Papers of the Week

Chronic/refractory immune thrombocytopenia (ITP) is a rare and pathophysiologically heterogenous disorder with variable responsiveness to available treatments. Sutimlimab, a first-in-class humanized monoclonal anti-C1s IgG4 antibody, selectively inhibits the classical pathway. This Phase 1 study (NCT03275454) assessed safety, efficacy, pharmacokinetics, and pharmacodynamics of biweekly sutimlimab in patients with chronic/refractory ITP with inadequate response to ≥2 therapies (platelet count ≤30×109/L). Twelve patients (median age 42 years) received sutimlimab for a median 20.5 weeks followed by a median 2-week washout period (Part A). In Part B, 7/12 eligible patients received sutimlimab re-treatment for a median 113 weeks. In Part A, mean (standard deviation) platelet count increased from 25×109/L (17) to 54×109/L (60) 24 hours after starting sutimlimab, maintaining ≥50×109/L throughout Part A. Five patients (42%) achieved durable platelet count responses (≥50×109/L in ≥50% of follow-up visits) and 4 achieved complete response (platelet count ≥100×109/L). Mean platelet count returned to baseline during washout, increasing upon re-treatment in Part B. Mean platelet count improvements accompanied rapid classical pathway inhibition. There were 74 treatment-emergent adverse events in Part A (n=10) and 70 in Part B (n=6). Five serious adverse events were observed; one event (migraine) was assessed by the investigator as related to sutimlimab. These results demonstrate that in some ITP patients autoantibodies activate the classical complement pathway, accelerating platelet destruction or impairing platelet production, contributing to treatment failure. C1s inhibition may be a safe and beneficial therapeutic approach for patients with chronic/refractory ITP.