontinuation (ED) Visit date is missing, participants are censored at the last known visit date. Participants who discontinue from the study within 7 days post-transplant are treated as having developed DGF.

[0321] The stratified Cox proportional hazard model is used to analyze the primary endpoint with strata determined by donor kidney type. The treatment effect is assessed as the (hazard) ratio of reaching freedom from dialysis between ravulizumab and placebo. Point estimate of the (hazard) ratio, its 95% CI, and the p-value is provided from this model.

[0322] As a supplementary analysis, the treatment effect is estimated as the difference in the restricted mean time to freedom from dialysis between ravulizumab and placebo, using the RMST method (see, e.g., Royston P, Parmar MK., BMC Medical Research Methodology.

[0323] 2013;13:1-15). The same approach of handling ICEs and censoring is applied in this analysis. The restricted mean time to freedom from dialysis by treatment group, the difference between treatment groups, the 95% CI for the difference, and the p-value are provided.

[0324] Sensitivity analyses as variations of the primary analysis are performed to evaluate the robustness of the treatment effect. Table 5 lists the variations to the primary estimand used in the sensitivity analyses, while the other elements for the primary estimand remain the same. Full details for the sensitivity analyses are provided in statistical analysis plan.

[0325] Table 5: Sensitivity Analyses

[0326] >

[0327]

[0328] AXJ-313PC ALXN-1002-PCT01-NP

[0329]

[0330] All key secondary endpoints are analyzed on the ITT set and tested. Additionally, summary statistics for all secondary endpoints are presented based on the participants who develop DGF in the ITT set.

[0331] DGF incidence is defined as the requirement of having at least 1 dialysis session within 7 days post-transplant. Table 6 sets forth how ICE handling strategies are applied.

[0332] Table 6: ICE Handling Strategies

[0333]

[0334] In addition, participants who discontinue from the study within 7 days without dialysis are treated as having developed DGF.

[0335] Treatment effect is assessed as the absolute risk difference in DGF incidence between ravulizumab and placebo. The point estimate of the risk difference, the 95% CI for the difference in DGF incidence, and the p-value is provided using Cochran-Mantel-Haenszel test stratifying donor kidney type (DBD, DCD).

[0336] The number of dialysis sessions is derived based on all dialysis sessions that occur after surgery through 90 days post-transplant, including dialysis in participants who do not develop DGF (i.e., who have first dialysis session after 7 days post-transplant). Dialysis sessions that are ongoing at 90 days post-transplant are included.

[0337] The ICEs for this endpoint include graft loss, death, and use of protocol prohibited intervention after study intervention is administered. Treatment policy strategy is applied to handle these ICEs. Missing data is not imputed.

[0338] A negative binomial regression model is used to compare the number of dialysis sessions between ravulizumab and placebo with a factor variable for treatment group and a log offset term for follow-up time. Treatment effect is assessed as the rate ratio between ravulizumab andAXJ-313PC ALXN-1002-PCT01-NP placebo. The point estimate for the rate ratio, its 95% CT, and the p-value is provided using this model.

[0339] Time to first occurrence of eGFR > 30 mL / min / 1.73 m2through 90 days post-transplant is assessed as the number of days between transplant and the date when eGFR level reaches 30 mL / min / 1.73 m2for the first time. Table 7 sets forth how the following ICE handling strategies are applied.

[0340] Table 7: ICE Handling Strategies

[0341]

[0342] Participants who discontinue early from the study (not due to graft loss or death) are censored at the early discontinuation Visit date. If that date is missing, the participants are censored at the last known visit date.

[0343] The proportional hazard model stratifying donor kidney type (DBD, DCD) is used to analyze this endpoint. Treatment effect is assessed as the (hazard) ratio of eGFR reaching 30 mL / min / 1.73m2between ravulizumab and placebo through 90 days post-transplant. The point estimate for the hazard ratio, the 95% CI for the hazard ratio, and the p-value is provided.

