Dosage and administration of anti-C5 antibodies to prevent or minimize cardiac surgery-associated acute kidney injury (CSA-AKI) and / or subsequent major adverse kidney events (MAKE) in patients with chronic kidney disease

Abstract

Provided herein are methods for preparing a human patient for surgery (e.g., cardiac surgery with cardiopulmonary bypass (CPB)) in specific subpopulations (e.g., human patients with renal disease, including chronic kidney disease (CKD)), inhibiting terminal complement activation in a human patient, treating a human patient with CKD before cardiac surgery with CPB, preventing or reducing cardiac surgery-associated acute kidney injury (CSA-AKI) in a human patient with CKD, and preventing or reducing one or more MAKEs in a human patient with CKD. These methods comprise administering to the patient an anti-C5 antibody, e.g., ravulizumab or eculizumab, or an antigen-binding fragment thereof, according to a specific clinical dosing regimen and according to a specific schedule.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 410,753, filed September 28, 2022, and U.S. Provisional Patent Application No. 63 / 440,968, filed January 25, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] The presence of chronic kidney disease (CKD) in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) confers a high risk for poor outcomes, and postoperative acute kidney injury (AKI) further enhances these risks (e.g., Meersch M, et al., Current Opinion in Anaesthesiology. 2016;29(3):413-420; Mehta RH, et al., Circulation. 2006;114(21):2208-2216; Nashef SA, et al. EuroSCORE II. Eur J Cardiothorac Surg. 2012;41(4):734-744; Thakar CV, et al., Kidney Int. 2005;67(3):1112-1119; and Thakar CV, et al. (See, e.g., J. Am. Soc. Nephrol. 2005;16(1):162-168.) Post-CPB AKI is characterized by a rapid deterioration of renal excretory function after cardiac surgery, typically manifested as a reduction in glomerular filtration rate (GFR). AKI occurs in approximately 25% of patients after CPB surgery (see, e.g., Corredor C, et al., J. Cardiothorac. Vasc. Anesth. 2016;30(1):69-75, and Hu J, et al., J. Cardiothorac. Vasc. Anesth. 2016;30(1):82-89), and in up to 60%-80% of patients with moderate to severe CKD (calculated from Priyanka P, et al., J. Thorac. Cardiovasc. Surg. 2021;162(1):143-151.e147).

[0003] AKI after CPB is associated with in-hospital mortality, the need for renal replacement therapy (KRT; also known as renal replacement therapy or RRT), permanent loss of kidney function (with risk of progression to CKD, including end-stage renal disease), high resource utilization, and poor long-term survival (e.g., Peng et al., Anesth. Analg. 2022 Oct 1;135(4):744-756; Chawla LS, et al., N. Engl. J. Med. 2014;371(1):58-66; Chawla LS, et al., Kidney Int. 2011;79(12):1361-1369; Coca SG, et al., Am. J. Kidney Dis. 2009;53(6):961-973; Dasta JF, et al. al.,Nephrology,Dialysis,Transplantation:Official Publication of the European Dialysis and Transplant Association-European Renal Association;2008;23(6):1970-1974, Ishani A,et al.,J.Am.Soc.Nephrol.2009;20(1):223-228,Mangano CM,et al.,The Multicenter Study of See Perioperative Ischemia Research Group. Ann Intern Med. 1998;128(3):194-203; Thakar CV, et al., Incidence and outcomes of acute kidney injury in intensive care units: a Veterans Administration study. Crit Care Med. 2009;37(9):2552-2558). One large meta-analysis showed that the in-hospital mortality rates after cardiac surgery for patients without AKI compared with patients with AKI were 1.7% and 10.7%, respectively.The long-term (1-5 year) mortality rates were 11.9% and 30%, respectively (Hu, 2016). Sustained kidney dysfunction (SKD) after AKI increases short- and long-term mortality risk many-fold compared with transient or no AKI (see, e.g., Brown JR, et al., Ann. Thorac. Surg. 2010;90(4):1142-1148; Corredor C, et al., J. Cardiothorac. Vasc. Anesth. 2016;30(1):69-75; Swaminathan M, et al., Ann. Thorac. Surg. 2010;89(4):1098-1104), and increases the risk of new-onset CKD or accelerates the progression of existing CKD (see, e.g., Chawla LS, et al., N. Engl. J. Med. 2014;371(1):58-66; Chawla LS, et al., Kidney Int. 2011;79(12):1361-1369, and Kellum JA, et al., Nat. Rev. Dis. Primer. 2021;7(1):52). The risk of developing end-stage renal disease after AKI is substantially greater in patients with pre-existing CKD (see, e.g., Ishani A, et al., J. Am. Soc. Nephrol. 2009;20(1):223-228. 2009, and Wu VC, et al., Kidney Int. 2011;80(11):1222-1230).

[0004] The need for KRT due to AKI after CPB occurs in approximately 2% of patients undergoing cardiac surgery (see, e.g., Hu J, et al., J. Cardiothorac. Vasc. Anesth. 2016;30(1):82-89), but appears to be increased in patients with underlying CKD, reaching 13.3% in severe CKD (see, e.g., Chawla LS, et al., J. Am. Soc. Nephrol. 2012;23(8):1389-1397; Mehta RH, et al., Circulation. 2006;114(21):2208-2216; Thakar CV, et al., Kidney Int. 2005;67(3):1112-1119; Thakar CV, et al., J. Am. Soc. Nephrol. 2005;16(1):162-168). In-hospital mortality is extremely high, ranging from 33% to >50% (e.g., Chawla LS, et al., J. Am. Soc. Nephrol. 2012; 23(8): 1389-1397; Dasta JF, et al., Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association-European Renal Association. 2008; 23(6): 1970-1974; Landoni G, et al., European Journal of Anaesthesiology. 2006; 23(1): 17-22), and Thakar CV, et al., Kidney Int. 2005; 67(3): 1112-1119; Thakar CV, et al. al., J. Am. Soc. Nephrol. 2005;16(1):162-168).

[0005] Multiple therapeutic approaches have failed to demonstrate a reduction in post-CPB AKI or the poor clinical outcomes associated with AKI, i.e., SKD at risk for progressive CKD, the need for KRT, and mortality (see, e.g., Schurle A, et al., J. Clin. Med. 2021;10(24)). There remains a high unmet medical need to develop therapies that reduce the risk and consequences of AKI in patients with CKD undergoing cardiac surgery on CPB. Therefore, an objective of the present disclosure is to provide improved methods for preventing and / or minimizing cardiac surgery-associated kidney injury (CSA-AKI) and / or subsequent major adverse kidney events (MAKE) in patients with CKD. Summary of the Invention

[0006] The present disclosure relates to compositions and methods for preventing and / or treating acute kidney injury (AKI) in human patients with chronic kidney disease (CKD) undergoing cardiopulmonary bypass (CPB). The methods improve upon existing therapeutic modalities, such as intraoperative and postoperative strategies, which are provided in an inpatient setting and target inflammatory mediators of AKI. In contrast to common methods for reducing AKI, the compositions and methods of the present disclosure can be administered in an outpatient setting and are effective in preventing AKI, significantly improving clinical outcomes, including reducing major adverse events and even death, in patients with unmet need.

[0007] Provided herein are methods involving preparing a human patient for surgery (e.g., cardiac surgery with cardiopulmonary bypass (CPB)) in specific subpopulations (e.g., human patients with renal disease, including chronic kidney disease (CKD)), comprising administering to the patient an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered (or is for administration) according to a specific clinical dosing regimen (e.g., in a single, weight-based dose) and according to a specific schedule (e.g., at least 1-7 calendar days prior to surgery).

[0008] Also provided herein are methods for inhibiting terminal complement activation in a human patient, methods for treating a human patient with CKD prior to cardiac surgery with CPB, methods for preventing or reducing (e.g., minimizing) cardiac surgery-associated acute kidney injury (CSA-AKI) in a human patient with CKD, and methods for preventing or reducing (e.g., minimizing) one or more major adverse renal events (MAKEs) in a human patient with CKD.

[0009] Any suitable anti-C5 antibody or antigen-binding fragment thereof can be used in the methods described herein. An exemplary anti-C5 antibody is ravulizumab (ULTOMIRIS®), comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively, or antigen-binding fragments and variants thereof. In other embodiments, the antibody comprises the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises the heavy chain constant region set forth in SEQ ID NO: 13.

[0010] In another embodiment, the antibody comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, of native human IgG Fc constant region according to EU numbering rules.

[0011] In another embodiment, the antibody comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, of native human IgG Fc constant region according to EU numbering conventions.

[0012] In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the BNJ421 antibody (described in WO 2015 / 134894 and U.S. Pat. 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 U.S. Pat. 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 U.S. Pat. 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 U.S. Pat. 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.

[0013] In another embodiment, the anti-C5 antibody is a biosimilar of eculizumab (SOLIRIS®). For example, in one embodiment, the anti-C5 antibody is, for example, ABP959 antibody (manufactured by Amgen Inc., USA), ELIZARIA® (manufactured by Generium JNC, Russia), SB12 (manufactured by Samsung Bioepis, Incheon, South Korea), ISU305 (eculizumab biosimilar from ISU Abxis, South Korea), ABLYZE® (eculizumab biosimilar from CinnaGen, Iran), BCD148 (eculizumab biosimilar from Biocad Medical, Quebec, Canada), tesidolumab (manufactured by Novartis), crovalimab (manufactured by Roche), CAN106 (manufactured by CanBridge Pharmaceuticals, China), or pozelimab (manufactured by Regeneron).

[0014] In another embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as any of the above-mentioned antibodies, hi another embodiment, the antibody has at least about 90% variable region amino acid sequence identity to any of the above-mentioned antibodies (e.g., at least about 90%, 95%, or 99% variable region identity to SEQ ID NO: 12 or SEQ ID NO: 8).

[0015] In another embodiment, the antibody has a K in the range 0.1 nM≦K at pH 7.4 and 25° C. D Affinity dissociation constant (K) ≦1 nM D In another embodiment, the antibody binds to human C5 with an affinity dissociation constant (K) of about 0.5 nM at pH 7.4 and 25°C. D In another embodiment, the antibody binds to human C5 at a K D In another embodiment, the antibody binds to human C5 with a K of about 22 nM at pH 6.0 and 25° C. DIn yet another embodiment, the K of the antibody or antigen-binding fragment thereof against human C5 at pH 6.0 and 25°C is D ) / (K of an antibody or antigen-binding fragment thereof against human C5 at pH 7.4 and 25°C D )] is over 25.

[0016] The methods described herein can be utilized in conjunction with any type of cardiac surgery. In another embodiment, the cardiac surgery is a coronary artery bypass graft (CABG). In another embodiment, the surgery is a valve replacement or repair. In another embodiment, the surgery is the insertion of a pacemaker or implantable cardioverter defibrillator (ICD). In another embodiment, the surgery is a Maze procedure. In another embodiment, the surgery is a heart transplant. In another embodiment, the surgery is the insertion of a ventricular assist device (VAD). In another embodiment, the surgery is the insertion of a total artificial heart (TAH). In another embodiment, the surgery is the insertion of a transcatheter structural heart procedure. In a specific embodiment, the surgery is cardiac surgery with CPB.

[0017] In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to the patient at least one calendar day prior to surgery (e.g., cardiac surgery with CPB). In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered 1 to 7 calendar days prior to surgery. For example, in one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered 1, 2, 3, 4, 5, 6, or 7 calendar days prior to surgery.

[0018] Anti-C5 antibodies or antigen-binding fragments thereof are administered to patients in weight-based doses (e.g., single, pre-operative weight-based doses) according to the methods described herein. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 2700 mg to a patient weighing ≥ 30 kg to < 40 kg. In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3300 mg to a patient weighing ≥ 60 kg to < 100 kg. In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3600 mg to a patient weighing ≥ 100 kg.

[0019] In one aspect, a method of preparing a human patient (e.g., a human patient with renal disease, including CKD) for surgery (e.g., cardiac surgery with CPB) is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once prior to the surgery.

[0020] In one embodiment, a method of preparing a human patient with CKD for cardiac surgery with CPB is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery. a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0021] In another aspect, a method is provided for inhibiting terminal complement activation in a human patient (e.g., a human patient with renal disease, including CKD) prior to surgery (e.g., cardiac surgery with CPB), the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once prior to surgery.

[0022] In one embodiment, a method of inhibiting terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery. a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0023] In some embodiments, terminal complement activation is inhibited in a human patient according to the methods described herein as assessed by any suitable assay. In one embodiment, the method inhibits terminal complement activation in a human patient by, for example, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0024] In another aspect, a method is provided for treating a human patient with renal disease (e.g., CKD) before cardiac surgery (e.g., by CPB), the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once before the surgery.

[0025] In one embodiment, a method of treating a human patient with CKD prior to cardiac surgery with CPB is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery. a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0026] In another aspect, a method for preventing or reducing (e.g., minimizing) CSA-AKI in a human patient with a renal disease (e.g., CKD), the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody or antigen-binding fragment thereof is administered once before cardiac surgery (e.g., by CPB).

[0027] In one embodiment, a method of preventing or reducing (e.g., minimizing) CSA-AKI in a human patient with CKD is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody or antigen-binding fragment thereof is administered prior to cardiac surgery (e.g., by CPB): a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0028] In another aspect, a method for preventing or reducing (e.g., minimizing) one or more MAKEs in a human patient with renal disease (e.g., CKD), the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody or antigen-binding fragment thereof is administered once before cardiac surgery (e.g., by CPB).

[0029] In one embodiment, a method is provided for preventing or reducing (e.g., minimizing) one or more MAKEs in a human patient with CKD, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody or antigen-binding fragment thereof is administered prior to cardiac surgery (e.g., by CPB): a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0030] In certain embodiments, the methods described herein provide an optimal desired response (e.g., inhibiting terminal complement activation in a human patient (e.g., a human patient with renal disease, including CKD) prior to surgery (e.g., cardiac surgery on CPB), preventing or reducing CSA-AKI in a human patient with renal disease (e.g., CKD) undergoing surgery (e.g., cardiac surgery on CPB), and / or preventing or reducing one or more MAKEs in a human patient with renal disease (e.g., CKD) undergoing surgery (e.g., cardiac surgery on CPB)).

[0031] In certain embodiments, the methods described herein are sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. For example, in one embodiment, the methods provide a serum trough concentration 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, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 500, 510, 520, 530, 540, 550, 560, 570, 58 15, 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, 400, 40 5, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575 , 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700 μg / mL or greater. In one embodiment, the method maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of at least 100 μg / mL, at least 150 μg / mL, at least 200 μg / mL, at least 250 μg / mL, at least 300 μg / mL, at least 350 μg / mL, at least 400 μg / mL, or at least 450 μg / mL. In another embodiment, the method maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof between 100 μg / mL and 700 μg / mL, preferably between 300 μg / mL and 600 μg / mL. In another embodiment, the method maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof between about 475 μg / mL.In another embodiment, the method comprises administering a concentration of about 1800, 1780, 1760, 1740, 1720, 1700, 1680, 1660, 1640, 1620, 1600, 1580, 1560, 1540, 1520, 1500, 1480, 1460, 1440, 1420, 1400, 1380, 1360, 1340, 132 ... In another embodiment, the method maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at or below 900 μg / mL, 1280 μg / mL, 1260 μg / mL, 1240 μg / mL, 1220 μg / mL, 1200 μg / mL, 1180 μg / mL, 1160 μg / mL, 1140 μg / mL, 1120 μg / mL, 1100 μg / mL, 1080 μg / mL, 1060 μg / mL, 1040 μg / mL, 1020 μg / mL, 1000 μg / mL, 980 μg / mL, 960 μg / mL, 940 μg / mL, 920 μg / mL, or 900 μg / mL. In another embodiment, the method maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 1350 μg / mL.

[0032] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered in a concentration of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 200 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 260 μg, 265 μg, 270 μg, 275 μg, 280 μg, 285 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 2 00μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 26 0μg, 270μg, 280μg, 290μg, 300μg, 320μg, 340μg, 360μg, 380μg, 400μg, 420μg, 440μg, 460 μg, 480μg, 500μg, 550μg, 600μg, 650μg, 700μg, 750μg, 800μg, 850μg, 900μg, 950μg, 1000

[0046] The antibody may be administered to a patient in an amount and frequency to maintain a constant antibody concentration of 1000 μg, 1050 μg, 1100 μg, 1150 μg, 1200 μg, 1250 μg, 1300 μg, 1350 μg, 1400 μg, 1450 μg, 1500 μg, 1550 μg, 1600 μg, 1650 μg, 1700 μg, 1750 μg or more, e.g., 1800 μg.

[0033] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to the patient in an amount and frequency sufficient to maintain a minimum free C5 concentration. In one embodiment, for example, the anti-C5 antibody or antigen-binding fragment thereof is administered to the patient in an amount and frequency sufficient to maintain a free C5 concentration of 0.5 μg / mL or less (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0034] The anti-C5 antibody or antigen-binding fragment thereof can be administered to the patient by any suitable means. In one embodiment, the antibody is formulated for intravenous administration.

[0035] The efficacy of the methods provided herein can be assessed using any suitable means, in one embodiment, a single pre-operative, weight-based dose of an anti-C5 antibody or antigen-binding fragment thereof results in complete C5 inhibition for at least 18 days.

[0036] In another embodiment, the method prevents the need for renal replacement therapy (KRT).

[0037] In another embodiment, the method prevents or reduces CSA-AKI in a human patient with CKD. In one embodiment, CSA-AKI is a) An increase in serum creatinine (sCr) or serum cystatin C (sCysC) of ≥ 0.3 mg / dL in a 48-hour period within 7 days after CPB, and / or b) Characterized by an increase in sCr or sCysC of ≥ 1.5-fold above baseline within 7 days post-CPB or at 15, 30, 60, or 90 days post-CPB.

[0038] In another embodiment, after treatment, the human patient: No severe CSA-AKI (stage 2 or 3) based on the highest sCr observed within 7, 30, 45, 60, or 90 days after CPB as assessed by modified Kidney Disease Improving Global Outcome (KDIGO) criteria.

[0039] In another embodiment, after treatment, the human patient does not have severe CSA-AKI based on the highest sCr observed within 7, 30, 45, 60, or 90 days after CPB as assessed by the modified Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) criteria.

[0040] In another embodiment, the method results in complete recovery from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, where complete recovery is characterized by an sCr<1.1×baseline.

[0041] In another embodiment, the method results in partial recovery from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, where partial recovery is characterized by an sCr≧1.1 to <1.5×baseline.

[0042] In another embodiment, the method results in improvement from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, where the improvement is characterized by an sCr≧1.5 to <2.0×baseline.

[0043] In another embodiment, the method results in stable CSA-AKI characterized by sCr≧2.0 to <3.0×baseline within 7, 30, 45, 60, or 90 days after surgery.

[0044] In another embodiment, the method prevents or reduces one or more MAKEs in a human patient with CKD. In one embodiment, the one or more MAKEs is persistent renal dysfunction (SKD), defined as an estimated glomerular filtration rate (eGFR) >25% below baseline after CPB, e.g., a decrease in eGFR determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on serum cystatin C (sCysC) or serum creatinine (sCr). In another embodiment, the one or more MAKEs is the occurrence of renal replacement therapy (KRT) after CPB. In another embodiment, the one or more MAKEs is death from any cause after CPB.

[0045] In another embodiment, the method results in a change from baseline in quality of life as assessed via a Quality of Life Assessment. For example, in one embodiment, the quality of life assessment is the Kidney Disease Quality of Life Index (KDQOL-36). In another embodiment, the quality of life assessment is the European Quality of Life Group's 5 dimension 5-level (EQ-5D-5L). In another embodiment, the quality of life assessment is the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale.

