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

Abstract

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.

Graphical abstract

Figure 1.

Effect of sutimlimab on a composite primary endpoint comprising Hb levels, transfusions, and need for CAD medications in patients with CAD. For the composite primary endpoint, sutimlimab was compared with placebo using the Cochran-Mantel-Haenszel method, stratified by baseline Hb (< median vs ≥ median) and geographic region (Asia/Other, North America, and Europe). Hb increase from baseline of ≥1.5 g/dL was analyzed at the treatment assessment timepoint, defined as the mean average of weeks 23, 25, and 26. Requirements for transfusion included Hb < 9 g/dL and patient symptomatic or Hb < 7 g/dL and patient asymptomatic. One patient in the sutimlimab arm discontinued treatment prematurely owing to an adverse event (increased blood IgM) and started rituximab treatment during the 9-week posttreatment follow-up period; 2 patients in the sutimlimab arm discontinued prior to week 23, and their statuses were therefore “unknown” for this analysis. BL, baseline.

Figure 2.

Effect of sutimlimab on Hb levels from baseline to week 26. Sutimlimab treatment resulted in rapid and sustained increase in Hb levels. B, baseline.

Figure 3.

Effect of sutimlimab on markers of hemolysis from baseline to week 26. (A) Analysis of the change from baseline in bilirubin excluded patients with either a positive Gilbert syndrome genetic test or no test result. Overall, 21 of 22 patients in the sutimlimab arm and 18 of 20 patients in the placebo arm consented to receive Gilbert syndrome testing. Of these, no patient had a positive result, and 1 patient had unknown result and was excluded from the analyses. The normal range for bilirubin was defined as 5.1 to 20.5 µmol/L. (B) Normalization of haptoglobin was defined as greater than the level of haptoglobin detection. (C) Parameters for reticulocyte normalization were not defined for this study. (D) The normal range for LDH was defined as 120 to 246 U/L. B, baseline.

Figure 4.

Effect of sutimlimab on FACIT-Fatigue Scale scores from baseline to week 26. FACIT-Fatigue Scale scores range from 0 to 52, with a higher score indicating less fatigue. In CAD, a change of 5 is estimated to be a clinically important change. B, baseline.

Figure 5.

Effect of sutimlimab on classical complement pathway activity. (A) In the Wieslab Complement System Classical Pathway assay, the normal range in serum is 69% to 129%. (B) The International System of Units reference range for serum C4 is 0.18 to 0.45 g/L. Baseline classical complement pathway activity and total C4 levels below the normal ranges are expected in CAD and are consistent with the nature of this disease. B, baseline; C4, complement component 4; CP, classical complement pathway.