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.