Doses and administrations of anti c5 antibodies to treat hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA)

Abstract

To provide doses and administrations of anti- C5 antibodies for treating hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA).SOLUTION: Methods are provided for clinical treatment of hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA), e.g., TMA following HSCT, in human patients using anti- C5 antibodies, or antigen-binding fragments thereof. Provided herein are compositions and methods for treating hematopoietic stem cell transplant-related thrombotic microangiopathy (HSCT-TMA), e.g., TMA following HSCT, in human patients comprising administering to the patients anti- C5 antibodies, or antigen-binding fragments thereof, wherein the anti- C5 antibodies, or antigen-binding fragments thereof, are administered according to (or are for administering according to) a particular clinical dosage regimen (e.g., at a particular dose, according to a defined dosing schedule).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 065,107, filed August 13, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on August 10, 2021, is named 0630_WO_SL.txt, and is 58,856 bytes in size. [Background technology]

[0003] Thrombotic microangiopathy (TMA) is a post-transplant complication of hematopoietic stem cell transplantation (HSCT) that can affect 10% to 35% of HSCT recipients (Dvorak et al., Front Pediatr. 2019;7:133; Jodele et al., Blood Rev. 2015;29(3):191-204; Seaby et al., Pediatr Nephrol. 2018;33(9):1489-1500). It manifests through endothelial injury, affecting the kidneys and other organs. An estimated 30% of patients with HSCT TMA develop severe disease (Rosenthal et al., J. Blood Med. 2016;7:181-186). In these cases, patients with HSCT-TMA develop systemic vascular injury, manifested by renal injury, serositis, pulmonary hypertension, and multiple organ failure. The 1-year survival rate for patients with HSCT-TMA has been reported to range from 18% to 40% (Wanchoo et al., Am. J. Kidney Dis. 2018;72(6):857-865). Severe HSCT-TMA is associated with approximately 80% long-term morbidity and mortality. Studies have shown that the majority of patients die within 6 months (Cho et al., Bone Marrow Transplant. 2008;41(9):813-820; Cho et al., Transplantation. 2010;90(8):918-926; Oran, 2007). Another study showed that the overall survival rate for patients with severe HSCT-TMA who did not receive TMA-targeted therapy was 9%, with all deaths occurring within 10 months of TMA diagnosis (Jodele, et al., Blood. 2014b;124(4):645-653).

[0004] In pediatric patients, HSCT-TMA typically occurs early after allogeneic HSCT, with a median occurrence of 35–47 days after HSCT, with 88%–92% occurring before day +100. However, cases have been reported up to 2 years after HSCT. Autologous recipients may develop HSCT TMA even earlier, with a median occurrence of 18 days after HSCT (Dvorak et al., Front Pediatr. 2019;7:133).

[0005] Endothelial injury is fundamental to the pathogenesis of HSCT-TMA, and dysregulation of complement activation may be a consequence of endothelial injury. Risk factors associated with the development of HSCT-TMA that also cause endothelial injury include calcineurin inhibitors (CNIs), infections, and conditioning regimens (high-dose chemotherapy or total-body irradiation) (Khosla, et al., Bone Marrow Transplant.2018;53(2):129-137;Masias, et al.,Blood.2017;129(21):2857-2863). Currently, there are no approved therapies for the treatment of HSCT-TMA. Primary interventions for HSCT-TMA include discontinuing the causative agent (e.g., CNI) and / or treating the precipitating condition (e.g., treating an infection) (Dvorak, et al., Front Pediatr. 2019;7:133; Seaby et al., Pediatr. Nephrol. 2018;33(9):1489-1500). In some patients, discontinuing the causative agent and / or treating any associated precipitating condition does not reverse HSCT-TMA. Therefore, an object of the present disclosure is to provide improved methods for treating patients with HSCT-TMA. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Dvorak et al.,Front Pediatr.2019;7:133 [Non-patent document 2] Jodele et al., Blood Rev. 2015; 29(3): 191 - 204

Non - Patent Document 3

Non - Patent Document 4

Non - Patent Document 5

Non - Patent Document 6

Non - Patent Document 7

Non - Patent Document 8

Non - Patent Document 9

Non - Patent Document 10

Summary of the Invention

Means for Solving the Problems

[0007] Provided herein are compositions and methods for treating hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), e.g., post-HSCT TMA, in a human patient, comprising administering to the patient an anti-C5 antibody, or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is for administration according to) a specific clinical dosage regimen (e.g., at a specific dose, according to a defined dosing schedule).

[0008] An exemplary anti-C5 antibody is ravulizumab (ULTOMIRIS®), which comprises 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 (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 a heavy chain constant region set forth in SEQ ID NO: 13.

[0009] 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 the EU numbering convention.

[0010] 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 the EU numbering convention.

[0011] In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the BNJ421 antibody (described in WO2015134894 and 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.

[0012] In another embodiment, the antibody competes for binding to and / or binds to the same epitope on C5 as any of the above antibodies, hi another embodiment, the antibody has at least about 90% variable region amino acid sequence identity with any of the above antibodies (e.g., at least about 90%, 95%, or 99% variable region identity with SEQ ID NO: 12 or SEQ ID NO: 8).

[0013] In another embodiment, the antibody has a K D Affinity dissociation constants (K) in the range of ≦1 nMD ) binds to human C5 at pH 7.4 and 25° C. In another embodiment, the antibody has an affinity dissociation constant (K D ) at pH 7.4 and 25°C. In another embodiment, the antibody binds to human C5 at pH 6.0 and 25°C. D In another embodiment, the antibody binds to human C5 with a K of about 22 nM at pH 6.0 and 25° C. D In 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.

[0014] In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. In one embodiment, for example, 300 mg or 600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥5 kg to <10 kg. In one embodiment, 300 mg or 600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥10 kg to <20 kg. In one embodiment, 300 mg, 900 mg, or 2100 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥20 kg to <30 kg. In one embodiment, 300 mg, 1200 mg, or 2700 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥30 kg to <40 kg. In one embodiment, 600 mg, 2400 mg, or 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 kg to < 60 kg. In one embodiment, 900 mg, 2700 mg, or 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 kg to < 100 kg. In one embodiment, 900 mg, 3000 mg, or 3600 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg. In certain embodiments, the dosage regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0015] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered in one or more administration cycles. In one embodiment, the treatment (e.g., administration cycle) is 26 weeks. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once on day 1 (e.g., of the administration cycle), once on day 5 (e.g., of the administration cycle), and once on day 10 (e.g., of the administration cycle). In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once on day 1 (e.g., of the administration cycle), once on day 5 (e.g., of the administration cycle), once on day 10 (e.g., of the administration cycle), and then every 4 or 8 weeks from day 15 onwards. In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every 4 or 8 weeks (e.g., a dosing cycle) after treatment for an extended period of up to 2 years (e.g., at a dose of 300 mg, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg).

[0016] In another embodiment, a method of treating a human patient having HSCT-TMA comprises administering to the patient (e.g., during an administration cycle) 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: (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) on day 15 and every four weeks thereafter at a dose of 300 mg to patients weighing ≥ 5 to < 10 kg or 600 mg to patients weighing ≥ 10 to < 20 kg; or on day 15 and every eight weeks thereafter at a dose of 2100 mg to patients weighing ≥ 20 to < 30 kg, 2700 mg to patients weighing ≥ 30 to < 40 kg, 3000 mg to patients weighing ≥ 40 to < 60 kg, 3300 mg to patients weighing ≥ 60 to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg.

[0017] In another embodiment, a method of treating a human patient having HSCT-TMA comprises administering to the patient (e.g., during an administration cycle) 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: (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) on day 15 and every 4 weeks thereafter at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg or 600 mg for patients weighing ≥ 10 to < 20 kg; or on day 15 and every 8 weeks thereafter at a dose of 2100 mg for patients weighing ≥ 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; wherein treatment results in a reduction of LDH levels to within normal levels or to within less than 50% of what is considered the ULN level (e.g., within 105-333 IU / L (International Units per Liter)); in some embodiments, treatment results in a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of at least 175 μg / mL or more, and / or 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).

[0018] In another embodiment, a method of treating a human patient having HSCT-TMA comprises administering to the patient (e.g., during an administration cycle) an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, 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 convention, wherein the anti-C5 antibody, or antigen-binding fragment thereof: (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) on day 15 and every four weeks thereafter at a dose of 300 mg to patients weighing ≥ 5 to < 10 kg or 600 mg to patients weighing ≥ 10 to < 20 kg; or on day 15 and every eight weeks thereafter at a dose of 2100 mg to patients weighing ≥ 20 to < 30 kg, 2700 mg to patients weighing ≥ 30 to < 40 kg, 3000 mg to patients weighing ≥ 40 to < 60 kg, 3300 mg to patients weighing ≥ 60 to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg.

[0019] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥5 to <10 kg in the following doses: (a) At a dose of 600 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 300 mg on day 15 and every 4 weeks thereafter.

[0020] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥10 to <20 kg in the following doses: (a) At a dose of 600 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 600 mg on day 15 and every 4 weeks thereafter.

[0021] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥20 to <30 kg in the following manner: (a) At a dose of 900 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 2100 mg on day 15 and every 8 weeks thereafter.

[0022] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥30 to <40 kg by: (a) At a dose of 1200 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 2700 mg on day 15 and every 8 weeks thereafter.

[0023] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥40 to <60 kg by: (a) At a dose of 2400 mg once on day 1; (b) at a dose of 600 mg once on day 5; (c) at a dose of 600 mg once on day 10; (d) at a dose of 3000 mg on day 15 and every 8 weeks thereafter.

[0024] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥60 to <100 kg by: (a) At a dose of 2700 mg once on day 1; (b) at a dose of 900 mg once on day 5; (c) at a dose of 900 mg once on day 10; (d) at a dose of 3300 mg on day 15 and every 8 weeks thereafter.

[0025] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≧100 kg by: (a) At a dose of 3000 mg once on day 1; (b) at a dose of 900 mg once on day 5; (c) at a dose of 900 mg once on day 10; (d) at a dose of 3600 mg on day 15 and every 8 weeks thereafter.

[0026] In one embodiment, the methods of treatment disclosed herein further comprise administering best supportive care (BSC) measures, including but not limited to transfusion support, corticosteroids, dialysis, and antihypertensive medications.

[0027] In one embodiment, the patient has not been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab and day 1 (e.g., of a dosing cycle) is 2 weeks or more after the patient's last dose of eculizumab.

[0028] In another aspect, the described treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof. In one embodiment, for example, the treatment regimen is 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, 515, 520, 525, 530, 535, 540, 545, maintains serum trough concentrations of anti-C5 antibody, or antigen-binding fragment thereof, of greater than or equal to 40, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 μg / mL. In one embodiment, the treatment regimen maintains serum trough concentrations of anti-C5 antibody, or antigen-binding fragment thereof, of greater than or equal to 100 μg / mL, greater than or equal to 150 μg / mL, greater than or equal to 200 μg / mL, greater than or equal to 250 μg / mL, or greater than or equal to 300 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody, or antigen-binding fragment thereof, between 100 μg / mL and 200 μg / mL, hi another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody, or antigen-binding fragment thereof, of about 175 μg / mL.

[0029] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered at 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, 15 ... In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 0 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, or 260 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 50 μg and 250 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain between 100 μg and 200 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain about 175 μg of antibody per milliliter of blood in the patient.

[0030] In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a minimal free C5 concentration to obtain an effective response. For example, in one embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains 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).

[0031] 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.

[0032] The effectiveness of the treatment methods provided herein can be assessed using any suitable means. In one embodiment, for HSCT-TMA patients, the treatment results in at least one therapeutic effect selected from the group consisting of a reduction or cessation of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serositis, pulmonary hypertension, and multiple organ failure compared to baseline.

[0033] In another embodiment, treatment consists of (a) a platelet count of ≥ 50,000 / mm without transfusion support for the past 7 days. 3 , (b) LDH < 1.5 × ULN, and (c) absence of schistocytes (if schistocytes were present at baseline).

[0034] In another embodiment, treatment consists of (a) a platelet count of ≥ 50,000 / mm without transfusion support for the past 7 days. 3 (b) LDH<1.5×ULN, (c) absence of schistocytes (if schistocytes were present at baseline), and (d) at least a 50% reduction from baseline in proteinuria. In one embodiment, proteinuria is a protein / creatinine ratio of ≧0.5 mg / mg.

[0035] In another embodiment, the treatment results in a favorable hematological response.

[0036] In another embodiment, treatment results in normalization of LDH, elimination of the need for red blood cell and platelet transfusions, and elimination of schistocytes.

[0037] In another embodiment, the treatment results in the patient's ability to maintain hemoglobin of ≧8 g / dL without transfusion support. In another embodiment, the treatment results in hemoglobin of ≧8 g / dL without transfusion support.

[0038] In another embodiment, treatment results in a decrease in LDH, an increase in platelets, and / or an increase in hemoglobin compared to baseline.

[0039] In another embodiment, treatment results in normal levels of serum creatinine compared to baseline.

[0040] In another embodiment, treatment results in an improvement in TMA-associated organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and / or GI systems compared to baseline.

[0041] In another embodiment, the treatment results in terminal complement inhibition.

[0042] In another embodiment, treatment results in a reduction in adverse events.

[0043] In another embodiment, treatment results in a shift to normal levels of biomarkers associated with vascular inflammation (e.g., shedding of tumor necrosis factor receptor 1 [TNF-R1]), endothelial injury and / or activation (e.g., shedding of thrombomodulin and vascular cell adhesion molecule 1 [VCAM-1]), renal damage (e.g., cystatin C), and / or complement proteins and complement activation pathway products.

[0044] In another embodiment, treatment results in a change from baseline in quality of life as assessed by a quality of life assessment (e.g., the Quality of Life Inventory (PedsQL) scale or the EQ-5D-5L questionnaire). Exemplary quality of life assessments are shown in Figures 4-10 and 15.

[0045] In another embodiment, treatment results in a reduction in hemolysis as assessed by lactate dehydrogenase (LDH) levels compared to baseline. In one embodiment, a patient treated according to the disclosed methods experiences a reduction in LDH levels to near normal levels, or to within 10% or more than 20% of what is considered normal (e.g., within 105-333 IU / L (International Units per Liter)). In another embodiment, the patient's LDH levels are normalized throughout the maintenance period of treatment. In another embodiment, the treated patient's LDH levels are normalized at least at least 95% of the time during the maintenance period of treatment. In another embodiment, the treated patient's LDH levels are normalized at least at least 90%, 85%, or 80% of the time during the maintenance period of treatment. In one embodiment, the patient's LDH levels are greater than 1.5 times the upper limit of normal (LDH ≥ 1.5 x ULN) prior to the start of treatment.

[0046] In one embodiment, a patient treated according to the disclosed methods experiences a reduction in LDH levels to within normal levels, or within 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 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%, or less than 50% of what is considered the ULN level (e.g., within 10-333 IU / L (International Units per Liter)). In one embodiment, the patient's LDH level is > 1.5 times the ULN (LDH > 1.5 x ULN) before treatment begins.

[0047] In one embodiment, patients treated according to the disclosed methods experience a 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 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%, 55%, 56%, 57%, 58%, 59%, or 60% change in LDH rate compared to baseline.

[0048] In one embodiment, a patient treated according to the disclosed methods maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of at least 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 μg / mL or more. In one embodiment, a patient treated according to the disclosed methods maintains a serum trough concentration of anti-C5 antibody, or antigen-binding fragment thereof, of at least 175 μg / mL or greater.

[0049] In one embodiment, a patient treated according to the disclosed methods has a free C5 concentration of 0.5 μg / mL or less (eg, 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0050] In another embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8. (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) An anti-C5 antibody or antigen-binding fragment thereof is provided for administration on day 15 and every four weeks thereafter at a dose of 300 mg to a patient weighing ≥ 5 to < 10 kg or 600 mg to a patient weighing ≥ 10 to < 20 kg; or on day 15 and every eight weeks thereafter at a dose of 2100 mg to a patient weighing ≥ 20 to < 30 kg, 2700 mg to a patient weighing ≥ 30 to < 40 kg, 3000 mg to a patient weighing ≥ 40 to < 60 kg, 3300 mg to a patient weighing ≥ 60 to < 100 kg, or 3600 mg to a patient weighing ≥ 100 kg.

[0051] In one embodiment, the antibody is determined to be safe, tolerable, and sufficiently non-immunogenic after multiple IV administrations for use in HSCT-TMA patients.

[0052] Further provided are kits comprising pharmaceutical compositions containing an anti-C5 antibody, such as ravulizumab, or an antigen-binding fragment thereof, and a pharmaceutically acceptable carrier in a therapeutically effective amount adapted for use in the methods described herein. In one embodiment, the kit comprises: (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof in the methods described herein.

[0053] In one embodiment, 300 mg or 600 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥5 kg to <10 kg. In another embodiment, 300 mg or 600 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥10 kg to <20 kg. In another embodiment, 300 mg, 900 mg, or 2100 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥20 kg to <30 kg. In another embodiment, 300 mg, 1200 mg, or 2700 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥30 kg to <40 kg. In another embodiment, 600 mg, 2400 mg, or 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥40 kg to <60 kg. In another embodiment, 900 mg, 2700 mg, or 3300 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥60 kg to <100 kg, hi another embodiment, 900 mg, 3000 mg, or 3600 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥100 kg.

[0054] In some embodiments, the present disclosure relates to a composition, e.g., a pharmaceutical composition or a drug, comprising an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, the composition comprising a heavy chain complementarity-determining region (HCDR) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and a light chain complementarity-determining region (LCDR) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, for use in treating hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), e.g., TMA after HSCT, in a human patient. Specifically, provided herein is a composition comprising an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof for treating HSCT-TMA, e.g., TMA after HSCT, in a human patient. In some embodiments, the effective amount includes the use of the above-mentioned dosing and schedule of an anti-C5 antibody, e.g., ravulizumab.

[0055] In some embodiments, the present disclosure relates to the use of an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising a heavy chain complementarity-determining region (HCDR) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and a light chain complementarity-determining region (LCDR) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, in the manufacture of a composition, e.g., a pharmaceutical composition or medicament, for treating hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), e.g., TMA after HSCT, in a human patient. Specifically, provided herein is the use of an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof in the manufacture of a composition, e.g., a pharmaceutical composition or medicament, for treating HSCT-TMA, e.g., TMA after HSCT, in a human patient. In some embodiments, the effective amount includes the use of the above-mentioned dosing and schedule of an anti-C5 antibody, e.g., ravulizumab. [Brief explanation of the drawings]

[0056] [Figure 1] FIG. 1 is a schematic diagram showing the overall design of the pediatric Phase 3 study. [Figure 2-1]1 shows the schedule of study visits and assessments through the completion of the 26-week treatment period of the pediatric Phase 3 clinical trial. [Figure 2-2] Same as above. [Figure 2-3] Same as above. [Figure 2-4] Same as above. [Figure 2-5] Same as above. [Figure 2-6] Same as above. [Figure 3-1] The schedule of study visits and assessments for the follow-up period of a pediatric Phase 3 clinical trial is shown. [Figure 3-2] Same as above. [Figure 3-3] Same as above. [Figure 4-1] This is a sample of the Pediatric Quality of Life Inventory (PedsQL) 4.0 General Core Scale for young children (2-4 years old). [Figure 4-2] Same as above. [Figure 5-1] This is a sample of children (5-7 years old) using the PedsQL 4.0 General Core Scale. [Figure 5-2] Same as above. [Figure 6-1] This is a second sample of children (5-7 years old) using the PedsQL 4.0 General Core Scale. [Figure 6-2] Same as above. [Figure 7-1] This is a sample of children (8-12 years old) using the PedsQL 4.0 General Core Scale. [Figure 7-2] Same as above. [Figure 8-1] This is a second sample of children (8-12 years old) using the PedsQL 4.0 General Core Scale. [Figure 8-2] Same as above. [Figure 9-1] This is a sample of children (13-18 years old) using the PedsQL 4.0 General Core Scale. [Figure 9-2] Same as above. [Figure 10-1] This is a second sample of children (13-18 years old) using the PedsQL 4.0 General Core Scale. [Figure 10-2] Same as above. [Figure 11] FIG. 1 is a schematic diagram showing the overall design of the adult Phase 3 trial. [Figure 12-1] 1 shows the activity schedule for the screening and treatment periods (Stage 1 and Stage 2 participants) of the adult Phase 3 clinical trial. [Figure 12-2] Same as above. [Figure 12-3] Same as above. [Figure 12-4] Same as above. [Figure 12-5] Same as above. [Figure 12-6] Same as above. [Figure 12-7] Same as above. [Figure 13-1] 1 shows the activity schedule for the treatment period (participants receiving ravulizumab salvage therapy) of the adult Phase 3 clinical trial. [Figure 13-2] Same as above. [Figure 13-3] Same as above. [Figure 13-4] Same as above. [Figure 14-1] The activity schedule for the follow-up period of the adult Phase 3 clinical trial is shown. [Figure 14-2] Same as above. [Figure 14-3] Same as above. [Figure 15-1] This is a sample of adult QOL. [Figure 15-2] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0057] I. Definition As used herein, the term "subject" or "patient" refers to a human patient (e.g., a patient with hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA)).

[0058] As used herein, the term "pediatric" patient is a human patient 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).

[0059] As used herein, the term "adult" patient is a human patient who has been classified as such by a physician or caregiver, e.g., not a neonate, infant, child, or adolescent, based on, e.g., age, developmental stage, physiological characteristics, etc. Typically, an adult patient is a patient who is 18 years of age or older (≧18 years of age).

[0060] HSCT-TMA is a multifactorial disorder caused by systemic vascular endothelial injury, which can be triggered by several mechanisms during the transplant process. This manifests through endothelial damage, affecting the kidney and other organs. It is estimated that 30% of patients with HSCT-TMA develop severe disease (Rosenthal et al., J. Blood Med. 2016;7:181-186). In these cases, patients with HSCT-TMA develop systemic vascular injury, manifested by renal injury, serositis, pulmonary hypertension, and multiple organ failure.

