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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.

Author information

1
Department of Internal Medicine, Division of Haematology, Medical University of Vienna, Vienna, Austria.
2
Waldenstroms, POEMS and Myeloma Clinics, University College London Hospitals, NHS Foundation Trust & Mount Vernon Cancer Centre, London, United Kingdom.
3
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
4
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
5
Department of Internal Medicine, Hanusch Krankenhaus, Vienna, Austria.
6
Department of Internal Medicine, Universitaetsklinikum St. Poelten, St. Poelten, Austria.
7
Bioverativ, a Sanofi company, Inc., Waltham, MA, United States.
8
Band Therapeutics, LLC, Belmont, MA, United States.
9
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; bernd.jilma@meduniwien.ac.at.

Abstract

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 https://clinicaltrials.gov/ as #NCT02502903.

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