Long Term Efficacy, Safety and PK/PD Profile of the Anti-C1s Antibody (BIVV009) in Primary Cold Agglutinin Disease Patients

Background: Cold agglutinin disease is an autoimmune hemolytic anemia with limited treatment options and no established standard of care. The pathophysiology is driven by the classical complement pathway in which IgM auto-antibodies bind erythrocytes and fix complement via initial binding and activation of the C1 complex generating active C1s protease. Anemia results from extravascular hemolysis of complement opsonized erythrocytes, primarily in the liver. The anti-C1s antibody BIVV009 inhibits C1s activity, and specifically blocks the classical complement pathway, leaving the alternate and lectin complement pathways intact. We hypothesized that classical complement pathway blockade using BIVV009 would prevent hemolysis, correct anemia, and obviate the need for transfusions in patients with primary cold agglutinin disease. Methods: Six patients primary cold agglutinin disease patients were enrolled in an open label Ph1/1b trial. The study was conducted in three parts: Part A, single ascending doses in healthy volunteers (HV); Part B, multiple ascending doses in HV; and Part C, multiple doses in patients with four classical complement mediated diseases including cold agglutinin disease. Patients in Part C received a test dose of 10 mg/kg BIVV009, followed by a full dose of 60 mg/kg 1-4 days later, and three additional weekly doses of 60 mg/kg. Biweekly fixed doses of 5.5g were used for maintenance therapy in a subsequent Named Patient Program. Results: All infusions were well tolerated without need for pre-medication, and pharmacokinetic data demonstrated that BIVV009 infusions supported biweekly treatment. BIVV009 concentrations >18µg/mL inhibited the classical pathway of complement activation (as assessed by the Wieslab-CP assay). BIVV009 infusion subsequently raised endogenous C4 levels 3.2-fold (95%CI: 2.4-4.0 fold; p3.5 g/dL (mean 4.3g/dl; 95%CI: 3.8-4.9 g/dL; individual best response; p Conclusion: BIVV009 was well tolerated and immediately stopped hemolysis in 6 of 6 severely anemic patients suffering from primary cold agglutinin disease, increasing hemoglobin by a mean of 4.3g/dl and precluding the need for transfusions while on BIVV009. Based on these encouraging results, BIVV009 received FDA Breakthrough Therapy designation and pivotal trials will be initiated to further define BIVV009 safety and efficacy profiles. Figure 1: individual hemoglobin response patterns in primary cold agglutinin disease patients during the initial exposure of 6 weeks Figure 1 Figure 1. Disclosures Jaeger: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. D'Sa: Janssen Cilag: Consultancy, Honoraria, Other: Education grant, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Patou: Inc., a Bioverativ Inc. Company: Employment. Panicker: Bioverativ, Inc.: Employment, Equity Ownership. Parry: Bioverativ Therapeutics Inc.: Employment. Gilbert: TrueNorth Therapeutics Inc., a Bioverativ Inc. Company: Other: formerly Employment. Jilma: Biomed: Research Funding; Recardio: Research Funding; Emcools: Research Funding; Bayer: Research Funding; Themis: Research Funding; Syntheract: Research Funding; Bioverativ: Research Funding; TrueNorth Therapeutics: Research Funding; JHL: Research Funding; Baxalta: Research Funding; Arsanis: Research Funding; VitaerisBios: Research Funding; TrueNorth Therapeutics Inc.: Consultancy; Valneva: Research Funding; Prediction Biosciences: Research Funding; Boehringer Ingelheim: Research Funding; Octapharma: Research Funding.