[0061] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, e.g., an improvement in at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement over baseline, e.g., an improvement over a measurement or observation made before initiation of therapy according to the method. Effective treatment can refer to a reduction in at least one symptom of HSCT-TMA (e.g., microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serositis, pulmonary hypertension, and multiple organ failure).

[0062] The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and / or prophylactic result. The result can be a reduction, amelioration, alleviation, reduction, delay, and / or amelioration of one or more signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In one example, an "effective amount" is an amount of an anti-C5 antibody, or antigen-binding fragment thereof, that has been clinically proven to reduce at least one symptom of HSCT-TMA (e.g., microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serositis, pulmonary hypertension, and multiple organ failure). An effective amount can be administered in one or more administrations.

[0063] As used herein, the term "loading dose" refers to the first dose administered (e.g., in a dosing cycle).

[0064] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to Phase 2 of treatment. In certain embodiments, treatment continues as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

[0065] As used herein, the term "serum trough level" refers to the lowest level at which a drug (e.g., an anti-C5 antibody, or an 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.

[0066] 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 well-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 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 altered by protein engineering techniques (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). An antibody can contain 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 and affect, for example, the half-life of the antibody in a patient, its effector functions, and / or the immune response thereto. The term antibody also includes artificial or engineered polypeptide constructs that contain at least one antibody-derived antigen-binding site.

[0067] II. Anti-C5 antibody The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit the cleavage of C5 into fragments C5a and C5b. As noted above, such antibodies also have improved pharmacokinetic properties compared to, for example, other anti-C5 antibodies used therapeutically (e.g., eculizumab).

[0068] Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the methods described herein can be generated using methods well known in the art. Alternatively, art-recognized anti-C5 antibodies can be used. Antibodies that compete with any of the art-recognized antibodies or antibodies described herein for binding to C5 can also be used.

[0069] Another 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. Ravulizumab (also known as ULTOMIRIS®, BNJ441, and ALXN1210) is described in WO 2015134894 and U.S. Pat. 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 document 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 3b) that are essential for microbial opsonization and immune complex clearance.

[0070] 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.

[0071] 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 WO2015134894 and U.S. Pat. No. 9,079,949, the entire teachings of which are incorporated herein by reference.

[0072] 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.

[0073] The exact boundaries of CDRs have been defined in various ways. 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 can be referred to as “combined Kabat-Chothia CDRs.” Thomas, C. et al. (Mol. Immunol., 33:1389-401, 1996) exemplifies the identification of CDR boundaries according to the numbering system of Kabat and Chothia.

[0074] 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.

[0075] Another exemplary anti-C5 antibody is the 8110 antibody, 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.

[0076] 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.

[0077] 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.

[0078] 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. Pat. 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.

[0079] 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 CDR2 comprising or consisting of the following amino acid sequence: [ka] The heavy chain variable region comprises:

[0080] In some embodiments, the anti-C5 antibodies described herein have the following amino acid sequence: [ka] The light chain variable region comprises:

[0081] In some embodiments, the anti-C5 antibodies described herein 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 was derived. The Fc constant region may, for example, contain one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions compared to the native human Fc constant region from which the variant human Fc constant region was derived. The substitutions may increase the binding affinity of an IgG antibody containing the variant Fc constant region to FcRn at pH 6.0 while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in an antibody's Fc constant region increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining the pH dependence of the interaction) are well known in the art and are exemplified in the Examples. See, for example, WO2015134894 and U.S. Pat. No. 9,079,949, the disclosures of each of which are incorporated herein by reference in their entireties.

[0082] Substitutions that improve the binding affinity of an antibody's Fc constant region to FcRn are well known in the art, and include, for example, (1) an M252Y / S254T / T256E triple substitution (Dall'Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) an M428L or T250Q / M428L substitution (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) an N434A or T307 / E380A / N434A substitution (Petkova, S. et al., J. Immunol., 176:346-56, 2006). al., Int. Immunol., 18:1759-69, 2006). Additional substitution pairs 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.

[0083] In some embodiments, the variant constant region has a substitution for valine at EU amino acid position 255. In some embodiments, the variant constant region has a substitution for asparagine at EU amino acid position 309. In some embodiments, the variant constant region has a substitution for isoleucine at EU amino acid position 312. In some embodiments, the variant constant region has a substitution at EU amino acid position 386.

[0084] In some embodiments, the variant Fc constant region comprises 30 or fewer (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2) amino acid substitutions, insertions, or deletions relative to the native constant region from which it 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, respectively, according to EU numbering, of the Fc constant region of native human IgG. 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.

[0085] In some embodiments, the exact positions of these mutations may be shifted from the native human Fc constant region positions due to antibody engineering. For example, the 428L / 434S double substitution, when used in an IgG2 / 4 chimeric Fc, may 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.

[0086] In some embodiments, the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382, ​​384, 385, 386, 387, 389, 424, 428, 433, 434, or 436 (EU numbering) relative to a native human Fc constant region. In some embodiments, the substitutions are, all in EU numbering, methionine for glycine at position 237; alanine for proline at position 238; lysine for serine at position 239; isoleucine for lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine for threonine at position 250; phenylalanine, tryptophan, or tyrosine for methionine at position 252; threonine for serine at position 254; glutamic acid for arginine at position 255; aspartic acid, glutamic acid, or glutamine for threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, or methionine for proline at position 257. 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;alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine for valine at position 308; alanine, aspartic acid, glutamic acid, proline, or arginine for leucine or valine at position 309; alanine, histidine, or isoleucine for glutamine at position 311; alanine or histidine for aspartic acid at position 312; at position 315, alanine or histidine for asparagine; at position 317, alanine for lysine; at position 325, glycine for asparagine; at position 332, valine for isoleucine; at position 334, leucine for lysine; at position 360, histidine for lysine; at position 376, alanine for aspartic acid; at position 380, alanine for 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, phenyl methyl ... alanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine; lysine in place of histidine at position 433; alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine in place of asparagine at position 434; and histidine in place of tyrosine or phenylalanine at position 436;

[0087] 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.

[0088] 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. (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. (otherwise under physiological conditions). D In some embodiments, the K of the anti-C5 antibody, or antigen-binding fragment thereof, 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 of about 22 nM at pH 6.0 and 25° C. (otherwise under physiological conditions). D binds to C5.

[0089] In another embodiment, the K D ) / (K of antibody against C5 at pH 7.4, 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, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, or greater than 8000.

[0090] Methods for determining whether an antibody binds to a protein antigen and / or the affinity of an antibody for a protein antigen are well known in the art. Binding of an antibody to a protein antigen can be detected and / or quantified using various 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; Joensson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Joensson, U. et al., Biotechniques, 11:620-7, 1991). Additionally, methods for measuring affinity (eg, dissociation and association constants) are provided in the Examples.

[0091] As used herein, the term "k a " refers to the rate constant for the association of an antibody to an antigen. d" refers to the rate constant for dissociation of an antibody from the antibody / antigen complex. And, the term "K D " 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 (see Examples). The kinetics of antibody binding to human C5 can be determined, for example, via SPR on a BIAcore3000 instrument using an anti-Fc capture method to immobilize the antibody at pH 8.0, 7.4, 7.0, 6.5, and 6.0.

[0092] In one embodiment, the anti-C5 antibody, or antigen-binding fragment thereof, blocks the cleavage of C5 into C5a and C5b, thereby inhibiting, for example, the pro-inflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) on the surface of cells.

[0093] Methods for determining whether a particular antibody described herein inhibits C5 cleavage are well known in the art. Inhibition of human complement component C5 can reduce the cytolytic ability of complement in a subject's body fluid. Such reduction in the cytolytic ability of complement present in a body fluid can be determined by methods well known in the art, such as, for example, conventional hemolytic assays, e.g., hemolytic assays (Kabat and Mayer (eds.), “Experimental Immunochemistry, 2 nd Edition,”135-240,Springfield,IL,CC Thomas (1961), pages 135-139), or conventional modifications of that assay, such as the chicken erythrocyte hemolysis assay (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 well known in the art (Evans, M. et al., Mol. Immunol., 32:1183-95, 1995). The concentrations and / or physiological activity of C5a and C5b in body fluids can be measured, for example, by methods well known in the art. For C5b, the hemolytic assay discussed herein or an assay for soluble C5b-9 can be used. Other assays well 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.

[0094] 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 an anti-C5 antibody, or antigen-binding fragment thereof, to inhibit the conversion of C5 to biologically active products. In some embodiments, the generation of C5a is measured. In some embodiments, a C5b-9 neoepitope-specific antibody is used to detect MAC formation.

[0095] 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 a serum test solution in vitro, for example, sheep red blood cells coated with hemolysin or chicken red blood cells sensitized with anti-chicken red blood cell antibodies are used as target cells. The percentage of lysis is normalized by considering 100% lysis to be equivalent to the lysis occurring in the absence of an inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, for example, as 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 fluorescent 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.

[0096] To determine the effect of anti-C5 antibodies, or antigen-binding fragments thereof, 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, which is equivalent to the lysis occurring in the absence of an inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, as utilized in, for example, the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, test serum is incubated with anti-C5 antibodies, or antigen-binding fragments thereof, 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 the fluorescence at an appropriate wavelength. As a control, test serum is incubated in the absence of anti-C5 antibodies, or antigen-binding fragments thereof.

[0097] 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 determines the amount required to obtain 50% lysis (CH50) using various dilutions of antibody-sensitized red blood cells and test serum as classical complement pathway activators. The hemolysis rate 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 responsible for the measured hemolysis. This assay is well 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 (CH50U Eq / mL).

[0098] Inhibition, e.g., with respect 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, e.g., in a hemolytic assay or CH50eq assay, compared to the effect of a control antibody (or antigen-binding fragment thereof) at an equimolar concentration under similar conditions. Significant 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 relative to the CDRs of eculizumab (i.e., SEQ ID NOs: 1-6) and still 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.

[0099] The anti-C5 antibodies described herein have a serum half-life in humans of at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55) days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of approximately 43 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of 39-48 days. Methods for measuring the serum half-life of an antibody are well 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)% longer 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).

[0100] In one embodiment, the antibody competes for and / or binds to the same epitope on C5 as an antibody 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 an antibody described herein include, for example, epitope mapping methods, such as X-ray analysis of crystals of antigen:antibody complexes and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor antibody binding to peptide antigen fragments or mutational variations of the antigen, where loss of binding due to altered amino acid residues within the antigen sequence is often considered an indication of epitope content. Additionally, combinatorial computational methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage-displayed peptide libraries. Antibodies with the same VH and VL or the same CDR1, CDR2 and CDR3 sequences are predicted to bind to the same epitope.

[0101] 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 well-known competition experiments. In some embodiments, an antibody competes with another antibody and inhibits the binding of the other antibody to a target 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).

[0102] The anti-C5 antibodies described herein, or antigen-binding fragments thereof, 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 familiar to those skilled in the art. Briefly, splenocytes from animals immunized with a desired antigen are immortalized, typically by fusion with myeloma cells (Koehler, 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 improved by various techniques, such as injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies, or binding fragments thereof, can be isolated by screening a DNA library derived from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0103] In some embodiments, the anti-C5 antibody is eculizumab (SOLIRIS®) or an antigen-binding fragment thereof (e.g., heavy and light chain complementarity determining regions (HCDRs) of eculizumab, respectively). 1~3 and LCDR 1~3 In some embodiments, the anti-C5 antibody is not a biosimilar of eculizumab (SOLIRIS®), e.g., ABP959 antibody (manufactured by Amgen Inc., USA), ELIZARIA® (manufactured by Generium JNC, Russia), or SB12 (manufactured by Samsung Bioepis, Incheon, South Korea).

[0104] 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 comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of 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.

[0105] The composition can be formulated as a pharmaceutical solution for administration to a subject for treatment of, for example, HSCT-TMA. Pharmaceutical compositions generally contain a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to and includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The composition may contain pharmaceutically acceptable salts, such as acid or base addition salts, sugars, carbohydrates, polyols, and / or tonicity-modifying agents.

[0106] Compositions can be formulated according to standard methods. Pharmaceutical compounding is a well-established art (see, e.g., Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 2000). th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN:0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3rd Edition (ISBN: 091733096X). In some embodiments, the compositions can be formulated, for example, as a buffer solution suitable for storage at 2-8°C (e.g., 4°C) at a suitable concentration. 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.

[0107] Pharmaceutical compositions can be in a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquids (e.g., injections and infusions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. For example, compositions containing compositions intended for systemic or local delivery can be in the form of injections or infusions. Thus, the compositions can be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). The terms "parenteral administration," "administering parenterally," 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, intrathecal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.

[0108] In some embodiments, the disclosure provides an effective amount of an anti-C5 antibody or a C5 antibody comprising heavy chain complementarity determining regions (HCDRs) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and light chain complementarity determining regions (LCDRs) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, for use in treating hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), e.g., TMA after HSCT, in a human patient. Regarding a composition, e.g., a pharmaceutical composition or drug, comprising the antigen-binding fragment thereof, wherein an effective amount is an anti-C5 antibody or antigen-binding fragment thereof (a) once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 2800 mg for patients weighing ≥ 100 kg; (b) once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, ...20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg. (d) on day 15 and every 4 weeks thereafter, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg or 600 mg for patients weighing ≥ 10 to < 20 kg; 300 mg for patients weighing ≥ 20 to < 30 kg; 300 mg for patients weighing ≥ 30 to < 40 kg; 600 mg for patients weighing ≥ 40 to < 60 kg; 900 mg for patients weighing ≥ 60 to < 100 kg; (d) on day 15 and every 4 weeks thereafter, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg or 600 mg for patients weighing ≥ 10 to < 20 kg;or on day 15 and every 8 weeks thereafter at a dose of 2100 mg to patients weighing ≥ 20 to < 30 kg, 2700 mg to patients weighing ≥ 30 to < 40 kg, 3000 mg to patients weighing ≥ 40 to < 60 kg, 3300 mg to patients weighing ≥ 60 to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg. In some embodiments, the present disclosure provides an HCDR comprising SEQ ID NOs: 19, 18, and 3; 1~3 , and LCDRs comprising SEQ ID NOs: 4, 5 and 6 1~3 The present disclosure relates to a composition, e.g., a pharmaceutical composition or a medicament, for use in treating HSCT-TMA in a human patient, e.g., TMA after HSCT, comprising an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof comprising: 1~3 and LCDR 1~3 The present invention relates to a pharmaceutical composition or medicament for use in the treatment of HSCT-TMA in a human patient, e.g., TMA after HSCT, comprising:

[0109] IV. Method Provided herein are methods for treating HSCT-TMA in a human patient, comprising administering to the patient an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody, or antigen-binding fragment thereof, is administered (or is for administration according to) a particular clinical dosage regimen (e.g., at a particular dose, according to a defined dosing schedule).

[0110] In one embodiment, the dose of the anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. In one embodiment, for example, 300 mg or 600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 5 kg to < 10 kg. In another embodiment, 300 mg or 600 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 10 kg to < 20 kg. In another embodiment, 300 mg, 900 mg, or 2100 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 20 kg to < 30 kg. In another embodiment, 300 mg, 1200 mg, or 2700 mg of the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 30 kg to < 40 kg. In another embodiment, 600 mg, 2400 mg, or 3000 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 kg to < 60 kg. In another embodiment, 900 mg, 2700 mg, or 3300 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 kg to < 100 kg. In another embodiment, 900 mg, 3000 mg, or 3600 mg of an anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 100 kg. In certain embodiments, the dosage regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0111] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered in one or more administration cycles. In one embodiment, the treatment (e.g., administration cycle) is 26 weeks. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once on day 1 (e.g., of the administration cycle), once on day 5 (e.g., of the administration cycle), and once on day 10 (e.g., of the administration cycle). In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered once on day 1 (e.g., of the administration cycle), once on day 5 (e.g., of the administration cycle), once on day 10 (e.g., of the administration cycle), and then every 4 or 8 weeks from day 15 onwards. In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered every 4 or 8 weeks (e.g., a dosing cycle) after treatment for an extended period of up to 2 years (e.g., at a dose of 300 mg, 600 mg, 900 mg, 1200 mg, 2100 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg).

[0112] In another embodiment, a method of treating a human patient having HSCT-TMA comprises administering to the patient (e.g., during an administration cycle) 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: (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) on day 15 and every four weeks thereafter at a dose of 300 mg to patients weighing ≥ 5 to < 10 kg or 600 mg to patients weighing ≥ 10 to < 20 kg; or on day 15 and every eight weeks thereafter at a dose of 2100 mg to patients weighing ≥ 20 to < 30 kg, 2700 mg to patients weighing ≥ 30 to < 40 kg, 3000 mg to patients weighing ≥ 40 to < 60 kg, 3300 mg to patients weighing ≥ 60 to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg.

[0113] In another embodiment, a method of treating a human patient having HSCT-TMA comprises administering to the patient (e.g., during an administration cycle) 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: (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) on day 15 and every 4 weeks thereafter at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg or 600 mg for patients weighing ≥ 10 to < 20 kg; or on day 15 and every 8 weeks thereafter at a dose of 2100 mg for patients weighing ≥ 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg; wherein treatment results in a reduction of LDH levels to within normal levels or to within less than 50% of what is considered the ULN level (e.g., within 105-333 IU / L (International Units per Liter)); in some embodiments, treatment results in a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of at least 175 μg / mL or more, and / or 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).

[0114] In another embodiment, a method of treating a human patient having HSCT-TMA comprises administering to the patient (e.g., during an administration cycle) an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, 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 convention, wherein the anti-C5 antibody, or antigen-binding fragment thereof: (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) on day 15 and every four weeks thereafter at a dose of 300 mg to patients weighing ≥ 5 to < 10 kg or 600 mg to patients weighing ≥ 10 to < 20 kg; or on day 15 and every eight weeks thereafter at a dose of 2100 mg to patients weighing ≥ 20 to < 30 kg, 2700 mg to patients weighing ≥ 30 to < 40 kg, 3000 mg to patients weighing ≥ 40 to < 60 kg, 3300 mg to patients weighing ≥ 60 to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg.

[0115] In another embodiment, the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥5 to <10 kg in the following doses: (a) At a dose of 600 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 300 mg on day 15 and every 4 weeks thereafter.

[0116] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥10 to <20 kg in the following doses: (a) At a dose of 600 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 600 mg on day 15 and every 4 weeks thereafter.

[0117] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥20 to <30 kg in the following manner: (a) At a dose of 900 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 2100 mg on day 15 and every 8 weeks thereafter.

[0118] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥30 to <40 kg by: (a) At a dose of 1200 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 2700 mg on day 15 and every 8 weeks thereafter.

[0119] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥40 to <60 kg by: (a) At a dose of 2400 mg once on day 1; (b) at a dose of 600 mg once on day 5; (c) at a dose of 600 mg once on day 10; (d) at a dose of 3000 mg on day 15 and every 8 weeks thereafter.

[0120] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≥60 to <100 kg by: (a) At a dose of 2700 mg once on day 1; (b) at a dose of 900 mg once on day 5; (c) at a dose of 900 mg once on day 10; (d) at a dose of 3300 mg on day 15 and every 8 weeks thereafter.

[0121] In another embodiment, the anti-C5 antibody is administered to a patient weighing ≧100 kg by: (a) At a dose of 3000 mg once on day 1; (b) at a dose of 900 mg once on day 5; (c) at a dose of 900 mg once on day 10; (d) at a dose of 3600 mg on day 15 and every 8 weeks thereafter.

[0122] In one embodiment, the methods of treatment disclosed herein further comprise administering best supportive care (BSC) measures, including but not limited to transfusion support, corticosteroids, dialysis, and antihypertensive medications.

[0123] In one embodiment, the patient has not been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab. In another embodiment, the patient has been previously treated with eculizumab and day 1 (e.g., of a dosing cycle) is 2 weeks or more after the patient's last dose of eculizumab.

[0124] In some embodiments, the disclosure relates to the use of heavy chain complementarity determining regions (HCDRs) comprising HCDR1, HCDR2, and HCDR3 sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and light chain complementarity determining regions (LCDRs) comprising LCDR1, LCDR2, and LCDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, in the manufacture of a composition, e.g., a pharmaceutical composition or medicament, for treating hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), e.g., TMA after HSCT, in a human patient. and (b) administering to a patient a single dose of the anti-C5 antibody or antigen-binding fragment thereof, the effective amount of which is 600 mg for a patient weighing ≥ 5 to < 10 kg, 600 mg for a patient weighing ≥ 10 to < 20 kg, 900 mg for a patient weighing ≥ 20 to < 30 kg, 1200 mg for a patient weighing ≥ 30 to < 40 kg, 2400 mg for a patient weighing ≥ 40 to < 60 kg, 2700 mg for a patient weighing ≥ 60 to < 100 kg, or 2800 mg for a patient weighing ≥ 100 kg, once on day 1. (b) once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, ...20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg. (d) on day 15 and every 4 weeks thereafter, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg or 600 mg for patients weighing ≥ 10 to < 20 kg; 300 mg for patients weighing ≥ 20 to < 30 kg; 300 mg for patients weighing ≥ 30 to < 40 kg; 600 mg for patients weighing ≥ 40 to < 60 kg; 900 mg for patients weighing ≥ 60 to < 100 kg; (d) on day 15 and every 4 weeks thereafter, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg or 600 mg for patients weighing ≥ 10 to < 20 kg;or on day 15 and every 8 weeks thereafter at a dose of 2100 mg to a patient weighing ≥ 20 to < 30 kg, 2700 mg to a patient weighing ≥ 30 to < 40 kg, 3000 mg to a patient weighing ≥ 40 to < 60 kg, 3300 mg to a patient weighing ≥ 60 to < 100 kg, or 3600 mg to a patient weighing ≥ 100 kg. In some embodiments, the disclosure provides use of an HCDR comprising SEQ ID NOs: 19, 18, and 3 in the manufacture of a composition, e.g., a pharmaceutical composition or medicament, for treating HSCT-TMA, e.g., TMA after HSCT, in a human patient. 1~3 , and LCDRs comprising SEQ ID NOs: 4, 5 and 6 1~3 wherein the anti-C5 antibody or antigen-binding fragment thereof comprises an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, the anti-C5 antibody further comprising a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), the variant human Fc constant region comprising Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc constant region. In particular, the present disclosure relates to the use of an HCDR of, for example, ravulizumab, in the manufacture of a composition, for example, a pharmaceutical composition or medicament, for treating HSCT-TMA, e.g., TMA after HSCT, in a human patient. 1~3 and LCDR 1~3 The present invention relates to the use of an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof, comprising:

[0125] V. Outcomes Provided herein are methods for treating HSCT-TMA in a patient, comprising administering an anti-C5 antibody to the patient. Symptoms of HSCT-TMA include, but are not limited to, microangiopathic hemolytic anemia, thrombocytopenia, endothelial injury, renal injury, renal failure, serositis, pulmonary hypertension, and multiple organ failure.

