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Blood. 2018 Dec 17. pii: blood-2018-06-856930. doi: 10.1182/blood-2018-06-856930. [Epub ahead of print]

Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial.

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Department of Internal Medicine, Division of Haematology, Medical University of Vienna, Vienna, Austria.
Waldenstroms, POEMS and Myeloma Clinics, University College London Hospitals, NHS Foundation Trust & Mount Vernon Cancer Centre, London, United Kingdom.
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
Department of Internal Medicine, Hanusch Krankenhaus, Vienna, Austria.
Department of Internal Medicine, Universitaetsklinikum St. Poelten, St. Poelten, Austria.
Bioverativ, a Sanofi company, Inc., Waltham, MA, United States.
Band Therapeutics, LLC, Belmont, MA, United States.
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria;


Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10 mg/kg sutimlimab followed by a full dose of 60 mg/kg 1-4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5; 95% confidence interval, 2.1-4.5) within 6 weeks (P = 0.005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3-4 weeks after the last dose of sutimlimab. Re-exposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. In conclusion, sutimlimab was safe, well tolerated, and rapidly stopped C1s complement-mediated hemolysis in patients with cold agglutinin disease significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at as #NCT02502903.

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