Sanofi's Complement C1s Inhibitor Sutimlimab Meets Primary Endpoint in Pivotal Phase 3 Trial for Cold Agglutinin Disease

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At the 2019 ASH Annual Meeting, Sanofi presented data from the pivotal Phase III CARDINAL study (NCT03347396) evaluating sutimlimab for the treatment of primary cold agglutinin disease (CAD).The results showed that the study met both the primary and secondary endpoints.

Cold agglutinin disease (CAD) is a rare, severe, chronic autoimmune hemolytic disorder in which the complement system of the immune system mistakenly attacks the body’s own healthy red blood cells. Patients with CAD suffer from chronic anemia, debilitating fatigue, acute hemolytic crises, and poor quality of life. Retrospective analyses have shown that patients with CAD experience other underlying complications, including thromboembolic events and increased early mortality.

Sutimlimab is a potential first-in-class, investigational, humanized monoclonal antibody specifically designed to target C1s, the serine protease within the C1 complex, which constitutes the initial step in activating the classical complement pathway of the immune system. Activation of the classical complement pathway is the central mechanism underlying hemolysis in cold agglutinin disease (CAD), and blockade of this pathway has the potential to prevent CAD-associated hemolysis. Sutimlimab features a novel mechanism of action and high target specificity, selectively inhibiting the upstream segment of the classical complement pathway during the disease process, while preserving the intact alternative and lectin complement pathways along with their immune surveillance functions.

Mechanism of Action of Sutimlimab【Image source: Blood (2019) 133 (9): 893-901】

CARDINAL is an open-label, single-arm study designed to evaluate the efficacy and safety of sutimlimab in adult patients with primary cold agglutinin disease (CAD) who have recently received transfusions. In the study, patients received fixed, weight-based intravenous doses of sutimlimab (6.5 g or 7.5 g) on Day 0 and Day 7, followed by administrations every other week until Week 26. The primary efficacy endpoint was the proportion of responders, defined as meeting all of the following composite criteria: an increase in hemoglobin level of ≥2 g/dL from baseline or achievement of a hemoglobin level ≥12 g/dL at the Week 26 efficacy assessment; no transfusions between Weeks 5 and 26; and no CAD treatments beyond those permitted by the study protocol. Secondary efficacy endpoints assessed improvements in key indicators of disease course, including hemoglobin, bilirubin, Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scores, lactate dehydrogenase, and transfusion utilization.

In the study, 24 patients (mean age 71.3 years) were enrolled and received at least one dose of sutimlimab; 62.5% of patients had received ≥1 targeted therapy in the past 5 years, and 2 patients withdrew from the study early for reasons unrelated to the study drug. Of the 22 patients who completed Part A of the study, all elected to enter Part B to continue sutimlimab treatment. Part B was an extension study assessing safety and durability of response.

The efficacy and safety data presented at the ASH meeting are as follows:

—The study met its predefined primary endpoint, with 54% of patients achieving the composite endpoint criteria; 62.5% of patients achieved a hemoglobin level ≥12 g/dL or an increase from baseline of ≥2 g/dL; and 71% of patients remained transfusion-free after Week 5.

—At the treatment assessment time point, the overall mean increase in hemoglobin was 2.6 g/dL, and 83% (n=20) of the 24 patients enrolled in the study achieved a clinically significant mean hemoglobin increase of ≥1 g/dL.

— Hemoglobin levels improved rapidly, with a mean increase from baseline of ≥1 g/dL in Week 1 and ≥2 g/dL in Week 3; thereafter, the mean hemoglobin level was maintained at ≥11 g/dL (mean baseline: 8.6 g/dL), demonstrating sustained efficacy throughout the treatment period.

——Mean total bilirubin is a key indicator of CAD-induced hemolysis, approaching normal levels after the first week of treatment, with standardized bilirubin levels remaining stable.

—The mean FACIT-Fatigue score showed a clinically meaningful improvement in fatigue, with an increase of 7.2 points during the first week of treatment, and a total mean increase of 10.9 points from baseline at the 26-week treatment assessment time point.

—Twenty-two patients experienced at least one treatment-emergent adverse event, and seven patients experienced at least one treatment-emergent serious adverse event; none were assessed by the study investigators as related to sutimlimab. No patients discontinued sutimlimab due to infection, and no cases of meningococcal infection were observed.

The aforementioned studies demonstrate that sutimlimab significantly improves hemolysis, anemia, and fatigue in patients by targeting the central mechanism of cold agglutinin disease (CAD), achieving clinically meaningful therapeutic outcomes.

Based on the study data, Sanofi plans to submit a Biologics License Application (BLA) for sutimlimab to the U.S. FDA. Previously, sutimlimab was granted Breakthrough Therapy designation by the FDA and orphan drug status by the FDA, the European EMA, and Japan’s PMDA.

Sutimlimab has the potential to become the first drug for treating this rare autoimmune hemolytic anemia. If approved for marketing, sutimlimab will transform the treatment paradigm for CAD.

For Sanofi, this also presents an opportunity to begin recouping part of the $11.6 billion spent on last year’s acquisition of Bioverativ. Prior to being acquired, Bioverativ acquired sutimlimab from True North Therapeutics for a $400 million upfront payment. At the time of Sanofi’s acquisition of Bioverativ, Citigroup analysts regarded sutimlimab as the company’s most promising pipeline asset.

Sanofi’s interest in sutimlimab extends beyond the CAD indication. The company is currently conducting an early-phase clinical trial to evaluate the potential of sutimlimab for the treatment of immune thrombocytopenic purpura (ITP).

References:

1、ASH: Sanofi eyes FDA filing as orphan blood drug hits late-phase goal

2、Sanofi : Positive results presented from pivotal Phase 3 trial of sutimlimab in people with cold agglutinin disease