[0126] Patients treated according to the methods disclosed herein experience an improvement in at least one symptom of HSCT-TMA. Treatment may result in, for example, at least one therapeutic effect selected from the group consisting of a reduction or cessation of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal injury, renal failure, serositis, pulmonary hypertension, and multiple organ failure compared to baseline.

[0127] In another embodiment, treatment consists of (a) a platelet count of ≥ 50,000 / mm without transfusion support for the past 7 days. 3 , (b) LDH < 1.5 × ULN, and (c) absence of schistocytes (if schistocytes were present at baseline).

[0128] In another embodiment, treatment consists of (a) a platelet count of ≥ 50,000 / mm without transfusion support for the past 7 days. 3 (b) LDH<1.5×ULN, (c) absence of schistocytes (if schistocytes were present at baseline), and (d) at least a 50% reduction from baseline in proteinuria. In one embodiment, proteinuria is a protein / creatinine ratio of ≧0.5 mg / mg.

[0129] In another embodiment, the treatment results in a favorable hematological response.

[0130] In another embodiment, treatment results in normalization of LDH, elimination of the need for red blood cell and platelet transfusions, and elimination of schistocytes.

[0131] In another embodiment, the treatment results in the patient's ability to maintain hemoglobin of ≧8 g / dL without transfusion support. In another embodiment, the treatment results in hemoglobin of ≧8 g / dL without transfusion support.

[0132] In another embodiment, treatment results in a decrease in LDH, an increase in platelets, and / or an increase in hemoglobin compared to baseline.

[0133] In another embodiment, treatment results in normal levels of serum creatinine compared to baseline.

[0134] In another embodiment, treatment results in an improvement in TMA-associated organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and / or GI systems compared to baseline.

[0135] In another embodiment, the treatment results in terminal complement inhibition.

[0136] In another embodiment, treatment results in a reduction in adverse events.

[0137] In another embodiment, treatment results in a shift to normal levels of biomarkers associated with vascular inflammation (e.g., shedding of tumor necrosis factor receptor 1 [TNF-R1]), endothelial injury and / or activation (e.g., shedding of thrombomodulin and vascular cell adhesion molecule 1 [VCAM-1]), renal damage (e.g., cystatin C), and / or complement proteins and complement activation pathway products.

[0138] In another embodiment, treatment results in a change from baseline in quality of life as assessed by a quality of life assessment (e.g., the Quality of Life Inventory (PedsQL) scale or the EQ-5D-5L questionnaire). Exemplary quality of life assessments are shown in Figures 4-10 and 15.

[0139] In another embodiment, lactate dehydrogenase (LDH) levels can be used to assess response to therapy. LDH is a marker of intravascular hemolysis (Hill, A. et al., Br. J. Haematol., 149:414-25, 2010; Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004; Parker, C. et al., Blood, 106:3699-709, 2005). Erythrocytes contain large amounts of LDH, and a correlation between cell-free hemoglobin and LDH concentration has been reported in vitro (Van Lente, F. et al., Clin. Chem., 27:1453-5, 1981) and in vivo (Kato, G. et al., Blood, 107:2279-85, 2006). The results of hemolysis are unrelated to anemia (Hill, A. et al., Hematologica, 93(s1):359 Abs.0903, 2008; Kanakura, Y. et al., Int. J. Hematol., 93:36-46, 2011). The normal LDH range is 105-333 IU / L (International Units per Liter).

[0140] LDH levels can be measured using any suitable test or assay, such as those described by Ferri FF, ed. Ferri's Clinical Advisor 2014. Philadelphia: PA: Elsevier Mosby; 2014: Section IV - Laboratory tests and interpretation of results. LDH concentrations can be measured in various samples obtained from a patient, particularly serum samples. As used herein, the term "sample" refers to biological material from a subject. While serum LDH concentrations are of interest, samples can be derived from other sources, such as single cells, multiple cells, tissues, tumors, body fluids, biological molecules, or supernatants or extracts of any of the above. Examples include tissue removed for biopsy, tissue removed during resection, blood, urine, lymphatic tissue, lymphatic fluid, cerebrospinal fluid, mucosa, and fecal samples. The sample used can vary based on the assay format, detection method, and the nature of the tumor, tissue, cells, or extract to be assayed. Methods for preparing samples are well known in the art and can be readily adapted to obtain a sample that is compatible with the method being utilized.

[0141] In one embodiment, a patient treated according to the disclosed methods experiences a reduction in LDH levels to normal levels or to within 10% or more than 20% of what is considered normal (e.g., within 10-333 IU / L). For example, patients treated according to the disclosed methods experience a reduction in LDH levels to within normal levels, or within 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 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%, or less than 50% (e.g., within 105-333 IU / L (International Units per Liter)) of what is considered the ULN level. In one embodiment, the patient's LDH level is > 1.5 times the ULN (LDH > 1.5 x ULN) before treatment begins.

[0142] In one embodiment, patients treated according to the disclosed methods experience a 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 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%, 55%, 56%, 57%, 58%, 59%, or 60% change in LDH rate compared to baseline.

[0143] In one embodiment, a patient treated according to the disclosed methods maintains a serum trough concentration of an anti-C5 antibody, or antigen-binding fragment thereof, of at least 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 μg / mL or more. In one embodiment, a patient treated according to the disclosed methods maintains a serum trough concentration of anti-C5 antibody, or antigen-binding fragment thereof, of at least 175 μg / mL or greater.

[0144] In one embodiment, a patient treated according to the disclosed methods has a free C5 concentration of 0.5 μg / mL or less (eg, 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0145] VI. Kits and Unit Dosage Forms Also provided herein are kits containing pharmaceutical compositions containing an anti-C5 antibody or antigen-binding fragment thereof, such as ravulizumab or BNJ421, and a pharmaceutically acceptable carrier in a therapeutically effective amount suitable for use in the aforementioned methods. The kits may also optionally contain instructions, including, for example, an administration schedule, to enable a practitioner (e.g., a physician, nurse, or patient) to administer the contained composition to a patient with HSCT-TMA. The kits may also contain a syringe.

[0146] Optionally, the kit includes multiple packages of single-dose pharmaceutical compositions, each containing an effective amount of anti-C5 antibody or its antigen-binding fragment for single administration according to the method provided above. Instructions or devices required for administering the pharmaceutical compositions can also be included in the kit. For example, the kit can provide one or more pre-filled syringes containing a certain amount of anti-C5 antibody or its antigen-binding fragment.

[0147] In one embodiment, a kit for treating HSCT-TMA in a human pediatric patient includes: (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof according to any of the methods described herein.

[0148] In one embodiment, the kit comprises a dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 5 to < 10 kg at: (a) At a dose of 600 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 300 mg on day 15 and every 4 weeks thereafter.

[0149] In another embodiment, the kit comprises a dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 10 to < 20 kg at: (a) At a dose of 600 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 600 mg on day 15 and every 4 weeks thereafter.

[0150] In another embodiment, the kit comprises a dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 20 to < 30 kg at: (a) At a dose of 900 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 2100 mg on day 15 and every 8 weeks thereafter.

[0151] In another embodiment, the kit comprises a dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥30 to <40 kg at: (a) At a dose of 1200 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) at a dose of 2700 mg on day 15 and every 8 weeks thereafter.

[0152] In another embodiment, the kit comprises a dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 40 to < 60 kg at: (a) At a dose of 2400 mg once on day 1; (b) at a dose of 600 mg once on day 5; (c) at a dose of 600 mg once on day 10; (d) at a dose of 3000 mg on day 15 and every 8 weeks thereafter.

[0153] In another embodiment, the kit comprises a dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≥ 60 to < 100 kg at: (a) At a dose of 2700 mg once on day 1; (b) at a dose of 900 mg once on day 5; (c) at a dose of 900 mg once on day 10; (d) at a dose of 3300 mg on day 15 and every 8 weeks thereafter.

[0154] In another embodiment, the kit comprises a dose of an anti-C5 antibody or antigen-binding fragment thereof, wherein the anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧100 kg at: (a) At a dose of 3000 mg once on day 1; (b) at a dose of 900 mg once on day 5; (c) at a dose of 900 mg once on day 10; (d) at a dose of 3600 mg on day 15 and every 8 weeks thereafter.

[0155] The following examples are illustrative only 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 review of this disclosure. The contents of all publications, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference. [Example]

[0156] Example 1: A Phase 3, Open-Label, Single-Arm, Multicenter Study of ULTOMIRIS in Addition to Best Supportive Care in Pediatric Participants (1 Month to <18 Years of Age) With Thrombotic Microangiopathy (TMA) After Hematopoietic Stem Cell Transplantation (HSCT) An open-label, single-arm, multicenter study will be conducted to evaluate the safety, efficacy, PK, and PD of ULTOMIRIS (ULTOMIRIS®) administered intravenously (IV) infusion in pediatric participants aged 1 month to less than 18 years with HSCT TMA. Participants with HSCT-TMA who have persistent TMA for at least 72 hours after discontinuation or change of TMA-inducing agent and / or treatment of the underlying inducing condition will be enrolled.

[0157] 1. Purpose The primary objective of this study is to assess the efficacy of ULTOMIRIS plus best supportive care (BSC) in treating pediatric participants with HSCT-TMA via patient TMA response during the 26-week treatment period. TMA response is defined as meeting all of the following: (a) platelet count ≥ 50,000 cells / mm3 without transfusion support for the past 7 days; 3, (b) LDH < 1.5 × ULN and absence of schistocytes (if schistocytes were present at baseline), and (c) at least a 50% reduction from baseline in proteinuria. Participants must meet each response criterion on two separate assessments obtained at least 28 days apart; all intervals during which each criterion is met must overlap by at least 1 day. Proteinuria is defined as a protein / creatinine ratio ≥ 2 mg / mg.

[0158] One of the secondary objectives is to characterize TMA response after treatment with ravulizumab by: a) time to TMA response (measured as the number of days from Day 1 to the first day the participant met all criteria for TMA response); b) TMA response at weeks 26 and 52; c) response and time to response for the individual components of the TMA response during the 26-week randomized treatment period; d) Hematologic response defined as: platelet count ≥ 50,000 cells / mm without transfusion support for the past 7 days 3 AND LDH<1.5×ULN AND absence of schistocytes (if schistocytes were present at baseline) e) Time to hematologic response. The criterion must be met on two separate assessments obtained at least 28 days apart; f) hemoglobin response (ability to maintain hemoglobin ≥ 8 g / dL without transfusion support; criteria must be met on two separate assessments obtained at least 28 days apart); g) partial response (participant meets one or more but not all criteria for TMA response); and h) Loss of TMA response (participant achieves TMA response and fails to meet criteria for one or more components of the TMA response at a subsequent visit, confirmed by a second test result at least 24 hours apart).

[0159] Additional secondary objectives include assessing: a) improvement in organ dysfunction (change from baseline in TMA-related organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and GI systems at 6 months and 1 year); b) duration of TMA relapse and response (on-study TMA relapse (participants meet criteria for TMA diagnosis after achieving TMA response and duration of TMA response); c) overall survival (6 months and 1 year); d) non-relapse mortality (non-relapse mortality is defined as the death of a participant from any cause during the study, but excluding death due to progression or recurrence of underlying disease); and e) platelet response (platelet response is defined as a platelet count ≥ 100,000 / mm3 without transfusion support in the past 7 days; the criterion must be met on two separate assessments obtained at least 28 days apart).

[0160] Additional objectives include assessment of pharmacokinetics (PK) / pharmacodynamics (PD) (e.g., change in serum concentrations of ULTOMIRIS over time, change in serum free C5 concentrations over time, and change in serum total C5 concentrations over time) and characterization of the safety profile of ULTOMIRIS + BSC in pediatric participants with HSCT-TMA (e.g., incidence of treatment-emergent AEs and treatment-emergent SAEs, change from baseline in vital signs and laboratory parameters, incidence of ADAs, and evaluation of immunogenicity).

[0161] Exploratory objectives include assessment of biomarkers in pediatric participants with HSCT-TMA (exploratory biomarker analysis will evaluate change from baseline in biomarkers, which may include, but are not limited to, markers of vascular inflammation, endothelial activation, renal injury, and complement dysregulation); improvement in QoL patient-reported outcomes in pediatric participants with HSCT-TMA (change from baseline in QoL measured by PedsQL); complement pathway genetic mutations (incidence of specific complement dysregulation-associated mutations) in pediatric participants with HSCT-TMA; and description of healthcare resource utilization in pediatric participants with HSCT-TMA ((1) number, reasons, and duration of hospitalizations (including intensive care unit stays); (2) number and volume of RBC and platelet transfusions; and (3) number of outpatient visits (including physician or emergency room visits) and underlying reasons).

[0162] 2. Overall Study Design This study is an open-label, single-arm, multicenter study to evaluate the safety, efficacy, PK, and PD of intravenous (IV) infusion of ravulizumab in pediatric participants aged 1 month to less than 18 years with HSCT TMA. An overview of the study is shown in Figure 1. The schedule of study visits and assessments through the completion of the 26-week treatment period is shown in Figure 2. The schedule of study visits and assessments during the follow-up period is shown in Figure 3.

[0163] Participants with HSCT-TMA who have persistent TMA for at least 72 hours after discontinuation or change of TMA inducer and / or treatment of the underlying inducer condition will be enrolled. All participants will receive best supportive care (BSC) for the duration of the study. Approximately 40 participants will be enrolled. The study will consist of three periods: a screening period of up to 7 days, a 26-week treatment period, and a 26-week follow-up period.

[0164] Participants will receive a loading dose of ULTOMIRIS IV on days 1, 5, and 10, followed by a maintenance dose of ULTOMIRIS IV on day 15, and then once every 8 weeks (q8w) for participants weighing 20 kg or more, or once every 4 weeks (q4w) for participants weighing less than 20 kg. The first 10 treated participants will receive the following weight-based ULTOMIRIS dosing regimen via IV infusion, as shown in Table 1:

[0165] [Table 1]

[0166] Additional doses of ULTOMIRIS will be administered after red blood cell (RBC) and / or platelet transfusions. Further doses of ULTOMIRIS will be permitted on an individual basis for documented clinical deterioration.

[0167] After completing the 26-week treatment period, all participants will enter a follow-up period and remain in the study for 26 weeks without further administration of ULTOMIRIS.

[0168] If extended treatment is clinically indicated (e.g., if a participant begins to demonstrate a TMA response later in the treatment period), the Investigator and Medical Monitor may mutually agree to administer additional doses during the follow-up period based on a weight-based dosing regimen.

[0169] If a participant meets the criteria for TMA recurrence or loss of TMA response during the follow-up period, the participant may receive re-treatment with ULTOMIRIS.

[0170] For participants who discontinued the study or who received ULTOMIRIS during the follow-up period, a safety follow-up phone call will be conducted 8 weeks after the last dose of ULTOMIRIS if this is later than the date of the End of Study (EoS) or Early Discontinuation (ED) visit.

[0171] 3. Study population Approximately 40 previously treated pediatric participants with HSCT-TMA will be enrolled in this trial. Participants will be enrolled at approximately 50 study sites worldwide and assigned to treatment with ULTOMIRIS. At least three Japanese participants are included in the trial.

[0172] Selection criteria Participants were eligible to enroll in the study only if they met all of the following criteria: 1. Participants must be between 1 month and under 18 years of age at the time of signing the informed consent or assent form; 2. Pediatric participants who have undergone HSCT within the past 6 months at screening; 3. TMA diagnosis based on all of the following criteria occurring simultaneously: New-onset thrombocytopenia or platelet transfusion refractoriness, where new-onset thrombocytopenia is defined as a new decrease in platelet count to ≤50,000 cells / mm3, and transfusion refractoriness is defined as a platelet increase that does not exceed the transfusion trigger 10-60 minutes after transfusion or a rise of <10 x 109 cells / L 20-24 hours after transfusion after at least two platelet transfusions. New-onset anemia (defined as a new decrease in hemoglobin to ≤8 g / dL) or increased transfusion requirements (defined as the need for more frequent transfusions to maintain hemoglobin ≥8 g / dL) Any of the following hemolytic markers: lactate dehydrogenase >1.5 × ULN or the presence of schistocytes in ≥2 high-power fields (HPF) on a peripheral blood smear Proteinuria on spot urine testing, where proteinuria is defined as a protein / creatinine ratio ≥ 2 mg / mg. The presence of proteinuria must be confirmed by a second measurement (at least 4 hours apart). · Presence of hypertension defined as: systolic blood pressure (SBP) and / or diastolic blood pressure (DBP) ≥ 95th percentile for age, sex, and height on repeated measurements; 4. Participants must have HSCT-TMA lasting at least 72 hours after initial management of the inciting agent / condition (including discontinuation or dose reduction of the causative agent [e.g., CNI], treatment of any underlying infection, or treatment of underlying GVHD); 5. Weight ≥ 5 kg at screening; 6. Male or female [Contraception use by males or females must be consistent with local regulations regarding contraception methods for those participating in clinical studies. Male participants must agree to use contraception as detailed in the protocol during treatment and for at least 8 months after the final dose of ULTOMIRIS and to refrain from sperm donation during this period. Female participants are eligible if they are not pregnant, not lactating, and meet at least one of the following conditions: not a woman of childbearing potential (WOCBP), or are WOCBP and are using an effective and acceptable method of contraception during treatment and for at least 8 months after the final dose of ULTOMIRIS. WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose of ULTOMIRIS]: 7. Participants must be vaccinated against meningococcal infections, if clinically possible, according to institutional guidelines for immune reconstitution after HSCT. Participants must be revaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae, if clinically possible, according to institutional guidelines for immune reconstitution after HSCT. All participants will receive prophylactic antibiotic coverage according to institutional post-transplant infection prevention guidance, including coverage against N. meningiditis, for at least 2 weeks after meningococcal vaccination. Participants unable to receive meningococcal vaccination will receive antibiotic prophylaxis coverage against N. meningiditis throughout the treatment period and for 8 months after the final dose of ULTOMIRIS; 8. Participant or their legally authorized representative must be able to give a signed informed consent or assent form, including compliance with the requirements and restrictions listed in the informed consent or assent form and in this protocol.

[0173] b. Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria: 1. Known familial or acquired "A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13" (ADAMTS13) deficiency (activity <5%); 2. Known Shiga toxin-associated hemolytic uremic syndrome (ST-HUS) as evidenced by a positive test for Shiga toxin or culture of Shiga toxin-producing bacteria; 3. Positive direct Coombs test; 4. Diagnosis or suspicion of disseminated intravascular coagulation (DIC) according to the International Society on Thrombosis and Haemostasis (ISTH) scoring criteria as shown in Taylor et al., Thromb Haemost. 2001;86(5):1327-1330 and Tables 2-3. [ISTH is used only in participants with clinically suspected DIC (e.g., malignancy, severe infection or sepsis, obstetric complications, excessive bleeding in the setting of trauma). In the case of overt DIC, participants must have an underlying condition known to be associated with overt DIC in order to use the algorithm.] 5. Known bone marrow / transplant failure; 6. Diagnosis of veno-occlusive disease (VOD) according to the European Society for Blood and Marrow Transplantation (EBMT) criteria shown in Corbacioglu S, et al., Bone Marrow Transplant. 2018;53(2):138-145 and Table 4; 7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titers or documented negative HIV-1 / HIV-2 test within 6 months prior to screening); 8. Unresolved meningococcal disease; 9. Presence or suspicion of sepsis (treated or untreated) within 7 days prior to screening; 10. Pregnant or breastfeeding; 11. Hypersensitivity to mouse proteins or one of the excipients of ravulizumab; 12. Any medical or psychological condition that, in the opinion of the Investigator or Alexion, may increase the participant's risk from participating in the study or may confound the outcome of the study; 13. Previous or current treatment with a complement inhibitor; 14. Participation in another interventional treatment trial or use of an experimental treatment (excluding use of currently approved medications being investigated alone or in combination for treatment of underlying disease; conditioning regimens; GVHD prophylaxis, infection prophylaxis, or post-transplant infection treatment) within 30 days prior to initiation of ULTOMIRIS on Day 1 of this study, or within 5 half-lives of the investigational product, whichever is greater.

[0174] [Table 2]

[0175] [Table 3]

[0176] [Table 4]

[0177] 4. Study Intervention A study intervention is defined as an investigational intervention, marketed product, placebo, or medical device intended to be administered to study participants according to the study protocol. Details regarding ULTOMIRIS are provided in Table 5.

[0178] [Table 5]

[0179] In this study, all participants will receive best supportive care (BSC) as their baseline therapy. BSC will be determined by the study director according to institutional practice and participant characteristics. BSC measures include, but are not limited to, transfusion support, corticosteroids, dialysis, and antihypertensive medications.

[0180] Transfusion support is provided as needed based on the participant's clinical status, in accordance with institutional guidelines. In general, according to the Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Expert Advisory Committee (JAPC), transfusion support is recommended as follows: (a) red blood cell transfusions should be considered in participants with hemoglobin ≤7 g / dL or with symptomatic anemia (e.g., dyspnea and / or tachycardia) with hemoglobin ≤8 g / dL; (b) 10 × 10 9 (c) 20 × 10 9 An increase in the platelet transfusion threshold to 100 / L is warranted in participants with fever and / or receiving antibiotic therapy for suspected bacterial or fungal infection. Transfusion of RBCs or platelets requires an additional dose of ULTOMIRIS.