[0344] All other secondary endpoints are analyzed on the ITT set. Analyses for secondary and exploratory endpoints is described in detail in the statistical analysis plan.AXJ-313PC ALXN-1002-PCT01-NP For longitudinal eGFR level collected up to one-year post-transplant, a mixed-effect model for repeated measures (MMRM) is used. The MMRM includes the observed eGFR level at post-transplant visits as the response variable, categorical variables of treatment (ravulizumab, placebo), study visits, treatment-by-visit interaction, donor kidney type (DBD, DCD) as the fixed effect, and continuous baseline eGFR as a covariate. Additional covariates can be adjusted. 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-by-visit term at each scheduled visit. The point estimate and two-sided 95% CI for the least squares mean difference in eGFR between ravulizumab and placebo are estimated.

[0345] Number and percentage of participants with eGFR level > 30 mL / min / 1.73 m2is summarized at each scheduled post-transplant visits. The treatment effect is assessed as the difference in proportion of participants with eGFR level > 30 mL / min / 1.73 m2between ravulizumab and placebo. The associated 95% confidence interval and the nominal p- values are provided by Mantel-Haenszel test.

[0346] The safety of ravulizumab is assessed based on adverse events, clinical laboratory findings, and vital sign findings. All safety analyses are performed on the safety set (SS).

[0347] Analysis of adverse events collected in the study are stratified based on treatment exposure. Adverse events occurring from time of consent up to prior to dosing are analyzed as predosing adverse events. Adverse events with onset or existing events that worsen in severity from the day of study intervention dosing to Day 270 (within 5 terminal half-lives) of ravulizumab are analyzed as treatment emergent adverse events (TEAEs). Adverse events occurring after 5 terminal half-lives until the EOS (Day 360) are listed as postdosing AEs.

[0348] The incidence of TEAEs, TEAEs leading to withdrawal from the study, and TESAEs are summarized by treatment group. TEAEs are summarized overall, by System Organ Class (SOC) and Preferred Term (PT), by severity, and by relationship to study intervention. Detailed byparticipant listings of TEAEs, treatment emergent serious adverse events (TESAEs), related TEAEs, and TEAEs leading to withdrawal from the study are provided. Participants having multiple adverse events within a category (e.g., overall, SOC, PT) are counted once in that category. For severity tables, a participant’s most severe event within a category is counted. AEsAXJ-313PC ALXN-1002-PCT01-NP and their intensity will also be reported as serious or non-serious. All AEs are coded using the MedDRA, Version 26.1 or higher.

[0349] Observed values and changes from baseline in vital signs and weight are summarized descriptively by treatment group at baseline and postbaseline timepoints wherever applicable.

[0350] Observed values and changes from baseline in clinical chemistry, hematology, and urine test are summarized descriptively by treatment group at baseline and at each postbaseline timepoint. For laboratory results that can be classified as normal, low, or high based on normal range values, shifts from baseline in classification are summarized for all study visits.

[0351] The PK / PD analyses include all data in the pharmacokinetic analysis set (PKAS) and pharmacodynamic analysis set (PDAS), respectively.

[0352] To assess pharmacokinetics (PK), descriptive statistics are calculated for serum ravulizumab concentration data at each sampling time, as appropriate. Graphs of mean serum ravulizumab concentration-time profiles are constructed. Graphs of serum ravulizumab concentration-time profiles for individual participants can also be provided.

[0353] To assess pharmacodynamic (PD), descriptive statistics are calculated for the serum free C5 and serum total C5 data at each sampling time, as appropriate. The PD effects of ravulizumab are evaluated by the absolute values and changes and percentage changes from baseline, as appropriate.

[0354] All immunogenicity analyses are performed on the immunogenicity analysis set (IAS). Immunogenicity variables include ADA status categories, ADA response categories, ADA and NAb incidence. ADA titer is summarized over the duration of the study. Definitions of the ADA status and response categories are provided in the statistical analysis plan. ADA status and ADA response categories as listed below are summarized as absolute occurrence (n) and percentage of all participants.

