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

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 = .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. This trial was registered at www.clinicaltrials.gov as #NCT02502903.

• Authors: 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
• Journal: Blood (Blood) Vol. 133 Issue 9 Pg. 893-901 (02 28 2019) ISSN: 1528-0020 [Electronic] United States
• PMID: 30559259 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Antibodies, Monoclonal, Humanized
• Complement C1s
• sutimlimab

Topics

• Aged
• Anemia, Hemolytic (etiology, prevention & control)
• Anemia, Hemolytic, Autoimmune (complications, drug therapy)
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Complement C1s (antagonists & inhibitors, immunology)
• Female
• Follow-Up Studies
• Hemolysis (drug effects)
• Humans
• Male
• Middle Aged
• Prognosis
• Prospective Studies
• Severity of Illness Index