Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody, quickly stopped hemolysis in the single-arm CARDINAL trial in recently transfused patients with cold agglutinin disease (CAD). Sutimlimab preferentially inhibits the classical complement pathway at C1s. Sutimlimab’s safety and effectiveness in patients with CAD who had no recent (within 6 months of enrolment) transfusion history were evaluated in the 26-week CADENZA randomized, placebo-controlled phase 3 trial.

Sutimlimab (n = 22) or a placebo (n = 20) were given to 42 patients with screening hemoglobin ≤10 g/dL, increased bilirubin, and ≥1 CAD symptom on days 0 and 7, followed by bimonthly. Sixteen patients (73%) receiving sutimlimab and 3 patients (15%) receiving placebo met the 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]) (odds ratio, 15.9 [95% CI, 2.9, 88.0; P<.001].

At the treatment evaluation timepoint, sutimlimab substantially raised mean hemoglobin and FACIT-Fatigue ratings, but not placebo. By week 1, sutimlimab stabilized mean bilirubin. A near-complete suppression of the classical complement pathway (2.3% mean activity at week 1) and normalization of C4 were associated with improvements. ≥1 treatment-emergent adverse event was reported by 21 (96%) sutimlimab participants and 20 (100%) placebo patients. Sutimlimab was associated with an increase in the frequency of headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis, with a difference of ≥3 patients across groups. Three sutimlimab patients stopped taking it due to side effects; no placebo individuals stopped using it.

The findings suggested that sutimlimab may represent a significant breakthrough in managing CAD.