Advertisement

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 and Bernd Jilma

Key points

  • Seven of ten patients with cold agglutinin disease responded to the anti-C1s antibody with a median 4 g/dL increase in hemoglobin levels.

  • Upstream inhibition of the classical complement cascade is an effective treatment for patients with cold agglutinin disease.

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.

  • Submitted June 8, 2018.
  • Accepted October 9, 2018.