Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Results from the Phase 3 Cardinal Study

Introduction

CAD is a rare autoimmune hemolytic anemia with an estimated prevalence of 16 per 1 million. Hemolysis is driven by activation of the classical complement pathway (CP), resulting in erythrocyte opsonization with predominant extravascular destruction and ensuing anemia. Patients with CAD have an increased early mortality and risk of thromboembolism. There are no approved treatments.

Sutimlimab (formerly BIVV009) is a first-in-class humanized monoclonal anti-C1s antibody that selectively inhibits the C1 complex of complement, preventing CP activation, while leaving the alternative and lectin pathways intact. The objective of the Cardinal study (NCT03347396) is to assess efficacy and safety of sutimlimab in adults with CAD who have a recent history of transfusion.

Methods

Cardinal is a pivotal Phase 3, open-label, single-arm, multicenter study of 26 weeks' duration (Part A) with an ongoing extension (Part B). Data is available from Part A. Patients with confirmed diagnosis of CAD were enrolled. Eligibility criteria included baseline hemoglobin (Hb) ≤10 g/dL, total bilirubin level above normal, and ≥1 blood transfusion in the prior 6 months. Sutimlimab was administered intravenously on Days 0 and 7, followed by biweekly infusions. Patients weighing <75 kg or ≥75 kg received a 6.5 g or 7.5 g dose, respectively.

The primary efficacy endpoint was response rate based on a composite of Hb increase ≥2 g/dL or Hb ≥12 g/dL at treatment assessment (average from Weeks 23, 25, and 26) and transfusion avoidance from Weeks 5 to 26. Secondary efficacy endpoints included change from baseline in hemolytic markers (eg, bilirubin) and quality of life (QOL) measured by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Scale. The proportion of responders for analysis of the primary endpoint was calculated with a 95% exact Clopper-Pearson confidence interval (CI). All secondary endpoints were analyzed using descriptive statistics, frequency, percentage, or CIs.

Results

Twenty-four patients enrolled and received ≥1 dose of sutimlimab. The mean (standard deviation) age was 71.3 (8.2) years with 62.5% females. Mean (range) baseline Hb was 8.6 (4.9-11.1) g/dL. The median (range) number of transfusions within 6 months prior to enrollment was 2 (1-19) and 62.5% of patients had failed prior therapies. Out of 24 patients, 22 completed Part A; 2 patients were withdrawn early for reasons unrelated to the study drug.

The estimated mean (standard error [SE]) Hb increase at treatment assessment time point was 2.6 (0.4) g/dL. Hb improved rapidly after the first dose of sutimlimab with 1.2 g/dL and 2.3 g/dL increases by Weeks 1 and 3, respectively. Mean overall Hb was maintained above 11 g/dL after Week 3 (Figure 1A). Twenty (83.3%) patients had a mean Hb increase ≥1 g/dL. Mean total bilirubin was normalized by Week 3. Seventeen (70.8%) patients remained free of transfusions from Weeks 5 to 26. FACIT-F scores improved within 1 week, peaking by Week 5, and remained stable through Week 26. The estimated mean (SE) FACIT-F score increase at the treatment assessment time point was 10.9 (1.4), consistent with a clinically meaningful response. Hb, bilirubin, and FACIT-F improvements correlated with rapid normalization of complement C4 and near-complete inhibition of CP activity (Figure 1B). The prespecified primary endpoint was met (13 [54.2%] patients).

Twenty-two (91.7%) patients experienced ≥1 treatment-emergent adverse event (TEAE), with 7 (29.2%) patients experiencing a serious TEAE (TESAE). There were no TESAEs assessed as related to sutimlimab. There was 1 death in a patient with hepatic cancer that was assessed as unrelated to the study drug. Serious infections were reported, but no meningococcal infections were identified. There were no thromboembolisms and decreases in mean D-dimer and thrombin-antithrombin III complex thrombotic markers were observed. All 22 patients that completed Part A enrolled in Part B.

Conclusions

The Phase 3 Cardinal study shows that sutimlimab, a first-in-class selective inhibitor of the CP, has a rapid and sustained treatment effect in CAD by preventing hemolysis, significantly increasing Hb, and improving QOL (FACIT-F). These results demonstrate that targeting the CP represents a novel, effective therapeutic approach for the management of CAD and indicate that sutimlimab has the potential to change treatment practices for patients with this condition.

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