[0355] A. ADA status categories: ADA negative or ADA positive.

[0356] B. Participants who are ADA positive are further categorized into ADA response: Preexisting immunoreactivity, Treatment-emergent ADA responses, or Treatment- boosted ADA responses.

[0357] C. Participants with a treatment-emergent or treatment-boosted ADA response are further categorized as follows: Persistent responses, Indeterminate responses, or Transient responses.AXJ-313PC ALXN-1002-PCT01-NP D. ADA positive samples are further characterized for neutralizing activity in the NAb assay. NAb status categories are as follows: NAb positive or NAb negative. Subgroup analyses of the primary and key secondary endpoints are conducted to assess consistency of the investigational intervention effect across the following donor and recipient characteristics (not limited to):

[0358] • Donor characteristics:

[0359] o Age (< 60 years,

[0360]

[0361] years)

[0362] o Kidney type (DBD, DCD)

[0363] o Preservation solution (HTK, UW, IGL-1®, Celsior, HC-A, other)

[0364] o KDPI (<85%, 3? 85%)

[0365] o Actual cold ischemia time (<12 hours, 12 hours)

[0366] o BMI (<35 kg / m2, %35 kg / m2)

[0367] o History of diabetes (yes, no)

[0368] o History of hypertension (yes, no)

[0369] o History of cerebral accident (yes, no)

[0370] • Recipient characteristics:

[0371] o Age (<60 years, %60 years)

[0372] o BMI (<35 kg / m2, A 35 kg / m2)

[0373] o Region (North America, Europe, Asian & Pacific, Latin America)

[0374] o History of previous transplant (yes, no)

[0375] o History of diabetes (yes, no)

[0376] o History of hypertension (yes, no)

[0377] o Length of dialysis (<2 years, %2 years)

[0378] o Baseline BMI (<35 kg / m2, A 35 kg / m2)

[0379] Given that the number of participants in some subgroups may be limited, subgroup categories can be combined or redefined as appropriate. Otherwise, the subgroup analysis cannot be performed if deemed infeasible based on sample size. Forest plots are used to present the estimated treatment effect on subgroups and the associated 95% Cis. A full list of subgroups and further details on the statistical analysis is provided in the statistical analysis plan.AXJ-313PC ALXN-1002-PCT01-NP Two optional interim analyses are planned for the study. An independent Data Monitoring Committee (IDMC) evaluates the results from both interim analyses and makes recommendations to the study. Investigators, participants, and the study team who are involved in the conduct of the study remain blinded to individual treatment assignments until the final database lock. A Study Integrity Plan is developed in which blinding method and unblinding process are pre- specified. The statistical analysis plan describes the planned interim analyses in detail. Enrollment is not paused during interim analyses.

[0380] At the time of any interim analysis, if the pre-specified futility criterion or early efficacy criterion is met, the Data Monitoring Committee (DMC) may recommend early stopping of the study.

[0381] An interim analysis for futility is planned no later than when approximately

[0382] 180 participants have completed the 90-day Primary Evaluation Period. The futility is assessed using an approximation to the Bayesian predictive probability of final study success, i.e., primary endpoint achieving statistical significance at the end of study. If the predictive probability of final study success is below 0.0025, the DMC may recommend terminating the study due to futility.

[0383] A second interim analysis is conducted when 338 participants have completed the 90-day Primary Evaluation Period, with the aim of assessing futility and efficacy for early stopping for regulatory submission. The futility criterion is that the predictive probability of final study success is below 0.03. The overall type I error of the study for this interim and the final analysis is controlled at 1-sided 0.025 using the O’Brien-Fleming method for alpha spending. If the p-value for the primary endpoint analysis at this interim analysis is less than 0.0096. the DMC may recommend stopping the study early due to efficacy. If the study is continued to the end after this interim analysis, the significance level for the primary analysis at the final analysis is 0.0221.

[0384] The sample size determination of N = 450 was based on the following assumptions: A. The proportional hazards model is used to compare ravulizumab and placebo in the time to freedom from dialysis.