[0181] Supportive care of the underlying disease (e.g., HSCT, GVHD) is permitted during the course of the study. The use of currently approved medications is being investigated alone or in combination for treatment of the underlying disease, conditioning regimen, GVHD prophylaxis regimen, GVHD treatment, infection prophylaxis, or infection treatment. The investigator may consider other concomitant medications on a case-by-case basis.

[0182] The following medications and therapies are not permitted: (a) eculizumab or other agents acting on the complement pathway, (b) use of plasma exchange, (c) use of rituximab, (d) IV immunoglobulin (Ig) (in the absence of unrelated medical need, such as hypergammaglobulinemia), (d) defibrotide (except for participants with VOD confirmed to have developed during the study), and (e) use of experimental interventions or therapies.

[0183] The appropriateness of the proposed dosing regimen will be confirmed by initial PK / PD analysis of the first 10 participants enrolled. If the proposed dose regimen does not result in the expected degree of free C5 inhibition, the dosing regimen will be modified (increased) for subsequent participants according to the PK / PD data.

[0184] Participants will not receive any additional treatment with ULTOMIRIS as part of the protocol after completing or withdrawing from the study. Upon completion of the participant's last study visit (i.e., EoS or ED visit), participants will return to care with their primary physician.

[0185] 5. Study Intervention In rare cases, participants may need to permanently discontinue the study intervention (definitive discontinuation). Participants should consider discontinuing the intervention if any of the following occur during the study: (a) a severe hypersensitivity reaction, (b) use of unauthorized medications, (c) pregnancy or planned pregnancy, or (d) if the study director determines it is necessary for the participant. If the study intervention is definitively discontinued, every effort should be made to have the participant continue study visits according to the safety follow-up activity schedule. If the participant does not agree to continue the activity schedule visits, the following activities must be completed: (1) an early discontinuation assessment conducted as indicated in the activity schedule; (2) the site must follow the participant for at least 8 weeks after the last dose of ULTOMIRIS via safety phone calls to collect any AEs and / or concomitant medications; and (3) information on vital status at 6 months and 1 year after the first dose of ULTOMIRIS. If the participant's vital status is not available at the time of discontinuation, the site will attempt to collect the status (e.g., via public records or telephone).

[0186] Participants are considered lost to follow-up if they repeatedly fail to return for scheduled visits and cannot be contacted by the study site.

[0187] 6. Test Assessment and Procedures A review of demographic parameters will be conducted, including age, sex, race, and ethnicity. The participant's relevant medical history (including TMA diagnosis), treatment history, and family history of relevant diseases, including previous and concurrent conditions / disorders, will be assessed at the screening visit by the Investigator and recorded on source documents and CRF. Information collected will include the following: transplant modality, origin of hematopoietic stem cells, transplant indication, history of previous HSCT, conditioning regimen, presence of GVHD (Section 10.11), engraftment status, any other transplant complications, and other relevant information regarding the peri-transplant period.

[0188] At the scheduled dosing visit, administration of ULTOMIRIS IV will occur after all other tests and procedures have been completed, except for post-dose sample collection (PK / PD / biomarkers). Weight-based dosing will be based on the participant's weight recorded on the day of the infusion visit. If weight on the day of infusion is not available, weight recorded at a previous study visit may be used.

[0189] ULTOMIRIS will be administered by IV infusion according to the dosing regimen in Table 1. If extended treatment is clinically indicated (e.g., if a participant begins to demonstrate a TMA response later in the treatment period), the investigator and medical monitor may mutually agree to administer additional doses during the follow-up period based on the weight-based dosing regimen in Table 1. Unscheduled visits may be arranged as needed for ULTOMIRIS administration. The following assessments must be performed at any unscheduled visits where ULTOMIRIS is administered: (a) urine pregnancy test (WOCBP only), (b) simplified physical exam, (c) PK / PD blood sample collection, (d) vital signs, (e) laboratory tests, (f) C5b-9 blood sample collection, and (g) C5b-9 urine sample collection.

[0190] Additional doses of ULTOMIRIS will be permitted during treatment according to the criteria outlined in Table 5.

[0191] [Table 6]

[0192] Unscheduled visits may be arranged as needed for additional ULTOMIRIS doses. The following assessments must be performed at any unscheduled visit where ULTOMIRIS is administered: (a) urine pregnancy test (WOCBP only), (b) simplified physical examination, (c) PK / PD blood sample collection, (d) vital signs, (e) laboratory tests, (f) C5b-9 blood sample collection, and (g) C5b-9 urine sample collection.

[0193] Participants are expected to receive treatment for a 26-week treatment period, followed by a 26-week follow-up period where they will discontinue treatment. Participants may receive ULTOMIRIS retreatment if they meet any of the following criteria during the follow-up period: (1) the participant meets criteria for TMA relapse, (2) the participant meets criteria for TMA loss of response, or (3) the investigator believes the participant may benefit from retreatment and initiates a discussion with the medical monitor and provides a medical justification. If retreatment is deemed necessary, participants will continue to follow their activity schedule as planned. Participants will receive a weight-based dose of ULTOMIRIS according to the dosing regimen described in Table 1.

[0194] Unscheduled visits may be arranged as needed for ULTOMIRIS administration. The following assessments must be performed at any unscheduled visit where ULTOMIRIS is administered: (a) urine pregnancy test (WOCBP only), (b) simplified physical examination, (c) PK / PD blood sample collection, (d) vital signs, (e) laboratory tests, (f) C5b-9 blood sample collection, and (g) C5b-9 urine sample collection.

[0195] The number and amount of transfusions during the screening period will be recorded on the Transfusion History CRF. Information collected will include the date of transfusion, number of units, and amount of each blood component administered. Transfusions during the study will be recorded on the Transfusion CRF. Information collected will include the date of transfusion, number of units, and amount of each blood component administered.

[0196] Due to its mechanism of action, use of ULTOMIRIS increases participants' susceptibility to infection with N. meningitidis. To reduce the risk of infection, participants will be vaccinated against N. meningitidis, if clinically feasible. Vaccines against serotypes A, C, Y, W135, and B, where available, are recommended to protect against common pathogenic meningococcal serotypes.

[0197] Because HSCT results in immunosuppression due to ablative therapy, concomitant medications, or underlying disease, vaccine antibody titers will decline 1 to 4 years after transplant unless patients are revaccinated. Institutions are encouraged to follow relevant immune reconstitution guidelines or local practice guidelines regarding immune reconstitution for revaccination of participants who have undergone HSCT.

[0198] Participants will receive antibiotic prophylaxis for meningococcal infection for at least two weeks after vaccination. Vaccination may not be sufficient to prevent meningococcal infection. Official guidance and local practice regarding the appropriate use of prophylactic antibiotics should be considered. All participants will be monitored for early signs of meningococcal infection, and any suspected infection will be evaluated promptly and treated with appropriate antibiotics as needed. Participants who cannot receive vaccination must receive antibiotic prophylaxis throughout their ULTOMIRIS treatment period and for eight months after their final ULTOMIRIS dose.

[0199] If clinically feasible, participants will also be vaccinated against Hib and S. pneumoniae according to appropriate immune reconstitution guidelines, and participants who have undergone HSCT must be revaccinated. Participants who cannot be vaccinated must receive antibiotic prophylaxis throughout their ULTOMIRIS treatment and for 8 months after their final ULTOMIRIS dose.

[0200] 7.Effectiveness Assessment Laboratory assessments to determine TMA response will be performed according to the Activity Schedule and assessed against the predefined criteria for TMA response. For time to TMA response, partial TMA response, loss of TMA response, and TMA relapse, relevant clinical laboratory assessments will be performed according to Table 7 and the Activity Schedule and assessed against the predefined criteria for TMA response.

[0201] [Table 7]

[0202] [Table 8]

[0203] [Table 9]

[0204] Participant vital status will be collected continuously throughout the study. Information on any deaths occurring during the study and the cause of death will be collected.

[0205] Changes from baseline in organ dysfunction (end-organ involvement, i.e., renal, cardiovascular, CNS, pulmonary, and GI systems) will be described for participants. The parameters listed in Table 8 will be assessed at the time points specified in the activity schedule.

[0206] [Table 10]

[0207] 8.Safety Assessment A complete physical examination will include, at a minimum, assessment of the following organs / body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, chest, heart, abdomen, extremities, musculoskeletal, and neurological status. A brief physical examination will include, at a minimum, examination of relevant body systems based on the investigator's judgment and the participant's symptoms. The investigator will pay particular attention to clinical signs associated with prior serious illness. Weight and height will also be measured and recorded.

[0208] Additional physical examinations will be performed as medically indicated during the study.

[0209] Oral temperature (°C or °F), heart rate, respiratory rate, systolic and diastolic blood pressure (mmHg), and pulse oximetry will be assessed at screening and at each subsequent study visit. Blood pressure and heart rate measurements will be assessed with participants seated using fully automated devices. Manual methods will be used only if automated devices are not available.

[0210] Prior to blood pressure and heart rate measurements, participants will rest for at least 5 minutes in a quiet, undisturbed environment. Ideally, the same arm will be used for measurements for each participant. O2 saturation (%) will be collected using pulse oximetry. Vital signs will be collected pre- and post-dose at each ULTOMIRIS dosing visit.

[0211] A single 12-lead electrocardiogram will be performed to obtain heart rate, PR, QRS, QT, and QTc intervals (QT interval will be corrected for heart rate using Fridericia's formula [QTcF]). Participants must be supine approximately 5-10 minutes before ECG collection and remain supine but awake during ECG collection. The Investigator or Co-Investigator is responsible for reviewing the ECG to assess whether it is within normal limits and to determine the clinical significance of the results. These assessments will be recorded on the source documents and CRF.

[0212] Both posteroanterior and lateral chest x-rays will be obtained during the participant's full inspiration at the time points specified in the SoA. The Investigator or designated Subinvestigator is responsible for reviewing the x-rays to assess the clinical significance of the results. These assessments will be recorded on the source documents and CRF. Particular attention should be paid to determining whether signs of pulmonary or cardiovascular involvement (including, but not limited to, pulmonary hypertension, pleural effusion, and pulmonary edema) are present.

[0213] Transthoracic echocardiography will be performed according to the schedule of activities. The Study Principal Investigator or designated Sub-Study Principal Investigator is responsible for reviewing the echocardiogram to assess the clinical significance of the results. These assessments will be recorded in the source documents and on the CRF. Particular attention should be paid to determining whether signs of pulmonary hypertension (right ventricular dysfunction, tricuspid regurgitation) or serositis (pericardial effusion) are present.

[0214] If a participant has symptoms of PRES at study entry or develops symptoms during the study, an MRI will be performed to look for bilateral white matter abnormalities in vascular basins consistent with PRES. If the presence of PRES is confirmed, an MRI will be performed at the time of symptom resolution and at the EoS / ED visit. Additional MRIs may be performed during the study.

[0215] All laboratory tests with values ​​considered clinically significantly abnormal during study participation or within 8 weeks after the final dose of study intervention will be repeated until the value returns to normal or baseline or is no longer considered clinically significant by the Study Principal Investigator or medical monitor. If such values ​​do not return to normal / baseline within a time period deemed reasonable by the Study Principal Investigator, an etiology must be identified. All protocol-required laboratory assessments will be performed in accordance with the laboratory manual and activity schedule. If a laboratory value from a non-protocol-specified laboratory assessment performed at the site's on-site laboratory requires a change in participant management or is considered clinically significant by the Study Principal Investigator (e.g., serious adverse event (SAE) or adverse event (AE), or dose modification), the result must be recorded in the source document.

[0216] Human immunodeficiency virus testing for HIV-1 and HIV-2 will be required for all participants prior to enrollment. A confirmed history of negative HIV-1 and HIV-2 tests within 6 months prior to screening will be sufficient. HIV-positive participants will not be enrolled.

[0217] Pregnancy testing will be performed as described in the activity schedule. Pregnancy data from female participants and female spouses / partners of male participants will be collected and followed until pregnancy outcome is known from the signature of the ICF / consent form, even if the participant discontinues the study intervention or withdraws from the study. Female participants who become pregnant during study participation will discontinue the study intervention. Pregnancy is not considered an AE unless there is suspicion that the study intervention may have interfered with the effectiveness of the contraceptive. However, pregnancy complications and abnormal pregnancy outcomes are AEs and may meet the criteria for an SAE (e.g., ectopic pregnancy, spontaneous abortion, intrauterine fetal death, neonatal death, or congenital anomaly). Uncomplicated elective abortions should not be reported as adverse events.

[0218] Previous medications and / or vaccines (including vitamins, herbal preparations, and those described in the exclusion criteria and procedures (therapeutic interventions such as surgery / biopsy or physical therapy)) that participants have received or received within 30 days prior to the first dose of ULTOMIRIS on Day 1 will be recorded.

[0219] Concomitant medications (including medicines, vitamins, herbal preparations, or supplements) and procedures received after the start of the ULTOMIRIS IV infusion on Day 1. This includes supportive care medications and procedures, antibiotic prophylaxis, GVHD prophylaxis or treatment, and vaccinations. At each study visit, participants will be asked about any new medications or non-drug therapies or changes in concomitant medications and non-drug therapies since their last visit. Concomitant medications deemed necessary for the participant's care during the study or for the treatment of AEs may be administered at the investigator's discretion, along with other medications, except for those listed as unauthorized medications.

[0220] Data regarding blood component transfusions, including the date of transfusion, type of blood component administered, number of units, and amount, should be recorded on the CRF page.

[0221] 9.Safety Assessment An adverse event (AE) is an untoward medical occurrence in a participant that is temporally related to the use of a study intervention, whether or not considered related to the study intervention. Thus, an adverse event can be an untoward and unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally related to the use of the study intervention. Events that meet the definition of an AE are listed in Table 9. Events that do not meet the definition of an AE are listed in Table 10.

[0222] [Table 11]

[0223] [Table 12]

[0224] If an event is not an AE according to the above definition, it is not a serious adverse event (SAE), even if the criteria for seriousness are met (e.g., hospitalization due to signs / symptoms of the disease under study, death due to disease progression). An SAE is defined as any untoward medical occurrence that results in one of the events shown in Table 11 at any dose.

[0225] [Table 13]

[0226] A suspected unexpected serious adverse reaction (SUSAR) is defined as a serious event not listed in the Investigator's Brochure and identified by the Investigator as related to the study product or investigational procedures. 21 CFR 312.32 and the EU Clinical Trials Directive 2001 / 20 / EC and related detailed guidance or national regulatory requirements of participating countries require the reporting of SUSARs. Suspected unexpected serious adverse reactions will be reported to the national competent authority and IRB / IEC, if applicable.

[0227] All AEs will be reported by the participant (or, where appropriate, the caregiver, representative, or legally authorized representative of the participant) to the Study Principal Investigator or qualified designee. The Study Principal 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 AEs that continue to be considered serious, related to the study intervention or procedure, or that cause the participant to discontinue the study intervention.

[0228] All AEs and SAEs will be collected from the time of signing the ICF / consent form until the ED / EoS visit or 8 weeks after the last dose of ULTOMIRIS (whichever is later). All SAEs will be recorded and reported immediately and, under no circumstances, should this exceed 24 hours. The investigator is under no obligation to proactively solicit AE or SAE data after the end of study participation.

[0229] After the first AE / SAE report, the study director must actively follow up with each participant at subsequent visits / contacts. All SAEs will be followed up until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up. In this study, any dose of ULTOMIRIS beyond the protocol-specified dose will be considered an overdose.

[0230] An overdose is a medication error that is not considered an AE unless there is an adverse medical occurrence attributable to the overdose.

[0231] For recording and follow-up of AEs and / or SAEs, intensity will be assessed. An event is defined as "serious" if it meets at least one of the predefined outcomes as described in the SAE definition, not if it is rated as severe. The investigator will assess the intensity of each AE and SAE reported during the study and will use the results in accordance with the National Cancer Institute CTCAE published on November 27, 2017. v5.0 and assign it to one of the following categories: (a) Grade 1: mild (awareness of signs or symptoms but easily tolerated), (b) Grade 2: moderate (discomfort that interferes with normal activities), (c) Grade 3: severe (incapacitating, unable to perform normal activities), (d) Grade 4: life-threatening, or (e) Grade 5: fatal.

[0232] The investigator is responsible for assessing the relationship between the study intervention and the occurrence of each AE or SAE. For all AEs (both non-serious and serious), the investigator's causality assessment must be provided. This assessment must be recorded on the CRF 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 another more likely etiology; it may be due to an underlying or concurrent disease, a comorbid condition, a concomitant 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 an alternative possible etiology. The event corresponds to the known pharmacological profile of the study intervention. There is improvement on discontinuation and / or recurrence on rechallenge.

[0233] The Investigator will use clinical judgment to determine the 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. For marketed products, the Investigator will also refer to the Investigator Brochure (IB) and / or product information in their assessment. For each AE / SAE, the Investigator must document in the medical record that they have reviewed the AE / SAE and provided a causality assessment. There may be cases where an SAE occurs and the Investigator has minimal information to include in the initial report to Alexion. However, it is very important that the Investigator always assess the causality of all events before initially submitting SAE data to Alexion. The Investigator may change their opinion regarding causality in light of follow-up information and send an SAE follow-up report with an updated causality assessment. The causality assessment is one of the criteria used in determining regulatory reporting requirements.

[0234] Blood samples will be collected to measure serum ULTOMIRIS, free C5, and total C5 concentrations at the time points specified in the activity schedule. The timing of sampling may be modified over the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. Samples collected for PK / PD analysis may also be used to evaluate safety or efficacy aspects related to concerns that arise during or after the study.

[0235] For all participants receiving ULTOMIRIS: Pre-dose PK and PD blood samples will be collected within 90 minutes prior to the administration of ULTOMIRIS at the visit specified in the activity schedule. Pre-dose blood samples may be collected from the venous access created for the dose infusion prior to dose administration. Post-dose PK and PD blood samples will be collected within 60 minutes after the completion of the ULTOMIRIS infusion. Post-dose blood samples will be collected from the participant's contralateral, non-infused arm. PK / PD blood samples at non-dosing visits may be collected any time during the visit. In the event of an unscheduled visit, PK and PD blood samples will be collected as soon as possible. Pre-dose and post-dose PK and PD samples will be collected for all additional doses of ULTOMIRIS administered. If a participant's weight increases from <20 kg (ULTOMIRIS q4w) to ≥20 kg (ULTOMIRIS q8w), a change in dosing interval from q4w to q8w will only occur on Days 15, 71, or 127.

[0236] For participants who sign an additional optional consent, whole blood and oral swab samples for exploratory genetics may / will be collected at times specified in the activity schedule. Exploratory genetics may be performed to examine genetic variants in genes that may be associated with complement dysregulation or metabolism or the effectiveness of ULTOMIRIS.

[0237] Blood and urine samples for biomarker studies will be collected from all participants at the time points specified in the activity schedule. Whenever possible, collection of biomarker samples during the study, including samples collected during the screening period, will occur before participants receive blood transfusions or dialysis. Biomarkers will be measured and include, but are not limited to, assessment of: (1) vascular inflammation (e.g., tumor necrosis factor receptor 1 [TNF-R1] shedding), (2) endothelial injury and / or activation (e.g., thrombomodulin and vascular cell adhesion molecule 1 [VCAM-1] shedding), (3) renal injury (e.g., cystatin C), and (4) complement proteins and complement activation pathway products.

[0238] Anti-drug antibodies to ULTOMIRIS will be assessed in serum samples collected pre-dose (within 90 minutes before the start of ULTOMIRIS IV infusion) from all participants at the time points specified in the Assessment Schedule. Additionally, serum samples should also be collected at the final visit from participants who discontinue ULTOMIRIS or withdraw from the study. Serum samples will be screened for antibodies that bind to ULTOMIRIS, and titers of confirmed positive samples will be reported. Other analyses may be performed to further characterize the immunogenicity of ULTOMIRIS.

[0239] Detection and characterization of antibodies to ULTOMIRIS will be performed using validated assays. Samples collected for detection of antibodies to ULTOMIRIS will also be evaluated for ULTOMIRIS serum concentrations to enable interpretation of antibody data. Confirmed antibody-positive samples will be further evaluated for antibody titer and the presence of neutralizing antibodies.

[0240] The Pediatric Quality of Life Inventory (PedsQL) 4.0 General Core Scales is a multidimensional child self-report and parent proxy-report standardized instrument for measuring health-related quality of life (QoL) in children and adolescents aged 2–18 years.

[0241] A sample PedsQL is provided in Figures 4-10. The PedsQL will be administered at the study visit prior to any other study procedures (only for participants aged 2 years and older).

[0242] 10.Statistical considerations Approximately 40 participants will be enrolled in this study. This sample size is deemed adequate to provide complete safety information and the level of precision required for the planned estimates. Assuming a 50% proportion of participants achieving a TMA response, 40 participants would yield a 95% CI for the proportion of responses with a half-width of approximately 16%. The analysis population is defined in Table 12.

[0243] [Table 14]

[0244] Efficacy analyses will be performed in the Full Analysis Set (FAS). The primary efficacy endpoint analysis and selected secondary endpoint analyses will also be performed in the per-protocol population. Safety analyses will be performed in the safety population. Pharmacokinetic and PD analyses will be performed in all participants who receive at least one dose of ULTOMIRIS and have evaluable PK and / or PD data.

[0245] The statistical methods described in this section are further detailed in a separate Statistical Analysis Plan (SAP). Summary statistics will be calculated and displayed by visit where applicable, and by stratification factor where appropriate. Descriptive statistics for continuous variables will include, at a minimum, number of participants, mean, standard deviation, minimum, median, and maximum. For categorical variables, frequencies and percentages will be presented. Graphical displays will be provided where appropriate. Analyses will be performed using SAS® software, version 9.4 or later.

[0246] Analysis of the primary endpoint will be performed by subgroups, including but not limited to, the presence of GVHD, geographic region, and baseline weight. Further details will be provided in the SAP.

