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US-12617846-B2 - Subcutaneous (SC) administration of anti-C5 antibodies for treatment of complement-associated conditions

US12617846B2US 12617846 B2US12617846 B2US 12617846B2US-12617846-B2

Abstract

Provided are methods for clinical treatment of complement-associated conditions 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) subcutaneously according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule). In one embodiment, the patient has previously been treated with eculizumab (SOLIRIS®) or ravulizumab (ULTOMIRIS®); particularly intravenously administered SOLIRIS® or ULTOMIRIS®.

Inventors

  • Dino C. Miano
  • Hweirung Amy Wang
  • Tatyana MEZHEBOVSKY

Assignees

  • ALEXION PHARMACEUTICALS, INC.

Dates

Publication Date
20260505
Application Date
20210506

Claims (20)

  1. 1 . A method of treating a human patient with a complement-associated condition, 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 subcutaneously (SC) by an on-body delivery system (OBDS), and wherein the OBDS comprises a pharmaceutical formulation comprising ravulizumab (70 mg/mL) in 50 mM sodium phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection.
  2. 2 . The method of claim 1 , wherein the anti-C5 antibody or antigen binding fragment thereof is administered every week thereafter at a dose of 490 mg.
  3. 3 . The method of claim 1 , wherein the human patient receives an intravenous loading dose prior to subcutaneous administration.
  4. 4 . The method of claim 3 , wherein the loading dose is weight-based, wherein i. a dose of 2400 mg is administered to a patient weighing ≥40 to <60 kg, or ii. a dose of 2700 mg is administered to a patient weighing ≥60 to <100 kg.
  5. 5 . The method of claim 1 , wherein the anti-C5 antibody or antigen binding fragment thereof further comprises 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.
  6. 6 . The method of claim 3 , wherein the anti-C5 antibody or antigen binding fragment thereof is administered subcutaneously on Day 15 of the administration cycle and for at least seven weeks thereafter at a dose of 490 mg qlw.
  7. 7 . The method of claim 6 , wherein the administration cycle is a total of 10 weeks of treatment.
  8. 8 . The method of claim 2 , wherein the anti-C5 antibody or antigen binding fragment thereof is administered subcutaneously at a dose of 490 mg qlw 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.
  9. 9 . The method of claim 1 , wherein the patient has previously been treated with eculizumab.
  10. 10 . The method of claim 9 , wherein the administration cycle starts at least two weeks after the patient's last dose of eculizumab.
  11. 11 . The method of claim 1 , wherein the anti-C5 antibody or antigen-binding fragment thereof, comprises a heavy chain variable region of SEQ ID NO: 12 and a light chain variable region of SEQ ID NO: 8.
  12. 12 . The method of claim 1 , wherein the anti-C5 antibody or antigen-binding fragment thereof, further comprises a heavy chain constant region of SEQ ID NO: 13.
  13. 13 . The method of claim 1 , wherein the antibody or antigen-binding fragment thereof, comprises a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11.
  14. 14 . The method of claim 1 , wherein the anti-C5 antibody or antigen binding fragment thereof, (a) binds to human C5 at pH 7.4 and 25° C. with an affinity dissociation constant (KD) that is in the range 0.1 nM≤KD≤1 nM; and/or (b) binds to human C5 at pH 6.0 and 25° C. with a KD >10 nM.
  15. 15 . The method of claim 1 , wherein the anti-C5 antibody is a biosimilar of eculizumab.
  16. 16 . The method of claim 1 , wherein the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof, of 100 μg/mL or greater during the administration cycle.
  17. 17 . The method of claim 1 , wherein the complement-associated disorder is selected from the group consisting of atypical hemolytic uremic syndrome (aHUS), complement mediated thrombotic microangiopathy (CM-TMA), paroxysmal nocturnal hemoglobinuria (PNH), neuromyelitis optica spectrum disorder (NMOSD), hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), amyotrophic lateral sclerosis (ALS), preeclampsia hemolysis, elevated liver enzymes, low platelet count (PE-HELLP), pregnancy-induced aHUS (p-aHUS), generalized myasthenia gravis (gMG), dermatomyositis, Guillain-Barre syndrome (GBS).
  18. 18 . The method of claim 1 , wherein the treatment: (a) results in terminal complement inhibition; (b) results in a reduction of hemolysis as assessed by lactate dehydrogenase (LDH) levels; (c) produces 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; (d) produces 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; (e) produces 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); (f) produces a reduction in the need for blood transfusions and/or major adverse vascular events (MAVEs); and/or (g) produces 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.