[0385] B. 1:1 ravulizumab and placebo randomization.

[0386] C. At least 80% of randomized participants receive DBD kidneys and at most 20% receive DCD kidneys.AXJ-313PC ALXN-1002-PCT01-NP D. Placebo-treated participants receiving DBD kidneys have a 41 % DGF incidence with time to freedom from dialysis in participants with the development of DGF following a gamma distribution with mean and SD of 13.3 days and 20.3 days, respectively (Study ECU-DGF-201).

[0387] E. Placebo-treated participants receiving DCD kidneys have a 40% DGF incidence (SRTR database) with time to freedom from dialysis in participants experiencing DGF following a gamma distribution with mean and SD of 13.3 days and 20.3 days, respectively.

[0388] F. Ravulizumab treatment reduces DGF incidence by 42% and reduces the time to freedom from dialysis in participants with the development of DGF by 49%, resulting in a treatment difference in mean time to freedom from dialysis of 5.1 days among ITT participants.

[0389] G. The rate of graft loss and death is assumed:

[0390] - 2% among all participants prior to 7 days post-transplant,

[0391] - 12% among DGF participants after 7 days post- transplant.

[0392] H. The rate of early discontinuation (not due to death or graft loss) is assumed:

[0393] - 2% among all participants prior to 7 days post-transplant,

[0394] - 3% among DGF participants after 7 days post-transplant.

[0395] I. One-sided significance level of 2.5%.

[0396] J. An interim analysis for efficacy when 338 participants complete the Primary Evaluation Period with O’Brien-Fleming boundary for alpha spending.

[0397] With these assumptions, simulation demonstrates that a sample size of 450 participants provides an overall power of 91.4% to detect a treatment difference in time to freedom from dialysis with significance level of 0.0096 at interim and 0.0221 at the final analysis.

[0398] 12. Adverse Events and Serious Adverse Events

[0399] An adverse event (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 and do not meet the AE definition are set forth in Table 8.AXJ-313PC ALXN-1002-PCT01-NP Table 8: Adverse Events

[0400]

[0401] AXJ-313PC ALXN-1002-PCT01-NP

[0402]

[0403] If an event is not an AE per definition above, then it is not an serious adverse event (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 1 or more of the criteria set forth in Table 9.

[0404] Table 9: Serious Adverse Events (SAE)

[0405]

[0406] AXJ-313PC ALXN-1002-PCT01-NP

[0407]

[0408] A suspected unexpected serious adverse reaction (SUSAR) is defined as an event that is serious, that has at least a reasonable possibility of being related to the investigational medicinal product (IMP) and is not listed in the appropriate Reference Safety Information (Ravulizumab IB).

[0409] The Investigator makes an assessment of the severity for each AE and SAE reported during the study by using the National Cancer Institute CTCAE (version 5.0) toxicity grading (Grade 1 - 5), as well as the severity evaluation of the reported AE / SAE as mild, moderate, or severe based on the Investigator’s medical judgment of the perceived clinical significance of the AE / SAE: (1) Mild (awareness of sign or symptom, but easily tolerated), (2) Moderate (discomfort sufficient to cause interference with normal activities), or (3) severe (incapacitating, with inability to perform normal activities, including life-threatening or fatal).

[0410] 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.”

[0411] A 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 causalityAXJ-313PC ALXN-1002-PCT01-NP 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 is not ruled out.

[0412] Alternative causes, such as underlying disease(s). concomitant therapy, and other risk factors, as well as the temporal relationship of the event to study intervention administration, are considered and investigated.