[0247] The primary efficacy endpoint was TMA response during the 26-week treatment period. Participants must meet each TMA response criterion on two separate assessments taken at least 28 days apart; all intervals in which each criterion was met must overlap by at least 1 day to be classified as meeting the primary efficacy endpoint.

[0248] The primary analysis consisted of estimating the proportion of TMA responders among participants treated with ULTOMIRIS. This was performed by calculating the point estimate and 95% CI of the proportion of TMA responders among participants treated with ULTOMIRIS. The CI was based on exact confidence limits using the Clopper-Pearson method.

[0249] For time to TMA response, participants will be assigned as responders at the time of TMA response and censored at the time of discontinuation or at the end of available follow-up if no response has occurred by then. The cumulative incidence of TMA response will be estimated using competing risks survival analysis, considering death as a competing risk. Point estimates and 95% CIs are provided.

[0250] In addition to the primary analysis of TMA response during the 26-week treatment period, TMA response is also summarized over time by presenting the number and proportion of responders with two-sided 95%CI for each time point after baseline.This analysis is carried out using two different approaches.The first approach shows the number and proportion of responders at a specific time point among the participants who are still participating in the study until this time point.The second approach shows the cumulative number and proportion of responders among all participants until a specific time point.This analysis includes important time points such as 26th week and 52nd week.

[0251] Responses to the individual components of the TMA response over the 26-week treatment period are summarized by calculating point estimates of the proportion of responders and their 95% CIs. CIs are based on exact confidence limits using the Clopper-Pearson method. These responses are also summarized over time, with the number and proportion of responders presented along with two-sided 95% CIs for each post-baseline time point. This analysis is performed using two different approaches. The first approach shows the number and proportion of responders at a particular time point among participants who are still in the study up to this point. The second approach shows the cumulative number and proportion of responders up to a particular time point among all participants.

[0252] Response times for each criterion of TMA response will be assessed separately. Participants will be assigned as responders for a particular criterion upon response on that criterion and will be censored at discontinuation or at the end of available follow-up if no response has been received by then.

[0253] The cumulative incidence of the response criteria of interest will be estimated using competing risks survival analysis, considering death as a competing risk. Point estimates and 95% CIs are provided.

[0254] For hematologic response, participants must meet each response criterion on two separate assessments obtained at least 28 days apart; all intervals in which each criterion is met must overlap by at least 1 day to be classified as meeting this efficacy endpoint. Hematologic response during the 26-week treatment period will be summarized by calculating point estimates and 95% CIs for the proportion of responders. CIs are based on exact confidence limits using the Clopper-Pearson method. Responses will also be summarized over time, presenting the number and proportion of responders along with two-sided 95% CIs for each post-baseline time point.

[0255] This analysis is performed using two different approaches. The first approach shows the number and proportion of responders at a particular time point among participants who are still in the study up to this point. The second approach shows the cumulative number and proportion of responders up to a particular time point among all participants. For time to hematological response, participants are assigned as responders at the time of response and are censored at the time of discontinuation or at the end of available follow-up if there is no response by then. The cumulative incidence of hematological response is estimated using competing risks survival analysis, considering death as a competing risk. Point estimates and 95% CIs are provided.

[0256] For hemoglobin response, the following criteria must be met: hemoglobin ≥ 8 g / dL without the need for RBC transfusions. Participants must meet this criterion on two separate assessments obtained at least 28 days apart and should not receive RBC transfusions during this period.

[0257] Hemoglobin maintenance over the 26-week treatment period will be summarized by calculating point estimates of the proportion of responders and 95% CIs. CIs are based on exact confidence limits using the Clopper-Pearson method.

[0258] The number and proportion of responders are presented with two-sided 95%CI for each time point after baseline, and responses are also summarized over time.This analysis is carried out using two different approaches.The first approach shows the number and proportion of responders at a particular time point among the participants who are still participating in the study up to this point.The second approach shows the cumulative number and proportion of responders among all participants up to a particular time point.

[0259] Hematological parameters (hemoglobin, platelets, LDH, and schistocytes) will be summarized at baseline and each post-baseline time point using descriptive statistics for continuous variables and change from baseline in observed values.

[0260] Partial TMA response (participants meet criteria for one or more, but not all, TMA responses during the 26-week treatment period) is summarized by calculating point estimates of the proportion of responders and 95% CIs. CIs are based on exact confidence limits using the Clopper-Pearson method. This includes separate presentations for participants with 1) response to only one component; 2) response to at least one component but not all components; and 3) response to at least two components but not all components.

[0261] Partial TMA responses will also be summarized over time, with numbers and proportions of responders presented along with two-sided 95% CIs for each post-baseline time point.

[0262] The effect of treatment on organ dysfunction will be assessed in the following end-organ systems: renal, cardiovascular, CNS, pulmonary, and GI.

[0263] Renal function parameters (protein / creatinine ratio, serum creatinine, and eGFR) will be summarized at baseline and each post-baseline time point using descriptive statistics for continuous variables and change from baseline in observed values.

[0264] For participants requiring dialysis, the change from baseline in dialysis requirements will be summarized. Analyses will show the number and proportion of participants requiring dialysis over time. Two-sided 95% CIs for proportions will be provided. Participants will be considered dialysis-free at a particular post-baseline time point if they have not received dialysis for at least 5 days prior to that time point.

[0265] The presence of pulmonary hypertension, pleural effusion, pulmonary edema, and pericardial effusion will be summarized. Analyses will show the number and proportion of participants with any of these conditions over time. Two-sided 95% CIs for proportions will be provided. Additionally, the use of ventilation or respiratory support and change over time will be summarized.

[0266] Hypertension will be assessed by measuring blood pressure at each visit as part of vital sign collection, and by assessment according to percentile tables for age, sex, and height, as well as by assessment of the use of concomitant medications to control hypertension. The presence of hypertension will be summarized by presenting the number and proportion of participants whose hypertension status shifted from baseline to post-baseline visits. Selected echocardiographic parameters will be summarized over time.

[0267] The presence of persistent reversible encephalopathy syndrome (PRES) will be summarized, presenting the number and proportion of participants with a shift in the presence of PRES from baseline to post-baseline visits.

[0268] Signs and symptoms of GI involvement such as diarrhea, vomiting, pain, and bleeding will be compiled, and analyses will show the number and proportion of participants with any of these conditions over time.

[0269] The frequency and estimated volume of GI bleeding are also summarized.

[0270] Among participants who achieved a TMA response, TMA recurrence (participants who met TMA diagnostic criteria after achieving a TMA response) was summarized by calculating point estimates and 95% CIs for the proportion of participants with TMA recurrence. CIs are based on exact confidence limits using the Clopper-Pearson method. Analyses summarize the time from the time of response to TMA recurrence. Participants are censored at the end of available follow-up if they have not experienced a recurrence. Kaplan-Meier cumulative distribution curves are generated. Corresponding summary tables present the first, median, and third quartiles of time to TMA recurrence, along with the corresponding two-sided 95% CIs.

[0271] Loss of response occurs when a participant achieves a TMA response and then fails to meet criteria for one or more components of the TMA response at a subsequent visit (which must be confirmed by a second test result at least 24 hours apart). Participants who achieve loss of response are summarized by calculating a point estimate and 95% CI for the proportion of participants with loss of TMA response. CIs are based on exact confidence limits using the Clopper-Pearson method. Duration of response is assessed by analyzing the time from the time of response to loss of TMA response. Participants are censored at the end of available follow-up if they do not experience loss of response. Kaplan-Meier cumulative distribution curves are generated. Corresponding summary tables present the first, median, and third quartiles of time to loss of TMA response, along with the corresponding two-sided 95% CI.

[0272] Survival time is assessed as the number of days from treatment initiation to the death event. Surviving participants are censored at the last available follow-up. Kaplan-Meier cumulative distribution curves are generated. The corresponding summary table presents the first, median, and third quartile of survival time, along with the corresponding two-sided 95% CI.

[0273] Non-relapse mortality is defined as the death of a participant from any cause during the study, excluding death due to progression or recurrence of the underlying disease.

[0274] The cumulative incidence of non-relapse mortality is estimated using competing risk survival analysis, considering relapse-related mortality as a competing risk. Point estimates and 95% CIs are provided. Subjects who do not experience non-relapse mortality are censored at the last available follow-up.

[0275] For platelet response, the following criteria must be met: platelet count ≥ 100,000 / mm3 without transfusion support for the past 7 days. Participants must meet this criterion on two separate assessments obtained at least 28 days apart and should not receive transfusions during this period. Maintenance of platelet count ≥ 100,000 / mm3 during the 26-week treatment period will be summarized by calculating point estimates and 95% CIs for the proportion of responders. CIs are based on exact confidence limits using the Clopper-Pearson method.

[0276] The number and proportion of responders are presented with two-sided 95%CI for each time point after baseline, and responses are also summarized over time.This analysis is carried out using two different approaches.The first approach shows the number and proportion of responders at a particular time point among the participants who are still participating in the study up to this point.The second approach shows the cumulative number and proportion of responders up to a particular time point among all participants who have been enrolled.

[0277] This is a presumptive test and no multiplicity adjustment is performed.

[0278] All safety analyses will be performed in the safety population.

[0279] The definitions of AEs are shown in Table 13.

[0280] [Table 15]

[0281] The incidence of TEAEs, TEAEs leading to withdrawal from study, TEAEs leading to discontinuation of study treatment, drug-related TEAEs, TEAEs during ULTOMIRIS treatment, and SAEs will be summarized. All AEs will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA) version 22 or later and summarized by system organ class (SOC) and preferred term overall, severity, and relationship to treatment. A detailed list of TEAEs, SAEs, related TEAEs, TEAEs during ULTOMIRIS treatment, TEAEs leading to withdrawal from study, and TEAEs leading to discontinuation of study treatment by participant will be provided.

[0282] Clinically significant adverse changes from baseline in physical examination findings will be classified as AEs and analyzed accordingly. Vital signs will be summarized descriptively for changes from baseline at baseline and post-baseline time points.

[0283] Observed values ​​and changes from baseline for clinical chemistry, hematology, and urinalysis will be summarized narratively at baseline and each post-baseline time point. For test 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.

[0284] A data listing for each participant of ECG parameters will be provided. ECGs will be scored and summarized as normal, clinically insignificant abnormal, or clinically significant abnormal. Shifts from baseline to the worst ECG table during the study will be presented for ECG results. Observed values ​​and changes from baseline in ECG intervals (PR, RR, QT, and QTc) will be summarized narratively at baseline and each post-baseline time point. QT intervals will be corrected for heart rate using QTcF.

[0285] The incidence and titers of ADA to ULTOMIRIS at each post-baseline time point are tabulated. Additionally, all confirmed ADA-positive samples will be tested for antibody titers and the presence of neutralizing antibodies to ULTOMIRIS.

[0286] Individual PK / PD data will be collected for all participants.

[0287] A graph of the mean serum ULTOMIRIS concentration-time profile will be generated. Graphs of individual participant serum concentration-time profiles may also be provided. The actual dose and sampling time will be used for all calculations. Descriptive statistics of serum concentration data will be calculated by sampling time, as appropriate. The PD effect of ULTOMIRIS will be evaluated by assessing absolute values ​​and percent change from baseline in serum-free C5 and serum total C5 concentrations over time, as appropriate. Descriptive statistics of PD data will be calculated by sampling time, as appropriate.

[0288] Exploratory biomarker analyses will provide summary statistics of observed values, changes, and percent change from baseline. The relationship between ULTOMIRIS concentrations and exploratory biomarkers, or the correlation between clinical benefit and key exploratory biomarkers, will be assessed graphically. Exploratory analyses and potential relationships between clinical outcomes, PK / PD, genetic profiles, and biomarker levels may be performed and, if assessed, results will be summarized.

[0289] Quality of life will be assessed using the PedsQL for participants aged 2 years and older. Scales (physical functioning, emotional functioning, social functioning, school functioning), summary scores (psychosocial health and physical health), and total scale scores will be calculated based on site instructions. Missing items will also be handled according to instructions: if more than half of the items in any scale are missing, the scale score will not be calculated.

[0290] Scale, summary scores, and total scale scores will be summarized at baseline and each post-baseline time point using descriptive statistics for continuous variables and change from baseline in observed values.

[0291] Hospitalizations will be summarized in tables showing the number and proportion of participants requiring hospitalization, as well as the number, duration, and reason for hospitalization. Additionally, the number and proportion of participants requiring readmission due to TMA, as well as the number of readmissions due to TMA, will be summarized.

[0292] Transfusion requirements will be summarized by presenting the number and proportion of participants requiring RBC and / or platelet transfusions, as well as the number of transfusions.

[0293] Outpatient medical care incidence will be summarized, presenting the number and proportion of participants requiring a physician or emergency room visit and the underlying reasons.

[0294] Exploratory genetics can be performed to investigate genetic variants in genes known to be associated with HSCT TMA and to identify novel genetic variants associated with HSCT TMA, complement dysregulation, or ravulizumab metabolism or efficacy.

[0295] An early analysis of PK / PD data will begin when the 10th participant completes Visit 5 on Day 21. All PK and free C5 data collected in all participants up to that point will be analyzed to confirm the adequacy of the initial dosing regimen to achieve full C5 inhibition. If necessary, the dosing regimen will be adjusted.

[0296] Primary endpoint analyses will be conducted at the start of study treatment and throughout the 26-week treatment period, at an intermediate time point when all participants have been followed, or at the time of withdrawal from the initial 26-week treatment period. The SAP will describe the planned analyses in more detail. A final study analysis will be conducted at the end of the study.

[0297] Example 2: A Phase 3, Open-Label, Randomized, Multicenter Study of Ravulizumab in Adult and Adolescent Participants with Thrombotic Microangiopathy (TMA) After Hematopoietic Stem Cell Transplantation (HSCT) A two-stage, open-label, randomized, multicenter trial of ravulizumab in adolescent (12-17 years) and adult participants with HSCT-TMA will be conducted.

[0298] 1. Purpose The primary objective of this study is to assess the efficacy of ULTOMIRIS plus BSC versus BSC alone in the treatment of adult and adolescent participants with HSCT-TMA via patient TMA response. TMA response was assessed during the 26-week randomized treatment period. A TMA response was defined as meeting all of the following: (a) a platelet count ≥ 50,000 cells / mm3 without transfusion support for the past 7 days, (b) LDH < 1.5 × ULN and absence of schistocytes (if schistocytes were present at baseline), and (c) at least a 50% reduction in proteinuria from baseline. Proteinuria was defined as a protein / creatinine ratio ≥ 0.5 mg / mg. Participants must meet each response criterion on two separate assessments obtained at least 28 days apart; all intervals during which each criterion was met must overlap by at least 1 day.

[0299] Secondary objectives include characterizing the TMA response after treatment with ULTOMIRIS as assessed by: (a) time to TMA response measured in days from Day 1 to the first day the participant meets all criteria for a TMA response; (b) TMA response at Weeks 26 and 52; (c) response and time to response to individual components of the TMA response during the 26-week randomized treatment period; and (d) hematologic response defined as: platelet count ≥ 50,000 cells / mm without transfusion support for the past 7 days. 3 and LDH < 1.5 × ULN and absence of schistocytes (if schistocytes were present at baseline); (e) time to hematologic response; (f) hemoglobin response (ability to maintain hemoglobin ≥ 8 g / dL without transfusion support; (g) partial response (participant meets one or more, but not all, criteria for TMA response); and (h) loss of TMA response (participant achieves TMA response and, at a subsequent visit, fails to meet criteria for one or more components of TMA response, confirmed by a second test result at least 24 hours apart).

[0300] Additional secondary objectives include assessing: (a) improvement in organ dysfunction (change from baseline in TMA-related organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and GI systems at 6 months and 1 year); (b) duration of TMA relapse and response (relapse of TMA during the study (participants meet criteria for TMA diagnosis after achieving a TMA response) and duration of TMA response); (c) overall survival (6 months and 1 year); (d) non-relapse mortality (defined as death of a participant from any cause during the study, but excluding death due to progression or recurrence of underlying disease); and (e) platelet response (platelet response defined as a platelet count ≥ 100,000 / mm3 without transfusion support for the past 7 days). Criteria must be met on two separate assessments obtained at least 28 days apart.

[0301] Pharmacokinetic and pharmacodynamic endpoints will include assessment of the PK / PD of ULTOMIRIS in adult and adolescent participants with HSCT-TMA (e.g., via serum ULTOMIRIS concentrations over time, serum free C5 concentrations over time, and serum total C5 concentrations over time).

[0302] Safety objectives include characterization of the safety profile of ULTOMIRIS in adult and adolescent participants with HSCT-TMA (e.g., via incidence of treatment-emergent AEs and treatment-emergent SAEs, changes from baseline in vital signs and laboratory parameters, incidence of ADAs, and assessment of immunogenicity).

[0303] 2. Overall Study Design This is a two-stage, open-label, randomized, multicenter study of ULTOMIRIS in adolescent (12-17 years) and adult participants with HSCT-TMA. An overview of the study is shown in Figure 11. The activity schedule for the screening and treatment periods (Stage 1 and Stage 2 participants) is shown in Figure 12. The activity schedule for the treatment period (participants receiving ULTOMIRIS salvage therapy) is shown in Figure 13. The activity schedule for the follow-up period is shown in Figure 14.

[0304] In Stage 1, the dosing regimen of patients with HSCT-TMA will be identified. In Stage 2, participants will be randomized to receive either ULTOMIRIS plus best supportive care (BSC) or BSC alone. Eligible participants include adults and adolescents who underwent HSCT within 6 months prior to screening and subsequently developed TMA that does not resolve within 72 hours after discontinuation or adjustment of any medications associated with TMA and / or treatment of any associated underlying precipitating conditions.

[0305] Approximately 184 participants will be enrolled in the trial, including 10 participants in Stage 1 and 174 participants in Stage 2 (including at least 5 Japanese participants).

[0306] The study will be conducted in two stages: a dose-confirmation stage (Stage 1) of 10 participants, followed by a randomized treatment stage (Stage 2) after an appropriate dosing regimen has been confirmed in Stage 1. For all enrolled participants (Stage 1 and Stage 2 participants), the study will consist of three periods: a screening period of up to 7 days, a 26-week treatment period, and a 26-week follow-up period. All participants will receive a BSC for the duration of the study, or for as long as the study director deems necessary.

[0307] During Stage 1, all participants will receive ULTOMIRIS plus BSC. In Stage 2, participants will be randomized 1:1 to receive either ULTOMIRIS plus BSC or BSC alone. The expected duration of study participation for each participant is up to 53 weeks. This includes a screening period (up to 1 week), a treatment period (26 weeks), and a follow-up period (26 weeks). If necessary, a safety follow-up phone call will be conducted 8 weeks after the last dose of ULTOMIRIS. Participants receiving ULTOMIRIS salvage therapy are expected to have a longer study duration, as they will receive 26 weeks of ULTOMIRIS treatment followed by a 26-week follow-up period after the decision to administer ULTOMIRIS salvage therapy is made.

[0308] The 10 participants enrolled in Stage 1 will receive the following weight-based ravulizumab dosing regimen via intravenous (IV) infusion:

[0309] [Table 16]

[0310] For Stage 1 participants, PK and free complement component 5 (C5) data collected over the first 21 days will be analyzed to confirm the appropriateness of the initial dosing regimen to achieve full C5 inhibition. This analysis may result in modifications to the dosing regimen used in Stage 2. If necessary, additional participants may be enrolled in Stage 1 prior to analysis (e.g., if distribution of the first 10 participants is not optimal) or after analysis if the dosing regimen cannot be confirmed.

[0311] Following the dose-confirmation assessment in Stage 1, approximately 174 participants will be enrolled in Stage 2. In Stage 2, participants will be randomized 1:1 on Day 1 to receive either ULTOMIRIS + BSC or BSC alone. Permitted BSC measures include, but are not limited to, transfusion support, hemodynamic support, renal replacement therapy, and continued treatment of relevant comorbidities. Treatment with other complement inhibitors is not permitted during the study. Participants randomized to the ULTOMIRIS + BSC treatment group will be treated with IV ULTOMIRIS for 26 weeks. The ULTOMIRIS dosing regimen in Stage 2 will be either the initial dosing regimen (described above) or a modified dosing regimen (based on the analysis conducted in Stage 1).

[0312] Randomization will be stratified at Stage 2 baseline based on geographic region (East Asia vs. Rest of World) and graft-versus-host disease (GVHD) status at screening (no GVHD, grade I-II GVHD, or grade III-IV GVHD). The criteria outlined by the EBMT, National Institutes of Health (NIH), and Center for International Blood and Marrow Transplant Research (CIBMTR) (Schoemans HM, et al., Bone Marrow Transplant. 2018;53(11):1401-1415) are shown in Table 15 and will be used to assess GVHD grade in this study.

[0313] [Table 17]

[0314] After completing the 26-week treatment period, all participants will enter the follow-up period and remain in the study for 26 weeks without further ULTOMIRIS administration. If extended treatment is clinically indicated (e.g., if a participant begins to demonstrate a TMA response later in the treatment period), the investigator and medical monitor can mutually agree to additional dosing during the follow-up period based on a weight-based dosing regimen.

[0315] For participants who received ULTOMIRIS and discontinued the study, or who received ULTOMIRIS during the follow-up period, a safety follow-up phone call will be conducted 8 weeks after the last dose of ULTOMIRIS if this is later than the date of the End of Study (EoS) visit.

[0316] If a participant who received ULTOMIRIS treatment at any stage meets the criteria for TMA recurrence or loss of TMA response during the follow-up period, the participant may receive ULTOMIRIS retreatment.

[0317] Assessment of early non-response assignment (based on clinical worsening or lack of improvement) will be conducted for both treatment groups, and participants will be assigned early non-response if they meet the defined criteria for clinical worsening or lack of improvement 21 days after treatment initiation. ULTOMIRIS rescue therapy will be permitted for participants assigned as early non-responders who are randomized to the BSC-only treatment group. These participants will enter a 26-week ULTOMIRIS treatment period, followed by a 26-week follow-up period, after the decision to administer ULTOMIRIS rescue therapy is made.

