Sanofi's First-in-Class Complement C1s Inhibitor Sutimlimab Shows Rapid Improvement in Hemolysis, Anemia, and Fatigue Within One Week in Cold Agglutinin Disease

April 09, 2021 /BioValleyBIOON/ -- Sanofi recently announced that the final results from Part A of the pivotal Phase 3 CARDINAL open-label, single-arm study have been published in the international medical journal The New England Journal of Medicine (NEJM). For the full article, see:Sutimlimab in Cold Agglutinin DiseaseThis study evaluated the safety and efficacy of sutimlimab in adult patients with primary cold agglutinin disease (CAD) over 26 weeks. The results showed that the study met its primary and secondary endpoints. Sutimlimab demonstrated sustained inhibition of classical complement pathway-mediated hemolysis (C1-activated hemolysis, the abnormal destruction of healthy red blood cells), improvement in anemia, and reduction in fatigue within one week of treatment, with sustained therapeutic effects throughout the study period. Functional assays confirmed rapid inhibition of classical complement pathway activity, and the observed increases in hemoglobin levels, decreases in bilirubin levels, and reductions in fatigue were consistent with the inhibition of the classical complement pathway.

CAD is a rare, severe, chronic,AutoimmunityCold agglutinin disease (CAD) is a hemolytic anemia in which the complement system of the immune system mistakenly attacks healthy red blood cells, leading to their rupture (hemolysis). Patients with CAD may experience chronic anemia, severe fatigue, acute hemolytic crises, and other potential complications, including an increased risk of thromboembolic events and premature death. It is estimated that there are approximately 5,000 patients with CAD in the United States.

Sutimlimab is a first-in-class investigational humanized monoclonal antibody specifically designed to selectively target and inhibit C1s, the serine protease within the C1 complex, which constitutes the initial step in activating the classical complement pathway of the immune system. The classical complement pathway is part of the innate immune system, and its activation represents the central mechanism underlying hemolysis in cold agglutinin disease (CAD). By selectively inhibiting C1s, sutimlimab is believed to block the activation of the classical complement pathway, thereby preventing C1-mediated hemolysis in CAD.

Cold Agglutinin Disease - CAD (Image source: medicine-science-and-more.com)

Sutimlimab targets the underlying cause of hemolysis in cold agglutinin disease (CAD) by selectively inhibiting complement C1s. Sutimlimab features a novel mechanism of action and high target specificity, selectively inhibiting the upstream classical complement pathway during the disease process while preserving the intact alternative and lectin complement pathways and their immune surveillance functions.

Currently, sutimlimab is under review by the U.S. FDA.If approved, sutimlimab will become the first and only drug for treating hemolysis in CAD.Previously,FDASutimlimab has been granted Breakthrough Therapy Designation (BTD) and Orphan Drug Designation (ODD). Currently, Sanofi is also evaluating sutimlimab in the Phase III CADENZA trial for patients with cold agglutinin disease (CAD) who have not recently received transfusions, and the company is also investigating sutimlimab for the treatment of patients with immune thrombocytopenia (ITP).

Notably, in November 2020, the U.S. FDA issued a Complete Response Letter (CRL) regarding the Biologics License Application (BLA) for sutimlimab, citing certain deficiencies identified during the pre-approval inspection (PAI) of the third-party manufacturing facility. The CRL did not identify any clinical or safety-related deficiencies associated with the application. Before the BLA can be approved, the third-party manufacturer must satisfactorily address the deficiencies noted in the CRL. Sanofi willFDAMaintain close contact with third-party manufacturers to facilitate timely resolution of issues.

Sutimlimab - Mechanism of Action

The article published in NEJM includes the efficacy and safety results from Part A of the Phase 3 CARDINAL study. This was a 26-week, open-label, single-arm study enrolling patients with cold agglutinin disease (CAD) who had a recent history of transfusion (n=24). The study demonstrated that sutimlimab met the prespecified primary composite efficacy endpoint, defined as the proportion of patients achieving all of the following criteria: an increase in hemoglobin level of ≥2 g/dL from baseline or attainment of a hemoglobin level ≥12 g/dL at the 26-week efficacy assessment time point, no transfusions during weeks 5–26, and no receipt of other CAD-related therapies. Specifically, 54% (n=13) of patients achieved the composite endpoint; 62.5% (n=15) achieved a hemoglobin level ≥12 g/dL or an increase of at least 2 g/dL from baseline; and 71% (n=17) required no transfusions during weeks 5–26.

Furthermore, the trial demonstrated that sutimlimab also met key secondary endpoints, showing improvements in critical indicators of disease progression, including increased hemoglobin levels, normalization of bilirubin, and improved scores on the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale. Results showed that at the treatment assessment timepoint, the mean overall increase in hemoglobin was 2.6 g/dL. By Week 3, hemoglobin levels had increased by a mean of ≥2 g/dL from baseline. After Week 3, mean hemoglobin levels were maintained at >11 g/dL (mean baseline level: 8.6 g/dL), indicating sustained efficacy throughout the remainder of the treatment period. Mean total bilirubin decreased from 55 μmol/L (2.7 times the upper limit of normal [ULN]) at baseline to 15 μmol/L (0.8 times ULN) at the treatment assessment timepoint. A clinically meaningful reduction in fatigue was observed as early as Week 1 of treatment and was maintained throughout the study.

During the 26-week core treatment period (Part A) of the CARDINAL study, 22 out of 24 patients (91.7%) experienced at least one treatment-emergent adverse event (TEAE). The most commonAdverse Reactionswere elevated blood pressure and infusion-related reactions. Seven patients (29.2%) experienced at least one treatment-emergent serious adverse event (TESAE), including two patients (8.3%) who experienced at least one TESAE caused by infection; one patient died due to an unrelated event (Liver Cancer). No reports of meningococcal infection events, and no patients progressed to systemicLupus Erythematosus. Upon completion of the 26-week treatment period in Part A of the CARDINAL study, eligible patients continued to receive sutimlimab for an additional 24 months (Part B) to evaluate long-term safety and the durability of response.(Bioon.com)

Original Source: Positive Results from the Sutimlimab Pivotal Trial for People with Cold Agglutinin Disease Published in New England Journal of Medicine