[0046] In another embodiment, the method results in a shift to normal levels of a biomarker associated with vascular inflammation (e.g., shed tumor necrosis factor receptor 1 (TNF-R1) or shed tumor necrosis factor receptor 1 (sTNF-R1)). In another embodiment, the method results in a shift to normal levels of a biomarker associated with endothelial injury and / or activation (e.g., thrombomodulin). In another embodiment, the method results in a shift to normal levels of a biomarker associated with kidney injury (e.g., neutrophil gelatinase-associated lipocalin (NGAL)). In another embodiment, the method results in a shift to normal levels of a biomarker associated with inducers of cell cycle arrest (e.g., tissue inhibitor of metalloproteinase-2 (TIMP-2)). In another embodiment, the method results in a shift to normal levels of complement proteins and complement activation pathway products (e.g., soluble C5b-9).

[0047] Further provided are kits that include a pharmaceutical composition containing an anti-C5 antibody or antigen-binding fragment thereof, such as eculizumab (SOLIRIS®) or ravulizumab (ULTOMIRIS®), in a therapeutically effective amount adapted for use in the methods described herein, and a pharmaceutically acceptable carrier.

[0048] In one embodiment, the kit comprises (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof, the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof in the methods described herein.

[0049] In another aspect, an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab (ULTOMIRIS®)) is provided for use in preparing a human patient with CKD for cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0050] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof is provided for use in inhibiting terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0051] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof is provided for use in treating a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0052] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof for use in preventing or reducing CSA-AKI in a human patient with CKD is provided, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0053] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof for use in preventing or reducing one or more MAKEs in a human patient with CKD is provided, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0054] In a further aspect, the present invention provides the use of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab (ULTOMIRIS®)) to prepare a human patient with CKD for cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0055] In one embodiment, there is provided a use of an anti-C5 antibody or antigen-binding fragment thereof to inhibit terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0056] In another embodiment, there is provided a use of an anti-C5 antibody or antigen-binding fragment thereof for the treatment of a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0057] In another embodiment, there is provided a use of an anti-C5 antibody or antigen-binding fragment thereof in preventing or reducing CSA-AKI in a human patient with CKD, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single unit dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0058] In another embodiment, there is provided a use of an anti-C5 antibody or antigen-binding fragment thereof in preventing or reducing one or more MAKEs in a human patient with chronic kidney disease, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery at a dose, e.g., a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) Use in patients weighing ≥ 100 kg, administered as a single unit dose of 3600 mg. [Brief explanation of the drawings]

[0059] [Figure 1] FIG. 1 is a schematic diagram of the clinical trial protocol. [Figure 2A]

[0023] Described below is a schedule of activities for the clinical trial protocol described in Example 1. The following abbreviations are used in the schedule of activities: ADA = anti-drug antibodies; AE = adverse events; AKI = acute kidney injury; CPB = cardiopulmonary bypass; CT = computed tomography; D and d = days; ECG = electrocardiogram; ED = premature discontinuation; eGFR = estimated glomerular filtration rate; EQ 5D 5L = European Quality of Life Group Five Dimensions 5 Levels; FACIT Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; ICU = intensive care unit; KDQOL36 = Kidney Disease Quality of Life Index-36 items; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; sCysC = serum cystatin C; RBC = red blood cells; STS = Society of Thoracic Surgeons; and WOCBP = women of childbearing potential. [Figure 2B]

[0023] Described below is a schedule of activities for the clinical trial protocol described in Example 1. The following abbreviations are used in the schedule of activities: ADA = anti-drug antibodies; AE = adverse events; AKI = acute kidney injury; CPB = cardiopulmonary bypass; CT = computed tomography; D and d = days; ECG = electrocardiogram; ED = premature discontinuation; eGFR = estimated glomerular filtration rate; EQ 5D 5L = European Quality of Life Group Five Dimensions 5 Levels; FACIT Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; ICU = intensive care unit; KDQOL36 = Kidney Disease Quality of Life Index-36 items; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; sCysC = serum cystatin C; RBC = red blood cells; STS = Society of Thoracic Surgeons; and WOCBP = women of childbearing potential. [Figure 2C]

[0023] Described below is a schedule of activities for the clinical trial protocol described in Example 1. The following abbreviations are used in the schedule of activities: ADA = anti-drug antibodies; AE = adverse events; AKI = acute kidney injury; CPB = cardiopulmonary bypass; CT = computed tomography; D and d = days; ECG = electrocardiogram; ED = premature discontinuation; eGFR = estimated glomerular filtration rate; EQ 5D 5L = European Quality of Life Group Five Dimensions 5 Levels; FACIT Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; ICU = intensive care unit; KDQOL36 = Kidney Disease Quality of Life Index-36 items; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; sCysC = serum cystatin C; RBC = red blood cells; STS = Society of Thoracic Surgeons; and WOCBP = women of childbearing potential. [Figure 2D]

[0023] Described below is a schedule of activities for the clinical trial protocol described in Example 1. The following abbreviations are used in the schedule of activities: ADA = anti-drug antibodies; AE = adverse events; AKI = acute kidney injury; CPB = cardiopulmonary bypass; CT = computed tomography; D and d = days; ECG = electrocardiogram; ED = premature discontinuation; eGFR = estimated glomerular filtration rate; EQ 5D 5L = European Quality of Life Group Five Dimensions 5 Levels; FACIT Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; ICU = intensive care unit; KDQOL36 = Kidney Disease Quality of Life Index-36 items; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; sCysC = serum cystatin C; RBC = red blood cells; STS = Society of Thoracic Surgeons; and WOCBP = women of childbearing potential. [Figure 2E]

[0023] Described below is a schedule of activities for the clinical trial protocol described in Example 1. The following abbreviations are used in the schedule of activities: ADA = anti-drug antibodies; AE = adverse events; AKI = acute kidney injury; CPB = cardiopulmonary bypass; CT = computed tomography; D and d = days; ECG = electrocardiogram; ED = premature discontinuation; eGFR = estimated glomerular filtration rate; EQ 5D 5L = European Quality of Life Group Five Dimensions 5 Levels; FACIT Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; ICU = intensive care unit; KDQOL36 = Kidney Disease Quality of Life Index-36 items; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; sCysC = serum cystatin C; RBC = red blood cells; STS = Society of Thoracic Surgeons; and WOCBP = women of childbearing potential. [Figure 2F]

[0023] Described below is a schedule of activities for the clinical trial protocol described in Example 1. The following abbreviations are used in the schedule of activities: ADA = anti-drug antibodies; AE = adverse events; AKI = acute kidney injury; CPB = cardiopulmonary bypass; CT = computed tomography; D and d = days; ECG = electrocardiogram; ED = premature discontinuation; eGFR = estimated glomerular filtration rate; EQ 5D 5L = European Quality of Life Group Five Dimensions 5 Levels; FACIT Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; ICU = intensive care unit; KDQOL36 = Kidney Disease Quality of Life Index-36 items; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; sCysC = serum cystatin C; RBC = red blood cells; STS = Society of Thoracic Surgeons; and WOCBP = women of childbearing potential. [Figure 2G-01]

[0023] Described below is a schedule of activities for the clinical trial protocol described in Example 1. The following abbreviations are used in the schedule of activities: ADA = anti-drug antibodies; AE = adverse events; AKI = acute kidney injury; CPB = cardiopulmonary bypass; CT = computed tomography; D and d = days; ECG = electrocardiogram; ED = premature discontinuation; eGFR = estimated glomerular filtration rate; EQ 5D 5L = European Quality of Life Group Five Dimensions 5 Levels; FACIT Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; ICU = intensive care unit; KDQOL36 = Kidney Disease Quality of Life Index-36 items; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; sCysC = serum cystatin C; RBC = red blood cells; STS = Society of Thoracic Surgeons; and WOCBP = women of childbearing potential. [Figure 2G-02]

[0023] Described below is a schedule of activities for the clinical trial protocol described in Example 1. The following abbreviations are used in the schedule of activities: ADA = anti-drug antibodies; AE = adverse events; AKI = acute kidney injury; CPB = cardiopulmonary bypass; CT = computed tomography; D and d = days; ECG = electrocardiogram; ED = premature discontinuation; eGFR = estimated glomerular filtration rate; EQ 5D 5L = European Quality of Life Group Five Dimensions 5 Levels; FACIT Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; ICU = intensive care unit; KDQOL36 = Kidney Disease Quality of Life Index-36 items; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; pRBC = packed red blood cells; sCysC = serum cystatin C; RBC = red blood cells; STS = Society of Thoracic Surgeons; and WOCBP = women of childbearing potential. DETAILED DESCRIPTION OF THE INVENTION

[0060] I. Definition As used herein, the term "subject" or "patient" refers to a human patient (eg, a patient with a kidney disease, eg, chronic kidney disease).

[0061] As used herein, the term "pediatric" patient is a human patient who has been classified by a physician or caregiver as belonging to a non-adult category and may include, for example, newborns (both preterm and full-term), infants, children, and adolescents. Typically, a pediatric patient is a patient under the age of 18 (<18 years old).

[0062] As used herein, the term "adult" patient is a human patient who has been classified as such by a physician or caregiver, e.g., a person who is not a neonate, infant, child, or adolescent, e.g., based on age, developmental status, physiological characteristics, etc. Typically, an adult patient is a patient who is 18 years of age or older (≧18 years of age).

[0063] As used herein, the phrase "chronic kidney disease" (CKD) (also known as chronic kidney disease) refers to a condition characterized by the gradual loss of kidney function over time. Diabetes and high blood pressure or hypertension are responsible for two-thirds of chronic kidney disease cases. Other conditions or circumstances that can cause kidney disease include, but are not limited to, glomerulonephritis, genetic disorders (e.g., polycystic kidney disease (PKD)), prenatal abnormalities of the kidneys and urinary tract, autoimmune diseases, or other causes, such as blockages caused by kidney stones or tumors, prostate enlargement in men, or recurrent urinary tract infections. Symptoms of CKD include, but are not limited to, fatigue and decreased energy, difficulty concentrating, loss of appetite, sleep disturbances, nighttime muscle cramps, swelling of the feet and ankles, swelling around the eyes, dry, itchy skin, and / or the need to urinate more frequently, especially at night.

[0064] CKD is often diagnosed by one or more of the following tests. One test is an albumin-to-creatine ratio urine test. Albumin is a protein that should not be found in urine and indicates problems with kidney function. Another test is a creatinine blood test. This test determines if there is too much creatinine (a waste product) in the blood. A third option is to test the patient's glomerular filtration rate (GFR). GFR is calculated using the results from the test and other factors such as age and gender. GFR results are the best way to measure a patient's level of kidney function and determine the stage of kidney disease.

[0065] As used herein, the phrase "major adverse renal event" (MAKE) refers to (1) persistent renal dysfunction (SKD), defined as an estimated glomerular filtration rate (eGFR) >25% lower than baseline after CPB (e.g., reduction in eGFR determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on serum cystatin C (sCysC) or serum creatinine (sCr)), (2) the occurrence of renal replacement therapy (KRT) after CPB, and / or (3) death from any cause after CPB.

[0066] As used herein, the phrase "cardiac-associated acute kidney injury" (CSA-AKI) refers to an event characterized by a rapid deterioration of renal function after cardiac surgery, as evidenced by a reduction in glomerular filtration rate (GFR). CSA-AKI is the second most common cause of AKI in the intensive care setting and is associated with increased mortality. The pathophysiology of CSA-AKI is highly complex and likely involves renal ischemia-reperfusion injury, inflammation, oxidative stress, hemolysis, and / or nephrotoxins. CSA-AKI is characterized by an increase in serum creatinine (sCr) or serum cystatin C (sCysC) of ≥ 0.3 mg / dL in a 48-hour period within 7 days after CPB, and / or an increase in sCr or sCysC of ≥ 1.5 times baseline within 7 days after CPB. Severe CSA-AKI refers to stage 2 or 3 according to the modified Kidney Disease International Outcomes Improvement Committee (KDIGO) criteria. Human patients are considered not to have severe CSA-AKI based on the highest sCr observed after CPB (e.g., within 7, 30, 45, 60, or 90 days after CPB) as assessed by the modified "Risk, Injury, Failure, Loss of Renal Function, and End-Stage Renal Disease" (RIFLE) criteria. Complete recovery from CSA-AKI is characterized by an sCr < 1.1 × baseline after CPB (e.g., within 7, 30, 45, 60, or 90 days after CPB). Partial recovery from CSA-AKI is characterized by an sCr ≥ 1.1 to < 1.5 x baseline (e.g., within 7, 30, 45, 60, or 90 days after CPB). Improvement from CSA-AKI is characterized by an sCr ≥ 1.5 to < 2.0 x baseline (e.g., within 7, 30, 45, 60, or 90 days after CPB). Stable CSA-AKI is characterized by an sCr ≥ 2.0 to < 3.0 x baseline (e.g., within 7, 30, 45, 60, or 90 days after CPB).

[0067] As used herein, the phrase "cardiac surgery" (also known as cardiovascular surgery or heart surgery) refers to any surgical procedure involving the heart or the blood vessels that carry blood to and from the heart. Examples of cardiac surgery include, but are not limited to, coronary artery bypass grafting (CABG), valve replacement or repair, insertion of a pacemaker or implantable cardioverter defibrillator (ICD), Maze surgery, heart transplantation, and insertion of a ventricular assist device (VAD) or total artificial heart (TAH), and transcatheter structural heart surgery.

[0068] CABG (also known as cardiac bypass or coronary artery bypass surgery) is one of the most common types of heart surgery and involves removing a healthy artery or vein from elsewhere in the body and connecting it to provide blood flow past a blocked coronary artery. The transplanted artery or vein bypasses the blocked section of the coronary artery, creating a new pathway for blood to flow to the heart muscle. Often, this is done on two or more coronary arteries during the same surgery.

[0069] In heart valve repair or replacement, surgeons either repair the valve or replace it with an artificial valve or a biological valve made from porcine, bovine, or human heart tissue. One repair option is to insert a catheter through a large blood vessel, guide it to the heart, and inflate and deflate a small balloon at the tip of the catheter to open up the narrow valve.

[0070] Medications are usually the first treatment option for conditions involving arrhythmias, heartbeats that are too fast, too slow, or irregular. If medications fail, surgeons can implant a pacemaker, or ICD, under the skin in the chest or abdomen, along with wires connecting it to the ventricles. This device uses electrical pulses to control the heart rhythm when sensors detect that the heart rhythm is abnormal. ICDs function similarly, but deliver an electrical shock to restore a normal rhythm when they detect a dangerous arrhythmia.

[0071] In the Maze procedure, surgeons create a pattern of scar tissue in the upper chambers of the heart to redirect electrical signals along a controlled pathway to the lower ventricles. The procedure blocks stray electrical signals that cause atrial fibrillation, the most common type of serious arrhythmia.

[0072] During aneurysm repair, a weakened section of the artery or heart wall is replaced with a patch or graft to repair a balloon-like bulge in the artery or wall of the heart muscle.

[0073] During a heart transplant, the diseased heart is removed and replaced with a healthy heart from a deceased donor.

[0074] A VAD is a mechanical pump that supports heart function and blood flow. A TAH replaces the two lower chambers of the heart.

[0075] In addition to these procedures, a minimally invasive alternative to open-heart surgery that is becoming more common is transcatheter structural heart surgery. This involves guiding a long, thin, flexible tube called a catheter into the heart through a blood vessel that can be accessed through the groin, thigh, abdomen, chest, neck, or collarbone. A small incision is required. This type of surgery includes transcatheter aortic valve implantation to replace a defective aortic valve with a valve made from animal tissue, MitraClip® placement for mitral valve abnormalities, and WATCHMAN® placement for patients with non-valvular atrial fibrillation.

[0076] As used herein, "cardiopulmonary bypass" (CPB) refers to a heart-lung machine used during cardiac surgery. CPB provides cardiac and pulmonary support to a patient while bypassing the heart and lungs. CPB artificially provides three physiological processes or functions for the patient: (1) oxygenating the blood, (2) pumping or circulating the blood through both the cardiopulmonary bypass circuit and the patient, and (3) removing excess carbon dioxide from the blood. To accomplish this, a surgeon inserts cannulae into the patient's major veins (typically the superior vena cava and inferior vena cava) and arteries (typically the aorta). When the patient's cannulae are connected to the cardiopulmonary bypass circuit, blood is drained from the veins into the heart-lung machine while it is pumped into the oxygenator (oxygenator), which adds oxygen and removes carbon dioxide. The oxygenated blood is then pumped back into the aorta to provide oxygen to the patient's tissues and organs. CPB may include a sternotomy and / or aortic cross-clamp.

[0077] As used herein, "effective treatment" refers to treatment that results in a beneficial effect, e.g., an improvement in at least one symptom of a disease or disorder. The beneficial effect can take the form of an improvement over baseline, e.g., an improvement over a measurement or observation made before initiation of therapy according to the method.

[0078] The term "effective amount" refers to an amount of an agent that provides a desired result (e.g., biological, therapeutic, and / or prophylactic result). That result can be prevention, reduction, amelioration, amelioration, delay, and / or alleviation of one or more of the events or signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An effective amount can be administered in one or more administrations.

[0079] As used herein, the term "serum trough level" refers to the lowest level at which a drug (e.g., an anti-C5 antibody or antigen-binding fragment thereof) or medication is present in the serum. In contrast, "peak serum level" refers to the highest level of a drug in the serum. "Mean serum level" refers to the average level of a drug in the serum over time.

[0080] The term "antibody" describes a polypeptide comprising at least one antibody-derived antigen-binding site (e.g., a VH / VL region or Fv, or a CDR). Antibodies include known forms of antibodies; for example, an antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. An antibody can also be a Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or single-domain antibody. An antibody can also be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, IgE, or a combination thereof. An antibody can be a naturally occurring antibody or an antibody that has been modified by protein engineering techniques (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). An antibody can comprise one or more variant amino acids (compared to a naturally occurring antibody) that, for example, alters the properties (e.g., functional properties) of the antibody. Many such modifications are known in the art that affect, for example, the half-life, effector functions, and / or the immune response to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that contain at least one antibody-derived antigen-binding site.

[0081] II. Anti-C5 antibody The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit cleavage of C5 into fragments C5a and C5b. As described above, such antibodies also have improved pharmacokinetic properties compared to, for example, other anti-C5 antibodies used for therapeutic purposes (e.g., eculizumab).

[0082] 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 with any of these art-recognized antibodies or the antibodies described herein for binding to C5 can also be used.

[0083] An exemplary anti-C5 antibody is ravulizumab, or an antigen-binding fragment or variant thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively. Ravulizumab (also known as ULTOMIRIS®, BNJ441, and ALXN1210) is described in WO 2015 / 134894 and U.S. Patent No. 9,079,949, the entire teachings of which are incorporated herein by reference. The terms ravulizumab, BNJ441, and ALXN1210 may be used interchangeably throughout this specification and all refer to the same antibody. Ravulizumab selectively binds to the human complement protein C5 and inhibits its cleavage into C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9, while preserving the proximal or early components of complement activation (e.g., C3 and C3b) essential for microbial opsonization and immune complex clearance.

