Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease

Abstract Cold agglutinin disease (CAD) is a rare, autoimmune, classical complement pathway (CP)‐mediated hemolytic anemia. Sutimlimab selectively inhibits C1s of the C1 complex, preventing CP activation while leaving the alternative and lectin pathways intact. In Part A (26 weeks) of the open‐label, single‐arm, Phase 3 CARDINAL study in patients with CAD and a recent history of transfusion, sutimlimab demonstrated rapid effects on hemolysis and anemia. Results of the CARDINAL study Part B (2‐year extension) study, described herein, demonstrated that sutimlimab sustains improvements in hemolysis, anemia, and quality of life over a median of 144 weeks of treatment. Mean last‐available on‐treatment values in Part B were improved from baseline for hemoglobin (12.2 g/dL on‐treatment versus 8.6 g/dL at baseline), bilirubin (16.5 μmol/L on‐treatment versus 52.1 μmol/L at baseline), and FACIT‐Fatigue scores (40.5 on‐treatment versus 32.4 at baseline). In the 9‐week follow‐up period after sutimlimab cessation, CP inhibition was reversed, and hemolytic markers and fatigue scores approached pre‐sutimlimab values. Overall, sutimlimab was generally well tolerated in Part B. All 22 patients experienced ≥1 treatment‐emergent adverse event (TEAE); 12 (54.5%) patients experienced ≥1 serious TEAE, including seven (31.8%) with ≥1 serious infection. Three patients discontinued due to a TEAE. No patients developed systemic lupus erythematosus or meningococcal infections. After cessation of sutimlimab, most patients reported adverse events consistent with recurrence of CAD. In conclusion, the CARDINAL 2‐year results provide evidence of sustained sutimlimab effects for CAD management, but that disease activity reoccurs after treatment cessation. NCT03347396. Registered November 20, 2017.