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

Ulrich Jäger, Shirley D’sa, Christian Schörgenhofer, Johann Bartko, Ulla Derhaschnig, Christian Sillaber, Petra Jilma-Stohlawetz, Michael Fillitz, Thomas Schenk, Gary Patou, Sandip Panicker, Graham c. Parry, James c. Gilbert, Bernd Jilma

Research output: Journal article (peer-reviewed)Journal article

81 Citations (Scopus)

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 to 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 g/dL; 95% confidence interval, 2.1-4.5) within 6 weeks (P 5 .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 to 4 weeks after the last dose of sutimlimab. Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. 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.

Original languageEnglish
Pages (from-to)893-901
Number of pages9
JournalBlood
Volume133
Issue number9
DOIs
Publication statusPublished - 28 Feb 2019

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