[0084] The polypeptide sequence of ravulizumab registered in the KEGG DRUG database (https: / / www.kegg.jp / entry / D11054) provides that the N-terminal amino acid of the variable heavy chain is "X," but the database does not state what X is. The Chemical Abstracts (CAS) for ravulizumab (CAS 1803171-55-2) also provides that the N-terminal X is pyroglutamic acid (designated "chain 1 pyroglutamic acid-1" in the CAS report). This information may appear to be different from the VH sequence of ravulizumab, e.g., a heavy chain variable region polypeptide comprising the amino acids set forth in SEQ ID NO: 12 and / or a heavy chain polypeptide comprising the amino acids set forth in SEQ ID NO: 14, but may be different from the VH sequence of ravulizumab, e.g., a heavy chain variable region polypeptide comprising the amino acids set forth in SEQ ID NO: 14, where the N-terminal Q in the polypeptide and / or antibody sequence cyclizes during process development to form the VH sequence of ravulizumab, e.g., a heavy chain variable region polypeptide comprising the amino acids set forth in SEQ ID NO: 12 and / or a heavy chain polypeptide comprising the amino acids set forth in SEQ ID NO: 14, as described by Liu et al. (J Pharm Sci. 2019 Oct;108(10):3194-3200) https: / / pubmed.ncbi.nlm.nih.gov / 31145921 / and Nguyen et al. (Int. J. Mol. Sci. 2017 Jul 20;18(7):1575) There is an alignment between the patent sequence and the drug database / CAS sequence as it is recognized in the art to result in nearly 100% conversion of the drug product to pyroglutamate (Pryo-Q) as disclosed in https: / / www.researchgate.net / figure / Cyclization-reactions-of-N-terminal-glutamine-and-glutamate-residues-in-a-polypeptide_fig4_318926365.Additional information is provided on page 7 and Table 4 of Xu et al. (MAbs, 2019 Feb / Mar;11(2):239-264), as well as the following referenced publications: (1) Yu et al., "Investigation of N-terminal glutamate cyclization of recombinant monoclonal antibody in formulation development," J. Pharm. Biomed. Anal., 2006, 42, 455-463, and Dick et al., "Determination of the origin of the N-terminal pyro-glutamate variation in monoclonal antibodies using model peptides," Biotechnol. Bioeng., 2007, 97, 544-553, the disclosures of which are incorporated by reference in their entireties.

[0085] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Thus, 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.

[0086] Another exemplary anti-C5 antibody is antibody BNJ421, or antigen-binding fragments and variants thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively. BNJ421 (also known as ALXN1211) is described in WO 2015 / 134894 and U.S. Pat. No. 9,079,949, the teachings of which are incorporated herein by reference in their entireties.

[0087] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises 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.

[0088] The exact boundaries of CDRs are defined differently according to different methods. In some embodiments, the locations of 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, USDapartment of Health and Human Services, Bethesda, MD]. In such cases, the CDRs may be referred to as "Kabat CDRs" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In some embodiments, the locations of the CDRs of a light or heavy chain variable region are as defined by Chothia et al. (Nature, 342:877-83, 1989). Accordingly, these regions may be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the locations of the CDRs of light and heavy chain variable regions may be defined by the combined Kabat-Chothia definition. In such embodiments, these regions may be referred to as “combined Kabat-Chothia CDRs.” Thomas, C. et al. (Mol. Immunol., 33:1389-401, 1996) provides examples of identifying CDR boundaries according to the Kabat and Chothia numbering schemes.

[0089] Another exemplary anti-C5 antibody is the 7086 antibody, described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 24, 25, and 26, respectively. In another embodiment, the antibody or antigen-binding fragment thereof comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO: 27, and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO: 28.

[0090] Another exemplary anti-C5 antibody is the 8110 antibody, which is also described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 29, 30, and 31, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 32, 33, and 34, respectively. In another embodiment, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO: 35, and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO: 36.

[0091] Another exemplary anti-C5 antibody is the 305LO5 antibody described in U.S. Patent No. 9,765,135. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 37, 38, and 39, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 40, 41, and 42, respectively. In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence set forth in SEQ ID NO: 43, and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO: 44.

[0092] Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. et al., Sci. Rep., 7:1080, 2017). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 45 and a light chain comprising SEQ ID NO: 46.

[0093] 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 U.S. Patent No. 10,633,434). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises the heavy chain variable region sequence set forth in SEQ ID NO: 47 and the 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 the heavy chain sequence set forth in SEQ ID NO: 49 and the light chain sequence set forth in SEQ ID NO: 50.

[0094] In another embodiment, the anti-C5 antibody is a biosimilar to eculizumab (SOLIRIS®). For example, in one embodiment, the anti-C5 antibody is, for example, ABP959 antibody (eculizumab biosimilar from Amgen Inc., USA), ELIZARIA® (eculizumab biosimilar from Generium JNC, Russia), SB12 (eculizumab biosimilar from Samsung Bioepis, Incheon, South Korea), ISU305 (eculizumab biosimilar from ISU Abxis, South Korea), ABLYZE® (eculizumab biosimilar from CinnaGen, Iran), BCD148 (eculizumab biosimilar from Biocad Medical, Quebec, Canada), Tesidolumab (from Novartis), Crovalimab (from Roche), CAN106 (from CanBridge Pharmaceuticals, China), or Pozelimab (from Regeneron).

[0095] In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR1 comprising or consisting of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR2 comprising or consisting of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain variable region comprising the following amino acid sequence:

[0096] [Table 1]

[0097] In some embodiments, the anti-C5 antibodies described herein comprise a light chain variable region comprising the following amino acid sequence:

[0098] [Table 2]

[0099] In some embodiments, the anti-C5 antibodies described herein can comprise a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with higher affinity than the affinity of the native human Fc constant region from which the variant human Fc constant region is derived. The Fc constant region can comprise one or more (e.g., two, three, four, five, six, seven, or eight or more) amino acid substitutions, for example, compared to the native human Fc constant region from which the variant human Fc constant region is derived. The substitutions can increase the binding affinity of an IgG antibody containing the variant Fc constant region for FcRn at pH 6.0 while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining the pH dependence of the interaction) are known in the art and are exemplified in the Examples. See, for example, WO 2015 / 134894 and U.S. Pat. No. 9,079,949, the disclosures of each of which are incorporated herein by reference in their entirety.

[0100] Substitutions that enhance the binding affinity of antibody Fc constant regions to FcRn are known in the art, and include, for example, (1) M252Y / S254T / T256E triple substitutions (Dall'Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) 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) N434A or T307 / E380A / N434A substitutions (Petkova, S. et al., J. Immunol., 176:346-56, 2006). al., Int. Immunol., 18:1759-69, 2006). Additional substitution pairings include: P257I / Q311I, P257I / N434H, and D376V / N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007), the disclosures of each of which are incorporated herein by reference in their entirety.

[0101] 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.

[0102] In some embodiments, the variant Fc constant region comprises 30 or fewer (e.g., 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 or fewer) amino acid substitutions, insertions, or deletions compared to the native constant region from which it is derived. In some embodiments, the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of M252Y, S254T, T256E, N434S, M428L, V259I, T250I, and V308F. In some embodiments, the variant human Fc constant region comprises a methionine at position 428 and an asparagine at position 434 of the native human IgG Fc constant region, each according to EU numbering. In some embodiments, the variant Fc constant region comprises a 428L / 434S double substitution, for example, as described in US Pat. No. 8,088,376.

[0103] In some embodiments, the exact positions of these mutations may be shifted from those of the native human Fc constant region due to antibody engineering. For example, the 428L / 434S double substitution, when used in an IgG2 / 4 chimeric Fc, can correspond to 429L and 435S as in the M429L and N435S variant found in ravulizumab and described in U.S. Patent No. 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.

[0104] 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) compared to a native human Fc constant region. In some embodiments, the substitutions are: 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; and alanine, glycine, isoleucine, leucine, methionine for proline at position 257, all in EU numbering. , asparagine, serine, threonine, or valine; 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;at position 308, alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine instead of valine; at position 309, alanine, aspartic acid, glutamic acid, proline, or arginine instead of leucine or valine; at position 311, alanine, histidine, or isoleucine instead of glutamine; at position 312, alanine or histidine instead of aspartic acid; at position 314, lysine or arginine instead of leucine; at position 315, alanine or histidine instead of asparagine; at position 317, alanine instead of lysine; at position 325, glycine instead of asparagine; at position 332, valine instead of isoleucine; at position 334, leucine instead of lysine; at position 360, histidine instead of lysine; at position 376, alanine instead of aspartic acid; at position 380, alanine instead of glutamic acid; at position 382, alanine for glutamic acid at position 384; 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.

[0105] 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, 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: 20 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0106] In one embodiment, the antibody has an affinity dissociation constant (K) of at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, or 0.975) nM at pH 7.4 and 25°C (and otherwise under physiological conditions). D In one embodiment, the antibody binds to C5 with an affinity dissociation constant (K) of about 0.5 nM at pH 7.4 and 25° C. (and otherwise under physiological conditions). D In some embodiments, the K D is 1 nM or less (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 nM or less). In some embodiments, the antibody has a K at pH 6.0 and 25° C. (and otherwise under physiological conditions) that is about 22 nM. D binds to C5.

[0107] In another embodiment, the K of an antibody against C5 at pH 6.0 and 25°C D ) / (K of antibody against C5 at pH 7.4 and 25°C D)] is greater than 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910 (greater than 0, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, or 8000).

[0108] Methods for determining whether an antibody binds to a protein antigen and / or the affinity of an antibody for a protein antigen are known in the art. Binding of antibodies to protein antigens can be detected and / or quantified using a variety of techniques, including, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme-linked immunosorbent assay (ELISA; Benny KC Lo (2004) "Antibody Engineering: Methods and Protocols," Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160:191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Jonsson, U. et al., Biotechniques, 11:620-7, 1991). In addition, methods for measuring affinity (eg, dissociation and association constants) are described in the Examples.

[0109] As used herein, "k a The term "k" refers to the rate constant for the association of an antibody to an antigen. dThe term "K" refers to the rate constant for dissociation of an antibody from the antibody / antigen complex. D The term "antibody-antigen interaction" refers to the equilibrium dissociation constant of the antibody-antigen interaction. The equilibrium dissociation constant is the ratio of the kinetic rate constants, K D =k a / k d Such determinations can be made, for example, at 25° C. or 37° C. The kinetics of antibody binding to human C5 can be determined, for example, via SPR on a BIAcore 3000 instrument using an anti-Fc capture method to immobilize the antibody at pH 8.0, 7.4, 7.0, 6.5, and 6.0.

[0110] In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof blocks the cleavage of C5 into C5a and C5b, which inhibits, for example, the pro-inflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) on the surface of cells.

[0111] 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 cytolytic ability of complement in a subject's body fluid. Such a reduction in the cytolytic ability of complement present in a body fluid can be measured, for example, by a conventional hemolytic assay, such as a hemolytic assay (Kabat and Mayer (eds.), "Experimental Immunochemistry, 2002, Vol. 1, No. 1, pp. 111-114, 2002). ndEdition," 135-240, Springfield, IL, CC Thomas (1961), pages 135-139), or conventional modifications 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 the forms C5a and C5b are known in the art (Evans, M. et al., Mol. Immunol., 32:1183-95, 1995). The concentrations and / or physiological activities of C5a and C5b in body fluids can be measured, for example, by methods known in the art. For C5b, a hemolytic assay or the assay for soluble C5b-9 discussed herein can be used. Other assays known in the art can also be used. These or other suitable types of assays can be used to screen candidate agents capable of inhibiting human complement component C5.

[0112] Immunological techniques, such as, but not limited to, ELISA, can be used to measure protein concentrations of C5 and / or its cleavage products to determine the ability of anti-C5 antibodies or antigen-binding fragments thereof to inhibit the conversion of C5 to biologically active products. In some embodiments, C5a production is measured. In some embodiments, a C5b-9 neoepitope-specific antibody is used to detect MAC formation.

[0113] A hemolytic assay can be used to determine the inhibitory activity of an anti-C5 antibody or its antigen-binding fragment on complement activation. To determine the effect of an anti-C5 antibody or its antigen-binding fragment on classical complement pathway-mediated hemolysis in an in vitro serum test solution, for example, sheep red blood cells coated with hemolysin or chicken red blood cells sensitized with anti-chicken red blood cell antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis to be equal to the lysis occurring in the absence of an inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, such as that used in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or its antigen-binding fragment in the presence of a human IgM antibody. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring absorbance at an appropriate wavelength. As a control, test serum is incubated in the absence of anti-C5 antibody or an antigen-binding fragment thereof. In some embodiments, the test serum is C5-deficient serum reconstituted with C5 polypeptide.

[0114] To determine the effect of anti-C5 antibodies or their antigen-binding fragments on alternative pathway-mediated hemolysis, naive rabbit or guinea pig red blood cells can be used as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis to be equal to the lysis occurring in the absence of an inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, such as those utilized in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, test serum is incubated with anti-C5 antibodies or their antigen-binding fragments in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring fluorescence at an appropriate wavelength. As a control, test sera are incubated in the absence of anti-C5 antibody or antigen-binding fragment thereof.

[0115] In some embodiments, C5 activity or its inhibition is quantified using a CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. This test is a lytic assay that uses antibody-sensitized red blood cells as classical complement pathway activators and various dilutions of test serum to determine the amount required to give 50% lysis (CH50). Percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, since TCC itself is directly involved in the hemolysis measured. The assay is known and commonly performed by those skilled in the art. Briefly, to activate the classical complement pathway, an undiluted serum sample (e.g., a reconstituted human serum sample) is added to a microassay well containing antibody-sensitized red blood cells, thereby generating TCC. The activated serum is then diluted in a microassay well coated with a capture reagent (e.g., an antibody that binds to one or more components of TCC). TCC present in the activated sample binds to the monoclonal antibody coating the surface of the microassay well. The wells are washed, and a detectably labeled detection reagent that recognizes the bound TCC is added to each well. The detectable label can be, for example, a fluorescent label or an enzyme label. Assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).

[0116] Inhibition, e.g., when it relates to terminal complement activity, includes at least a 5% (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60%) decrease in terminal complement activity in, e.g., a hemolytic assay or a CH50eq assay, compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at an equimolar concentration. Substantial inhibition, as used herein, refers to at least 40% (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% or more) inhibition of a given activity (e.g., terminal complement activity). In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions compared to the CDRs of eculizumab (i.e., SEQ ID NOS: 1-6), but retain at least 30% (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%) of the complement inhibitory activity of eculizumab in a hemolytic assay or a CH50eq assay.

[0117] The anti-C5 antibodies described herein have a serum half-life in humans that is at least 20 days (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 days). In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans that is at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans that is about 43 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans that is 39-48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibodies or antigen-binding fragments thereof described herein have a serum half-life that is at least 20 (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, or 500)% greater than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the Examples (e.g., a C5-deficient / NOD / scid mouse or an hFcRn transgenic mouse model system).

[0118] In one embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as the antibodies described herein. The term "binds to the same epitope" with respect 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 an antibody binds to the same epitope on C5 as the antibodies described herein include, for example, x-ray analysis of a crystal of the antigen:antibody complex and epitope mapping methods such as hydrogen / deuterium exchange mass spectrometry (HDX-MS). Antibodies with the same VH and VL or the same CDR1, CDR2, and CDR3 sequences are expected to bind to the same epitope.

[0119] An antibody that "competes with another antibody for binding to a target" refers to an antibody that inhibits (partially or completely) the binding of the other antibody to a target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition experiments. In certain embodiments, an antibody competes with the binding of another antibody to a target and inhibits it by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition can vary depending on which antibody is the "blocking antibody" (i.e., the antibody that is first incubated with the target). Competing antibodies can, for example, bind to the same epitope, overlapping epitopes, or adjacent epitopes (e.g., as evidenced by steric hindrance).

[0120] The anti-C5 antibodies or antigen-binding fragments thereof described herein used in the methods described herein can be produced using a variety of art-recognized techniques. Monoclonal antibodies can be obtained by a variety of techniques well known to those skilled in the art. Briefly, spleen cells from animals immunized with a desired antigen are immortalized, typically by fusion with myeloma cells (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 to the antigen, and the yield of monoclonal antibodies produced by such cells can be enhanced by a variety of techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or binding fragments thereof can be isolated by screening DNA libraries from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0121] III. Composition Also provided herein are compositions comprising an anti-C5 antibody or an antigen-binding fragment thereof. In one embodiment, the composition comprises an anti-C5 antibody or an antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively.

[0122] The composition can be formulated, for example, as a pharmaceutical solution for administration to a subject according to any of the methods described herein. Pharmaceutical compositions generally contain a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to and includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible. The composition can include pharmaceutically acceptable salts, such as acid addition salts or base addition salts, sugars, carbohydrates, polyols, and / or tonicity adjusting agents.

[0123] Compositions can be formulated according to standard methods. Pharmaceutical formulation is a well-established technique (see, e.g., Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20 th Edition, Lippincott, Williams & Wilkins (ISBN:0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7 thEdition, Lippincott Williams & Wilkins Publishers (ISBN:0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3 rd (See, for example, the "Issue of the Invention" Edition (ISBN: 091733096X)). In some embodiments, the compositions can be formulated, for example, as a buffer solution at a suitable concentration and suitable for storage at 2-8°C (e.g., 4°C). In some embodiments, the compositions can be formulated for storage at temperatures below 0°C (e.g., -20°C or -80°C). In some embodiments, the compositions can be formulated for storage at 2-8°C (e.g., 4°C) for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years). Thus, in some embodiments, the compositions described herein are stable upon storage at 2-8°C (e.g., 4°C) for at least 1 year.

[0124] Pharmaceutical compositions can be in various forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. Compositions containing compositions intended for systemic or local delivery can be, for example, in the form of an injectable or infusible solution. Thus, the composition can be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). The terms "parenteral administration," "parenterally administered," and other grammatically equivalent phrases, as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.

[0125] IV. Method Provided herein are methods involving preparing a human patient for surgery (e.g., cardiac surgery with cardiopulmonary bypass (CPB)) in specific subpopulations (e.g., human patients with renal disease, including chronic kidney disease (CKD)), methods of inhibiting terminal complement activation in a human patient, methods of treating a human patient with CKD prior to cardiac surgery with CPB, methods of preventing or reducing (e.g., minimizing) cardiac surgery-associated acute kidney injury (CSA-AKI) in a human patient with CKD, and methods of preventing or reducing (e.g., minimizing) one or more MAKEs in a human patient with CKD.

[0126] In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. For example, in one embodiment, a 2700 mg dose of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 kg to < 40 kg. In another embodiment, a 3000 mg dose of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, a 3300 mg dose of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 kg to < 100 kg. In another embodiment, a 3600 mg dose of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg. In certain embodiments, the dosing regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0127] In one aspect, a method of preparing a human patient (e.g., a human patient having renal disease, including CKD) for surgery (e.g., cardiac surgery with CPB) is provided, the method comprising administering an effective amount of an anti-C5 antibody or antigen-binding fragment thereof to the patient, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once prior to the surgery.

[0128] In another embodiment, a method of preparing a human patient (e.g., a human patient with renal disease, including CKD) for surgery (e.g., cardiac surgery with CPB) is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once before the surgery.

[0129] In another embodiment, a method of preparing a human patient having CKD for cardiac surgery with CPB is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery. e) 2700 mg for patients weighing ≥ 30 kg to < 40 kg f) 3000 mg for patients weighing ≥ 40 kg to < 60 kg g) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or h) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0130] In another aspect, a method is provided for inhibiting terminal complement activation in a human patient (e.g., a human patient having renal disease, including CKD) prior to surgery (e.g., cardiac surgery with CPB), the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once prior to the surgery.

[0131] In one embodiment, a method for inhibiting terminal complement activation in a human patient (e.g., a human patient with renal disease, including CKD) prior to surgery (e.g., cardiac surgery with CPB) is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once prior to surgery.

[0132] In another embodiment, a method of inhibiting terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery. a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0133] In some embodiments, terminal complement activation is inhibited in a human patient according to the methods described herein as assessed by any suitable assay. In one embodiment, the method inhibits terminal complement activation in a human patient by, for example, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0134] In another aspect, a method is provided for treating a human patient having renal disease (e.g., CKD) prior to cardiac surgery (e.g., by CPB), the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once prior to the surgery.

[0135] In one embodiment, a method is provided for treating a human patient with renal disease (e.g., CKD) before cardiac surgery (e.g., by CPB), the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once before the surgery.

[0136] In another embodiment, a method of treating a human patient with CKD prior to cardiac surgery with CPB is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery. a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0137] In another aspect, a method of preventing or reducing CSA-AKI in a human patient with renal disease (e.g., CKD) is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once prior to cardiac surgery (e.g., by CPB).

[0138] In one embodiment, a method for preventing or reducing CSA-AKI in a human patient with a kidney disease (e.g., CKD) is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody or antigen-binding fragment thereof is administered once before cardiac surgery (e.g., by CPB).