[0318] 3. Study population Approximately 184 participants will be enrolled in the trial, including 10 participants in Stage 1 and 174 participants in Stage 2 (including at least 5 Japanese participants).

[0319] Participants were eligible to enroll in the study only if they met all of the following criteria: 1. Participants must be 12 years of age or older at the time of signing the Informed Consent Form (ICF) or assent form; 2. Adult and adolescent participants who have undergone HSCT within the past 6 months at screening; 3. TMA diagnosis based on all of the following criteria occurring simultaneously: (a) new-onset thrombocytopenia or platelet transfusion refractoriness, where new-onset thrombocytopenia is a platelet count ≤ 50,000 / mm 3 Transfusion refractoriness was defined as a new decrease in platelet count to 10 × ... 9(b) new-onset anemia (defined as a new decrease in hemoglobin to ≤8 g / dL) or increased transfusion requirements (defined as the need for more frequent transfusions to maintain hemoglobin ≥8 g / dL); (c) any of the following markers of hemolysis: LDH >1.5 × ULN or the presence of schistocytes in ≥2 high-power fields (HPF) on a peripheral blood smear; (d) proteinuria on spot urine testing, where proteinuria is defined as a protein / creatinine ratio ≥0.5 mg / mg. The presence of proteinuria must be confirmed by a second measurement (two measurements at least 4 hours apart); (e) the presence of hypertension, defined as the presence of any one of three conditions: systolic blood pressure ≥ 139 mmHg or diastolic blood pressure > 80 mmHg in two consecutive measurements at least 1 hour apart; the need for new antihypertensive medication after HSCT (for participants not taking antihypertensive medication before HSCT), or for participants with underlying hypertensive disease, a change in antihypertensive regimen or the addition of a new antihypertensive medication required to treat hypertension; 4. Participants must have HSCT-TMA that persists (lasts at least 72 hours after administration of the inducing agent / condition) despite initial management of the inducing condition (discontinuation or dose reduction of the causative agent (e.g., CNI), treatment of any underlying infection, or treatment of underlying GVHD); 5. Weight ≥ 30 kg at screening; 6. Male or Female. Contraceptive use by males or females is consistent with local regulations regarding contraceptive methods for those participating in clinical research. Male participants agree to use contraception during treatment and for at least 8 months after the final dose of ULTOMIRIS and to refrain from donating sperm during this period. Female participants were eligible if they were not pregnant, not breastfeeding, and met at least one of the following criteria: not a woman of childbearing potential (WOCBP) or a WOCBP, and using highly effective and acceptable contraception during treatment and for at least 8 months after the last dose of ULTOMIRIS. WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose of ravulizumab; 7. Participants must be vaccinated against meningococcal infections, if clinically possible, according to institutional guidelines for immune reconstitution after HSCT. Participants under 18 years of age must be revaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae, if clinically possible, according to institutional guidelines for immune reconstitution after HSCT. All participants will receive prophylactic antibiotic coverage according to institutional post-transplant infection prevention guidance, including coverage against N. meningiditis, for at least 2 weeks after meningococcal vaccination. Participants unable to receive meningococcal vaccination must receive antibiotic prophylaxis coverage against N. meningiditis throughout the treatment period and for 8 months after the final dose of ULTOMIRIS; 8. Able to give signed informed consent or assent.

[0320] Participants will be excluded from the study if they meet any of the following criteria: 1. Known familial or acquired "A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13" (ADAMTS13) deficiency (activity <5%); 2. Known Shiga toxin-associated hemolytic uremic syndrome (ST-HUS) as evidenced by a positive test for Shiga toxin or culture of Shiga toxin-producing bacteria; 3. Positive direct Coombs test; 4. Diagnosis or suspicion of disseminated intravascular coagulation (DIC) according to the International Society on Thrombosis and Haemostasis (ISTH) scoring criteria as shown in Taylor et al., Thromb Haemost. 2001;86(5):1327-1330 and Tables 2-3; 5. Known bone marrow / transplant failure; 6. Diagnosis of veno-occlusive disease (VOD) according to the European Society for Blood and Marrow Transplantation (EBMT) criteria set out in Mohty M, et al., Bone Marrow Transplant. 2016;51(7):906-912 and Table 16, regardless of severity; 7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titers or documented negative HIV-1 / HIV-2 test within 6 months prior to screening); 8. Unresolved meningococcal disease; 9. Presence or suspicion of sepsis (treated or untreated) within 7 days prior to screening; 10. Pregnant or breastfeeding; 11. Hypersensitivity to mouse proteins or one of the excipients of ravulizumab; 12. Any medical or psychological condition that, in the opinion of the investigator or sponsor, may increase the participant's risk from participating in the study or may confound the outcome of the study; 13. Previous or current treatment with a complement inhibitor; 14. Participation in another interventional trial or use of an experimental treatment (excluding use of currently approved medications being investigated alone or in combination for treatment of underlying disease; conditioning regimens; GVHD prophylaxis, infection prophylaxis, or post-transplant infection treatment) within 30 days prior to initiation of ULTOMIRIS on Day 1 of this study, or within 5 half-lives of the investigational product, whichever is greater.

[0321] [Table 18]

[0322] 4. Study Intervention A study intervention is defined as an investigational intervention, marketed product, placebo, or medical device intended to be administered to study participants according to the study protocol. Details regarding ULTOMIRIS are provided in Table 5.

[0323] This study will be conducted in an open-label manner. To minimize bias, participants will be randomized on Day 1 after the investigator confirms their eligibility. Randomization will be stratified by region (East Asia vs. Rest of the World) and GVHD status at screening (no GVHD, grade I-II GVHD, or grade III-IV GVHD, where grades are assigned using the International Bone Marrow Transplant Registry Severity Index for grading acute GVHD as shown in Table 15). Participants will be randomized 1:1 to receive ravulizumab plus BSC or BSC alone. Randomization will be performed centrally using Interactive Response Technology (IRT).

[0324] To prevent potential bias due to rescue in the assessment of the primary endpoint, early assignment assessment of non-response based on clinical worsening or no improvement will be performed for both treatment groups.

[0325] During this study, participants will receive all ULTOMIRIS doses directly from the study director or designee under medical supervision at the study site. The date and time of each dose administered at the clinic will be recorded on the source documentation and case report form (CRF). The dose of study intervention and the identity of the study participant will be verified at the time of administration by a member of study site staff other than the person administering the study intervention.

[0326] In this study, all participants will receive BSC as baseline therapy. BSC will be determined by the study director according to institutional practices and participant characteristics. BSC measures include, but are not limited to, the following: (a) Transfusion Support: Transfusion support will be provided as needed based on the participant's clinical status, in accordance with institutional guidelines. In general, according to the Joint United Kingdom (UK) Blood Transfusion and Tissue Transplant Services Expert Advisory Committee (JAPC), transfusion support is recommended as follows: Red blood cell transfusions should be considered in participants with hemoglobin ≤7 g / dL or in participants with symptomatic anemia (e.g., dyspnea and / or tachycardia) with hemoglobin ≤8 g / dL, and should be ≥10 x 10 9 With a transfusion trigger of 20 × 10 cells / L, participants should receive prophylactic platelet transfusions as needed. 9 An increase in the platelet transfusion threshold to 100 / L is warranted in participants who are febrile and / or receiving antibiotic therapy for suspected bacterial or fungal infection. Participants receiving RBC or platelet transfusions require additional administration of ravulizumab, (b) corticosteroids, (c) dialysis, and antihypertensive medications. Supportive care measures will be recorded on the appropriate CRF.

[0327] Supportive care of the underlying disease (e.g., HSCT, GVHD) is permitted during the course of the study. The use of currently approved medications is being investigated alone or in combination for treatment of the underlying disease, conditioning regimen, GVHD prophylaxis regimen, GVHD treatment, infection prophylaxis, or infection treatment. The investigator may consider other concomitant medications on a case-by-case basis.

[0328] The following are not permitted: (a) eculizumab or other agents acting on the complement pathway, (b) use of PE is prohibited during the study, (c) use of rituximab, (d) IV immunoglobulin (Ig) (unless there is unrelated medical need, such as hypergammaglobulinemia), (e) defibrotide (except for participants with VOD confirmed to have developed during the study), and (f) use of experimental interventions or therapies.

[0329] Participants in the BSC-only treatment group are permitted rescue with ULTOMIRIS. The date and time of rescue medication administration must be recorded.

[0330] The appropriateness of the proposed dosing regimen will be confirmed by initial PK / PD analysis of the first 10 participants enrolled in Stage 1. If the proposed dosing regimen does not result in the expected degree of free C5 inhibition, the dosing regimen will be modified (increased) for subsequent participants according to the PK / PD data.

[0331] After the study ends, participants will no longer receive ULTOMIRIS. After the final study visit, participants will return to their physician's care.

[0332] 5. Discontinuation of study intervention In rare cases, participants may need to permanently discontinue the study intervention (definitive discontinuation). Participants should consider discontinuing the intervention if any of the following occur during the study: (1) a severe hypersensitivity reaction, (2) use of unauthorized medications, (3) pregnancy or plans to become pregnant, or (4) if it is deemed necessary for the participant.

[0333] If the study intervention is definitively discontinued, every effort should be made to have the participant continue with study visits according to the safety follow-up activity schedule. If the participant does not agree to continue with the activity schedule visits, the following activities must be completed: (1) the early discontinuation (ED) assessment to be conducted is indicated on the activity schedule, (2) the site must follow the participant for at least 8 weeks after the last dose of ULTOMIRIS via safety phone to collect any AEs and / or concomitant medications, and (3) information must be collected regarding vital status at 6 months and 1 year after the first dose of ULTOMIRIS (Stage 1 participants) or after randomization (Stage 2 participants). If the participant's vital status is not available at the time of discontinuation, the site must attempt to collect the status (e.g., from public records or by telephone).

[0334] Every effort should be made to confirm that participants are willing to participate in the study before conducting screening procedures. Study staff should notify Alexion and its site monitors of any study discontinuation as soon as possible. The reason for participant discontinuation should be recorded on the source documents and CRF.

[0335] Participants may withdraw from the study at any time at their own request or may be withdrawn at any time at the discretion of the study director for safety, behavioral, compliance, or administrative reasons.

[0336] When discontinuing the study, an ED visit should be conducted, if possible, as indicated in the Schedule of Activities. If the participant does not consent to an ED visit, the site will follow the participant for at least 8 weeks after the last dose of ULTOMIRIS via safety phone calls to collect any AEs and / or concomitant medications. Additionally, information on vital status will be collected at 6 months and 1 year after the first dose of ULTOMIRIS (Stage 1 participants) or after randomization (Stage 2 participants). If the participant's vital status is not available at the time of discontinuation, the site will attempt to collect the status (e.g., via public records or telephone). The participant will be permanently discontinued from both the study intervention and the current study. 7.3.

[0337] Participants are considered lost to follow-up if they repeatedly fail to return for scheduled visits and cannot be contacted by the study site.

[0338] 6. Test Assessment and Procedures In Stage 1, ULTOMIRIS will be administered by IV infusion according to the dosing regimen in Table 17. The dose confirmation analysis will occur when the 10th participant completes Visit 5 on Day 21 and will include all PK / PD data collected to that point. This analysis will confirm the adequacy of the initial and additional dosing regimens to achieve and maintain complete suppression of C5 throughout the dosing interval. This analysis may result in adjustments to the dosing regimens of Stage 1 participants and those enrolled in Stage 2. Stage 1 participants will receive the adjusted dosing regimen for the remainder of the treatment period.

[0339] [Table 19]

[0340] If extended treatment is clinically indicated (e.g., if the participant begins to demonstrate a TMA response later in the treatment period), the Investigator and Medical Monitor may mutually agree to additional dosing during the follow-up period based on the weight-based dosing regimen in Table 17. Unscheduled visits may be arranged as needed for ULTOMIRIS administration. The following assessments must be performed at any unscheduled visit where ULTOMIRIS is administered: (a) urine pregnancy test (WOCBP only), simplified physical exam, PK / PD blood sample collection, vital signs, laboratory tests, C5b-9 blood sample collection, and C5b-9 urine sample collection.

[0341] Additional doses of ULTOMIRIS are permitted according to the criteria outlined in Table 18.

[0342] [Table 20]

[0343] Unscheduled visits may be arranged if needed for additional ULTOMIRIS doses. The following assessments must be performed at any unscheduled visit where ULTOMIRIS is administered: urine pregnancy test (WOCBP only), simplified physical exam, PK / PD blood sample collection, vital signs, laboratory tests, C5b-9 blood sample collection, and C5b-9 urine sample collection.

[0344] Participants entering Stage 1 will receive treatment for a 26-week treatment period, followed by a 26-week follow-up period where they are expected to discontinue treatment. Participants may receive ULTOMIRIS during the follow-up period if they meet the criteria for TMA relapse or loss of TMA response, the investigator believes the participant may benefit from retreatment, initiates a discussion with the medical monitor, and provides a medical justification.

[0345] If retreatment is deemed necessary, participants will continue to follow their activity schedule as planned. Participants will receive a weight-based dose of ULTOMIRIS according to the dosing regimen described in Table 17.

[0346] Unscheduled visits may be arranged as needed for ULTOMIRIS administration. The following assessments must be performed at any unscheduled visit where ULTOMIRIS is administered: urine pregnancy test (WOCBP only), simplified physical exam, PK / PD blood sample collection, vital signs, laboratory tests, C5b-9 blood sample collection, and C5b-9 urine sample collection.

[0347] Stage 2 participants randomized to ULTOMIRIS + BSC will receive the appropriate dosing regimen confirmed by the Stage 1 PK / PD analysis. If extended treatment is clinically indicated (e.g., if the participant begins to demonstrate a TMA response later in the treatment period), the investigator and medical monitor may mutually agree to additional dosing during the follow-up period based on the weight-based dosing regimen in Table 17. Unscheduled visits may be arranged as needed for ULTOMIRIS administration. The following assessments must be performed at any unscheduled visit where ULTOMIRIS is administered: urine pregnancy test (WOCBP only), simplified physical examination, PK / PD blood sample collection, vital signs, laboratory tests, C5b-9 blood sample collection, and C5b-9 urine sample collection.

[0348] Assessment of early assignment for non-response (based on clinical worsening or no improvement) to both treatment arms will be conducted, and rescue therapy with ravulizumab will be permitted for participants assigned as early non-responders who are randomized to the BSC-only treatment arm.

[0349] Participants were assigned early nonresponse if they met any of the following criteria: (1) defined clinical deterioration, i.e., the presence of two or more of the following: increase in LDH >25% compared to baseline, decrease in platelets >25% compared to baseline, decrease in hemoglobin >10% compared to baseline, or platelet count ≥20,000 cells / mm ; 3 (1) an incremental increase in platelet transfusion requirements to maintain hemoglobin ≥ 8 g / dL, an incremental increase in RBC transfusion requirements to maintain hemoglobin ≥ 8 g / dL, a doubling of serum creatinine from baseline, or (2) no improvement after Day 21, as determined by a <10% increase in platelet count relative to baseline. Participants assigned as early non-responders and receiving salvage ULTOMIRIS will receive the ULTOMIRIS dosing regimen confirmed in Stage 1 and follow the activity schedule outlined for participants receiving salvage ULTOMIRIS.

[0350] Additional administration of ULTOMIRIS will be permitted for participants treated with ULTOMIRIS in Stage 2. The criteria for additional administration will be the same as those for Stage 1.

[0351] Unscheduled visits may be arranged if needed for additional ULTOMIRIS doses. The following assessments must be performed at any unscheduled visit where ULTOMIRIS is administered: urine pregnancy test (WOCBP only), simplified physical exam, PK / PD blood sample collection, vital signs, laboratory tests, C5b-9 blood sample collection, and C5b-9 urine sample collection.

[0352] Participants entering Stage 2 will receive treatment for a 26-week treatment period, followed by a 26-week follow-up period where they are expected to discontinue treatment. Participants may receive ULTOMIRIS during the follow-up period if they meet the criteria for TMA relapse or loss of TMA response. Retreatment dosing for Stage 2 will be the same as for Stage 1.

[0353] If retreatment is deemed necessary, participants will continue to follow their activity schedule as planned. Participants will receive a weight-based dose of ULTOMIRIS according to the dosing regimen described in Table 17.

[0354] Unscheduled visits may be arranged as needed for ULTOMIRIS administration. The following assessments must be performed at any unscheduled visit where ULTOMIRIS is administered: urine pregnancy test (WOCBP only), simplified physical exam, PK / PD blood sample collection, vital signs, laboratory tests, C5b-9 blood sample collection, and C5b-9 urine sample collection.

[0355] Participants' relevant medical history (including TMA diagnosis), treatment history, and family history of relevant diseases, including previous and concurrent conditions / disorders, will be assessed at screening by the investigator and recorded on source documents and CRFs.

[0356] Information collected includes the following: transplant modality, origin of hematopoietic stem cells, indication for transplant, medical history of previous HSCT, conditioning regimen, presence of GVHD, engraftment status, and any other relevant information regarding transplant complications or the peri-transplant period.

[0357] The number and amount of transfusions during the screening period will be recorded on the Transfusion History CRF. Information collected will include the date of transfusion, number of units, and amount of each blood component administered. Transfusions during the study must be recorded on the Transfusion CRF. Information collected will include the date of transfusion, number of units, and amount of each blood component administered.

[0358] Due to its mechanism of action, use of ULTOMIRIS increases participants' susceptibility to infection with N. meningitidis. To reduce the risk of infection, participants should be vaccinated against N. meningitidis, if clinically feasible. Vaccines against serotypes A, C, Y, W135, and B, where available, are recommended to prevent common pathogenic meningococcal serotypes.

[0359] Because HSCT results in immunosuppression due to ablative therapy, concomitant medications, or underlying disease, vaccine antibody titers will decline 1 to 4 years after transplant unless patients are revaccinated. Institutions are encouraged to follow relevant immune reconstitution guidelines or local practice guidelines regarding immune reconstitution for revaccination of participants who have undergone HSCT.

[0360] Participants will receive antibiotic prophylaxis for meningococcal infection for at least two weeks after vaccination. Vaccination may not be sufficient to prevent meningococcal infection. Official guidance and local practice regarding the appropriate use of prophylactic antibiotics should be considered. All participants should be monitored for early signs of meningococcal infection and, if infection is suspected, should be evaluated promptly and treated with appropriate antibiotics as needed. Participants who cannot receive vaccination must receive antibiotic prophylaxis throughout the treatment period and for eight months after the final dose of ULTOMIRIS.

[0361] If clinically feasible, participants under the age of 18 years will also be vaccinated against Hib and S. pneumoniae according to appropriate immune reconstitution guidelines, and participants who have undergone HSCT must be revaccinated. Participants who cannot be vaccinated will receive antibiotic prophylaxis throughout the treatment period and for 8 months after the last dose of ULTOMIRIS. Vaccination status and administration of any vaccines, including those against N. meningitidis, Hib, and S. pneumoniae, will be recorded on the CRF.

[0362] 7.Effectiveness Assessment Laboratory assessments to determine TMA response will be conducted according to the activity schedule and assessed against predefined criteria for TMA response.

[0363] For time to TMA response, partial TMA response, loss of TMA response, and TMA relapse, relevant clinical laboratory assessments will be performed according to the activity schedule and assessed against predefined criteria for TMA response.

[0364] Clinical laboratory assessments will be performed according to the activity schedule and assessed against predefined criteria for hematological response.

[0365] Participant vital status will be collected throughout the study. Information on any deaths occurring during the study and the cause of death will be collected.

[0366] Changes from baseline in organ dysfunction (end-organ involvement, i.e., renal, cardiovascular, CNS, pulmonary, GI) will be described for participants in each randomized treatment group and for participants who received salvage therapy with ULTOMIRIS. The following parameters for assessing organ dysfunction will be assessed:

[0367] Renal dysfunction: Renal status will be assessed by measuring the protein / creatinine ratio, serum creatinine, and calculating the estimated glomerular filtration rate (eGFR). For participants requiring dialysis, the change from baseline in dialysis requirements will be recorded.

[0368] Cardiopulmonary Involvement: Chest x-ray, electrocardiogram (ECG), and echocardiogram will be performed to assess for the presence of signs of pulmonary or cardiovascular involvement (including but not limited to pulmonary hypertension, pleural effusion, and pulmonary edema). Additionally, the use of ventilation or respiratory support will be reported on the participant's CRF along with relevant oximetry.

[0369] Hypertension will be assessed by measuring blood pressure at each visit as part of vital signs collection and by analysis of concomitant medications to control hypertension.

[0370] Central nervous system involvement: Participants will be assessed at each visit for signs of persistent reversible encephalopathy syndrome (PRES), including headache, confusion, blurred vision, and seizures. If PRES is suspected, magnetic resonance imaging (MRI) will be performed to confirm.

[0371] Gastrointestinal involvement: Participants will be assessed for signs and symptoms of GI involvement (e.g., diarrhea, vomiting, pain, and bleeding). The frequency and estimated amount of GI bleeding will be recorded on the participant's CRF.

[0372] A complete physical examination includes, at a minimum, an assessment of the following organ / body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, chest, heart, abdomen, extremities, musculoskeletal, and neurological status.

[0373] The brief physical examination will include, at a minimum, a body system-related examination based on the investigator's judgment and the participant's symptoms.

[0374] The study director will pay particular attention to clinical signs associated with prior serious illness. Additional physical examinations will be performed as medically indicated during the study, at the discretion of the study director. Height and weight will be measured and recorded.

[0375] Vital signs will be monitored: oral temperature (°C or °F), heart rate, respiratory rate, systolic and diastolic blood pressure (mmHg), and pulse oximetry will be assessed.

[0376] Blood pressure and heart rate measurements will be assessed while participants are seated using fully automated devices. Manual methods will be used only if automated devices are not available. Prior to blood pressure and heart rate measurements, participants will rest for at least 5 minutes in a quiet environment free of distractions (e.g., television, cell phones). Ideally, the same arm will be used for measurements for each participant. O2 saturation (%) will be collected using pulse oximetry. Vital signs will be collected pre- and post-dose at ULTOMIRIS dosing visits.

