Real-world safety of sutimlimab in patients with CAD/CAS: A multinational, multi-center, observational, prospective cohort Study

Abstract Background: Cold agglutinin disease (CAD) and cold agglutinin syndrome (CAS) are cold antibody driven autoimmune hemolytic anemias, characterized by hemolysis via the classical complement pathway; CAS, unlike CAD, is typically linked to an underlying condition.CADENCE is the first global, prospective registry for patients with CAD or CAS, and collects data on over 400 patients to better characterize the long-term clinical and patient-reported outcomes. The CADENCE registry documents real-world treatment patterns and regimens, including a sutimlimab-treated cohort, in patients with CAD/CAS. Sutimlimab is a humanized monoclonal antibody that selectively inhibits the classical complement pathway by inactivating C1s; it is the first approved treatment for CAD. Aims: This analysis focuses on the sutimlimab cohort, with the aim of describing the long-term safety of sutimlimab in patients with CAD in a real-world setting. Methods: Between 12 December 2019 and 4 February 2025, 442 patients were enrolled in the registry; all patients were ≥18 years of age. Of these, 63 were treated with sutimlimab, including 58 diagnosed with CAD, 4 with CAS, and 1 patient for whom diagnosis information was not provided during the reporting period. Patient enrollment in the study is now complete. Results: Atotal of 63 patients were included in the sutimlimab cohort across the US (n=24), Germany (n=20), Japan (n=7), Italy (n=6), Austria (n=2), Spain (n=2), and France (n=2). The mean (SD) age of patients treated with sutimlimab was 72.7 (8.8) years at the time of enrollment and the percentage of female patients was 76.2%. At data cut-off, the mean (SD) and median (Q1; Q3) sutimlimab treatment duration was 25.1 (18.7) and 22.7 (10.4; 32.6) months, respectively. In the sutimlimab cohort, a total of 159 adverse events (AEs) were reported in 33 (52.4%) patients, including 156 AEs in 31 (53.4%) patients with CAD and 3 AEs in 2 (50%) patients with CAS. AEs considered related to sutimlimab by the investigator were reported in a total of 6 patients (9.5%), including 5 AEs in 5 (8.6%) patients with CAD and 1 AE in 1 (25.0%) patient with CAS. A total of 37 serious adverse events (SAEs) were reported in 11 (17.5%) patients; 36 SAEs were reported in 10 (17.2%) patients with CAD, and 1 SAE was reported in 1 (25.0%) patient with CAS. The SAE experienced by the patient with CAS (chest pain/stable angina) was a suspected unexpected SAE and considered related to sutimlimab. Furthermore, 1 death was reported in a patient with CAD (SAE of low right lung pneumonia) unrelated to sutimlimab. Adverse events of special interest (AESIs) were observed within the sutimlimab cohort in patients diagnosed with CAD, including 3 patients who experienced serious infections (sepsis, urinary tract infection, positive Gram-negative rods blood culture [klebsiella], cellulitis, and bilateral pneumonia), 2 patients who experienced arterial hypertension (reported as non-serious), and 3 patients with concomitant use of rituximab; none of of these AESIs were considered related to sutimlimab. Non-serious AESIs of acrocyanosis were reported in 8 patients; 2 were considered possibly related to sutimlimab. Other AESIs monitored during this reporting period were thromboembolic events, autoimmune disorders (including systemic lupus erythematosus), hypersensitivity reactions and anaphylaxis, and meningococcal infection, none of which were observed in this cohort of patients. Conclusion: After a mean treatment duration of over 2 years, no new safety concerns were identified in this updated analysis of CADENCE registry patients with CAD and CAS chronically treated with sutimlimab. Safety findings are consistent with earlier clinical trial data and continue to support the long-term safety profile of sutimlimab in patients with CAD. Final follow-up results are expected from the CADENCE registry in 2031 and will further inform the understanding of the long-term safety and efficacy of sutimlimab. CADENCE adds to the growing body of evidence supporting the role of sutimlimab in continued classical complement pathway inhibition in patients with CAD.