[0139] In another embodiment, a method for preventing or reducing CSA-AKI in a human patient with CKD is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody or antigen-binding fragment thereof is administered prior to cardiac surgery (e.g., by CPB): a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0140] In another aspect, a method of preventing or reducing one or more MAKEs in a human patient having a kidney disease (e.g., CKD) is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered once prior to cardiac surgery (e.g., by CPB).

[0141] In one embodiment, a method for preventing or reducing one or more MAKEs in a human patient with a renal disease (e.g., CKD) is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody or antigen-binding fragment thereof is administered once before cardiac surgery (e.g., by CPB).

[0142] In another embodiment, a method for preventing or reducing one or more MAKEs in a human patient with CKD is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and the anti-C5 antibody or antigen-binding fragment thereof is administered prior to cardiac surgery (e.g., by CPB): a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0143] In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to the patient at least one calendar day prior to surgery (e.g., cardiac surgery with CPB). In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered 1 to 7 calendar days prior to surgery. For example, in one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered 1, 2, 3, 4, 5, 6, or 7 calendar days prior to surgery.

[0144] V. Outcomes In certain embodiments, the methods described herein provide an optimal desired response (e.g., inhibiting terminal complement activation in a human patient (e.g., a human patient with renal disease, including CKD) prior to surgery (e.g., cardiac surgery on CPB), preventing or reducing CSA-AKI in a human patient with renal disease (e.g., CKD) undergoing surgery (e.g., cardiac surgery on CPB), and / or preventing or reducing one or more MAKEs in a human patient with renal disease (e.g., CKD) undergoing surgery (e.g., cardiac surgery on CPB)).

[0145] In certain embodiments, the methods described herein are sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. For example, in one embodiment, the methods provide a serum trough concentration 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, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 500, 510, 520, 530, 540, 550, 560, 570, 58 15, 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, 400, 40 5, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575 , 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700 μg / mL or greater. In one embodiment, the method maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of at least 100 μg / mL, at least 150 μg / mL, at least 200 μg / mL, at least 250 μg / mL, at least 300 μg / mL, at least 350 μg / mL, at least 400 μg / mL, or at least 450 μg / mL. In another embodiment, the method maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof between 100 μg / mL and 700 μg / mL, preferably between 300 μg / mL and 600 μg / mL. In another embodiment, the method maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof between about 475 μg / mL.In another embodiment, the method comprises administering a concentration of about 1800, 1780, 1760, 1740, 1720, 1700, 1680, 1660, 1640, 1620, 1600, 1580, 1560, 1540, 1520, 1500, 1480, 1460, 1440, 1420, 1400, 1380, 1360, 1340, 132 ... In another embodiment, the method maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at or below 900 μg / mL, 1280 μg / mL, 1260 μg / mL, 1240 μg / mL, 1220 μg / mL, 1200 μg / mL, 1180 μg / mL, 1160 μg / mL, 1140 μg / mL, 1120 μg / mL, 1100 μg / mL, 1080 μg / mL, 1060 μg / mL, 1040 μg / mL, 1020 μg / mL, 1000 μg / mL, 980 μg / mL, 960 μg / mL, 940 μg / mL, 920 μg / mL, or 900 μg / mL. In another embodiment, the method maintains a peak serum concentration of the anti-C5 antibody or antigen-binding fragment thereof at about 1350 μg / mL.

[0146] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered in a concentration of at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 200 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 260 μg, 265 μg, 270 μg, 275 μg, 280 μg, 285 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 2 00μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 26 0μg, 270μg, 280μg, 290μg, 300μg, 320μg, 340μg, 360μg, 380μg, 400μg, 420μg, 440μg, 460 μg, 480μg, 500μg, 550μg, 600μg, 650μg, 700μg, 750μg, 800μg, 850μg, 900μg, 950μg, 1000

[0046] The antibody may be administered to a patient in an amount and frequency to maintain a constant antibody concentration of 1000 μg, 1050 μg, 1100 μg, 1150 μg, 1200 μg, 1250 μg, 1300 μg, 1350 μg, 1400 μg, 1450 μg, 1500 μg, 1550 μg, 1600 μg, 1650 μg, 1700 μg, 1750 μg or more, e.g., 1800 μg.

[0147] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to the patient in an amount and frequency sufficient to maintain a minimum free C5 concentration. In one embodiment, for example, the anti-C5 antibody or antigen-binding fragment thereof is administered to the patient in an amount and frequency sufficient to maintain a free C5 concentration of 0.5 μg / mL or less (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0148] The efficacy of the methods provided herein can be assessed using any suitable means, in one embodiment, a single pre-operative, weight-based dose of an anti-C5 antibody or antigen-binding fragment thereof results in complete C5 inhibition for at least 18 days.

[0149] In one embodiment, the method inhibits terminal complement activation in a human patient as assessed by any suitable assay, e.g., by 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0150] In another embodiment, the methods described herein prevent the need for renal replacement therapy (KRT).

[0151] In another embodiment, the method prevents or reduces CSA-AKI in a human patient with CKD. In one embodiment, CSA-AKI is a) An increase in serum creatinine (sCr) or serum cystatin C (sCysC) of ≥ 0.3 mg / dL in a 48-hour period within 7 days after CPB, and / or b) Characterized by an increase in sCr or sCysC of ≥ 1.5-fold above baseline within 7 days post-CPB or at 15, 30, 60, or 90 days post-CPB.

[0152] In another embodiment, the human patient does not have severe CSA-AKI (stage 2 or 3) based on the highest sCr observed within 7, 30, 45, 60, or 90 days after CPB as assessed by the modified Kidney Disease International Committee on Improving Outcomes (KDIGO) criteria, as described in Table 1 in the Examples (see also KDIGO., Kidney Inter. Suppl. 2013;3:1-150, and Khwaja A., Nephron. Clin. Pract. 2012;120(4):c179-184).

[0153] In another embodiment, the human patient does not have severe CSA-AKI based on the highest sCr observed within 7, 30, 45, 60, or 90 days after CPB as assessed by the modified "Risk, Injury, Failure, Loss of Renal Function, and End-Stage Renal Disease" (RIFLE) criteria, as described in Table 2 in the Examples (see also Bellomo R, et al., Acute Dialysis Quality Initiative workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy, and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204-R212).

[0154] In another embodiment, the method results in an improvement in the stage of renal function after CSA-AKI, as described in Table 3 in the Examples (see also Chawla LS, et al., Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol. 2017;13(4):241-257).

[0155] In another embodiment, the method results in stable CSA-AKI characterized by sCr≧2.0 to <3.0×baseline within 7, 30, 45, 60, or 90 days after surgery.

[0156] In another embodiment, the method results in improvement from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, where the improvement is characterized by an sCr≧1.5 to <2.0×baseline.

[0157] In another embodiment, the method results in partial recovery from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, where partial recovery is characterized by an sCr≧1.1 to <1.5×baseline.

[0158] In another embodiment, the method results in complete recovery from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, where complete recovery is characterized by an sCr<1.1×baseline.

[0159] In another embodiment, the method prevents or reduces one or more MAKEs in a human patient with CKD. In one embodiment, the one or more MAKEs is persistent renal dysfunction (SKD), defined as an estimated glomerular filtration rate (eGFR) >25% lower than baseline after CPB, e.g., a decrease in eGFR determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on serum cystatin C (sCysC) or serum creatinine (sCr). In another embodiment, the one or more MAKEs is the occurrence of renal replacement therapy (KRT) after CPB. In another embodiment, the one or more MAKEs is death from any cause after CPB.

[0160] In another embodiment, the method provides a change from baseline in quality of life as assessed via a quality of life assessment. For example, in one embodiment, the quality of life assessment is the Kidney Disease Quality of Life Index (KDQOL-36™). The KDQOL-36™ is a 36-item kidney-specific health-related quality of life measure that includes the general core Short-Form Health Survey 12 Item (SF-12) plus the burden of kidney disease, kidney disease symptoms / problems, and effect of kidney disease scales.

[0161] In another embodiment, the quality of life assessment is the European Quality of Life Group Five Dimensions, 5 Levels (EQ-5D-5L). The EQ-5D-5L is a standardized self-assessment measure of health-related quality of life and is used across a wide range of health conditions. The EQ 5D 5L includes five dimensions, each describing a different aspect of health: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression.

[0162] In another embodiment, the quality of life assessment is the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale. The FACIT scale is a 13-item questionnaire assessing self-reported fatigue over the past seven days and its impact on daily activities and function.

[0163] In another embodiment, the method results in a shift to normal levels of a biomarker associated with vascular inflammation (e.g., shed tumor necrosis factor receptor 1 [TNF-R1]). In another embodiment, the method results in a shift to normal levels of a biomarker associated with endothelial injury and / or activation (e.g., thrombomodulin). In another embodiment, the method results in a shift to normal levels of a biomarker associated with kidney injury (e.g., neutrophil gelatinase-associated lipocalin [NGAL]). In another embodiment, the method results in a shift to normal levels of a biomarker associated with inducers of cell cycle arrest (e.g., tissue inhibitor of metalloproteinase-2 [TIMP-2]). In another embodiment, the method results in a shift to normal levels of complement proteins and complement activation pathway products (e.g., soluble C5b-9).

[0164] VI. Kits and Unit Dosage Forms Also provided herein are kits containing a pharmaceutical composition containing an anti-C5 antibody, such as ravulizumab, or an antigen-binding fragment thereof, in a therapeutically effective amount adapted for use in the aforementioned methods, and a pharmaceutically acceptable carrier. The kit may optionally also contain instructions, including, for example, an administration schedule, to enable a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to a patient. The kit may also include a syringe.

[0165] Optionally, the kit includes multiple packages of single-dose pharmaceutical compositions, each containing an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, for single administration according to the method provided above. The kit may also include an instrument or device necessary for administering the pharmaceutical composition. For example, the kit may provide one or more pre-filled syringes containing a certain amount of an anti-C5 antibody or antigen-binding fragment thereof.

[0166] In one embodiment, the kit comprises (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof, the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof in any of the methods described herein.

[0167] VI.Use In another aspect, an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab (ULTOMIRIS®)) is provided for use in preparing a human patient with CKD for cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0168] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof is provided for use in inhibiting terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0169] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof is provided for use in treating a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0170] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof for use in preventing or reducing CSA-AKI in a human patient with CKD is provided, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0171] In another embodiment, an anti-C5 antibody or antigen-binding fragment thereof for use in preventing or reducing one or more MAKEs in a human patient with CKD is provided, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0172] In a further aspect, the present invention provides the use of an anti-C5 antibody or antigen-binding fragment thereof (e.g., ravulizumab (ULTOMIRIS®)) to prepare a human patient with CKD for cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery. a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0173] In one embodiment, there is provided a use of an anti-C5 antibody or antigen-binding fragment thereof to inhibit terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0174] In another embodiment, there is provided a use of an anti-C5 antibody or antigen-binding fragment thereof for the treatment of a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0175] In another embodiment, there is provided a use of an anti-C5 antibody or antigen-binding fragment thereof in preventing or reducing CSA-AKI in a human patient with CKD, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) A single dose of 3600 mg is administered to patients weighing ≥ 100 kg.

[0176] In another embodiment, there is provided a use of an anti-C5 antibody or antigen-binding fragment thereof in preventing or reducing one or more MAKEs in a human patient with chronic kidney disease, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg, or d) Use: Administered once at a dose of 3600 mg to patients weighing ≥ 100 kg.

[0177] The following examples are merely illustrative and should not be construed as limiting the scope of the disclosure in any way, as numerous variations and equivalents will become apparent to those skilled in the art upon reading this disclosure. The contents of all references, Genbank entries, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference. [Example]

[0178] Example: A Phase 3 Study of ravulizumab (ULTOMIRIS®) to Protect Patients with Chronic Kidney Disease (CKD) from Cardiac Surgery-Associated Kidney Injury (CSA-AKI) and / or Subsequent Major Adverse Renal Events (MAKE) Patients with CKD undergoing cardiac surgery on CPB are at high risk for CSA-AKI. In the broader population undergoing cardiac surgery on CPB, CSA-AKI occurs in 20-25% of patients, but in the setting of CKD, it occurs in 60-80% of patients, and MAKE occurs in 20-30% of patients. Inhibiting terminal complement damage to the kidney and vasculature can reduce the incidence, severity, and duration of postoperative CSA-AKI, reduce subsequent MAKE, improve long-term survival and freedom from renal replacement therapy (KRT), and reduce CKD progression.

[0179] Therefore, a randomized, placebo-controlled, double-blind study design will be implemented to minimize bias and balance the effects of confounding factors in this complex and highly comorbid population. Participants in both treatment arms will receive standard of care as background therapy throughout the study.

[0180] 1. Study Design This is a phase 3, randomized, double-blind, placebo-controlled, multicenter study of ravulizumab to reduce the risk of postoperative AKI and subsequent MAKE 90 days after surgery (MAKE90) in adult participants with CKD and stable heart disease undergoing non-emergency sternotomy on CPB for coronary artery bypass grafting (CABG), valve replacement or repair, or combined procedures. A schematic diagram of the study design is described in Figure 1. Participants considered at risk for AKI after CPB had an eGFR of ≥ 20 to < 60 mL / min / 1.73 m2 and a minimum Society of Thoracic Surgeons (STS) calculator renal failure risk score of 3%.

[0181] The study consisted of a screening period of up to 28 days with randomization and medication within 1 to 7 days before surgery with CPB, a primary evaluation period of 90 days after CPB, and a survival follow-up period of 365 days after CPB.

[0182] Approximately 736 participants will be randomized 1:1 to treatment with either ULTOMIRIS or placebo. Randomization will be stratified by baseline CKD stage (3A, 3B, 4) and surgery type (mitral valve replacement or combined procedure vs. other single procedure).

[0183] Eligible participants will be randomized to receive a single, weight-based dose of ULTOMIRIS or placebo. Randomization and dosing will occur on the same day, except in cases where the study intervention requires preparation the day before dosing. Dosing must occur at least one day before surgery, and surgery must occur within one to seven days of dosing. The dosing day is day 1 for each participant. All treated participants will be followed for 90 days after the CPB procedure during the primary evaluation period, and survival follow-up will be completed on day 365 after CPB. The total study duration will be approximately 400 days. Participants will be considered to have completed the study if they complete the primary evaluation period.

[0184] The analysis of the primary evaluation period will be conducted when all participants have completed this period. In addition, two interim analyses of the study will be conducted to assess early futility in the first interim analysis and the need for sample size adjustment in the second interim analysis after approximately 30% and 50% of randomized participants have completed the primary evaluation period, respectively.

[0185] The end of the study was defined as the date on which the last participant completed the last visit indicated on the Schedule of Activities (see Figures 2A-G).

[0186] This is a two-arm, parallel-treatment study in which participants and investigators are blinded. ULTOMIRIS is being evaluated for reducing the risk of death, the need for KRT, and sustained reduction in renal function in adult patients with CKD undergoing CPB for CABG, valve replacement or repair, or combined procedures.

[0187] Randomized participants will receive a single weight-based dose of ravulizumab or placebo within 1 to 7 days before the CPB procedure (i.e., no later than 1 day before surgery).

[0188] 2. Objectives, Estimators, and Endpoints The primary objective of the study was to evaluate the effectiveness of ULTOMIRIS in reducing the risk of MAKE90 after CPB. Primary estimators included: (1) Treatment: ravulizumab or placebo, (2) Population: Adult participants with CKD; (3) Endpoints / variables: MAKE at 90 days post-CPB (MAKE90), defined as meeting at least one of the following criteria: a decrease from baseline in eGFR (CKD-EPI equation using sCysC) of ≥ 25% at 90 days post-CPB, or initiation of KRT by 90 days post-CPB, or death from any cause by 90 days post-CPB; (4) Intercurrent events (IE): IE1: iodinated contrast exposure up to 90 days after CPB after treatment was administered; IE2: surgery performed without CPB or surgery with CPB not performed within 15 days after treatment was administered; and IE3: use of a confounding intervention before surgery or use of a disallowed intervention up to 90 days after CPB after treatment was administered. Treatment Policy Strategy: Collected endpoints will be analyzed regardless of IE. (5) Summary measure: Difference between treatment groups in the proportion of participants experiencing MAKE at 90 days after CPB, regardless of any IE.

[0189] The key secondary efficacy objectives of the study are to evaluate the efficacy of ULTOMIRIS in reducing the risk of AKI (based on sCr) after CPB based on: (1) freedom from CSA-AKI at 90 days after CPB; (2) freedom from severe CSA-AKI (KDIGO stage 2 or 3) based on the highest sCr observed within 7 days after CPB; (3) freedom from any severe AKI (RIFLE injury or failure criteria) based on the highest sCr observed within 30 days after CPB; (4) freedom from any severe AKI (KDIGO stage 2 or 3) based on the highest sCr observed within 30 days after CPB; (5) freedom from RIFLE failure criteria based on the highest sCr observed within 30 days after CPB; and (6) all-cause mortality from randomization to 90 days after CPB.

[0190] Additional secondary efficacy objectives are to evaluate the efficacy of ULTOMIRIS in reducing the risk of MAKE (based on sCysC), MAKE (based on sCr), AKI (based on sCr), and related outcomes after CPB. Corresponding endpoints and / or estimators include: (1) MAKE and its components (excluding sCysC-based MAKE90) at 30, 60, and 90 days after CPB, occurrence of KRT or death at 30, 60, and 90 days after CPB, (2) highest CSA-AKI stage within 3 and 7 days after CPB, (3) absence of CSA-AKI at 15, 30, and 60 days after CPB, (4) absence of any AKI at 3, 7, 15, 30, 60, and 90 days after CPB, and (5) AKI progression at 15, 30, 60, and 90 days after CPB for those experiencing CSA-AKI within 7 days after CPB: complete recovery, partial recovery, improvement, stable, or worsening.

[0191] Healthcare resource utilization The objectives were to evaluate the effect of ULTOMIRIS on healthcare resource utilization in participants with CKD undergoing non-emergency CPB, as assessed by (1) length of index hospital and ICU stay, (2) number of ventilator-free days through days 30 and 90 after CPB, (3) hospital readmission rates (all-cause or AKI-related) through days 30 and 90 after CPB, and (4) days of KRT through days 30 and 90 after CPB.

[0192] Health-related QoL objectives are to assess the effect of ULTOMIRIS on quality of life in participants with CKD undergoing non-emergency CPB by, for example, (1) change from baseline in KDQOL-36™ at 30, 60, and 90 days post-CPB, (2) change from baseline in EQ-5D-5L at 30, 60, and 90 days post-CPB, and (3) change from baseline in FACIT-Fatigue at 30, 60, and 90 days post-CPB.

[0193] A further objective is to evaluate the PK and PD of ULTOMIRIS in participants with CKD undergoing non-emergency CPB via, for example, ULTOMIRIS serum concentrations and absolute values, change from baseline, and percent change from baseline in serum free C5 concentrations.

[0194] A further objective is to assess the safety of ULTOMIRIS IV in participants with CKD undergoing non-emergency CPB, e.g., via the incidence of TEAEs and TESAEs and changes from baseline in laboratory parameters at scheduled visits.

[0195] A further objective is to evaluate the immunogenicity of ULTOMIRIS IV in participants with CKD undergoing non-emergency CPB via, for example, ADA incidence, ADA response category, and titers at 90 days post-CPB.

[0196] Exploratory objectives include, for example, assessing biomarkers at baseline and changes in response to treatment via biomarker assessments, which may include, but are not limited to, complement pathway activation (e.g., plasma and urinary soluble C5b-9), kidney injury (e.g., urinary neutrophil gelatinase-associated lipocalin [NGAL]), and endothelial injury (e.g., plasma thrombomodulin [TM]).

[0197] The ultimate objective is to evaluate the efficacy of ULTOMIRIS in reducing the risk of sCysC-based CSA-AKI, e.g., via AKI within 7 days of sCysC-based CPB: the highest AKI stage according to the KDIGO criteria and no severe AKI (KDIGO stage 2 or 3).