[0377] A single 12-lead electrocardiogram will be performed to obtain heart rate, PR, QRS, QT, and QTc intervals. (The QT interval will be corrected for heart rate using the Fridericia formula [QTcF].) Participants must be supine approximately 5-10 minutes before ECG collection and remain supine but awake during ECG collection. The Investigator or Co-Investigator is responsible for reviewing the ECG to assess whether it is within normal limits and to determine the clinical significance of the results. These assessments will be recorded on the source documents and CRF.

[0378] Both posteroanterior and lateral chest x-rays will be obtained during the participant's full inspiration at the time points specified in the SoA. The Investigator or designated Subinvestigator is responsible for reviewing the x-rays to assess the clinical significance of the results. These assessments will be recorded on the source documents and CRF. Particular attention will be paid to determining whether signs of pulmonary or cardiovascular involvement (including, but not limited to, pulmonary hypertension, pleural effusion, and pulmonary edema) are present.

[0379] Transthoracic echocardiography will be performed according to the schedule of activities. The Study Principal Investigator or designated Sub-Study Principal Investigator is responsible for reviewing the echocardiogram to assess the clinical significance of the results. These assessments will be recorded in the source documents and on the CRF. Particular attention will be paid to determining whether signs of pulmonary hypertension (right ventricular dysfunction, tricuspid regurgitation) or serositis (pericardial effusion) are present.

[0380] If a participant has symptoms of PRES at study entry or develops symptoms during the study, an MRI will be performed to look for bilateral white matter abnormalities in vascular basins consistent with PRES. If the presence of PRES is confirmed, an MRI will be performed at the time of symptom resolution and at the EoS / ED visit. Additional MRIs may be performed during the study.

[0381] The Investigator must review the laboratory reports, document this review, and record any clinically relevant changes that occurred during the study in the AE section of the CRF. Laboratory reports must be submitted with the source documentation. Clinically significant abnormal laboratory findings are not related to the underlying disease unless the Investigator determines that the participant's condition is more severe than expected.

[0382] All laboratory tests with values ​​considered clinically significant abnormal during study participation or within 8 weeks after the final dose of study intervention will be repeated until the values ​​return to normal or baseline or are no longer considered clinically significant by the study director or medical monitor. If such values ​​do not return to normal / baseline within a time period deemed reasonable by the study director, an etiology will be identified. All laboratory assessments required by the protocol will be performed in accordance with the test manual and activity schedule.

[0383] Human immunodeficiency virus testing for HIV-1 and HIV-2 will be required for all participants prior to enrollment. A confirmed history of negative HIV-1 and HIV-2 tests within 6 months prior to screening will be sufficient. HIV-positive participants will not be enrolled.

[0384] Pregnancy testing will be performed as described in the assessment schedule.

[0385] Previous medications and / or vaccines (including vitamins, herbal preparations, and those described in the Exclusion Criteria and Procedures (therapeutic interventions such as surgery / biopsy or physical therapy)) administered or received by participants within 30 days prior to Day 1 (Stage 1) or within 30 days prior to randomization (Stage 2) will be recorded. See Inclusion / Exclusion Criteria for pre-medication considerations related to eligibility. Additionally, certain medications will not be allowed during the study. Information regarding HSCT procedures will be recorded on the HSCT Information CRF page.

[0386] Previous medications and procedures will be recorded in the participant's source document / medical record and CRF, along with the reason for use (indication), dates of administration including start and end dates (if the participant is expected to continue the medication during the study, it should be recorded as continuous), and administration information including dose and frequency.

[0387] Concomitant medications (including medicines, vitamins, herbal preparations, or supplements) and procedures received from Day 1 onward (for Stage 1), after randomization for participants in the BSC-only treatment group (Stage 2), or after initiation of the ULTOMIRIS IV infusion for participants in the ULTOMIRIS + BSC treatment group (Stage 3). This includes supportive care medications and procedures, antibiotic prophylaxis, GVHD prophylaxis or treatment, and vaccinations. At each study visit, participants will be asked about any new medications or non-pharmacological therapies or changes in concomitant medications and non-pharmacological therapies since their last visit. Concomitant medications will be recorded in the participant's source document / medical record and CRF, along with the reason for use (indication), dates of administration including start and end dates (if the participant is expected to continue the medication during the study, it should be recorded as ongoing), and administration information including dose and frequency.

[0388] Concomitant medications deemed necessary for the participant's care during the study or for the treatment of AEs may be administered at the investigator's discretion, along with other medications, other than those listed as unauthorized medications. However, it is the investigator's responsibility to ensure that all medication details are fully recorded in the participant's source documents / medical record and CRF page.

[0389] Data regarding blood component transfusions, including the date of transfusion, type of blood component administered, number of units, and amount, are recorded on the transfusion CRF page.

[0390] 8. Adverse Events An adverse event (AE) is an untoward medical occurrence in a participant that is temporally related to the use of a study intervention, whether or not considered related to the study intervention. Thus, an adverse event can be an untoward and unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally related to the use of the study intervention. Events that meet the definition of an AE are listed in Table 9. Events that do not meet the definition of an AE are listed in Table 10.

[0391] If an event is not an AE according to the above definition, it is not a serious adverse event (SAE), even if the criteria for seriousness are met (e.g., hospitalization due to signs / symptoms of the disease under study, death due to disease progression). An SAE is defined as any untoward medical occurrence that results in one of the events shown in Table 11 at any dose.

[0392] A suspected unexpected serious adverse reaction (SUSAR) is defined as a serious event not listed in the Investigator's Brochure and identified by the Investigator as related to the study product or investigational procedures. 21 CFR 312.32 and the EU Clinical Trials Directive 2001 / 20 / EC and related detailed guidance or national regulatory requirements of participating countries require the reporting of SUSARs. Suspected unexpected serious adverse reactions will be reported to the national competent authority and IRB / IEC, if applicable.

[0393] All AEs will be reported by the participant (or, where appropriate, the caregiver, representative, or legally authorized representative of the participant) to the Study Principal Investigator or qualified designee. The Study Principal 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 AEs that continue to be considered serious, related to the study intervention or procedure, or that cause the participant to discontinue the study intervention.

[0394] All AEs and SAEs will be collected from the time of signing the ICF / consent form until the ED / EoS visit or 8 weeks after the last dose of ULTOMIRIS (whichever is later). All SAEs will be recorded and reported immediately and, under no circumstances, should this exceed 24 hours. The investigator is under no obligation to proactively solicit AE or SAE data after the end of study participation.

[0395] For recording and follow-up of AEs and / or SAEs, intensity will be assessed. An event is defined as "serious" if it meets at least one of the predefined outcomes as described in the SAE definition, not if it is rated as severe. The investigator will assess the intensity of each AE and SAE reported during the study and will use the results in accordance with the National Cancer Institute CTCAE published on November 27, 2017. v5.0 and assign it to one of the following categories: (a) Grade 1: mild (awareness of signs or symptoms but easily tolerated), (b) Grade 2: moderate (discomfort that interferes with normal activities), (c) Grade 3: severe (incapacitating, unable to perform normal activities), (d) Grade 4: life-threatening, or (e) Grade 5: fatal.

[0396] The investigator is responsible for assessing the relationship between the study intervention and the occurrence of each AE or SAE. For all AEs (both non-serious and serious), the investigator's causality assessment must be provided. This assessment must be recorded on the CRF 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 another more likely etiology; it may be due to an underlying or concurrent disease, a comorbid condition, a concomitant 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 an alternative possible etiology. The event corresponds to the known pharmacological profile of the study intervention. There is improvement on discontinuation and / or recurrence on rechallenge.

[0397] The Investigator will use clinical judgment to determine the 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. For marketed products, the Investigator will also refer to the Investigator Brochure (IB) and / or product information in their assessment. For each AE / SAE, the Investigator must document in the medical record that they have reviewed the AE / SAE and provided a causality assessment. There may be cases where an SAE occurs and the Investigator has minimal information to include in the initial report to Alexion. However, it is very important that the Investigator always assess the causality of all events before initially submitting SAE data to Alexion. The Investigator may change their opinion regarding causality in light of follow-up information and send an SAE follow-up report with an updated causality assessment. The causality assessment is one of the criteria used in determining regulatory reporting requirements.

[0398] 9. Pharmacokinetics and Pharmacodynamics Blood samples will be collected to measure serum ULTOMIRIS, free C5, and total C5 concentrations at the time points specified in the activity schedule. The timing of sampling may be modified over the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. Samples collected for PK / PD analysis may also be used to evaluate safety or efficacy aspects related to concerns that arise during or after the study.

[0399] Instructions for collection and handling of biological samples, including blood volume requirements, are provided in the test manual. Record the actual date and time (24-hour clock) of each sample.

[0400] For all Stage 1 participants, Stage 2 participants randomized to the ULTOMIRIS + BSC treatment group, participants receiving salvage ULTOMIRIS therapy, and participants receiving retreatment with ULTOMIRIS: Pre-dose PK and PD blood samples will be collected within 90 minutes prior to the administration of ULTOMIRIS at the visit specified in the Assessment Schedule. Pre-dose blood samples may be collected from the venous access created for the dose infusion prior to administration of the dose. Post-dose PK and PD blood samples will be collected within 60 minutes after the completion of the ULTOMIRIS infusion. Post-dose blood samples will be collected from the participant's contralateral, non-infused arm. PK / PD blood samples at non-dose visits can be collected at any time during the visit.

[0401] For participants randomized to the BSC-only treatment arm in Stage 2: PD blood samples (free C5 and total C5) may be collected at any visit specified in the Assessment Schedule. In the event of an unscheduled visit, PK and PD blood samples will be collected as soon as possible. Pre-dose and post-dose PK and PD samples will be collected for all additional doses of ULTOMIRIS administered.

[0402] 10. Genetics For participants who sign an additional optional consent, whole blood and oral swab samples for exploratory genetics will be collected at the time points specified in the assessment schedule. Exploratory genetics may be performed to examine genetic variants in genes that may be associated with complement dysregulation or metabolism or with ULTOMIRIS efficacy.

[0403] 11. Biomarkers Blood and urine samples for biomarker studies will be collected from all participants at the times specified in the assessment schedule. Whenever possible, collection of biomarker samples during the study, including samples collected during the screening period, will occur before participants receive blood transfusions or dialysis.

[0404] Biomarkers measured include, but are not limited to, assessment of: (a) vascular inflammation (e.g., shedding of tumor necrosis factor receptor 1 [TNF-R1]), (b) endothelial injury and / or activation (e.g., shedding of thrombomodulin and vascular cell adhesion molecule 1 [VCAM-1]), renal damage (e.g., cystatin C), and (d) complement proteins and complement activation pathway products.

[0405] 12. Immunogenicity Assessment Anti-drug antibodies will be assessed in serum samples collected pre-dose (within 90 minutes before the start of ULTOMIRIS IV infusion) from all participants at the time points specified in the assessment schedule. In addition, serum samples will be collected at the final visit from participants who discontinue ULTOMIRIS or withdraw from the study.

[0406] Serum samples will be screened for antibodies that bind to ULTOMIRIS, and titers of confirmed positive samples will be reported. Other analyses can be performed to further characterize the immunogenicity of ULTOMIRIS.

[0407] Detection and characterization of antibodies to ULTOMIRIS will be performed using validated assays. Samples collected for detection of antibodies to ULTOMIRIS will also be evaluated for ULTOMIRIS serum concentrations to enable interpretation of antibody data. Confirmed antibody-positive samples will be further evaluated for antibody titer and the presence of neutralizing antibodies.

[0408] 13. Exploratory Assessment The EuroQoL 5-Dimensions 5-Level (EQ-5D-5L) is a self-assessment standardized instrument for measuring health-related quality of life (QoL) and is used across a wide range of health conditions. A sample QoL is shown in Figure 15. EQ The 5D 5L will be administered electronically by the study director or qualified site staff at the visit specified in the activity schedule and prior to any other study procedures.

[0409] 14.Statistical considerations The primary analysis will compare the ravulizumab + BSC treatment group with the BSC only treatment group based on the following null and alternative hypotheses. Hypothesis testing will be two-sided, with a significance level of 0.05. The null and alternative hypotheses for the primary analysis are as follows: H0:P rav+BSC =P BSC vs. H A :P rav+BSC ≠P BSC In the formula, P rav+BSC is the proportion of participants in the ravulizumab + BSC treatment group who achieved a TMA response, P BSC is the proportion of participants in the BSC-only treatment group who achieved a TMA response.

[0410] The primary analysis will compare the proportion of participants randomized to ULTOMIRIS plus BSC treatment who achieved a TMA response during the 26-week treatment period with those randomized to BSC treatment alone, based on a two-sided Fisher's exact test conducted at a 5% significance level. A sample size of 174 (87 participants per treatment group) will have 90% power to detect a statistically significant (p ≤ 0.05) treatment difference of 25 percentage points in the proportion of responders, assuming a responder rate of 30% for BSC alone and 55% for ULTOMIRIS plus BSC, at a two-sided significance level of 0.05.

[0411] The analysis sets are defined in Table 19. These analysis set definitions apply to participants enrolled in both Stage 1 and Stage 2 of the study. However, data from each stage will be analyzed and reported separately, except for selected safety analyses where results from both stages may be combined.

[0412] [Table 21]

[0413] Efficacy analyses will be performed in the Full Analysis Set (FAS). The primary efficacy endpoint analysis and selected secondary endpoint analyses will also be performed in the per-protocol population. Safety analyses will be performed in the safety population. Pharmacokinetic and PD analyses will be performed in all participants who receive at least one dose of ULTOMIRIS and have evaluable PK or PD data.

[0414] The statistical methods described in this section are further detailed in a separate Statistical Analysis Plan (SAP). Summary statistics will be calculated and displayed by treatment group, and by visit, where applicable, and by stratification factor, where appropriate. Descriptive statistics for continuous variables will include, at a minimum, number of participants, mean, standard deviation, minimum, median, and maximum. For categorical variables, frequencies and percentages will be presented. Graphical displays will be provided where appropriate.

[0415] Analyses will be performed using SAS® software version 9.4 or later. The primary set of analyses focuses on comparing results between the two treatment groups. However, if a large proportion of participants in the BSC-only treatment group receive salvage ravulizumab, comparisons between treatment groups may not be meaningful for secondary endpoints. Participants receiving salvage therapy will begin a new visit schedule from the start of salvage therapy. This visit schedule will be equivalent to that of participants randomized to the ravulizumab + BSC treatment group at the start of the study. Data collected from the start of salvage therapy will be compiled separately, allowing for evaluation of TMA response (independent of the early assignment of non-response used in the primary endpoint analysis) and other endpoints for these participants. Analyses showing or based on change from baseline for participants receiving salvage therapy will have baseline values ​​assigned as the value obtained from the last assessment before the start of salvage therapy.

[0416] Furthermore, one set of analyses of efficacy endpoints will be performed without considering early assignment of nonresponse and rescue therapy, and results will be presented solely by randomized treatment group, even for data obtained after early assignment of nonresponse or initiation of rescue therapy. Analyses of the primary endpoint will be performed by subgroups, including, but not limited to, the presence of GVHD, geographic region, and baseline weight.

[0417] The primary efficacy endpoint was TMA response during the initial 26-week randomized treatment period. Participants must meet each TMA response criterion on two separate assessments taken at least 28 days apart; all intervals in which each criterion was met must overlap by at least 1 day to be classified as meeting the primary efficacy endpoint.

[0418] The proportion of participants who achieved a TMA response during the 26-week randomized treatment period will be summarized by treatment group. The primary analysis will compare the proportion of participants randomized to ravulizumab + BSC treatment with those randomized to BSC alone who achieved a TMA response during the 26-week randomized treatment period based on a two-sided Fisher's exact test performed at a 5% significance level.

[0419] Analyses will be conducted based on randomized treatment assignment. To avoid bias and confounding of results due to available rescue therapy for participants randomized to the BSC-only group, only participants assigned as non-responders through early non-response assignment will be eligible for such rescue therapy. Even if rescue therapy is only available to the BSC-only group, early non-response assignment will be applied in the same manner to both treatment groups. Participants assigned as early non-responders will be classified as non-responders for the primary endpoint of TMA response during the 26-week randomized treatment period, regardless of any outcomes that may be observed after early non-response assignment.

[0420] Among participants who received salvage therapy, the proportion of participants who achieved a TMA response during the 26-week treatment period from the start of salvage therapy will be summarized. Early assignment of non-responders required to receive salvage therapy will not be considered in this analysis. Only data collected from the start of salvage therapy will be used to determine TMA response.

[0421] For time to TMA response, participants will be assigned as responders at the time of TMA response and censored at the earliest of early non-response assignment, discontinuation, or end of available follow-up if no response has occurred by then. The cumulative incidence of TMA response will be estimated using competing risks survival analysis, considering death as a competing risk. Point estimates and 95% CIs are provided.

[0422] This analysis will be repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis will also be repeated without considering early assignment of nonresponse and rescue therapy, and results will be presented simply by randomized treatment group for data obtained after early assignment of nonresponse or initiation of rescue therapy.

[0423] In addition to the primary analysis of TMA response during the 26-week randomized treatment period, TMA response will also be summarized over time by treatment group, presenting the number and proportion of responders with two-sided 95% CIs for each post-baseline time point. This analysis will be performed using two different approaches. The first approach will show the number and proportion of responders at a particular time point among participants still in the study up to this point. The second approach will show the cumulative number and proportion of responders up to a particular time point among all randomized participants. This analysis will include key time points, such as weeks 26 and 52. This analysis will be repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis will also be repeated without considering early assignment of nonresponse and rescue therapy, and results will be presented simply by randomized treatment group for data obtained after early assignment of nonresponse or the start of rescue therapy.

[0424] Responses to the individual components of the TMA response during the 26-week randomized treatment period are summarized by treatment group, with point estimates of the proportion of responders and 95% CIs calculated. CIs are based on exact confidence limits using the Clopper-Pearson method. These responses are also summarized over time and by treatment group, with the number and proportion of responders presented along with two-sided 95% CIs for each post-baseline time point. This analysis is performed using two different approaches. The first approach shows the number and proportion of responders at a particular time point among participants still in the study up to that point. The second approach shows the cumulative number and proportion of responders up to a particular time point among all randomized participants. This analysis is repeated among participants receiving rescue therapy, using only data from the start of rescue therapy. This analysis is also repeated without considering early assignment of nonresponse and rescue therapy, and results are presented simply by randomized treatment group for data obtained after early assignment of nonresponse or the start of rescue therapy.

[0425] Response time for each criterion of TMA response will be assessed separately. Participants will be assigned as responders for a particular criterion at the time of response for that criterion and censored at discontinuation, early non-response assignment, or end of available follow-up if there is no response by then. The cumulative incidence of the response criterion of interest will be estimated using competing risks survival analysis, considering death as a competing risk. Point estimates and 95% CIs will be provided. This analysis will be repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis will also be repeated without considering early non-response assignment and rescue therapy, and results will be presented simply by randomized treatment group for data obtained after early non-response assignment or initiation of rescue therapy.

[0426] Participants must meet each response criterion on two separate assessments obtained at least 28 days apart; all intervals in which each criterion is met must overlap by at least 1 day to be classified as meeting this efficacy endpoint. Hematologic responses during the 26-week randomized treatment period will be summarized by treatment group, with point estimates and 95% CIs for the proportion of responders calculated. CIs are based on exact confidence limits using the Clopper-Pearson method.

[0427] Responses by treatment group are also summarized over time, with the number and proportion of responders presented along with two-sided 95% CIs for each post-baseline time point. This analysis is performed using two different approaches. The first approach shows the number and proportion of responders at a particular time point among participants who are still in the study up to that point. The second approach shows the cumulative number and proportion of responders up to a particular time point among all randomized participants. This analysis is repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis is also repeated without taking into account early assignment of non-response and rescue therapy, and results are presented simply by randomized treatment group for data obtained after early assignment of non-response or the start of rescue therapy.

[0428] For time to hematologic response, participants are assigned as responders upon response and censored at the earliest of early non-response assignment, discontinuation, or end of available follow-up if there is no prior response. The cumulative incidence of hematologic response is estimated using competing risks survival analysis, considering death as a competing risk. Point estimates and 95% CIs are provided. This analysis will be repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis will also be repeated without considering early non-response assignment and rescue therapy, and results will be presented simply by randomized treatment group for data obtained after early non-response assignment or start of rescue therapy.

[0429] For hemoglobin response, the following criterion must be met: hemoglobin ≥ 8 g / dL. Participants must meet this criterion on two separate assessments obtained at least 28 days apart and should not receive blood transfusions during this period. Hemoglobin maintenance during the 26-week randomized treatment period will be summarized by treatment group, with point estimates and 95% CIs calculated for the proportion of responders. CIs are based on exact confidence limits using the Clopper-Pearson method.

[0430] Responses by treatment group are also summarized over time, with the number and proportion of responders presented along with two-sided 95% CIs for each post-baseline time point. This analysis is performed using two different approaches. The first approach shows the number and proportion of responders at a particular time point among participants who are still in the study up to that point. The second approach shows the cumulative number and proportion of responders up to a particular time point among all randomized participants. This analysis is repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis is also repeated without taking into account early assignment of non-response and rescue therapy, and results are presented simply by randomized treatment group for data obtained after early assignment of non-response or the start of rescue therapy.

[0431] Hematological parameters (hemoglobin, platelets, LDH, and schistocytes) will be summarized by treatment group at baseline and at each post-baseline time point using descriptive statistics for continuous variables and change from baseline in observed values. This analysis will be repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis will also be repeated without considering early assignment of nonresponse and rescue therapy, and results will be presented simply by randomized treatment group for data obtained after early assignment of nonresponse or the start of rescue therapy.