[0413] The Investigator reviews and provide an assessment of causality for each AE / SAE and document this in the medical notes. The Investigator can change their opinion of causality in light of follow-up information and send an SAE follow-up report with the updated causality assessment. The causality assessment is one of the criteria used when determining regulatory reporting requirements.AXJ-313PC ALXN-1002-PCT01-NP

[0414] SEQUENCE SUMMARY

[0415]

[0416] AXJ-313PC ALXN-1002-PCT01-NP

[0417]

[0418] AXJ-313PC ALXN-1002-PCT01-NP

[0419]

[0420] AXJ-313PC ALXN-1002-PCT01-NP

[0421]

Claims

AXJ-313PC ALXN-1002-PCT01-NP CLAIMSWhat is claimed is:

1. A method of reducing the severity of delayed graft function (DGF) in a human kidney transplant recipient, the method comprising administering to the recipient 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 to the recipient prior to transplantation at a dose of:(a) 2700 mg to a recipient weighing > 30 to < 40 kg;(b) 3000 mg to a recipient weighing > 40 to < 60 kg;(c) 3300 mg to a recipient weighing > 60 to < 100 kg; or(d) 3600 to a recipient weighing > 100 kg.

2. A method of treating a human kidney transplant recipient, the method comprising administering to the recipient 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 to the recipient prior to transplantation at a dose of:(a) 2700 mg to a recipient weighing > 30 to < 40 kg;(b) 3000 mg to a recipient weighing > 40 to < 60 kg;(c) 3300 mg to a recipient weighing > 60 to < 100 kg; or(d) 3600 to a recipient weighing > 100 kg.

3. The method of claim 1 or 2, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered intravenously to the recipient prior to transplantation.AXJ-313PC ALXN-1002-PCT01-NP 4. The method of any one of the preceding claims, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered intravenously to the recipient 24 hours or less prior to the start of transplantation.

5. The method of any one of the preceding claims, wherein the anti-C5 antibody, or antigen binding fragment thereof, wherein the intravenous administration to the recipient is complete at least 30 minutes before the start of transplantation.

6. The method of any one of the preceding claims, wherein dialysis is performed between administration of the anti-C5 antibody, or antigen binding fragment thereof, to the recipient and before the start of transplantation.

7. The method of claim 6, wherein dialysis is initiated no earlier than 60 minutes after administration of the anti-C5 antibody, or antigen binding fragment thereof, to the recipient.

8. The method of claim 2, wherein the treatment reduces the severity of delayed graft function (DGF) in a human kidney transplant recipient.

9. The method of any one of the preceding claims, wherein freedom from dialysis posttransplant is indicative of a reduction in severity of DGF.

10. The method of claim 9, wherein freedom from dialysis at least 1 month, 2 months, 3 months, 6 months, 9 months, or one-year post-transplant is indicative of a reduction in severity of DGF.

11. The method of any one of the preceding claims, wherein a decrease in number of dialysis sessions for the recipient post-transplant compared to number of dialysis sessions for the recipient prior to transplant is indicative of a reduction in severity of DGF.

12. The method of claim 11, wherein a decrease in number of dialysis sessions for the recipient post-transplant at 1 month, 2 months, 3 months, 9 months, or one-year post-transplantAXJ-313PC ALXN-1002-PCT01-NP compared to number of dialysis sessions for the recipient prior to transplant is indicative of a reduction in severity of DGF.

13. The method of any one of the preceding claims, wherein a reduction in severity of DGF is achieved when the recipient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2in the absence of dialysis post-transplant.

14. The method of claim 13, wherein a reduction in severity of DGF is achieved when the recipient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2in the absence of dialysis at 1 month, 2 months, 3 months, 9 months, or one-year post-transplant.

15. The method of any one of the preceding claims, wherein a reduction in severity of DGF is assessed by rejection-free graft survival post-transplant.

16. The method of claim 15, wherein the recipient maintains rejection-free graft survival through 1 month, 2 months, 3 months, 9 months, or one-year post-transplant.

17. The method of any one of the preceding claims, wherein the recipient receives a kidney from donation after circulatory death (DCD).

18. The method of any one of the preceding claims, wherein the recipient receives a kidney from donation after brain death (DBD).

19. The method of any one of the preceding claims, wherein the recipient has dialysisdependent end-stage kidney disease (ESKD) prior to transplant.