[0198] The endpoint definitions listed in Table 1 will be used in this study.

[0199] [Table 3] Abbreviations: AKI = acute kidney injury; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; CPB = cardiopulmonary bypass; CSA-AKI = cardiac surgery-associated acute kidney injury; eGFR = estimated glomerular filtration rate; KDIGO = Kidney Disease Outcomes Improvement International; KRT = renal replacement therapy; MAKE = major adverse renal events; RIFLE = risk, damage, failure, loss of kidney function, and end-stage renal disease; sCr = serum creatinine; sCysC = serum cystatin C

[0200] The primary estimator for this study estimates the treatment effect using a treatment policy strategy based on the intent-to-treat analysis set, regardless of any current events (IE) and participant compliance with IP dosing. The estimator is intended to provide a population-level estimate of the treatment effect on the binary endpoint MAKE90 after CPB among CKD patients who meet the study eligibility criteria and are randomized into the study. The primary estimator includes the following four attributes: A. Population: Adult participants with CKD as defined by inclusion and exclusion criteria B. Variable: MAKE at 90 days after CPB (MAKE90) C. Current Event (IE): IE1: Iodinated contrast exposure up to 90 days after CPB once treatment is administered IE2: Surgery was performed without CPB or surgery with CPB was not performed within 15 days of treatment administration IE3: Use of a confounding intervention before surgery or use of a disallowed intervention after treatment is administered up to 90 days post-CPB. Note: Treatment Policy Strategy: Endpoints collected will be analyzed without regard to IE. D. Summary Measure: Difference between treatment groups in the proportion of participants experiencing MAKE at 90 days post-CPB, regardless of any IE.

[0201] The key secondary estimators are intended to provide population-level estimates of the treatment effect for the five binary endpoints, regardless of any IE. The estimators for each key secondary are directed to the same estimator as for the primary endpoint, as follows: A. Population: Adult participants with CKD as defined by inclusion and exclusion criteria B. Variables: No CSA-AKI at 90 days after CPB; No severe CSA-AKI (Kidney Disease International Outcomes Improvement Group [KDIGO] stage 2 or 3) based on the highest sCr observed within 7 days after CPB not having any severe AKI (Risk, Injury, Failure, Loss of Renal Function, and End-Stage Renal Disease [RIFLE] injury or failure criteria) based on the highest sCr observed within 30 days after CPB; not having any severe AKI (KDIGO stage 2 or 3) based on the highest sCr observed within 30 days after CPB; not having any RIFLE failure criteria based on the highest sCr observed within 30 days after CPB; All-cause mortality from randomization to 90 days after CPB C. Current Event (IE): IE1: iodinated contrast exposure up to 90 days after CPB after treatment was administered; IE2: surgery was performed without CPB or surgery with CPB was not performed within 15 days after treatment administration; IE3: Use of a confounding intervention before surgery or use of an unauthorized intervention up to 90 days after CP after treatment has been administered

[0202] Treatment Policy Strategy: Collected endpoints will be analyzed regardless of IE. Summary measure: Difference between treatment groups in the proportion of participants experiencing key secondary endpoint events.

[0203] 3.MAKE and CSA-AKI The primary outcome measure (MAKE) is thought to capture clinical outcomes after AKI and is defined as mortality, need for KRT, and SKD defined as an estimated glomerular filtration rate (eGFR) >25% lower than baseline by the CKD-EPI equation (see, e.g., Billings FT, et al., Nephron. Clin. Pract. 2014;127(1-4):89-93; Haverich A, et al., Ann. Thorac. Surg. 2006;82(2):486-492; Levey AS, et al., Ann. Intern. Med. 2009;150(9):604-612; and Palevsky PM, et al., Clin. J. Am. Soc. Nephrol. 2012;7(5):844-850). SKD occurs due to non-recovery of AKI and represents a persistent worsening of CKD at 90 days. SKD is associated with a many-fold increased risk of long-term mortality and progression to ESKD when compared with those who did not have AKI or who recovered from AKI (see, e.g., Ishani A, et al., J. Am. Soc. Nephrol. 2009; 20(1): 223-228; Wu VC, et al., Kidney Int. 2011; 80(11): 1222-1230; and Cho JS, et al., J. Thorac. Cardiovasc. Surg. 2021; 161(2): 681-8).

[0204] Skeletal muscle atrophy is a widely recognized complication after cardiac surgery (van Venrooij LM, et al., Nutrition (Burbank, Los Angeles County, Calif). 2012;28(1):40-45) and can confound sCr-based assessment of eGFR. As recommended for such situations in the KDIGO guidelines (KDIGO, 2013), sCysC is used to calculate SKD in the MAKE endpoint. Data from observational and randomized controlled intervention trials reporting AKI and MAKE outcomes after cardiopulmonary bypass were used to inform the 25% MAKE90 placebo rate assumption.

[0205] The occurrence of postoperative CSA-AKI was defined based on the modified KDIGO criteria as the presence of one of the following observations within 7 days after surgery with CPB: (1) an increase in sCr of ≥ 0.3 mg / dL in a 48-hour period or (2) an increase in sCr to ≥ 1.5 times baseline within 7 days after CPB.

[0206] The highest AKI stage according to the modified KDIGO criteria occurring within 3 and 7 days after CPB is determined as defined in Table 2 (see also KDIGO., Kidney Inter. Suppl. 2013;3:1-150, and Khwaja A., Nephron. Clin. Pract. 2012;120(4):c179-184). Additionally, this staging is used to assess AKI at any time within 30 days after CPB based on the highest observed sCr, as well as at 15, 30, 60, and 90 days after CPB. While the KDIGO criteria have been widely adopted, some settings (e.g., the STS Renal Failure Risk Calculator) are more familiar with the RIFLE criteria (e.g., O'Brien SM, et al., Ann Thorac Surg. 2018;105(5):1419-1428). Therefore, AKI staging based on the modified RIFLE criteria was performed on patients assessed for AKI at any time within 30 days after CPB based on the highest observed sCysC. The staging criteria are outlined in Table 3. (See also Bellomo R, et al., Acute Dialysis Quality Initiative workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy, and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204-R212.) In the setting of AKI, reliable interpretation of sCysC changes is exploratory in this study because it has not yet been defined and is not currently commonly used to define or stage AKI.

[0207] [Table 4]

[0208] [Table 5]

[0209] Changes in post-AKI progression (based on need for sCr or KRT) relative to the highest CSA-AKI stage observed during the first 7 days after CPB were assessed from days 15 to 90 after CPB to characterize AKI progression (recovery, improvement, stable, or worsening). Stages of post-AKI progression are defined in Table 4 (see also Chawla LS, et al., Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol. 2017;13(4):241-257).

[0210] [Table 6]

[0211] There are uncertainties in the assumptions underlying the specific background MAKE rate in this risk population and the treatment effect assumptions. Therefore, two interim analyses of this study will be performed to determine the need for futility and sample size re-estimation.

[0212] The safety outcomes assessed are commonly used in clinical studies according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Good Clinical Practice (GCP) guidelines.

[0213] 4. Dosage Justification The dose in this study is identical to the approved and safety-established weight-based maintenance dose of ULTOMIRIS for adults with aHUS, PNH, or gMG.

[0214] This dose ensures that ULTOMIRIS serum concentrations are ≥ 175 μg / mL to achieve complete terminal complement inhibition, while maintaining maximum ULTOMIRIS serum concentrations below 3000 μg / mL, the highest observed value from all completed clinical studies, for at least 18 days in the target patient population. The 175 μg / mL threshold was previously identified as the minimum therapeutic concentration of ULTOMIRIS required to achieve complete terminal complement inhibition.

[0215] To support this dosing regimen, a model-based simulation was performed (Ravulizumab CSA-AKI Dose Rationale, 2022). Briefly, the population PK model used for the simulation was from the aHUS label extension dossier. Factors that could potentially affect ravulizumab PK in the target patient population were integrated into the model simulation, including the effects of proteinuria, red blood cell transfusions, and postoperative hemodilution.

[0216] Other unquantifiable factors, such as drug loss or activated complement pathways due to CPB, were not included in the simulation. Therefore, a dose capable of achieving ULTOMIRIS concentrations greater than 175 μg / mL for at least 18 days is desirable in the setting of CSA-AKI, as predicted by the proposed single-dose, weight-based ULTOMIRIS dose.

[0217] Participants were considered to have completed the study if they completed the primary assessment period. The end of the study was defined as the date the last participant completed the last visit indicated on the Schedule of Activities.

[0218] 5. Study population To be eligible to participate in the study, participants must meet all of the following criteria: 1. Age ≥ 18 to ≤ 90 years at the time of signing the informed consent. 2. Male or Female. Female participants of childbearing potential and male participants must follow protocol-specified contraceptive guidance. 3.Weight ≥ 30 kg at screening. 4. Planned non-emergency sternotomy with CPB procedures for the following surgeries: multivessel CABG, valve replacement or repair; ascending aortic surgery permitted when combined with aortic valve replacement / repair, combined CABG and valve surgery; inclusion of single-vessel CABG permitted when combined with valve replacement / repair. Note: Surgery should be scheduled to occur within 35 days of screening (maximum 28-day screening period with randomization and medications within 1-7 days prior to CPB). 5. Known CKD (stage 3A, 3B, or 4) for at least 3 months with eGFR ≥ 20 to < 60 mL / min / 1.73 m2. eGFR was confirmed at screening (may be repeated once during screening) and randomization using the CKD-EPI equation with sCr or sCysC measurements obtained by a local or central laboratory. There is a risk for postoperative AKI as defined by a minimum STS calculator renal failure risk score of 6.3%. 7. Able to give signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form and this protocol.

[0219] Participants will be excluded from the study if any of the following criteria apply: 1. Emergency or salvage cardiac surgery is anticipated at screening or randomization, as assessed by the investigator. 2. Single-vessel CABG without valve surgery is planned. 3. Off-pump surgery is planned (e.g., surgery without CPB). 4. Any use of KRT or presence of AKI within 30 days of randomization, excluding transient (≦5 days) stage 1 AKI after iodinated contrast exposure (AKI defined as a 1.5-fold increase in sCr versus baseline). 5. Recipient of a solid organ or bone marrow transplant. 6. Cardiogenic shock, hemodynamic instability, use of an intra-aortic balloon pump, extracorporeal membrane oxygenation, or left ventricular assist device within 72 hours of randomization. 7. Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization. 8. Participants with a history of human immunodeficiency virus (HIV) who are not on antiretroviral therapy or, if on therapy, have a known detectable viral load within 1 year of screening. 9. Congenital immunodeficiency. 10. History of recurrent infections of unknown cause. 11. Known medical or psychological condition, including substance abuse, or any risk factor that, in the investigator's opinion, may prevent the participant from fully participating in the study, may impose any additional risk on the participant, or may confound the participant's assessment or the outcome of the study. 12. History of or unresolved N. meningitidis infection. 13. Hypersensitivity to any component contained in the study intervention, including hypersensitivity to mouse proteins. 14.Currently undergoing treatment for malignant tumor or malignant tumor 15. Use of any complement inhibitors within 1 year prior to screening, or plasma exchange or plasmapheresis, or planned use during the course of the study. 16. Planned use of any pharmacological agent specifically for the prevention or treatment of AKI. 17. Planned use of KRT, intra-aortic balloon pump, extracorporeal membrane oxygenation, or left ventricular assist device between randomization and surgery. 18. Participation in another interventional treatment study or use of any experimental therapy within 30 days prior to the start of the study intervention on Day 1 in this study, or within 5 half-lives of its IP, whichever is greater, or planned participation / use during the course of the study. 19. Presence of a do-not-resuscitate order or life expectancy of <3 months. 20. Pregnant, breastfeeding, or attempting to become pregnant within 8 months of receiving the study intervention. 21. Participant is unwilling to be vaccinated against N meningitidis or to receive appropriate antibiotic prophylactic treatment if necessary.

[0220] A screening failure is defined as a participant who consents to participate in a clinical study but is not subsequently randomly assigned to a study intervention. A minimum set of screening failure information is required to meet the Consolidated Standards of Reporting Trials (CONSORT) disclosure requirements and to ensure transparent reporting of screening failure participants in order to respond to inquiries from regulatory authorities. The minimum information includes demographics, details of the screening failure (e.g., failed eligibility criteria), and any serious adverse events (SAEs) occurring during the screening period, including any adverse events (AEs) and any associated concomitant medications.

[0221] Individuals who do not meet the criteria for participation in this study (screening failure) due to reasons that are expected to resolve or have resolved may be re-screened upon consideration and consent. Participants who are re-screened outside of the screening window will be required to sign a new informed consent form (ICF).

[0222] 6. Research intervention A study intervention is defined as any investigational intervention, marketed product, or placebo intended to be administered to study participants according to the study protocol.

[0223] Participants will be randomized to either ULTOMIRIS or placebo. ULTOMIRIS is formulated at pH 7.0 and supplied in 30 mL single-use vials. Each vial of ULTOMIRIS contains 300 mg of ULTOMIRIS (10 mg / mL) in 10 mM sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and water for injection. The comparator product (placebo) will be formulated as a compatible sterile solution containing the same buffer components but no active ingredient. Additional details are provided in Table 5.

[0224] [Table 7]

[0225] Participants randomized to the ULTOMIRIS group will receive a single, weight-based dose of ULTOMIRIS 1 to 7 days (i.e., at least 1 calendar day) before the CPB procedure. The dose is identical to the approved weight-based ULTOMIRIS maintenance dose for adult patients with aHUS, PNH, or gMG (Table 6).

[0226] [Table 8]

[0227] At a minimum, study interventions will be labeled with the protocol number, lot number / expiry date, name and address, and instructions for use and storage. Study interventions will be labeled in accordance with national regulatory requirements.

[0228] Upon arrival of the study intervention at the study site, the study intervention kit will be removed from the shipping container and stored in its original carton under refrigerated conditions at 2°C-8°C (35°F-47°F), protected from light. Study interventions will not be frozen. The investigator must ensure that proper temperature conditions are maintained during transport for all study interventions received and that any malfunctions are reported and resolved before use of the study intervention. Study interventions will be stored in a secure, limited-access storage area, and body temperature will be monitored daily.

[0229] Study intervention infusions will be prepared using aseptic technique. Ravulizumab and placebo will be further diluted in a 1:1 ratio with compatible diluents. Ravulizumab and placebo will be administered through a 0.2 micron filter during infusion.

[0230] Only participants enrolled in the study may receive the study intervention, and only authorized site staff may supply or administer the study intervention. All study interventions must be stored in a secure, environmentally controlled, and monitored (manual or automated) area according to labeled storage conditions, with access limited to the investigator and authorized site staff.

[0231] In this study, participants in both treatment arms will receive standard of care as background therapy.

[0232] Eligible participants will be randomized to either the ULTOMIRIS or placebo group in a 1:1 allocation ratio. Randomization will be performed centrally using Interactive Response Technology (IRT).

[0233] To balance the effects of potential confounders between the ravulizumab and placebo arms, randomization will be stratified by baseline CKD stage (3A, 3B, 4) confirmed at screening and baseline based on the CKD-EPI using sCr or sCysC (regional or central laboratory results), and by surgical type (mitral valve replacement or combined procedure vs. other single procedure).

[0234] Participants, all investigational site personnel, and any designees directly associated with the conduct of the study will be blinded to the participant's treatment assignment throughout the study. Blinding will be maintained by using identical study intervention kits and labels for ULTOMIRIS and placebo. The placebo will have an identical appearance to that of ULTOMIRIS. Randomization codes will be maintained by the IRT provider.

[0235] Infusion of study interventions into participants will be under the supervision of the investigator or his / her designee to ensure participants receive the appropriate dose at the appropriate time during the study. Record the date and time of dose administration. Concomitant medications

[0236] Any medications or therapies (including over-the-counter or prescription drugs, vaccines, vitamins, and / or herbal supplements) deemed necessary for the participant's care during the study or for the treatment of any adverse occurrence may be given at their discretion, along with any other medications other than those listed as unauthorized medications. It is the investigator's responsibility to record all medications along with the reason for use, dates of administration including start and end dates, and dosing information including dose and frequency.

[0237] Participants are prohibited from receiving any of the following medication endpoints (90 days post-CPB): eculizumab, ravulizumab (other than protocol-specified study interventions), or other agents acting on the complement pathway, plasma exchange or plasmapheresis, and the use of any pharmacological agents specifically for the prevention or treatment of AKI (e.g., experimental or investigational, such as fenoldapam, levosimenden, and neseritide). These therapies may be used for their approved indications.

[0238] The use of KRT, intra-aortic balloon pumps, extracorporeal membrane oxygenation, or left ventricular assist should be avoided after the study intervention is administered and before surgery unless clinically indicated. The use of these procedures after the study intervention is administered and before surgery is considered a confounding procedure because these procedures may induce AKI before CPB or may confound the appropriate diagnosis and staging of AKI (e.g., use of KRT). These procedures are considered standard of care during the surgical and postoperative phases and are permitted.

[0239] Dose modifications of the study intervention for individual participants will not be permitted in this trial.

[0240] 7. Study Assessment and Procedures Study procedures and their timing are summarized in the Schedule of Assessments, shown in Figure 2. Protocol waivers or exemptions will not be permitted. Adherence to study design requirements, including those specified in the Schedule of Assessments, is essential and required for study conduct. All screening assessments must be completed and reviewed to ensure potential participants meet all eligibility criteria. A screening log will be maintained to record details of all participants screened and to confirm eligibility or record reasons for screening failure, if applicable.

[0241] Procedures performed as part of a participant's routine clinical management (e.g., blood count) and obtained before signing the informed consent form may be utilized for screening purposes, provided the procedures meet protocol-specified criteria and are performed within the timeframe defined in the schedule of assessments.

[0242] Repeat or unscheduled samples may be obtained for safety reasons or technical problems with the samples.

[0243] The investigator or qualified designee must obtain a signed and dated informed consent form for each participant before performing any study-related procedures. Every effort should be made to ensure participants are willing to participate in the study before performing screening procedures.

[0244] All inclusion and exclusion criteria must be reviewed by the investigator or qualified designee to ensure participants are eligible for study participation. The investigator will maintain a screening log as appropriate to record details of all participants screened and to confirm eligibility or record reasons for screening failure, if applicable. Eligibility to participate will be determined prior to randomization.

[0245] The study is intended to enroll non-emergency cardiac surgery participants, as determined by the investigator. For guidance, elective cardiac surgery is described by Bojar RM., "Manual of Perioperative Care in Adult Cardiac Surgery", Sixth Edition 2021 Print ISBN: 9781119582557, as follows: The patient's cardiac function is stable in the days or weeks prior to surgery, and / or the procedure can be postponed without increasing the risk of impaired cardiac outcome.

[0246] Emergency cardiac surgery is defined as a procedure required during the same hospitalization to minimize the possibility of further clinical deterioration. This includes, but is not limited to, worsening or sudden chest pain, heart failure, acute myocardial infarction, underlying anatomy, unstable angina due to intravenous nitroglycerin (IV NTG), and rest angina. Any of these conditions require the patient to remain in the hospital until surgery can be performed, allowing the patient to wait until the next available OR scheduled time. Delays in surgery may be necessitated by attempts to improve the patient's condition, the availability of a spouse or parent for informed consent, the availability of blood products, or the availability of essential laboratory procedures or test results. The definition of emergency procedures includes the use of an IABP; however, the use or planned use of an IABP is separately excluded in this study.

