Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial

• Published in: Blood 2022-09, Vol.140 (9), p.980-991
• Main Authors: Röth, Alexander, Berentsen, Sigbjørn, Barcellini, Wilma, D'Sa, Shirley, Jilma, Bernd, Michel, Marc, Weitz, Ilene C., Yamaguchi, Masaki, Nishimura, Jun-ichi, Vos, Josephine M.I., Storek, Michael, Wong, Nancy, Patel, Parija, Jiang, Xiaoyu, Vagge, Deepthi S., Wardęcki, Marek, Shafer, Frank, Lee, Michelle, Broome, Catherine M.
• Format: Article
• Language: English
• Subjects: Anemia, Hemolytic, Autoimmune - blood; Anemia, Hemolytic, Autoimmune - drug therapy; Antibodies, Monoclonal, Humanized - therapeutic use; Bilirubin - blood; Clinical Trials and Observations; Double-Blind Method; Hemoglobins - analysis; Humans; Treatment Outcome
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021014955

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422. •Sutimlimab reduced hemolysis, anemia, and fatigue in patients with CAD without transfusion requirement.•Sutimlimab treatment was generally well tolerated, with adverse events consistent with an older and medically complex patient population. [Display omitted]