S285: INHIBITION OF COMPLEMENT C1S WITH SUTIMLIMAB IN PATIENTS WITH COLD AGGLUTININ DISEASE (CAD): 2-YEAR FOLLOW-UP FROM THE CARDINAL STUDY

Abstract

Background: CAD is a rare chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis. Sutimlimab is a first-in-class humanized monoclonal antibody that selectively inhibits C1s of the C1 complex, preventing CP activation, while leaving the alternative and lectin pathways intact. One-year interim follow-up from the CARDINAL study (NCT03347396) have previously demonstrated that sutimlimab resulted in sustained improvements in hemolytic markers and quality of life. Aims: To report 2-year sutimlimab efficacy and safety from the CARDINAL Part B extension. Methods: CARDINAL was a Phase 3, open-label, single-arm study with a 26-week treatment period (Part A) and a 2-year extension (Part B) after the last patient (pt) finishes Part A. Sutimlimab was administered through intravenous infusions on Days 0 and 7, followed by biweekly dosing. Efficacy data through Week 131, the last data recording within the 2-year Part B period, are reported here. Efficacy endpoints included change from baseline in hemolytic markers, pharmacodynamic (PD) markers and blood transfusions. Quality of life (QOL) was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale. Safety was recorded until end-of-study visit 9 weeks after their last dose; endpoints included incidence of treatment-emergent adverse event (TEAE) and serious TEAE (TESAE). Descriptive statistics, frequency, and percentage were used to analyze outcomes. Results: Of the 24 pts enrolled in Part A, 22 completed Part A and entered Part B, with 19 (86.4%) pts completing Part B. Sutimlimab treatment improved mean (SD) hemoglobin (Hb) levels within one week; mean Hb remained >11 g/dL from Week 5–131 (baseline: 8.64 (1.67) (Figure). Mean total bilirubin was normalized from Week 3–131 (Figure). Mean FACIT-Fatigue scores improved within 1 week and remained ≥5 from Week 1–123 (Figure), consistent with a clinically meaningful change. Improvements in Hb, bilirubin, and FACIT-Fatigue correlated with normalization of C4 and near-complete inhibition of CP activity. Normalization of mean absolute reticulocyte count was observed alongside normalized haptoglobin levels and reductions in LDH. From Week 26–131, 15 (68.2%) pts remained transfusion-independent. All 22 pts experienced ≥1 TEAE; 12 (54.5%) pts experienced ≥1 TESAE. Serious infections were reported in 7 (31.8%) pts, including one pt with sepsis due to streptococcus pneumoniae. No meningococcal infections were reported. Three pts discontinued the study due to AEs (cyanosis and klebsiella pneumoniae (n=1); vitreous hemorrhage (n=1); cyanosis and gastrointestinal symptoms including erosive gastritis (n=1)). No pts developed systemic lupus erythematosus, serious hypersensitivity or anaphylaxis. Two pts died during the study (klebsiella pneumoniae (n=1); exacerbation of CAD (n=1) in a patient with a femoral neck fracture and complex medical history including myelodysplastic syndrome, approximately 1.5 months after receiving the last dose of sutimlimab). Image:Summary/Conclusion: Sutimlimab, a first-in-class selective anti-C1s classical complement pathway inhibitor, maintained mean Hb levels >11g/dL, achieved sustained normalization of mean bilirubin, haptoglobin and reticulocyte count. Sutimlimab continued to improve FACIT-Fatigue scores, with no newly identified safety concerns at 2 years of treatment. This study has demonstrated that sutimlimab is an effective and well-tolerated long-term therapy for the management of chronic CAD through continued upstream inhibition of the classical CP.