[0247] Participants requiring emergency or salvage cardiac surgery, as determined by the investigator, will not be enrolled. For guidance, emergency cardiac surgery is defined as surgery indicated without any delay for ongoing, refractory (difficult, complex, and / or unmanageable) severe cardiac failure, with or without hemodynamic instability, and unresponsive to any form of therapy other than cardiac surgery. Examples include hemodynamic evidence of shock with chemical or mechanical support, such as IV inotropes or IABP to maintain cardiac output; pulmonary edema requiring intubation and ventilation; expanding myocardial infarction; signs of ongoing ischemia, i.e., ECG changes; acute native valve dysfunction (acute papillary muscle rupture or torn leaflet); prosthetic valve dysfunction with structural insufficiency (valve fracture or torn leaflet, thrombus formation, pannus formation obstructing flow through the valve orifice, or valve dehiscence); acute aortic dissection; rupture or dissection during cardiac catheterization; and perforation or tamponade after cardiac catheterization.

[0248] Salvage cardiac surgery is defined as a patient undergoing CPR en route to the OR before induction of anesthesia or with ECMO ongoing to sustain life.

[0249] Demographic parameters, including age, sex, race, and ethnicity (necessary to calculate the STS risk score and eGFR), are documented in the clinical study report (CRF).

[0250] Due to its mechanism of action, the use of ULTOMIRIS increases participants' susceptibility to meningococcal infection caused by N. meningitidis. To reduce the risk of infection, all participants must be vaccinated against N. meningitidis within 3 years prior to administration of the study intervention. If participants have not been vaccinated within 3 years of administration of the study intervention, vaccination will occur during screening or any time prior to hospital discharge. If administration of the study intervention occurs <2 weeks after the first vaccination, participants should receive prophylactic antibiotics for meningococcal infection up to 2 weeks after vaccination. Hospitalized participants may be vaccinated after administration of the study intervention but before hospital discharge. These participants will receive appropriate antibiotic prophylaxis from the date of dosing for at least 2 weeks after vaccination.

[0251] Vaccines against serogroups A, C, Y, W135, and, if available, serogroup B (if recommended by local guidelines) are recommended to prevent commonly pathogenic meningococcal serogroups. Participants must receive a complete primary vaccination series and be revaccinated if indicated according to current national vaccination guidelines. Vaccination may not be sufficient to prevent meningococcal disease.

[0252] Prophylactic antibiotic use should follow official guidance and local practice. Monitor all participants for early signs of meningococcal infection and immediately evaluate any suspected infection and treat with appropriate antibiotics if necessary.

[0253] To increase risk awareness and facilitate prompt disclosure of any potential signs or symptoms of meningococcal infection experienced by participants during the course of the study, participants will be provided with a Participant Safety Card to carry with them at all times. Additional discussion and explanation of potential risks, signs, and symptoms will occur as part of the review of the Participant Safety Card and at specific times throughout the study as described in the Schedule of Assessments.

[0254] Participants' relevant medical history, including previous and concomitant conditions / disorders, treatment history, and disease status of related diseases, will be assessed at screening and documented on source documents and CRFs. Record all medical history from the two years prior to screening and any medical history from any time related to cardiac or renal disease, including previous medications and procedures, and any identified cause of the participant's renal disease. Any changes to medical history that occur during the screening period and before dosing of the study intervention on Day 1 will be documented prior to administration of the study intervention.

[0255] The Society of Thoracic Surgeons (STS) risk calculator will be utilized to determine preoperative risk for severe AKI (RIFLE failure criteria) based on participant baseline characteristics required for the risk calculator. The risk score and participant characteristics used to determine the participant's risk score will be captured during a screening period prior to dosing of the study intervention on Day 1. The EuroScore will be calculated separately and the value will be recorded.

[0256] Home visits after discharge are permitted where available. Home visits will be conducted by qualified healthcare professionals in accordance with all federal, state, and local laws or regulations of relevant regulatory agencies. Telehealth visits may be conducted in conjunction with home visits.

[0257] All assessments may be conducted during the home visit under the supervision of the investigator. The collected information must be forwarded to the investigator's site for evaluation on the day of the visit. In case of any symptoms or signs indicative of a serious adverse event, further evaluation of the participant at the research site or an urgent care facility may be required.

[0258] 8.Efficacy evaluation For the primary efficacy endpoint, participants will be assessed for major acute renal events (MAKE) at 90 days after cardiac surgery on CPB. MAKE90 is defined as meeting at least one of the following criteria: (1) a decrease from baseline in eGFR (CKD-EPI equation using sCysC) of ≥ 25% at 90 days after CPB, or (2) initiation of KRT by 90 days after CPB, or (3) death from any cause by 90 days after CPB.

[0259] Additionally, secondary endpoints will assess both AKI and MAKE endpoints at additional time points. To enable these efficacy assessments, the investigator will collect and record the following: A. sCr and sCysC on the day of screening, day of medication (day 1), day of surgery before induction of anesthesia, days 1-7, 15, 30, 60, and 90 after CPB, and at hospital discharge: Daily collection of sCr and sCysC was performed on days 1-7 after CPB (168 hours, visit 5) unless the participant was discharged from the hospital before day 7 after CPB. However, the presence of AKI was tracked with daily laboratory tests until day 7 after CPB or until recovery (<1.5 × baseline), whichever came first, even if the participant was discharged from the hospital. B. Record the highest sCr observed by the local laboratory through day 30 after the end of CPB. C. Any use of KRT from randomization through Day 90 post-CPB. Record the type / modality, frequency, start / stop of KRT, and reason for start / stop. All attempts to collect with minimal KRT (with / without) must be made and recorded on Days 15, 30, 60, and 90. The use of surgical ultrafiltration as a standard of care procedure for routine management of fluid balance during cardiac surgery is not considered initiation of KRT and will be recorded as a concomitant procedure. D. Any death from randomization to 90 days post-CPB. Collect and record the date of death and report any associated adverse events / serious adverse events, including serious adverse events that contribute to death. All attempts to collect minimal vital status (alive, yes / no) must be made and recorded on days 15, 30, 60, and 90.

[0260] Every effort will be made to collect laboratory test samples, KRT status, KRT details, and vital status at every visit. However, if necessary, KRT status (yes / no), KRT details, and vital status can be confirmed directly via telephone or telehealth visit. If attempts to contact participants directly fail, KRT status and vital status can be obtained indirectly from family members, other healthcare providers, or local death registries.

[0261] The planned time points for all safety evaluations will be provided in the Schedule of Evaluations.

[0262] Symptom-directed testing may be performed at any time after screening as needed based on local practice / standard of care. Normal findings or findings consistent with the participant's medical history will not be recorded. Abnormal findings not attributable to the participant's medical history, new abnormalities, or worsening physical findings will be reported as adverse events. The investigator must pay particular attention to clinical signs associated with previous serious illness. Height will be measured only at screening. Weight will be measured before induction of anesthesia on the day of surgery. Daily weight will be measured for the first 7 days after CPB or until hospital discharge, whichever occurs first. If accurate weight cannot be obtained in the intensive care unit (ICU) environment, daily total fluid input and output will be recorded in lieu of weight measurement. Temperature (°C or °F), heart rate, respiratory rate, and systolic and diastolic blood pressure (mmHg) will be assessed. Blood pressure and pulse measurements will be assessed with the participant in a seated position using fully automated devices. If the participant cannot tolerate measurements in a sitting position (e.g., while undergoing mechanical ventilation in an ICU), measurements can be performed and recorded in the recumbent position. Manual techniques are used only if automated devices are not available. Before blood pressure and pulse measurements, participants are allowed to rest for at least 5 minutes in a quiet environment without distractions (e.g., television, cell phone). Ideally, the same arm of each participant is used for measurements. Vital signs are collected before dosing on Day 1.

[0263] Symptom-directed electrocardiograms (ECGs) may be performed at any time after screening as needed based on local practice / standard of care. Normal findings or findings consistent with the participant's medical history will not be recorded. Abnormal findings not attributable to the participant's medical history, new abnormalities, or worsening of previous ECG findings will be reported as adverse events. Participants must be supine for approximately 5-10 minutes prior to ECG collection and must remain supine but awake throughout ECG collection.

[0264] All required laboratory evaluations will be performed according to the laboratory manual and assessment schedule. Samples will be collected for clinical laboratory evaluations as follows: before administration of the study intervention on day 1, before induction of anesthesia on the day of surgery, at any time during other visits, and within 1 day of hospital discharge. Daily collection of samples for clinical laboratory evaluations will occur on days 1–7 after CPB as follows: sCr and sCysC will be collected on days 1, 2, 4, 5, and 6 after CPB during hospitalization, along with complete laboratory evaluations on days 3 and 7 after CPB. If hospital discharge occurs before day 7 after CPB and the participant does not have AKI, sCr and sCysC do not need to be collected on days 1, 2, 4, 5, or 6. Participants who develop any AKI (at least stage 1 according to the KDIGO criteria) within the first 7 days will be followed with daily laboratory tests, regardless of discharge status or recovery (<1.5 × baseline), whichever occurs first, until day 7 after CPB. On days 3 and 7, samples for clinical laboratory evaluation will be collected as described in the Schedule of Evaluations.

[0265] All safety laboratory tests with values ​​considered to be clinically significantly abnormal during study participation through the 90-day visit will be repeated until the values ​​return to normal or baseline or are no longer considered clinically significant. If such values ​​do not return to normal / baseline within a specified period of time, an etiology should be identified.

[0266] If a safety laboratory value from a non-protocol-specified laboratory evaluation performed in the site's local laboratory requires a change in participant management or is deemed clinically significant (e.g., an adverse event or serious adverse event, or dose modification), the result will be recorded on the CRF and the corresponding adverse event or serious adverse event will be reported.

[0267] Pregnancy testing will be performed for all women of childbearing potential (WOCBP) at protocol-specified times in the schedule of assessments. Pregnancy testing may also be performed at any time during the study. A negative pregnancy test is required for WOCBP before administration of the study intervention. Any female participant who becomes pregnant while participating in the study will be discontinued from the study intervention. Pregnancy is not considered an adverse event unless there is suspicion that the study intervention may have interfered with the effectiveness of the contraceptive. However, pregnancy complications and adverse pregnancy outcomes are adverse events and may meet the criteria for serious adverse events (e.g., ectopic pregnancy, spontaneous abortion, intrauterine fetal death, neonatal death, or congenital anomaly).

[0268] In the primary assessment period, vital status (yes / no) will be documented at 15, 30, 60, and 90 days after CPB. For participants who withdraw consent for further participation in the study, every effort will be made to collect data at the time of withdrawal. In the survival follow-up period, vital status will be documented 365 days after CPB or ED, whichever comes first.

[0269] Participant vital status may be obtained via telephone contact with the participant, the participant's family, by contact with another healthcare provider, or by contact with a local death registry.

[0270] 9. Adverse Events (AEs) and Serious Adverse Events (SAEs) An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship to this treatment. Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) temporally associated with the use of the study intervention, whether or not it is considered related to the study intervention.

[0271] The following events meet the AE definition: A. Any abnormal laboratory test result (hematology, clinical chemistry, or urinalysis) or other safety assessment (e.g., ECG, radiology scan, vital sign measurement), including any worsening from baseline that is deemed clinically significant (i.e., not related to progression of the underlying disease). B. An exacerbation of a chronic or intermittent pre-existing condition, including either an increase in frequency and / or intensity of the condition. C. A new condition that may have existed before the start of the study but is detected or diagnosed after administration of the study intervention. D. Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction. E. Signs, symptoms, or clinical sequelae of suspected overdose of either the study intervention or concomitant medication. Overdose itself will not be reported as an AE / SAE unless it is an intentional overdose with possible suicidal / self-harm intent. Such overdoses will be reported regardless of sequelae.

[0272] Events that do not meet the AE definition include the following: A. Medical or Surgical Procedures (e.g., endoscopy, appendectomy): The condition leading to the procedure is an AE, but the procedure itself is recorded as a concomitant procedure. Situations in which an adverse medical occurrence did not occur (e.g., hospitalization for elective surgery, admission for social or convenience reasons if planned before signing the ICF). B. Expected day-to-day fluctuations of pre-existing diseases or conditions present or detected at the start of the study that do not worsen. C. Medication errors (including intentional misuse, abuse, and product overdose) or uses other than those defined in the protocol will not be considered AEs unless there is an adverse medical occurrence as a result of the medication error. D. Cases of pregnancy occurring during maternal or paternal exposure to the study intervention will be reported within 24 hours of investigator / institutional awareness. Data regarding fetal outcomes and lactation will be collected for regulatory reporting and safety assessment. E. Any clinically significant abnormal laboratory finding or other abnormal safety assessment related to the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. F. The disease / disorder being studied, or the expected progression, signs, or symptoms of the disease / disorder being studied, unless it is more severe than expected for the participant's condition. G. Situations in which no adverse medical occurrence occurred (social and / or convenience admission to hospital). H. "Lack of efficacy" or "failure of expected pharmacological action" itself is not reported as an AE or SAE. Such instances are captured in the efficacy evaluation. However, signs, symptoms, and / or clinical sequelae resulting from lack of efficacy will be reported as an AE or SAE if they meet the definition of an AE or SAE.

[0273] If the event is not an AE according to the above definition, it cannot be an SAE even if serious conditions are met (e.g., hospitalization due to signs / symptoms of the disease under study, death due to disease progression).

[0274] An SAE is defined as any untoward medical occurrence, at any dose, that meets one or more of the listed criteria in Table 7.

[0275] [Table 9]

[0276] A suspected unexpected serious adverse reaction (SUSAR) is defined as an event rated as serious that is not listed in the appropriate Baseline Safety Information (IB) and that is assessed as having at least a reasonable possibility that the event is related to the investigational medicinal product.

[0277] The investigator will provide an intensity rating for each AE and SAE reported during the study and assign it to one of the following categories from the National Cancer Institute CTCAE v5.0 published November 27, 2017: Grade 1: mild (noticeable signs or symptoms but easily tolerated), Grade 2: moderate (sufficient discomfort to cause interference with normal activities), Grade 3: severe (disabling, unable to perform normal activities), Grade 4: life-threatening, or Grade 5: fatal. An event is defined as "serious" if it meets at least one of the predetermined outcomes as described in the SAE definition, rather than if it is rated as severe.

[0278] The investigator is obligated to assess the relationship between the study intervention and each occurrence of each AE or SAE. The investigator's causality assessment must be provided for all AEs (both non-serious and serious). This assessment must be recorded on the eCRF and any additional forms, as appropriate. The causality assessment is defined as follows: A. Unrelated: There is no reasonable possibility that the study intervention caused the AE. The AE has a more likely alternative etiology, which may be due to an underlying or concurrent disease, a comorbidity, a concurrent treatment, or the effect of another concomitant medication. The event does not follow a reasonable temporal relationship to the administration of the study intervention. B. Related: There is a reasonable possibility that the study intervention caused the AE. The AE has a temporal relationship to the administration of the study intervention. The event does not have a possible alternative etiology. The event corresponds to the known pharmacological profile of the study intervention. There is improvement on discontinuation and / or recurrence on rechallenge.

[0279] The investigator will use clinical judgment to determine relationship. Alternative causes, such as underlying disease, concomitant therapy, and other risk factors, as well as the temporal relationship of the event to the administration of the study intervention, will be considered and investigated. The investigator will also review the IB and / or product information for marketed products in the investigator's assessment. For each AE / SAE, the investigator must document in the medical note that they have reviewed the AE / SAE and provided an assessment of causality.

[0280] Intravenous and infusion-related reactions are potential risks associated with the use of monoclonal antibodies, and these reactions can be non-immune or immune-mediated (e.g., hypersensitivity reactions). Signs and symptoms may include headache, fever, facial flushing, itching, muscle pain, nausea, chest tightness, difficulty breathing, vomiting, erythema, abdominal discomfort, sweating, tremors, high blood pressure, dizziness, low blood pressure, palpitations, and somnolence. Signs and symptoms of a hypersensitivity or allergic reaction may include hives, swollen face, eyelids, lips, or tongue, or respiratory problems.

[0281] All administration-, IV-, and infusion-related reactions will be reported to the investigator and qualified designee. The investigator and qualified designee are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and for following up on events that are considered related to the study intervention or procedure or are serious enough to cause a participant to discontinue ULTOMIRIS. Participants who experience a reaction while receiving ULTOMIRIS will be treated according to institutional guidelines. Participants who experience a severe reaction while receiving ULTOMIRIS that leads to the discontinuation of ULTOMIRIS will undergo all scheduled safety, PK, and PD evaluations as required by the protocol. All AEs that may represent an infusion-related response will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 or higher.

[0282] If anaphylaxis occurs according to the criteria listed in Table 8, administration of subcutaneous epinephrine (1 / 1000, 0.3 mL to 0.5 mL, or equivalent) will be considered. In the case of bronchospasm, treatment with an inhaled beta-agonist will also be considered. Participants receiving antihistamines for the treatment or prevention of infusion-related reactions will receive appropriate warnings about drowsiness and impaired driving ability before discharge from the center.

[0283] [Table 10]

[0284] Meningococcal infections are considered to be adverse events of special interest (AESI).

[0285] For this study, any dose of study intervention greater than the protocol-specified dose will be considered an overdose. If the dose cannot be established due to blinding, a suspected overdose will be defined by the volume administered.

[0286] Accidental or suspected overdose without any association with laboratory abnormalities or clinical symptoms is not considered an AE. Overdoses, whether or not associated with an AE, must be reported by the investigator within 24 hours.

[0287] An overdose is a medication error that is not considered an AE unless there is an adverse medical occurrence attributable to the overdose.

[0288] 10. Pharmacokinetics (PK) and Pharmacodynamics (PD) Blood samples for determination of serum ULTOMIRIS concentrations and PD assessment (free C5) will be collected before and after administration of the study intervention at the time points specified in the schedule of assessments. The actual date and time (24-hour clock time) of each sample will be recorded.

[0289] Day 1 baseline PK and PD blood samples will be collected pre-dose within 30 minutes prior to administration of the study intervention at the visit specified in the assessment schedule. Day 1 pre-dose blood samples can be drawn prior to administration of the dose through the venous access created for the dose infusion.

[0290] Post-dose PK and PD blood samples will be collected within 30 minutes after completion of the study intervention infusion. Post-dose blood samples will be drawn from the participant's contralateral, non-infused arm. Samples may be collected at any visit after Day 1. In the event of an unscheduled visit, PK and PD blood samples will be collected as soon as possible.

[0291] Study intervention concentration information that could unblind the study will not be reported to the investigational site or blinded personnel until the study is unblinded.

[0292] Genetics was not evaluated in this study.

[0293] Blood (serum and plasma) samples for exploratory assessments will be collected from all participants at the time points specified in the assessment schedule. Biomarkers may include, but are not limited to, assessment of: (1) complement pathway activation (e.g., soluble C5b-9 [sC5b-9]), (2) endothelial injury and / or activation (e.g., thrombomodulin [TM]), (3) vascular inflammation (e.g., shed tumor necrosis factor receptor I [TNF-RI]), and (4) inducers of cell cycle arrest (e.g., tissue inhibitor of metalloproteinase-2 [TIMP-2]).

[0294] Urine samples for exploratory assessments will be collected from all participants at the time points specified in the activity schedule. Biomarkers will include, but are not limited to, assessment of: (1) complement pathway activation (e.g., sC5b-9) and (2) kidney injury (e.g., neutrophil gelatinase-associated lipocalin [NGAL]).

[0295] Residual blood and urine samples from exploratory biomarker, PK, PD, and immunogenicity studies will be stored for additional evaluation (e.g., related to study intervention targets, disease processes, pathways associated with disease states, other complement-related diseases, and / or ULTOMIRIS mechanism of action). Samples will be retained for no longer than 5 years after the end of the study, or other periods depending on local requirements.

[0296] The quality of life scale will be completed by participants at the visit specified in the assessment schedule and before any other study procedures.

[0297] Participants in both cohorts will complete the following validated quality of life scales:

[0298] The Kidney Disease Quality of Life Index-36 Items (KDQOL-36) (Section 10.7), a 36-item short-form survey, is a widely used measure for patients on dialysis. Participants are asked to answer questions about their health, their kidney disease, and the impact of their kidney disease on their daily lives.

