Granted Patent B2

US 12,460,012 · App. 17/057,898 · Granted Nov 4, 2025

Inventors: Lori Payton (Madison, CT); Andrew Denker (Ardmore, PA); Eugene Scott Swenson (Madison, CT); Rajendra Pradhan (New Haven, CT); Stephan Ortiz (Guilford, CT); Marc Vallee (Lexington, MA); Christian Mix (Wellesley, MA); Xiang Gao (Guilford, CT)

Assignee: Alexion Pharmaceuticals, Inc.

C07K16/2896A61P7/00A61K2039/505A61K2039/545C07K2317/34C07K2317/52C07K2317/76C07K2317/94

Abstract

Claims (66)

1 . A method of treating a human pediatric patient who is less than 18 years of age and has Atypical Hemolytic Uremic Syndrome (aHUS), the method comprising administering to the patient an effective amount of an anti-C5 antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:14 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:11, wherein the anti-C5 antibody or antigen binding fragment thereof, is administered:

(a) once on Day 1 at a loading dose of:

i. 600 mg to a patient weighing ≥5 to <10 kg,

ii. 600 mg to a patient weighing ≥10 to <20 kg,

iii. 900 mg to a patient weighing ≥20 to <30 kg,

iv. 1200 mg to a patient weighing ≥30 to <40 kg; and

(b) on Day 15 at a maintenance dose of:

i. 300 mg to a patient weighing ≥5 to <10 kg,

ii. 600 mg to a patient weighing ≥10 to <20 kg,

iii. 2100 mg to a patient weighing ≥20 to <30 kg,

iv. 2700 mg to a patient weighing ≥30 to <40 kg,

wherein patients weighing <20 kg receive additional maintenance doses every four weeks thereafter, and patients weighing ≥20 kg receive additional maintenance doses every eight weeks thereafter, and

wherein the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 100 μg/mL or greater and/or a free C5 concentration of 0.5 μg/mL or lower.

2 . The method of claim 1 , wherein the anti-C5 antibody binds to human C5 at pH 7.4 and 25° C. with an affinity dissociation constant (K D ) that is in the range 0.1 nM to 1 nM.

3 . The method of claim 1 , wherein the anti-C5 antibody binds to human C5 at pH 6.0 and 25° C. with a K D ≥10 nM.

4 . The method of claim 1 , wherein the anti-C5 antibody is administered to a patient weighing ≥5 to <10 kg:

(a) once on Day 1 at a loading dose of 600 mg; and

(b) once on Day 15 at a maintenance dose of 300 mg and every four weeks thereafter.

5 . The method of claim 1 , wherein the anti-C5 antibody is administered to a patient weighing ≥10 to <20 kg:

(a) once on Day 1 at a loading dose of 600 mg; and

(b) once on Day 15 at a maintenance dose of 600 mg and every four weeks thereafter.

6 . The method of claim 1 , wherein the anti-C5 antibody is administered to a patient weighing ≥20 to <30 kg:

(a) once on Day 1 at a loading dose of 900 mg; and

(b) once on Day 15 at a maintenance dose of 2100 mg and every eight weeks thereafter.

7 . The method of claim 1 , wherein the anti-C5 antibody is administered to a patient weighing ≥30 to <40 kg:

(a) once on Day 1 at a loading dose of 1200 mg; and

(b) once on Day 15 at a maintenance dose of 2700 mg and every eight weeks thereafter.

8 . The method of claim 1 , wherein the anti-C5 antibody is administered at a dose of:

(a) 300 mg or 600 mg every four weeks after the treatment for up to two years; or

(b) 2100 mg, 2700 mg, 3000 mg, 3300 mg or 3600 mg every eight weeks after the treatment for up to two years.

9 . The method of claim 1 , wherein the anti-C5 antibody is formulated for intravenous administration.

10 . The method of claim 1 , wherein the treatment is an administration cycle comprising a total of 26 weeks of treatment.

11 . The method of claim 1 , further comprising determining that the treatment:

(a) results in terminal complement inhibition;

(b) results in a complete thrombotic microangiopathy (TMA) response;

(c) results in a ≥25% reduction in serum creatinine levels compared to baseline;

(d) results in an increase in platelet count compared to baseline;

(e) results in a reduction of hemolysis compared to baseline as assessed by lactate dehydrogenase (LDH) levels;

(f) produces a reduction or cessation of at least one therapeutic marker selected from the group consisting of: severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia and renal function impairment, compared to baseline;

(g) produces a shift toward normal levels of a marker selected from the group consisting of: Factor Ba, soluble tumor necrosis factor receptor 1 (sTNFR1), soluble vascular adhesion molecule 1 (sVCAM1), thrombomodulin, D dimer and cystatin C, compared to baseline;

(h) produces a reduction in the need for blood transfusions compared to baseline;

(i) produces a reduction in major adverse vascular events (MAVEs) compared to baseline; and/or

(j) produces a change from baseline in quality of life, assessed via the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, version 4 or the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 Scale compared to baseline.

12 . A kit for treating Atypical Hemolytic Uremic Syndrome (aHUS) in a human pediatric patient, the kit comprising:

(a) a dose of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8; and

(b) instructions for using the anti-C5 antibody or antigen binding fragment thereof in the method of claim 1 .

13 . An anti-C5 antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:14 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:11, wherein the anti-C5 antibody or antigen binding fragment thereof is administered:

(a) once on Day 1 at a loading dose of:

i. 600 mg to a patient weighing ≥5 to <10 kg,

ii. 600 mg to a patient weighing ≥10 to <20 kg,

iii. 900 mg to a patient weighing ≥20 to <30 kg,

iv. 1200 mg to a patient weighing ≥30 to <40 kg,

v. 2400 mg to a patient weighing ≥40 to <60 kg,

vi. 2700 mg to a patient weighing ≥60 to <100 kg, or

vii. 3000 mg to a patient weighing ≥100 kg; and

(b) on Day 15 at a maintenance dose of:

i. 300 mg to a patient weighing ≥5 to <10 kg,

ii. 600 mg to a patient weighing ≥10 to <20 kg,

iii. 2100 mg to a patient weighing ≥20 to <30 kg,

iv. 2700 mg to a patient weighing ≥30 to <40 kg,

v. 3000 mg to a patient weighing ≥40 to <60 kg,

vi. 3300 mg to a patient weighing ≥60 to <100 kg, or

vii. 3600 mg to a patient weighing ≥100 kg;

wherein patients weighing <20 kg receive additional maintenance doses every four weeks thereafter, and patients weighing ≥20 kg receive additional maintenance doses every eight weeks thereafter.

14 . The method of claim 1 , wherein the treatment maintains a free C5 concentration of 0.309 to 0.5 μg/mL.

15 . The method of claim 1 , wherein the anti-C5 antibody is ravulizumab.

Assignments (1)

Continuity (3)

References Cited (383)