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.

Conflict of interest statement

Conflict-of-interest disclosure: U.J. reports personal fees from True North Therapeutics during the conduct of the study, grants and personal fees from Roche, grants and personal fees from Celgene, grants and personal fees from Gilead, personal fees from Amgen, grants and personal fees from Novartis, personal fees from Takeda, personal fees from AbbVie, and personal fees from Infinity; outside the submitted work, grants and personal fees from True North Therapeutics. G.P. is a consultant to Bioverativ and was an employee and stockholder of the study sponsor, True North Therapeutics, at the time the study was designed and conducted. G.C.P. is an employee of Bioverativ. S.P. was an employee and stockholder of the study sponsor, True North Therapeutics, at the time the study was designed and conducted, and was subsequently an employee of Bioverativ. J.C.G. was an employee and stockholder of the study sponsor, True North Therapeutics, at the time the study was designed and conducted. B.J. received reimbursement from True North Therapeutics related to travel costs for scientific presentations and scientific advice. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Extravascular hemolysis caused by cold agglutinin–induced complement-mediated opsonization. Cold agglutinins (mostly pentameric immunoglobulin M [IgM]) agglutinate erythrocytes and fix C1, triggering the classical complement cascade and leading to C3 split product opsonization of the red blood cell. Complement-opsonized erythrocytes then travel to the liver where they are phagocytosed, a process known as extravascular hemolysis. Although complement-mediated intravascular hemolysis can occur, which requires C5 cleavage and formation of the membrane attack complex, it is generally prevented by complement regulatory proteins on the erythrocyte surface (ie, CD55 and CD59). Regardless of the hemolytic mechanism, upstream C1s blockade prevents both extravascular and intravascular hemolysis. Figure adapted and modified from Berentsen and Sundic and from Shi et al.

Figure 2.

Sutimlimab infusion reduces plasma levels of complement C1s, gradually reduces the percentage of C3d-positive (C3d+) erythrocytes, and increases plasma C4 concentrations. Data are presented as medians with 25th to 75th percentiles for 10 patients.

Figure 3.

Sutimlimab rapidly normalized bilirubin levels and increased hemoglobin levels. The horizontal dotted lines indicate normal limits. Data are presented as medians with 25th to 75th percentiles for 10 patients (solid squares). The open triangles represent the median levels in the subgroup of patients with no concurrent lymphoma or mixed AIHA (n = 6). Reciprocal changes in bilirubin and hemoglobin levels occurred after effective drug levels washed out.

Figure 4.

Relationship between serum concentrations of sutimlimab and bilirubin. The horizontal dotted line represents sutimlimab 20 µg/mL, and the vertical dotted line represents 1.2 mg/dL of bilirubin (upper limit of normal).