[0299] The European Quality of Life Group Five Dimensions and Five Levels (EQ-5D-5L) (Section 10.7) is a self-rated standardized index for measuring health-related quality of life and is used across a wide range of health conditions. The EQ 5D 5L is a 5-scale participant-reported outcome tool measuring pain / discomfort, mobility, self-care, usual activities, and anxiety / depression.

[0300] The Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, version 4.0, is a 13-item questionnaire assessing self-reported fatigue over the past 7 days and its impact on daily activities and function.

[0301] Healthcare resource utilization related to medical encounters will be collected for all participants throughout the primary assessment period. Protocol-defined procedures, tests, and encounters will be excluded. Hospital stay from admission to discharge, including dates of admission to the ICU and discharge to another inpatient unit. Renal replacement therapy (KRT): type / modality, frequency, start and stop dates, and reason for start / stop. Duration of mechanical ventilation (date and start / stop time). Discharge destination (e.g., home, rehabilitation facility, hospice).

[0302] Hospital readmissions (emergency room or inpatient admissions; elective outpatient procedures performed in the hospital are not considered readmissions). Primary reason will be assessed as pre-operative, which is always the primary reason, cardiovascular event not requiring re-operation (e.g., MI, stroke, heart failure, arrhythmia), AKI, or other reason, if present. Hospitalization from readmission to discharge, including date of emergency room visit, inpatient admission date, discharge date, and date of ICU admission and discharge to another inpatient unit. Specific reason for readmission will be reported as AE / SAE.

[0303] Exploratory economic analyses can be performed using additional data collected (e.g., concomitant medications and outpatient diagnostic and therapeutic procedures).

[0304] Other exploratory endpoints include (1) AKI within 7 days after CPB based on sCysC, (2) highest AKI stage according to KDIGO criteria, and (3) no severe AKI (KDIGO stage 2 or 3).

[0305] The minimum follow-up for safety is 90 days from dosing of the study intervention (Day 1, Visit 2). Participants in this study receive a single, weight-based dose of the study intervention, undergo cardiac surgery on CPB within 1 to 7 days of dosing (in the event of an unanticipated delay in surgery, the maximum interval between dosing and cardiac surgery on CPB is 15 days), and undergo all study visits and procedures outlined in the schedule of assessments through the 90-day visit (Visit 9). The timing of post-surgery (post-CPB) visits on days 3, 7, 15, 30, 60, and 90 is based on the day of CPB, with post-CPB Day 1 defined as the day after the participant is weaned from CPB. However, additional scenarios may arise during the conduct of the study: If a participant is medicated with the study intervention and does not undergo cardiac surgery, or if surgery is delayed more than 15 days after dosing, the participant will receive all subsequent study visits and procedures outlined in the schedule of assessments through the 90-day visit, with visit timing based on the day of dosing (Day 1, Visit 2). If a participant is randomized but not medicated, the participant will receive all subsequent study visits and procedures outlined in the schedule of assessments through the 90-day visit, with visit timing based on the day of randomization (Day 1, Visit 2). If a participant withdraws, a decision will be made for early discontinuation (ED) and Visit 9 will be conducted immediately.

[0306] Anti-drug antibodies to ULTOMIRIS (i.e., anti-drug antibodies) will be assessed in serum samples collected from all participants according to the assessment schedule. Additionally, serum samples will be collected at the final visit from participants who discontinue the study intervention or withdraw from the study.

[0307] Serum samples will be screened for antibody binding to ULTOMIRIS, and titers of confirmed positive samples will be reported. Other analyses can be performed to further characterize the immunogenicity of ULTOMIRIS.

[0308] Detection and characterization of antibodies to ULTOMIRIS will be performed using a validated assay. Samples collected for detection of antibodies to ULTOMIRIS will be evaluated for ULTOMIRIS serum concentrations to assess the impact of ADA on the drug concentration profile of ADA-positive patients. ADA-positive samples will be further characterized for antibody titer and the presence of neutralizing antibodies.

[0309] ADA variables include ADA response category incidence and titer over the duration of the study as follows: ADA response category definitions and titer thresholds are provided in the statistical analysis plan (SAP). ADA response categories are ADA negative and ADA positive. Participants who are ADA positive will be classified as having: pre-existing immune reactivity or an ADA response that occurred during treatment.

[0310] 11.Statistical considerations The primary hypothesis to be tested for this study is that ULTOMIRIS is superior to placebo in reducing the risk of MAKE events at 90 days after CPB (MAKE90): H0:p1≧p0 H1:p1 <p0 where p1 and p0 represent the probability of experiencing a MAKE90 event in the ravulizumab group and the placebo group, respectively.

[0311] The treatment effect based on the MAKE90 endpoint is estimated by the difference in the proportion of participants experiencing MAKE90, regardless of any current events (IE), between the ULTOMIRIS group and the placebo group. A negative difference indicates a beneficial treatment effect for ULTOMIRIS.

[0312] The following key secondary hypotheses will be tested sequentially in the following hierarchical order, considering that the null hypothesis for the primary endpoint will be rejected: ULTOMIRIS is superior to placebo in the proportion of participants free of CSA-AKI at 90 days post-CPB. ULTOMIRIS is superior to placebo in the proportion of participants free of severe CSA-AKI (KDIGO stage 2 or 3) based on the highest sCr observed within 7 days post-CPB. ULTOMIRIS is superior to placebo in the proportion of participants free of severe AKI (RIFLE injury or failure criteria) based on the highest sCr observed within 30 days post-CPB. ULTOMIRIS is superior to placebo in the proportion of participants free of any severe AKI (KDIGO stage 2 or 3) based on the highest sCr observed within 30 days post-CPB. ULTOMIRIS is superior to placebo in the proportion of participants free of any RIFLE failure criteria based on the highest sCr observed within 30 days post-CPB. ULTOMIRIS was superior to placebo in the proportion of participants who died from any cause from randomization through 90 days after CPB.

[0313] Sample size estimation was based on the difference between the two rates using ordinary approximations to compare the treatment difference in the proportion of participants experiencing a MAKE event within 90 days after CPB between the ULTOMIRIS group and the placebo group. A sample size of 736 participants (368 participants per treatment group) would have 90% power to detect a statistically significant treatment difference of 10% at a two-sided significance level of 0.05 in the proportion of participants with a MAKE within 90 days after CPB, assuming a MAKE rate of 25% for the placebo group and 15% for the ULTOMIRIS group, and a dropout rate of approximately 10%. The assumption of a 25% MAKE rate in the placebo group was derived based on recent interventional and observational studies, as described below.

[0314] Recent intervention trials aimed at reducing CSA-AKI reported that 9% to 10% of participants receiving placebo achieved the MAKE endpoint at 30 days (see, e.g., Meersch M, et al., Intensive Care Med. 2017;43(11):1551-61; Jacob KA, et al., J. Am. Soc. Nephrol. 2015;26(12):2947-51; Venugopal H, et al., Kidney 360. 2020;1(6):530-3), and 13% to 22% at 90 days (see, e.g., Thielmann M, et al., Circulation. 2021;144(14):1133-1144, and Meersch M, et al., Intensive Care Med. 2017;43(11):1551-61). These studies included variable rates of participants with CKD (8%–47%). A post-hoc analysis of the subgroup with CKD (preoperative eGFR <60 mL / min / 1.73 m2) from the Dexamethasone for Cardiac Surgery study reported a MAKE30 rate of 16.5% in the placebo group (see Venugopal H, et al., Kidney 360. 2020;1(6):530-3). Because these studies did not exclusively enroll CKD patients, a higher placebo rate is expected in this study, which enrolled individuals at increased risk for AKI due to pre-existing CKD and at elevated risk for renal failure as predicted using the STS risk calculator.

[0315] There are limited data from other trials on the frequency of MAKE (or its individual component outcomes) in those with pre-existing CKD. Therefore, estimates of individual MAKE events were derived from observational studies along with this trial data to inform the 25% placebo rate assumption for the current study: KRT 7%–10%: Interventional trials reported KRT in 6.5%–7.5% of participants receiving placebo (see, e.g., Thielmann M, et al., Circulation. 2021;144(14):1133-1144, and Meersch M, et al., Intensive Care Med. 2017;43(11):1551-61). Observational studies from various healthcare systems have reported postoperative KRT in 7% to 30% of patients with pre-existing CKD (see, e.g., Wu VC, Kidney Int. 2011;80(11):1222-1230; Cho JS, et al., J. Thorac. Cardiovasc. Surg. 2021;161(2):681-8.e3; and Lau D, et al., J. Thorac. Cardiovasc. Surg. 2021;162(3):880-7). By exclusively recruiting participants with CKD, at least 7% of participants are expected to require KRT. The use of the STS kidney failure risk calculation threshold for study inclusion is also expected to overrepresent participants at highest risk for requiring KRT, particularly among those with pre-existing CKD stage 3a.

[0316] Mortality rate of 4%-7%: Interventional trials report a mortality rate of 2%-7% within 90 days after CPB (see, e.g., Thielmann M, et al., Circulation. 2021;144(14):1133-1144, and Meersch M, et al., Intensive Care Med. 2017;43(11):1551-61, Whitlock RP, et al., Lancet. 2015;386(10000):1243-53, and Dieleman JM, et al., JAMA. 2012;308(17):1761-7). Observational studies have shown that AKI is independently associated with the risk of death after CPB, with the highest risk in patients requiring acute KRT (see, for example, Lau D, et al., J. Thorac. Cardiovasc Surg. 2021;162(3):880-7, and Matsuura R, et al., Sci Rep. 2020;10(1):6490). Additionally, AKI superimposed on pre-existing CKD confers a higher risk of death (up to 11%) after cardiac surgery (Cho 2021). Therefore, by exclusively enrolling CKD patients, an overall mortality rate of approximately 5% to 6% is expected.

[0317] SKD 17%-25%: Using changes in sCr or sCr-based eGFR, 19%-22% of CKD populations reported in observational studies have SKD 3 months after CPB (see, e.g., Wu VC, Kidney Int. 2011;80(11):1222-1230; Xu J, et al., BMC Nephrol. 2019;20(1):427; Matsuura R, et al., Sci Rep. 2020;10(1):6490; and Cho JS, et al., J. Thorac. Cardiovasc. Surg. 2021;161(2):681-8.e3). AKI superimposed on CKD is the greatest risk factor for SKD, with 20%–30% experiencing nonrecovery to baseline renal function by 90 days (Cho 2021, Wu 2011, Matsuura 2020). Data from interventional trials to directly inform the rate of SKD in participants with pre-existing CKD are limited. Recent trials without fully inclusive CKD have reported SKD rates of 7%–12% in control / placebo groups (see, e.g., Thielmann M, et al., Circulation. 2021;144(14):1133–1144, and Meersch M, et al., Intensive Care Med. 2017;43(11):1551–61). The exclusive enrollment of participants with CKD is expected to increase the proportion of participants classified as SKD at 90 days compared to other CSA-AKI trials.

[0318] MAKE90 20%-30%: Individual participants often meet the criteria for >1 event within 90 days, so individual event frequencies are not additive. Recent clinical trials (see, e.g., Thielmann M, et al., Circulation. 2021;144(14):1133-1144 and Meersch M, et al., Intensive Care Med. 2017;43(11):1551-61) reported that approximately 30% of patients experienced two or more components of MAKE (KRT, death, SKD). Assuming a similar pattern in the current study, the expected proportion of participants in the placebo group achieving the MAKE endpoint at 90 days is estimated to be 20%-30% based on the integration of various data sources summarized herein. The assumed placebo rate in this study is 25%.

[0319] The population set used for analysis in this study is defined in Table 9.

[0320] [Table 11] Abbreviations: ADA = anti-drug antibodies; CPB = cardiopulmonary bypass; KRT = renal replacement therapy; PD = pharmacodynamics; PK = pharmacokinetics; SAP = statistical analysis plan; sCr = serum creatinine.

[0321] Evaluable PK, PD, and ADA data are defined as non-defective results generated from samples that meet sample integrity requirements during sample collection, storage, transport, and bioanalysis.

[0322] Generally, descriptive statistics (n, mean, median, standard deviation, first and third quantiles, minimum, and maximum) will be provided by treatment group and visit for each quantitative variable, and frequencies and percentages will be provided by treatment group and visit for each qualitative variable. Graphical displays will be provided as needed. Baseline is defined as randomization on Day 1 prior to administration of the study intervention, except as otherwise noted below. Final analysis and unblinding of the study will occur once the last enrolled participant completes the Day 90 visit or early withdrawal. Analyses will be performed using SAS® software, version 9.4 or higher.

[0323] The primary efficacy analysis is based on the intention-to-treat (ITT) analysis set. The primary endpoint is a MAKE event at 90 days post-CPB (MAKE90), defined as meeting at least one of the following criteria: (1) a decrease from baseline in eGFR of ≥ 25% at 90 days post-CPB, (2) the occurrence of KRT by 90 days post-CPB, or (3) death from any cause by 90 days post-CPB. Baseline and post-baseline eGFR will be calculated from sCysC using the CKD-EPI equation. Baseline eGFR is based on the average of sCysC collected during screening and on Day 1 before administration of the study intervention.

[0324] The observed proportion of participants experiencing MAKE90 is reported by treatment group. Treatment effects on MAKE90 endpoints are estimated using the continuity-corrected Cochran-Mantel-Haenszel (CMH) method, adjusting for stratification variables. For missing MAKE90 endpoints due to partial or complete missingness of individual components, missingness of KRT initiation or death is imputed as a non-event, and missingness of eGFR is handled by multiple imputation from mixed model repeated measures (MMRM), which assumes missingness at random by treatment group and is then dichotomized into a binary variable. The MMRM model uses all available data and includes baseline, CKD stage, surgery type, visit, treatment group, and treatment group by visit interaction as fixed effects, and participant as a random effect. Rubin's rules are used to combine results to obtain multiple imputation point estimates and standard errors. When the distribution of the CMH test statistic significantly deviates from normal, a Wilson-Hilferty transformation is applied before combining using Rubin's rules. The p-value and two-sided 95% confidence interval (CI) for the treatment difference in MAKE90 are reported.

[0325] Sensitivity analyses were performed to assess the robustness of the results to missing data estimation methods. Missing data in MAKE90 were multiple imputed by treatment group based on a logistic regression model. The logistic model included CKD stage, surgery type, visit, treatment group, and treatment group by visit interaction as covariates. The CMH test, along with Rubin's rules, was applied as in the primary analysis. If the CMH test statistic significantly deviated from the normality assumption, a Wilson-Hilferty transformation was applied.

[0326] A second sensitivity analysis will be performed based on multiple imputation using the jump-to-reference (J2R) model. For participants who discontinue the study without any further follow-up data, any missing values ​​after discontinuation will be imputed under the assumption that their outcomes will be similar to those in the placebo group with similar baseline characteristics. The CMH test will be performed in the same way as in the primary analysis.

[0327] Additionally, individual MAKE90 components will be analyzed. The proportion of participants with a ≥ 25% decrease in eGFR (CKD-EPI equation using sCysC) from baseline by day 90 post-CPB, or initiation of KRT by day 90 post-CPB, or death from any cause by day 90 post-CPB will be summarized by treatment group and visit. Point estimates for the treatment difference and associated two-sided 95% CIs will be presented by visit using the CMH method adjusting for stratification factors.

[0328] In addition to the primary treatment policy estimator, other supplementary estimators using the ITT population or other populations (i.e., modified intention-to-treat [mITT], per-protocol set [PPS], and post-operative set [POS]) are also defined to assess the robustness of the primary estimator effect. Details are provided in SAP.

[0329] Secondary efficacy analyses will be based on the ITT analysis set. Sequential study procedures will be performed for key secondary endpoints in the following order: A. No CSA-AKI at 90 days after CPB, defined as no AKI within the first 7 days after CPB or AKI recovery (stage 0) at 90 days after CPB. B. No severe CSA-AKI (KDIGO stage 2 or 3) based on the highest sCr observed within 7 days after CPB. C. No severe AKI (RIFLE injury or failure criteria) based on the highest sCr observed within 30 days after CPB. D. No severe AKI (KDIGO stage 2 or 3) based on the highest sCr observed within 30 days after CPB, and E. Absence of any RIFLE failure criteria based on highest sCr observed within 30 days after CPB. F. All-cause mortality from randomization to 90 days after CPB

[0330] The highest observed sCr was from a central laboratory sample collected at a designated study visit from daily local laboratory sCr results at any time during the first 30 days. Baseline sCr for defining AKI was based on the average of sCr collected during screening and on Day 1 before administration of the study intervention. Specifically, if the null hypothesis for the primary endpoint is rejected, key secondary endpoints are tested to the same significance level as the primary endpoint, and if any null hypotheses are not rejected, subsequent testing is terminated.

[0331] Analyses of key secondary endpoints will be the same as the primary analysis. The observed proportion of participants meeting each key secondary endpoint will be summarized by treatment group.

[0332] To estimate treatment effects on key secondary endpoints, missing data due to early withdrawal and all other events will be imputed by last observation carried forward (LOCF) where applicable; otherwise, missing data will be imputed as endpoint not reached. Point estimates and associated two-sided 95% CIs will be estimated using the CMH method adjusting for stratification factors.

[0333] If the test for the primary endpoint demonstrates statistical significance, the association between each of the key secondary endpoints 2–5 above and the following clinical outcomes will be examined: death, initiation of KRT, hospital readmission, duration of KRT (days), duration of ICU stay (days), duration of ventilation (days), and duration of hospitalization (days).

[0334] For binary clinical outcomes, including death, initiation of KRT, and hospital readmission, 2x2 contingency tables of clinical outcomes and key secondary endpoints are provided by treatment group and overall. Chi-square tests are performed to test for correlation between two variables.

[0335] For continuous clinical outcomes, summary statistics will be provided by key secondary endpoint category, treatment group, and overall. Linear regression will be applied using key secondary endpoints and treatment group as covariates.

[0336] Similar to the primary endpoint MAKE90, which is determined based on the CKD-EPI equation using sCysC, MAKE90 is also determined based on the CKD-EPI equation using sCr. In addition, MAKE30 and MAKE60 endpoints are similarly determined. The proportions of participants experiencing MAKE at 30, 60, and 90 days after CPB are summarized by treatment group and visit. Point estimates for treatment differences and associated p-values ​​and two-sided 95% CIs are presented using the CMH method, adjusting for stratification factors.

[0337] Additionally, individual MAKE components will be analyzed. The proportion of participants with a ≥ 25% decrease in eGFR from baseline by 30, 60, and 90 days post-CPB, or initiation of KRT by 30, 60, and 90 days post-CPB, or death from any cause by 30, 60, and 90 days post-CPB will be summarized by treatment group and visit. Point estimates for the treatment difference and associated 2-sided 95% CIs will be presented by visit using the CMH method adjusting for stratification factors.

[0338] Additional analyses can be investigated to examine the treatment effect for each individual component of MAKE at 30, 60, and 90 days post-CPB.

[0339] The proportion of participants with KRT or death occurring by 30, 60, and 90 days after CPB will be summarized by treatment group. Point estimates and associated two-sided 95% CIs will be provided using the CMH method adjusting for stratification factors.

[0340] The proportion of participants with CSA-AKI according to the highest stage observed within the first 3 and 7 days after CPB using modified KDIGO criteria will be summarized by treatment group.

[0341] The proportions of participants with no CSA-AKI and no AKI will be summarized by treatment group and visit at pre-specified visits. Point estimates and associated 2-sided 95% CIs will be estimated using the CMH method adjusting for stratification factors.

[0342] Among participants experiencing CSA-AKI within 7 days after CPB, the proportion of participants with AKI recovery (complete or partial), improvement in AKI, stable AKI, or progression of AKI at 15, 30, 60, and 90 days after CPB will be summarized by treatment group and visit. Point estimates and associated 2-sided 95% CIs will be estimated using the CMH method adjusting for stratification factors (if appropriate).