  19. 19 . The method of claim 1 , wherein the SC administration attenuates free C5 levels in the patient.
  20. 20 . The method of claim 1 , wherein the SC administration provides a threshold level of ravulizumab for complete complement inhibition in the patient.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is the U.S. National Phase Application of PCT/US2021/031141, filed on May 6, 2021, and claims priority to, and the benefit of, U.S. Provisional Application No. 63/043,613, filed on Jun. 24, 2020, the entire contents which are incorporated herein by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 28, 2021, is named 0633_WO_SL.txt and is 58,818 bytes in size. BACKGROUND The complement system acts in conjunction with other immunological systems of the body to defend against intrusion of cellular and viral pathogens. There are at least 25 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors. The plasma proteins make up about 10% of the globulins in vertebrate serum. Complement components achieve their immune defensive functions by interacting in a series of intricate but precise enzymatic cleavage and membrane binding events. The resulting complement cascade leads to the production of products with opsonic, immunoregulatory, and lytic functions. A concise summary of the biologic activities associated with complement activation is provided, for example, in The Merck Manual, 16th Edition. While a properly functioning complement system provides a robust defense against infecting microbes, inappropriate regulation or activation of the complement pathways has been implicated in the pathogenesis of a variety of disorders, including paroxysmal nocturnal hemoglobinuria (PNH). PNH is an ultra-rare disorder driven by chronic uncontrolled complement activation. The resulting inflammation and cellular damage lead to the devastating clinical manifestations of this disease. PNH is a condition in which uncontrolled complement activity leads to systemic complications, principally through intravascular hemolysis and platelet activation (see Socié G, et al., French Society of Haematology. Lancet. 1996; 348(9027):573-577 and Brodsky, R., Blood. 2014; 124(18):2804-2811). Persistent intravascular hemolysis may be triggered by various stressors, such as infection or physical exertion, which leads to smooth muscle contraction (free hemoglobin), chronic anemia, and an increased risk of severe thromboembolism. Thromboembolism, as the most common cause of mortality in patents with PNH, may lead to pulmonary hypertension and end-organ damage of vital organs, such as the liver, kidneys, brain, and intestines (Hillmen, P., et al, Am. J. Hematol. 2010; 85(8):553-559). Due to these adverse pathologic processes, patients with PNH have a decreased quality of life (QoL), which may include debilitating fatigue, chronic pain, poor physical function, shortness of breath, abdominal pain, erectile dysfunction, a need for anticoagulation, blood transfusions and in some instances, a need for dialysis (Weitz, I C., et al., Thromb Res. 2012; 130(3):361-368). Patients with PNH are at a substantial risk of morbidity and mortality. Accordingly, it is an object of the present invention to provide improved methods for treating patients with PNH. SUMMARY This instant application is based, in part, on the data obtained from a Phase 3, randomized, open-label, parallel-group, multicenter study evaluating subcutaneous ravulizumab (ULTOMIRIS® SC) compared with intravenous ravulizumab (ULTOMIRIS® IV) in the treatment of paroxysmal nocturnal hemoglobinuria (PNH). As described herein, subcutaneous ravulizumab (ULTOMIRIS® SC) can be administered, for example, using drug delivery devices to treat a variety of complement-mediated disorders, including, but not limited to PNH, atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), neuromyelitis optica spectrum disorder (NMOSD), hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), amyotrophic lateral sclerosis (ALS), complement mediated thrombotic microangiopathy (CM-TMA), preeclampsia hemolysis, elevated liver enzymes, low platelet count (PE-HELLP), pregnancy-induced aHUS (p-aHUS), particularly, PNH and aHUS. PNH is a serious ultra-rare blood disorder characterized by the destruction of red blood cells. Chronic hemolysis due to PNH may result in the formation of blood clots, which can occur in blood vessels throughout the body, damage vital organs, and potentially lead to premature death. Atypical HUS occurs when the complement system over-responds, leading the body to attack its own healthy cells. aHUS can cause progressive injury to vital organs, primarily the kidneys, via damage to the walls of blood vessels and blood clots. aHUS may lead to sudden organ failure or a slow loss of function over time—potentially resulting in the need for a transplant, and in some cases, death. It affects both adults and children, and many patients present in critical condition, often requiring supporti