20. The method of any one of the preceding claims, wherein the recipient is an adult recipient.

21. 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 toAXJ-313PC ALXN-1002-PCT01-NP 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.

22. 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.

23. 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.

24. 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.

25. 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).

26. 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).

27. The method of any one of the preceding claims, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 2700 mg to a recipient weighing > 30 to < 40 kg.

28. The method of any one of claims 1-26, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3000 mg to a recipient weighing > 40 to < 60 kg.

29. The method of any one of claims 1-26, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3300 mg to a recipient weighing > 60 to < 100 kg.AXJ-313PC ALXN-1002-PCT01-NP30. The method of any one of claims 1-26, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered at a dose of 3600 to a recipient weighing > 100 kg.

31. 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.

32. 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.

33. The method of any one of the preceding claims, wherein the recipient has previously been treated or is concurrently being treated with induction immunosuppression (e.g., antithymocyte globulin) and / or maintenance immunosuppression (e.g., a calcineurin inhibitor (tacrolimus), an antimetabolite (e.g... Mycophenolate mofetil or Mycophenolate sodium), and / or a corticosteroid (e.g., prednisone or prednisone equivalent).

34. The method of any one of the preceding claims, which results in a change in the recipient from baseline as assessed by EuroQoL-5 Dimension-5 Levels (EQ-5D-5L) compared to 7, 14, 30, 90, 180, and 360 days post-transplant.

35. The method of any one of the preceding claims, which results in a change in the recipient from baseline as assessed by “36-item Short Form Survey” (SF-36) compared to 7, 14, 30, 90, 180, and 360 days post-transplant.

36. The method of any one of the preceding claims, which results in a change in the recipient from baseline as assessed by “Kidney Transplant Questionnaire - 25-items” (KTQ-25) compared to 7, 14, 30, 90, 180, and 360 days post-transplant.

37. 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), NGAL, and IL- 18.AXJ-313PC ALXN-1002-PCT01-NP38. The method of any one of the preceding claims, wherein the treatment results in an improvement in estimated glomerular filtration rate (eGFR) in the recipient post-transplant compared to baseline, e.g., an improvement from baseline in eGFR at 1 month, 2 months, 3 months, 9 months, or one-year post-transplant compared to baseline.

39. The method of any one of the preceding claims, further comprising administering a supplemental dose of the antibody when plasmapheresis and / or plasma exchange (PP / PE) is administered to the recipient as rescue therapy; particularly, wherein the recipient receives concomitant PP / PE rescue therapy within the first 5-day period post-transplant.

40. The method of claim 39, wherein the supplemental dose of the anti-C5 antibody is started within 48 hours after a PP / PE session is completed; preferably wherein the supplemental dose of the anti-C5 antibody is administered based on the already administered scheduled single dose per Table 2.

41. The method of claim 39 or 40, wherein the supplemental dose comprises administering a dose of 1100 mg of the anti-C5 antibody to a recipient who is > 30 to < 40 kg; 1500 mg of the anti-C5 antibody to a recipient who is > 40 to < 60 kg; 1800 mg of the anti-C5 antibody to a recipient who is > 60 to < 100 kg; and 1800 mg of the anti-C5 antibody to a recipient who is > 100 kg.

42. A kit for treating a human kidney transplant recipient, 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.AXJ-313PC ALXN-1002-PCT01-NP 43. 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 to a human kidney transplant recipient prior to transplantation at a dose of:(a) 2700 mg to a recipient weighing > 30 to < 40 kg;(b) 3000 mg to a recipient weighing > 40 to < 60 kg;(c) 3300 mg to a recipient weighing > 60 to < 100 kg; or(d) 3600 to a recipient weighing > 100 kg.

44. The anti-C5 antibody, or antigen binding fragment thereof, of claim 40, wherein the anti-C5 antibody, or antigen binding fragment thereof, is determined to be safe, tolerable, efficacious and sufficiently non-immunogenic after multiple IV doses in human patients.

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