[0343] The duration of index hospital and ICU stay (days) was calculated for each participant based on the date of discharge minus the date of admission, where index hospital and ICU stay refers to hospital admission resulting from CPB surgery. For patients on mechanical ventilation, the duration on mechanical ventilation (days) was calculated based on the date of liberation from mechanical ventilation minus the date of initiation of mechanical ventilation. For patients on KRT, the duration of KRT (days) was calculated based on the last day of KRT minus the date of KRT initiation.

[0344] Duration will be summarized for each treatment group using descriptive statistics, including the number of observations in each treatment group, mean, standard deviation, median, minimum, maximum, interquartile range (IQR), first quartile, and third quartile values.

[0345] Hospital readmission rates (all-cause or AKI-related) up to 30 and 90 days after CPB will be summarized by treatment group and visit. Point estimates and associated two-sided 95% CIs will be estimated using the CMH method, adjusting for stratification factors (where appropriate).

[0346] The following quality of life assessments will be summarized by treatment group at baseline and each post-baseline time point using descriptive statistics for observed values ​​and changes from baseline: FACIT-Fatigue, EQ-5D-5L, and KDQOL-36.

[0347] Changes from baseline are also summarized for each treatment group from the MMRM analysis; no formal treatment comparisons were made. Point estimates and two-sided 95% CIs for the mean differences in these measurement scores are presented.

[0348] Analysis of exploratory biomarker data will be described in a separate analysis plan and will be summarized after study completion.

[0349] The multiple testing procedure involves testing for a primary endpoint followed by pre-specified hierarchical testing for key secondary endpoints. Statistical significance is assessed in hypothesis order. Secondary endpoints are tested in a fixed order only if the primary endpoint is statistically significant. Testing of key secondary endpoints continues down the hierarchy only if the test for the preceding secondary endpoint is statistically significant.

[0350] At the second interim analysis, i.e., when approximately 50% of participants have completed the primary assessment period, a re-estimation of the sample size is performed. Conditional power based on the observed treatment effect is calculated to determine whether enrollment will continue to achieve the planned or increased sample size. The primary endpoint will be tested in the final analysis when all enrolled participants have completed the primary assessment period, at a one-sided significance level of 0.025. If the test of the primary endpoint is statistically significant in the final analysis, statistical significance for key secondary endpoints will be evaluated in a fixed order.

[0351] Under this pre-specified multiple testing procedure and hierarchical testing strategy, the overall type I error is controlled at the one-sided 0.025 level for multiplicity across the primary and key secondary endpoints. Other interim analyses planned with a 30% sample size for early futility assessment will not pose a risk of type I error inflation.

[0352] Safety will be assessed based on AEs, clinical laboratory findings, and vital sign findings. All safety analyses will be performed on the safety set.

[0353] The incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to study withdrawal, and treatment-emergent serious adverse events (TESAEs) will be summarized by treatment group. A TEAE is defined as an AE involving a new or pre-existing event that worsens in severity from the start of study intervention dosing through 90 days after study intervention dosing. All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 24.1 or higher, and summarized by System Organ Class (SOC) and Preferred Term overall, severity, and relationship to the study intervention. A detailed list of TEAEs, TESAEs, related TEAEs, and TEAEs leading to study withdrawal per participant will be provided. Participants with multiple AEs within a category (e.g., overall, SOC, preferred term) will be counted once in that category. For severity tables, the participant's most severe event within a category will be counted. AESI (e.g., meningococcal infection) will be analyzed similarly.

[0354] Abnormal physical examination findings will be classified as AEs and analyzed accordingly.

[0355] Vital signs will be summarized descriptively by treatment group at baseline and post-baseline time points and change from baseline.

[0356] Observed values ​​and changes from baseline in clinical chemistry, hematology, and urinalysis will be summarized descriptively by treatment group at baseline and each post-baseline time point. For laboratory results that can be classified as normal, low, or high based on normal range values, shifts from baseline in classification will be summarized for all study visits.

[0357] The PK and PD analyses include all data in the PK analysis set and PD analysis set, respectively.

[0358] A graph of the mean serum ravulizumab concentration-time profile will be constructed. A graph of the serum concentration-time profile for each individual participant may also be provided. Descriptive statistics will be calculated for the serum concentration data at each sampling time, as appropriate.

[0359] The PD effect of ULTOMIRIS will be assessed by evaluating the absolute values ​​and the change and percentage change from baseline in serum free C5 concentrations over time, as appropriate. Descriptive statistics will be calculated for the PD data at each sampling time, as appropriate.

[0360] All antidrug antibody (ADA) assays are performed on the ADA Assay Set (AAS).

[0361] The incidence of ADA response categories will be summarized as absolute incidence (n) and percent (%) of all participants in the ravulizumab group at Days 30 and 90. Confirmed antibody-positive samples will be further evaluated for antibody titer and the presence of neutralizing antibodies. Maximum ADA titer levels will be listed and summarized for ADA-positive participants as absolute incidence (n) and percent (%) of all participants.

[0362] Associations between immunogenicity variables and effects on drug exposure, efficacy, and safety can be investigated.

[0363] Subgroup analyses of the primary and key secondary endpoints will be performed for the following subsets of participants: (1) participants with different CKD stages at baseline, (2) participants with different surgical types during CPB, (3) participants in age groups 18-60 years, 61-75 years, and >75 years, (4) participants with weight groups of ≥30-59 kg, 60-99 kg, and ≥100 kg at baseline, (5) participants with the following levels of albuminuria (measured as albumin to creatinine ratio [ACR]) at baseline (KDIGO2013): <30 mg albumin / g creatinine, ≥30-<300 mg albumin / g creatinine, and ≥300 mg albumin / g creatinine, and (6) participants with and without diabetes mellitus.

[0364] Two interim analyses are planned to be conducted by an independent data monitoring committee (DMC) after approximately 30% (approximately 220 participants) and 50% (approximately 368 participants) of the randomized participants have completed the primary evaluation period (i.e., the 90-day post-CPB visit). The purpose of the first interim analysis will be to evaluate early stopping for futility, and the second interim analysis is planned to perform sample size re-estimation.

[0365] For futility and sample size re-estimation assessment, the conditional power for the primary endpoint analysis is calculated at the interim analysis using the observed trend. If the conditional power is less than 20% at the first interim analysis, the study is considered for early stopping due to futility. However, the futility criteria are non-binding. In other words, if the primary endpoint meets the pre-specified futility criteria at the first interim analysis, the study can be continued without stopping due to futility.

[0366] For sample size re-estimation in the second interim analysis, if the conditional power falls within a promising zone (0.5, 0.9), the study sample size will be increased. This promising zone is selected to ensure that a conventional analysis at the end of the study will not inflate a type I error under the planned maximum sample size increase. To prevent potential unblinding of interim analysis results in the sample size re-estimation procedure, a step function is utilized to guide the sample size increase if the interim analysis results fall within a pre-specified promising zone. Details of the interim analysis will be documented in an interim statistical analysis plan (iSAP) prior to the interim analysis.

[0367] 12. Clinical Laboratory Tests Tests detailed in Table 10 will be performed by the study central laboratory unless otherwise noted. Local laboratory results are required only if central laboratory results are not available in time for eligibility, study intervention administration, and / or response assessment. If local samples are required, it is important that samples for central analysis be obtained simultaneously. Additionally, if local laboratory results are used to determine eligibility or study intervention or for response assessment, the results must be available in the participant's source documentation. Consider serum creatinine testing performed locally as standard of care during the first 30 days after CBP. Report the highest observed results on the CRF. Additional laboratory tests may be performed at any time during the study as determined necessary by the investigator or required by local regulations. WOCBPs will be enrolled only after a negative serum pregnancy test result at screening. Additional pregnancy tests will be performed at each time point specified in the schedule of assessments.

[0368] [Table 12] Abbreviations: ADA = anti-drug antibody; Ba = complement factor B; C5 = complement component 5; NAb = neutralizing antibody; PD = pharmacodynamic; PK = pharmacokinetics; RBC = red blood cells; WBC = white blood cells; WOCBP = women of childbearing potential

[0369] 13. Exploratory Biomarkers Blood and urine samples will be collected for exploratory evaluation of ULTOMIRIS or CSA-AKI and related diseases. These samples may also be used for further exploratory development of assays related to ULTOMIRIS mechanism of action, disease processes and / or pathways associated with the CSA-AKI disease state. Results of biomarker analysis may be reported in the CSR or later in a separate study summary.

[0370] 14. COVID-19 Vaccine Risk Assessment Currently, there is no information available to assess the safety and efficacy of COVID-19 vaccines in participants treated with ULTOMIRIS. Based on the mechanism of action of ULTOMIRIS, it is unlikely that the immune response to COVID-19 vaccines (and therefore the efficacy of vaccination) is diminished by ULTOMIRIS administration. It is also unlikely that COVID-19 vaccination affects the mechanism of action of ULTOMIRIS.

[0371] Vaccination may further activate complement. As a result, participants with complement-mediated diseases may experience an increase in signs and symptoms of their underlying disease. Therefore, participants should be closely monitored for disease symptoms after recommended vaccination. Because vaccines can activate complement, consider administering vaccination immediately after administration, if possible, when the underlying complement-mediated disease is clinically controlled and when systemic C5 inhibitor concentrations (and subsequent complement blockade) are relatively high. Local and national guidelines should be consulted for recommendations regarding COVID-19 vaccination.

[0372] The potential risks identified and the mitigation measures put in place in light of the COVID-19 vaccination rollout are provided in Table 11.

[0373] [Table 13] Abbreviations: COVID-19 = coronavirus disease 2019; CRF = case report form.

[0374] Array Overview

[0375] [Table 14-1]

[0376] [Table 14-2]

[0377] [Table 14-3]

[0378] [Table 14-4]

Claims

1. 1. A method of preparing a human patient having chronic kidney disease (CKD) for cardiac surgery with cardiopulmonary bypass (CPB), the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) A single dose of 3600 mg is administered to patients weighing ≧100 kg.

2. 1. A method of inhibiting terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery. a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) A single dose of 3600 mg is administered to patients weighing ≧100 kg.

3. 1. A method of treating a human patient with CKD prior to cardiac surgery by CPB, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) A single dose of 3600 mg is administered to patients weighing ≧100 kg.

4. 1. A method for preventing or reducing cardiac surgery-associated acute kidney injury (CSA-AKI) in a human patient with CKD, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof; the anti-C5 antibody or antigen-binding fragment thereof comprises I CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; the anti-C5 antibody or antigen-binding fragment thereof is administered prior to cardiac surgery with CPB, a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) A single dose of 3600 mg is administered to patients weighing ≧100 kg.

5. 1. A method for preventing or reducing one or more major adverse kidney events (MAKE) in a human patient with CKD, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof; the anti-C5 antibody or antigen-binding fragment thereof comprises the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; the anti-C5 antibody or antigen-binding fragment thereof is administered prior to cardiac surgery with CPB, a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) A single dose of 3600 mg is administered to patients weighing ≧100 kg.

6. The method of any one of claims 1 to 5, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at least one calendar day before the CPB.

7. 7. The method of any one of claims 1 to 6, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered 1 to 7 calendar days prior to the CPB.

8. 8. The method of any one of claims 1 to 7, wherein the anti-C5 antibody or antigen-binding fragment thereof further comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), and the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, of a native human IgG Fc constant region, according to EU numbering.

9. The method of any one of claims 1 to 8, 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.

10. The method of any one of claims 1 to 9, wherein the anti-C5 antibody further comprises a heavy chain constant region set forth in SEQ ID NO:

13.

11. The method of any one of claims 1 to 10, 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.

12. The anti-C5 antibody or antigen-binding fragment thereof has a K Ｄ an affinity dissociation constant (K) that is ≦1 nM (e.g., about 0.5 nM); Ｄ The method according to any one of claims 1 to 11, wherein the antibody binds to human C5 via the antibody.

13. The anti-C5 antibody or antigen-binding fragment thereof has a pH of 6.0 and a pH of 2.0 at 25° C. Ｄ The method of any one of claims 1 to 12, wherein the antibody binds to human C5 with a binding affinity of ≧10 nM (e.g., about 22 nM).

14. 14. The method of any one of claims 1 to 13, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 2700 mg to a patient weighing ≥ 30 kg to < 40 kg.

15. 14. The method of any one of claims 1 to 13, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg to a patient weighing ≥ 40 kg to < 60 kg.

16. 14. The method of any one of claims 1 to 13, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3300 mg to a patient weighing ≥ 60 kg to < 100 kg.

17. 14. The method of any one of claims 1 to 13, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered at a dose of 3600 mg to a patient weighing ≥ 100 kg.

18. 18. The method of any one of claims 1 to 17, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 175 μg / mL or greater.

19. 19. The method of any one of claims 1 to 18, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 200 μg / mL or greater.

20. The method of any one of claims 1 to 19, wherein the anti-C5 antibody or antigen-binding fragment thereof is formulated for intravenous administration.

21. 21. The method of any one of claims 1 to 20, wherein the cardiac surgery is selected from the group consisting of coronary artery bypass grafting (CABG), valve replacement or repair, insertion of a pacemaker or implantable cardioverter defibrillator (ICD), maze surgery, heart transplantation, and insertion of a ventricular assist device (VAD) or total artificial heart (TAH), and transcatheter structural heart surgery.

22. 22. The method of any one of claims 1 to 21, wherein a single pre-operative, weight-based dose of the anti-C5 antibody or antigen-binding fragment thereof results in complete C5 inhibition for at least 18 days.

23. 23. The method of any one of claims 1 to 22, wherein said method prevents the need for renal replacement therapy (KRT).

24. 24. The method of any one of claims 1 to 23, wherein the method prevents or reduces CSA-AKI in a human patient with CKD.

25. The human patient includes a patient with cardiac surgery-associated acute kidney injury (CSA-AKI), wherein the CSA-AKI is a) an increase in serum creatinine (sCr) or serum cystatin C (sCysC) of ≥ 0.3 mg / dL in a 48-hour period within 7 days after CPB, and / or 25. The method of any one of claims 1 to 24, characterized by b) an increase in sCr or sCysC of ≥ 1.5 times baseline within 7 days after CPB or at 15, 30, 60, or 90 days after CPB.

26. 26. The method of any one of claims 1-25, wherein the human patient does not have severe CSA-AKI based on the highest sCr observed within 7, 30, 45, 60, or 90 days after CPB as assessed by modified Kidney Disease International Outcomes Improvement (KDIGO) criteria.

27. 27. The method of any one of claims 1-26, wherein the human patient does not have severe CSA-AKI based on the highest sCr observed within 7, 30, 45, 60, or 90 days after CPB as assessed by the modified "Risk, Injury, Failure, Loss of Renal Function, and End-Stage Renal Disease" (RIFLE) criteria.

28. 28. The method of any one of claims 1-27, wherein the method results in stable CSA-AKI characterized by sCr > 2.0 to < 3.0 x baseline within 7, 30, 45, 60, or 90 days after surgery.

29. 29. The method of any one of claims 1-28, wherein the method results in improvement from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, wherein the improvement is characterized by an sCr > 1.5 to < 2.0 x baseline.

30. 29. The method of any one of claims 1-28, wherein the method results in partial recovery from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, wherein the partial recovery is characterized by an sCr > 1.1 to < 1.5 x baseline.

31. 29. The method of any one of claims 1-28, wherein the method results in complete recovery from CSA-AKI within 7, 30, 45, 60, or 90 days after surgery, wherein the complete recovery is characterized by an sCr<1.1 x baseline.

32. 32. The method of any one of claims 1 to 31, wherein the method prevents or reduces one or more MAKE in a human patient with CKD.

33. the one or more MAKEs a) persistent kidney dysfunction (SKD), defined as an estimated glomerular filtration rate (eGFR) >25% lower than baseline after CPB; b) incidence of renal replacement therapy (KRT) after CPB, and c) death from any cause after CPB.

34. 34. The method of claim 33, wherein the decrease in eGFR is determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on serum cystatin C (sCysC) or serum creatinine (sCr).

35. 35. The method of any one of claims 1 to 34, wherein the method results in a change from baseline in quality of life as assessed via a quality of life assessment.

36. 36. The method of claim 35, wherein the quality of life assessment is the Kidney Disease Quality of Life Index (KDQOL-36), the European Quality of Life Group Five Dimensions 5 Levels (EQ-5D-5L), or the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale.

37. 37. The method of any one of claims 1 to 36, wherein the method results in a shift to normal levels of biomarkers associated with vascular inflammation (e.g., shed tumor necrosis factor receptor 1 [TNF-R1 or sTNF-R1]), endothelial injury and / or activation (e.g., thrombomodulin), kidney injury (e.g., neutrophil gelatinase-associated lipocalin [NGAL]), inducers of cell cycle arrest (e.g., tissue inhibitor of metalloproteinase-2 [TIMP-2]), and / or complement proteins and complement activation pathway products (e.g., soluble C5b-9).

38. A kit comprising: (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively; (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof in the method of any one of claims 1 to 37.

39. 1. An anti-C5 antibody or antigen-binding fragment thereof for use in preparing a human patient with CKD for cardiac surgery with cardiopulmonary bypass (CPB), wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) An anti-C5 antibody or antigen-binding fragment thereof administered once at a dose of 3600 mg to a patient weighing ≧100 kg.

40. 1. An anti-C5 antibody or antigen-binding fragment thereof for use in inhibiting terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) An anti-C5 antibody or antigen-binding fragment thereof administered once at a dose of 3600 mg to a patient weighing ≧100 kg.

41. 1. An anti-C5 antibody or antigen-binding fragment thereof for use in treating a human patient with chronic kidney disease prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) An anti-C5 antibody or antigen-binding fragment thereof administered once at a dose of 3600 mg to a patient weighing ≧100 kg.

42. 1. An anti-C5 antibody or antigen-binding fragment thereof for use in preventing or reducing CSA-AKI in a human patient with chronic kidney disease, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) An anti-C5 antibody or antigen-binding fragment thereof administered once at a dose of 3600 mg to a patient weighing ≧100 kg.

43. 1. An anti-C5 antibody or antigen-binding fragment thereof for use in preventing or reducing one or more MAKE in a human patient with chronic kidney disease, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) An anti-C5 antibody or antigen-binding fragment thereof administered once at a dose of 3600 mg to a patient weighing ≧100 kg.

44. 1. Use of an anti-C5 antibody or antigen-binding fragment thereof to prepare a human patient with CKD for cardiac surgery by CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) Use in patients weighing ≥ 100 kg, administered as a single dose of 3600 mg.

45. 1. Use of an anti-C5 antibody or an antigen-binding fragment thereof to inhibit terminal complement activation in a human patient with CKD prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) Use in patients weighing ≥ 100 kg, administered as a single dose of 3600 mg.

46. 1. Use of an anti-C5 antibody or an antigen-binding fragment thereof for the treatment of a human patient with chronic kidney disease prior to cardiac surgery with CPB, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to the surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) Use in patients weighing ≥ 100 kg, administered as a single dose of 3600 mg.

47. 1. Use of an anti-C5 antibody or antigen-binding fragment thereof in preventing or reducing CSA-AKI in a human patient with chronic kidney disease, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery by: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) Use in patients weighing ≥ 100 kg, administered as a single dose of 3600 mg.

48. 1. Use of an anti-C5 antibody or antigen-binding fragment thereof in preventing or reducing one or more MAKE in a human patient with chronic kidney disease, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered prior to surgery: a) 2700 mg for patients weighing ≥ 30 kg to < 40 kg; b) 3000 mg for patients weighing ≥ 40 kg to < 60 kg; c) 3300 mg for patients weighing ≥ 60 kg to < 100 kg; or d) Use in patients weighing ≥ 100 kg, administered as a single dose of 3600 mg.

49. The anti-C5 antibody or antigen-binding fragment thereof according to any one of claims 39 to 44, wherein the anti-C5 antibody or antigen-binding fragment thereof is ravulizumab (ULTOMIRIS (registered trademark)).

50. The use of any one of claims 45 to 49, wherein the anti-C5 antibody or antigen-binding fragment thereof is ravulizumab (ULTOMIRIS®).

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