Granted Patent B2

US 12,240,893 · App. 17/289,178 · Granted Mar 4, 2025

Inventors: Lori Volles (New Haven, CT); Rajendra Pradhan (New Haven, CT); Douglas L. Sheridan (Branford, CT); Marc Vallee (Lexington, MA); Xiang Gao (Guilford, CT)

Assignee: Alexion Pharmaceuticals, Inc.

C07K16/18A61P7/00A61K2039/505A61K2039/545C07K2317/52C07K2317/565C07K2317/92C07K2317/94

Abstract

Claims (44)

1. A method of treating a human patient with Paroxysmal Nocturnal Hemoglobinuria (PNH), the method comprising administering to the patient during an administration cycle an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered:

(a) intravenously once on Day 1 of the administration cycle at a dose of:

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

ii. 2700 mg to a patient weighing ≥60 to <100 kg; and

(b) subcutaneously on Day 15 of the administration cycle and every week thereafter at a dose of 490 mg.

2. A method of treating a human patient with Paroxysmal Nocturnal Hemoglobinuria (PNH), the method comprising administering to the patient during an administration cycle an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered:

(a) intravenously on Day 1 of the administration cycle at a dose of:

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

ii. 2700 mg to a patient weighing ≥60 to <100 kg; and

(b) subcutaneously on Day 15 of the administration cycle and every week thereafter at a dose of 490 mg.

3. The method of claim 1 , wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing ≥40 to <60 kg:

(a) intravenously once on Day 1 of the administration cycle at a dose of 2400 mg; and

(b) subcutaneously on Day 15 of the administration cycle and every week thereafter at a dose of 490 mg.

4. The method of claim 1 , wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered to a patient weighing ≥60 to <100 kg:

(a) intravenously once on Day 1 of the administration cycle at a dose of 2700 mg; and

(b) subcutaneously on Day 15 of the administration cycle and every week thereafter at a dose of 490 mg.

5. The method of claim 1 , wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered subcutaneously on Day 15 of the administration cycle and for seven weeks thereafter at a dose of 490 mg.

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

7. The method of claim 1 , wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered subcutaneously at a dose of 490 mg once weekly after the administration cycle for up to 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, two years, or chronically for the remainder of the patient's life.

8. The method of claim 1 , wherein the patient has previously been treated with eculizumab.

9. The method of claim 8 , wherein the administration cycle starts at least two weeks after the patient's last dose of eculizumab.

10. The method of claim 8 , wherein the patient has been treated with eculizumab for at least 6 months prior to Day 1 of the administration cycle.

11. The method of claim 8 , wherein the patient has previously been treated with eculizumab at a dose of 900 mg every 2 weeks.

12. The method of claim 1 , wherein the anti-C5 antibody, or antigen-binding fragment thereof, further comprises:

(a) a heavy chain variable region depicted in SEQ ID NO:12 and a light chain variable region depicted in SEQ ID NO:8;

(b) a heavy chain constant region depicted in SEQ ID NO:13; or

(c) a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:11.

13. The method of claim 1 , wherein the anti-C5 antibody, or antigen-binding fragment thereof, 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≤K D ≤1 nM.

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

15. The method of claim 1 , wherein the treatment results in one or more of the following:

(a) a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of 100 μg/ml or greater during the administration cycle;

(b) terminal complement inhibition;

(c) a reduction of hemolysis as assessed by lactate dehydrogenase (LDH) levels;

(d) at least one therapeutic effect selected from the group consisting of a reduction or cessation in fatigue, abdominal pain, dyspnea, anemia, dysphagia, chest pain, and erectile dysfunction;

(e) a shift toward normal levels of a hemolysis-related hematologic biomarker selected from the group consisting of free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone and D-dimer;

(f) a shift toward normal levels of a chronic disease associated biomarker selected from the group consisting of estimated glomerular filtration rate (eGFR) and spot urine: albumin: creatinine and plasma brain natriuretic peptide (BNP);

(g) a reduction in the need for blood transfusions and/or major adverse vascular events (MAVEs); and/or

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

16. The method of claim 1 , wherein the anti-C5 antibody, or antigen binding fragment thereof, is:

(a) administered subcutaneously using an on-body delivery system (OBDS); or

(b) self-administered subcutaneously to the patient.

17. The method of claim 1 , wherein the antibody is ravulizumab.

18. The method of claim 17 , wherein the ravulizumab for subcutaneous administration comprises 262.5 mg ravulizumab (70 mg/mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection.

19. The method of claim 17 , wherein the ravulizumab for subcutaneous administration comprises 245 mg ravulizumab (70 mg/mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection.

Assignments (1)

Continuity (2)

References Cited (400)

Cited By (1)

US 12,617,846