[0432] Partial TMA responses (participants meet the criteria for one or more, but not all, TMA responses [Section 3]) during the 26-week treatment period will be summarized by treatment group, with point estimates and 95% CIs calculated for the proportion of responders. CIs are based on exact confidence limits using the Clopper-Pearson method. This includes separate presentations for participants responding to only one component, at least one component but not all components, two components only, and at least two components but not all components. Responses by treatment group will also be summarized over time, with the number and proportion of responders presented along with two-sided 95% CIs for each post-baseline time point. This analysis will be repeated among participants receiving rescue therapy, using only data from the initiation of rescue therapy. This analysis will also be repeated without considering early assignment of nonresponse and rescue therapy, and results will be presented simply by randomized treatment group for data obtained after early assignment of nonresponse or the initiation of rescue therapy.

[0433] Treatment effects on organ dysfunction will be assessed in the following end-organ systems: renal, cardiovascular, CNS, pulmonary, and GI. The following analyses will be repeated among participants receiving rescue therapy using only data from the start of rescue therapy.

[0434] Renal function parameters (protein / creatinine ratio, serum creatinine, and eGFR) will be summarized by treatment group at baseline and each post-baseline time point using descriptive statistics for continuous variables and change from baseline in observed values. For participants requiring dialysis, change from baseline in dialysis requirements will be summarized. Analyses will show the number and proportion of participants requiring dialysis over time. Two-sided 95% CIs for proportions will be provided. Participants will be considered not requiring dialysis at a particular post-baseline time point if they had not received dialysis for at least 5 days prior to that time point.

[0435] The presence of pulmonary hypertension, pleural effusion, pulmonary edema, and pericardial effusion will be summarized. Analyses will show the number and proportion of participants with any of these conditions over time. Two-sided 95% CIs for proportions will be provided. Additionally, the use of ventilation or respiratory support will be summarized as well.

[0436] Hypertension will be assessed by measuring blood pressure at each visit as part of vital sign collection and by analyzing concomitant medications to control hypertension. The presence of hypertension will be summarized by presenting the number and proportion of participants whose hypertension status shifted from baseline to post-baseline visits. Selected echocardiographic parameters will be summarized over time.

[0437] The presence of PRES will be summarized by presenting the number and proportion of participants with a shift in the presence of PRES from baseline to post-baseline visits.

[0438] Signs and symptoms of GI involvement such as diarrhea, vomiting, pain, and bleeding will be summarized. Analyses will show the number and proportion of participants with any of these conditions over time. The frequency and estimated amount of GI bleeding will also be summarized.

[0439] Among participants who achieved a TMA response, TMA recurrence (participants who met TMA diagnostic criteria after achieving a TMA response) will be summarized by treatment group, with point estimates and 95% CIs calculated for the proportion of participants with TMA recurrence. CIs are based on exact confidence limits using the Clopper-Pearson method.

[0440] The analysis summarizes the time from the time of response to TMA recurrence. Participants are censored at the end of available follow-up if they have not experienced a recurrence. Kaplan-Meier cumulative distribution curves are generated by treatment group. Corresponding summary tables present the first, median, and third quartiles of time to TMA recurrence, along with the corresponding two-sided 95% CI. This analysis is repeated among participants receiving rescue therapy using only data from the initiation of rescue therapy. This analysis is also repeated without considering early assignment of nonresponse and rescue therapy, and results are presented simply by randomized treatment group for data obtained after early assignment of nonresponse or the initiation of rescue therapy.

[0441] Loss of response occurs when a participant achieves a TMA response and then fails to meet criteria for one or more components of the TMA response at a subsequent visit (which must be confirmed by a second test result at least 24 hours apart). Participants who achieve loss of response are summarized by treatment group, with point estimates and 95% CIs calculated for the proportion of participants with loss of TMA response. CIs are based on exact confidence limits using the Clopper-Pearson method. Duration of response is assessed by analyzing the time from the time of response to loss of TMA response. Participants are censored at the end of available follow-up if they do not experience loss of response. Kaplan-Meier cumulative distribution curves are generated by treatment group. Corresponding summary tables present the first, median, and third quartiles of time to loss of TMA response, along with the corresponding two-sided 95% CI. This analysis will be repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis was also repeated without considering early assignment of nonresponse and rescue therapy, and results are presented simply by randomized treatment group for data obtained after early assignment of nonresponse or initiation of rescue.

[0442] Survival time is assessed as the number of days from randomization to the death event. Surviving participants are censored at the last available follow-up or when they start rescue therapy. Kaplan-Meier cumulative distribution curves are generated for each treatment group. Corresponding summary tables present the first, median, and third quartiles of survival time, along with the corresponding two-sided 95% CI, by treatment group. This analysis is repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis is also repeated without considering early assignment of nonresponse and rescue therapy, and results are presented simply by randomized treatment group for data obtained after early assignment of nonresponse or the start of rescue therapy.

[0443] Non-relapse mortality is defined as the death of a participant from any cause during the study, excluding death due to progression or recurrence of the underlying disease. The cumulative incidence of non-relapse mortality is estimated using competing risk survival analysis, considering relapse-related mortality as a competing risk. Point estimates and 95% CIs are provided. Subjects who do not experience non-relapse mortality are censored at the last available follow-up or when rescue therapy is initiated. This analysis will be repeated among participants receiving rescue therapy using only data from the initiation of rescue therapy. This analysis will also be repeated without considering early assignment of non-response and rescue therapy, and results will be presented solely by randomized treatment group for data obtained after early assignment of non-response or the initiation of rescue therapy.

[0444] Platelet response criteria must be met: platelet count ≥ 100,000 cells / mm3 without transfusion support for the past 7 days. Participants must meet this criterion on two separate assessments obtained at least 28 days apart and not receive transfusions during this period. Maintenance of platelet counts ≥ 100,000 cells / mm3 during the 26-week randomized treatment period will be summarized by treatment group, with point estimates and 95% CIs calculated. CIs are based on exact confidence limits using the Clopper-Pearson method. Responses by treatment group will also be summarized over time, with the number and proportion of responders presented along with two-sided 95% CIs for each post-baseline time point. This analysis will be performed using two different approaches. The first approach will show the number and proportion of responders at a particular time point among participants still in the study up to this point. The second approach will show the cumulative number and proportion of responders up to a particular time point among all randomized participants. This analysis will be repeated among participants receiving rescue therapy using only data from the start of rescue therapy. This analysis was also repeated without considering early assignment of nonresponse and rescue therapy, and results are presented simply by randomized treatment group for data obtained after early assignment of nonresponse or initiation of rescue therapy.

[0445] The primary analysis will compare the ravulizumab + BSC treatment group with the BSC-only treatment group based on the following null and alternative hypotheses: Hypothesis testing will be two-sided, with a significance level of 0.05. The null and alternative hypotheses for the primary analysis are as follows: H0:P rav+BSC =P BSC vs. H A :P rav+BSC ≠P BSC In the formula, P rav+BSC is the proportion of participants in the ravulizumab + BSC treatment group who achieved a TMA response, P BSC is the proportion of participants in the BSC-only treatment group who achieved a TMA response. If the null hypothesis is rejected, a hierarchical step-down closed testing procedure will be used to test for inequality in key secondary endpoints. Secondary endpoints will be tested in the following order until a non-significant test value is observed (at which point further testing of subsequent endpoints will not be performed): (1) time to TMA response for randomized treatment assignment, (2) hematologic response for randomized treatment assignment, (3) overall survival for randomized treatment assignment, (4) non-relapse mortality for randomized treatment assignment, and (5) change from baseline in eGFR for randomized treatment assignment.

[0446] Exploratory biomarker analyses provide summary statistics of observed values, changes, and percent change from baseline. The relationship between ULTOMIRIS concentrations and exploratory biomarkers, or the correlation between clinical benefit and key exploratory biomarkers, can be assessed graphically. Exploratory analyses and potential relationships between clinical outcomes, PK / PD, genetic profiles, and biomarker levels can also be performed, and results, if assessed, are summarized. Quality of life is assessed using the EQ-5D-5L. Visual assessment scale scores are obtained, and US composite time tradeoffs are calculated based on these measures. These are summarized at baseline and post-baseline time points using descriptive statistics of continuous variables of observed values ​​and change from baseline. This analysis is repeated among participants receiving rescue therapy using only data from the initiation of rescue therapy. This analysis is also repeated without considering early assignment of nonresponse and rescue therapy, and results are presented simply by randomized treatment group for data obtained after early assignment of nonresponse or the initiation of rescue therapy.

[0447] All safety analyses will be performed in the safety population and based on treatment received. Participants receiving rescue therapy will have BSC and rescue therapy data pooled separately. The following definitions will be used for AEs:

[0448] [Table 22]

[0449] The incidence of TEAEs, TEAEs leading to withdrawal from study, TEAEs leading to discontinuation of study treatment, drug-related TEAEs, TEAEs during ULTOMIRIS treatment, and SAEs will be summarized by treatment group. All AEs will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA) version 22 or later and summarized by system organ class (SOC) and preferred term overall, severity, and relationship to treatment. A detailed list of TEAEs, SAEs, related TEAEs, TEAEs during ULTOMIRIS treatment, TEAEs leading to withdrawal from study, and TEAEs leading to discontinuation of study treatment by participant will be provided.

[0450] Adverse changes from baseline in physical examination findings will be classified as AEs and analyzed accordingly. Vital signs will be summarized descriptively for changes from baseline at baseline and post-baseline time points.

[0451] Observed values ​​and changes from baseline for clinical chemistry, hematology, and urinalysis will be summarized narratively 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. Protocol-required safety laboratory assessments are shown in Table 20.

[0452] [Table 23]

[0453] [Table 24]

[0454] [Table 25]

[0455] A data listing for each participant of ECG parameters will be provided. Electrocardiograms will be scored and summarized as normal, clinically insignificant abnormal, or clinically significant abnormal. Shifts from baseline to the worst ECG table during the study will be presented for ECG results. Observed values ​​and changes from baseline in ECG intervals (PR, RR, QT, and QTc) will be summarized narratively at baseline and each post-baseline time point. QT intervals will be corrected for heart rate using Fridericia's formula (QTcF).

[0456] The incidence and titers of ADA to ULTOMIRIS at each post-baseline time point are tabulated. Additionally, all confirmed ADA-positive samples will be tested for antibody titers and the presence of neutralizing antibodies to ULTOMIRIS.

[0457] Individual PK / PD data will be collected for all participants. Graphs of the mean serum ULTOMIRIS concentration-time profile will be generated. Graphs of individual participant serum concentration-time profiles can also be provided. Actual doses and sampling times will be used for all calculations. Descriptive statistics of serum concentration data will be calculated by sampling time, as appropriate. The PD effect of ULTOMIRIS will be evaluated by assessing absolute values ​​and percent change from baseline and percentage change from baseline in serum-free C5 and serum total C5 concentrations over time, as appropriate. Descriptive statistics of PD data will be calculated by sampling time, as appropriate.

[0458] An early analysis of PK / PD data will begin when the 10th participant completes Visit 5 on Day 21. All PK and free C5 data collected in all participants up to that point will be analyzed to confirm the adequacy of the initial dosing regimen to achieve full C5 inhibition. If necessary, the dosing regimen will be adjusted.

[0459] The primary endpoint analysis will be performed at the midpoint of 26 weeks of follow-up for all Stage 2 participants from randomization, or when they have withdrawn from the first 26 weeks of the study.

[0460] Another analysis will be conducted when all participants who received salvage therapy have discontinued the study or 26 weeks have passed since the start of ULTOMIRIS treatment, and will consider data from the start of ULTOMIRIS treatment.

[0461] A final study analysis will be performed at the end of the study.

[0462] [Table 26]

[0463] [Table 27]

[0464] [Table 28]

[0465] [Table 29]

[0466] [Table 30] The present invention provides, for example, the following items. (Item 1) 1. A method of treating a human patient with hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), 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: (a) Once on day 1, 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, and 2400 mg for patients weighing ≥ 40 to < 60 kg. , at a dose of 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) On day 15 and every 4 weeks thereafter at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg or 600 mg for patients weighing ≥ 10 to < 20 kg; or on day 15 and every 8 weeks thereafter at a dose of 2100 mg for patients weighing ≥ 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. (Item 2) 1. A method of treating a human patient with hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), 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 comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, 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 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; (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) On day 15 and every 4 weeks thereafter at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg or 600 mg for patients weighing ≥ 10 to < 20 kg; or on day 15 and every 8 weeks thereafter at a dose of 2100 mg for patients weighing ≥ 20 to < 30 kg, 2700 mg for patients weighing ≥ 30 to < 40 kg, 3000 mg for patients weighing ≥ 40 to < 60 kg, 3300 mg for patients weighing ≥ 60 to < 100 kg, or 3600 mg for patients weighing ≥ 100 kg. (Item 3) 3. The method of item 1 or 2, wherein the anti-C5 antibody comprises a heavy chain variable region set forth in SEQ ID NO: 12 and a light chain variable region set forth in SEQ ID NO: 8. (Item 4) 4. The method according to any one of items 1 to 3, wherein the anti-C5 antibody further comprises a heavy chain constant region shown in SEQ ID NO: 13. (Item 5) 5. The method according to any one of Items 1 to 4, wherein the antibody comprises a heavy chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO: 11. (Item 6) The anti-C5 antibody has a K D Affinity dissociation constants (K) in the range of ≦1 nM (e.g., about 0.5 nM) D6. The method according to any one of items 1 to 5, wherein the antibody binds to human C5 at pH 7.4 and 25°C. (Item 7) The anti-C5 antibody is K D 7. The method of any one of items 1 to 6, wherein the antibody binds to human C5 at ≧10 nM (e.g., about 22 nM). (Item 8) The anti-C5 antibody is administered to patients weighing ≥5 to <10 kg: (a) At a dose of 600 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) The method of any one of items 1 to 7, wherein the dose is 300 mg on day 15 and every 4 weeks thereafter. (Item 9) The anti-C5 antibody is administered to patients weighing ≥ 10 < 20 kg: (a) At a dose of 600 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) The method of any one of items 1 to 8, wherein the dose is 600 mg on day 15 and every 4 weeks thereafter. (Item 10) The anti-C5 antibody is administered to patients weighing ≥20 to <30 kg: (a) At a dose of 900 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) The method of any one of items 1 to 9, wherein the dose is 2100 mg on day 15 and every 8 weeks thereafter. (Item 11) The anti-C5 antibody is administered to patients weighing ≥30 to <40 kg: (a) At a dose of 1200 mg once on day 1; (b) at a dose of 300 mg once on day 5; (c) at a dose of 300 mg once on day 10; (d) The method of any one of items 1 to 10, wherein the dose is 2700 mg on day 15 and every 8 weeks thereafter. (Item 12) The anti-C5 antibody is administered to patients weighing ≥ 40 to < 60 kg: (a) At a dose of 2400 mg once on day 1; (b) at a dose of 600 mg once on day 5; (c) at a dose of 600 mg once on day 10; (d) Item 1, administered at a dose of 3000 mg on day 15 and every 8 weeks thereafter. The method according to any one of claims 1 to 11. (Item 13) The anti-C5 antibody is administered to patients weighing ≥60 to <100 kg: (a) At a dose of 2700 mg once on day 1; (b) at a dose of 900 mg once on day 5; (c) at a dose of 900 mg once on day 10; (d) The method of any one of items 1 to 12, wherein the dose is 3300 mg on day 15 and every 8 weeks thereafter. (Item 14) The anti-C5 antibody is administered to a patient weighing ≥ 100 kg: (a) At a dose of 3000 mg once on day 1; (b) at a dose of 900 mg once on day 5; (c) at a dose of 900 mg once on day 10; (d) The method of any one of items 1 to 13, wherein the dose is 3600 mg on day 15 and every 8 weeks thereafter. (Item 15) 15. The method of any one of items 1 to 14, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 100 μg / mL or more. (Item 16) 16. The method of any one of items 1 to 15, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 200 μg / mL or more. (Item 17) 17. The method of any one of items 1 to 16, wherein the anti-C5 antibody is formulated for intravenous administration. (Item 18) 18. The method of any one of items 1 to 17, wherein the treatment is a dosing cycle comprising a total of 26 weeks of treatment. (Item 19) 19. The method of any one of items 1 to 18, wherein the treatment results in a reduction or cessation of microangiopathic hemolytic anemia, thrombocytopenia, endothelial damage, renal damage, renal failure, serositis, pulmonary hypertension, and multiple organ failure compared to baseline. (Item 20) The treatment is performed if: (a) a platelet count of ≥ 50,000 cells / mm without transfusion support for the past 7 days; 3 20. The method of any one of items 1 to 19, wherein the method results in (a) LDH<1.5×ULN, and (b) an absence of schistocytes (if schistocytes were present at baseline). (Item 21) The treatment is performed if: (a) a platelet count of ≥ 50,000 cells / mm without transfusion support for the past 7 days; 3 21. The method of any one of items 1 to 20, wherein the method results in (b) LDH<1.5×ULN, (c) absence of schistocytes (if schistocytes were present at baseline), and (d) at least a 50% reduction from baseline in proteinuria. (Item 22) 22. The method according to any one of items 1 to 21, wherein the treatment results in a favorable hematological response. (Item 23) 23. The method of any one of items 1 to 22, wherein the treatment results in normalization of LDH, elimination of the need for red blood cell and platelet transfusions, and disappearance of schistocytes. (Item 24) 24. The method of any one of items 1 to 23, wherein the treatment results in a hemoglobin of ≧8 g / dL without transfusion support. (Item 25) 25. The method of any one of items 1 to 24, wherein the treatment results in a decrease in LDH, an increase in platelets, and / or an increase in hemoglobin compared to baseline. (Item 26) 26. The method of any one of items 1 to 25, wherein the treatment results in a normal level of serum creatinine compared to baseline. (Item 27) 27. The method of any one of items 1 to 26, wherein the treatment results in improvement of TMA-associated organ dysfunction in the renal, cardiovascular, pulmonary, CNS, and / or GI systems compared to baseline. (Item 28) 28. The method of any one of items 1 to 27, wherein the treatment results in terminal complement inhibition. (Item 29) 29. The method of any one of items 1 to 28, wherein the treatment results in a reduction in adverse events. (Item 30) 30. The method of any one of paragraphs 1 to 29, wherein the treatment results in a shift to normal levels of biomarkers associated with vascular inflammation (e.g., shedding of tumor necrosis factor receptor 1 [TNF-R1]), endothelial injury and / or activation (e.g., shedding of thrombomodulin and vascular cell adhesion molecule 1 [VCAM-1]), renal damage (e.g., cystatin C), and / or complement proteins and complement activation pathway products. (Item 31) 31. The method of any one of items 1 to 30, wherein the treatment results in a change from baseline in quality of life as assessed by a quality of life assessment. (Item 32) 32. The method according to any one of items 1 to 31, wherein said quality of life assessment is assessed by the Quality of Life Inventory (PedsQL) scale or the EQ-5D-5L questionnaire. (Item 33) 33. The method of any one of items 1 to 32, wherein the treatment results in a reduction of lactate dehydrogenase (LDH) levels compared to baseline. (Item 34) 34. The method of any one of items 1 to 33, wherein the treatment results in a decrease in free C5 concentration or a reduction in red blood cell (RBC) hemolysis in the patient; in particular, the treatment results in a free C5 concentration of 0.5 μg / mL or less and / or RBC hemolysis of 20% or less compared to an untreated patient. (Item 35) 35. The method of any one of items 1 to 34, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody, or antigen-binding fragment thereof, in the patient of at least 175 μg / mL or greater. (Item 36) 36. The method of any one of items 1 to 35, wherein the human patient is a pediatric patient. (Item 37) 37. The method of any one of items 1 to 36, wherein the human patient is an adult patient. (Item 38) 38. The method of any one of items 1 to 37, further comprising the implementation of one or more best supportive care (BSC) measures. (Item 39) 39. The method of claim 38, wherein the one or more BSC measures are selected from the group consisting of transfusion support, corticosteroids, dialysis, and antihypertensive drugs. (Item 40) Treating hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) in human patients A kit for (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8; and (b) Instructions for using the anti-C5 antibody or antigen-binding fragment thereof in the method of any one of items 1 to 39. Kit including: (Item 41) An anti-C5 antibody or antigen-binding fragment thereof, comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8, wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) Once on day 1, at a dose of 600 mg for patients weighing ≥ 5 to < 10 kg, 600 mg for patients weighing ≥ 10 to < 20 kg, 900 mg for patients weighing ≥ 20 to < 30 kg, 1200 mg for patients weighing ≥ 30 to < 40 kg, 2400 mg for patients weighing ≥ 40 to < 60 kg, 2700 mg for patients weighing ≥ 60 to < 100 kg, or 3000 mg for patients weighing ≥ 100 kg; (b) Once on day 5, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (c) Once on day 10, at a dose of 300 mg for patients weighing ≥ 5 to < 10 kg, 300 mg for patients weighing ≥ 10 to < 20 kg, 300 mg for patients weighing ≥ 20 to < 30 kg, 300 mg for patients weighing ≥ 30 to < 40 kg, 600 mg for patients weighing ≥ 40 to < 60 kg, 900 mg for patients weighing ≥ 60 to < 100 kg, or 900 mg for patients weighing ≥ 100 kg; (d) An anti-C5 antibody or antigen-binding fragment thereof administered on day 15 and every 4 weeks thereafter at a dose of 300 mg to patients weighing ≥ 5 to < 10 kg or 600 mg to patients weighing ≥ 10 to < 20 kg; or on day 15 and every 8 weeks thereafter at a dose of 2100 mg to patients weighing ≥ 20 to < 30 kg, 2700 mg to patients weighing ≥ 30 to < 40 kg, 3000 mg to patients weighing ≥ 40 to < 60 kg, 3300 mg to patients weighing ≥ 60 to < 100 kg, or 3600 mg to patients weighing ≥ 100 kg. (Item 42) 42. The antibody of item 41, wherein the antibody is determined to be safe, tolerable, effective, and sufficiently non-immunogenic after multiple IV administrations for use in HSCT-TMA human patients.

Claims

[Claim 1] The invention described in the specification.

Images