Rare Daily Staff

Sanofi presented positive results from a late-stage study of sutimlimab in people with cold agglutinin disease, a serious and chronic autoimmune hemolytic anemia, without a recent history of blood transfusion showing it met the composite primary endpoint and secondary endpoints.

The data, which was presented at the European Hematology Association Congress 2021, demonstrated treatment with sutimlimab resulted in rapid and sustained inhibition of C1-activated hemolysis in people with CAD, noted within one week of treatment, and clinically significant improvements in hemoglobin and fatigue when compared to placebo during the study.

Cold agglutinin disease (CAD) is a rare, chronic autoimmune hemolytic anemia that causes the body’s immune system to mistakenly attack healthy red blood cells and cause their destruction (hemolysis) via activation of the classical complement pathway. CAD patients may experience chronic anemia, profound fatigue, acute hemolytic crisis, and other potential complications, including an increased risk of thromboembolic events and early death. CAD impacts the lives of an estimated 12,000 people in the United States, Europe, and Japan. Currently there are no approved therapies for CAD.

Sutimlimab is an investigational, humanized monoclonal antibody that is designed to selectively target and inhibit C1s in the classical complement pathway, which is part of the innate immune system. By blocking C1s, sutimlimab inhibits the activation of the classical complement pathway with the goal of halting C1-activated hemolysis in CAD to prevent the abnormal destruction of healthy red blood cells. By selectively inhibiting the classical pathway upstream at C1s, sutimlimab does not inhibit the lectin and alternative complement pathways.

CADENZA is a second pivotal phase 3 study investigating sutimlimab in the treatment of CAD. The primary efficacy outcome was the proportion of patients who met all three of the following components: improvement in hemoglobin ≥1.5 g/dL from baseline at treatment assessment timepoint, (average of Weeks 23, 25, and 26); avoidance of transfusions from Week 5 through Week 26; and avoidance of other CAD-related therapies beyond what was permitted from Week 5 through Week 26. The secondary efficacy measures assessed improvement from baseline in key indicators of the disease process including hemoglobin, bilirubin, lactate dehydrogenase (LDH) levels, and quality of life as measured by Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score.

“The results from CADENZA and data from the phase 3 CARDINAL study, presented as a late-breaker at the American Society of Hematology congress in 2019, will be the basis of our filing with the European Medicines Agency. Together, the studies highlight the promising potential of sutimlimab to have a meaningful impact for people living with CAD,” said Karin Knobe, head of development, Rare and Rare Blood Disorders, Sanofi. “Based on the robust clinical evidence we have to-date, sutimlimab significantly inhibits hemolysis and has the potential to be an important new treatment for CAD.”

The CADENZA trial is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of sutimlimab in patients with CAD without a recent history of blood transfusion (within the past 6 months). Eligible patients were randomized 1:1 to receive a fixed weight-based dose (6.5g or 7.5g) of sutimlimab or placebo via intravenous infusion on Day 0, Day 7 and then once every other week up to Week 26. The open-label Part B of the study is ongoing and will evaluate long-term safety as well as durability of response to sutimlimab in all participants with CAD.

Forty-two patients (mean age of 66.7 years) were enrolled and randomized to either sutimlimab (N=22) or placebo (N=20). Overall, 19 (86%) and 20 (100%) patients in the sutimlimab and placebo groups, respectively, completed Part A and continued into Part B. Three (14%) patients from the sutimlimab group discontinued Part A early due to adverse events.

Seventy-three percent (n=16) of patients treated with sutimlimab met the primary composite endpoint, demonstrating improvement in hemoglobin ≥1.5 g/dL from baseline at treatment assessment timepoint (Weeks 23, 25, and 26); avoidance of transfusions from Week 5 through Week 26; and avoidance of other CAD-related therapies beyond what was permitted from Week 5 through Week 26 compared to 15% (n=3) in the placebo group.

Data showed sutimlimab increased and sustained mean hemoglobin levels from baseline to treatment assessment timepoint (Week 26) representing a statistically significant least squares (LS) mean difference of 2.6 g/dL when compared with placebo. Hemoglobin improved rapidly, with a LS mean increase from baseline of ≥1 g/dL by Week 1 and ≥2 g/dL by Week 3. Overall mean hemoglobin levels were maintained >11 g/dL from Week 3 through treatment assessment timepoint, demonstrating a sustained effect throughout the remainder of the treatment period.

A statistically significant improvement in fatigue as measured by FACIT-Fatigue assessment was achieved in patients treated with sutimlimab when compared to the placebo group, 10.8 points versus 1.9, respectively, with a LS mean difference of 8.9 points. A 5 or greater point increase in FACIT-Fatigue score suggests a clinically important change.

Patients treated with sutimlimab had greater mean reductions in bilirubin, a key marker of hemolysis, from baseline to treatment assessment timepoint as compared with the placebo group (-22.1 μmol/L versus -1.8 μmol/L, respectively). Mean bilirubin levels were normalized below the upper limit of normal within 1 to 3 weeks in the sutimlimab group (upper limit of reference range 20.5 µmol/L) and maintained levels below the upper limit of normal to week 26.

Treatment with sutimlimab led to meaningful improvements in LDH, an additional hemolysis marker, from baseline to treatment assessment timepoint compared to placebo ( -150.8 U/L versus +7.6 U/L).

Twenty-one patients (95.5%) in the sutimlimab group and 20 patients (100%) in the placebo group experienced at least one treatment emergent adverse event. Three patients in the sutimlimab group and one patient in the placebo group experienced at least one treatment-emergent serious adverse event (n=4), including one that was assessed by the investigator as related to sutimlimab (cerebral venous thrombosis in a patient with a history of diabetes).

Treatment emergent adverse events reported more often in the sutimlimab group vs. placebo were headache, hypertension (, rhinitis, Raynaud’s phenomenon, and acrocyanosis. No deaths or meningococcal infections were reported.

Data from the CREDENZA study will be used to support a new drug application with the European Medicines Agency and a resubmission of its BLA with the U.S. Food and Drug Administration in the second half of 2021. Sanofi’s first BLA submission to the FDA was rejected in late 2020.

Sutimlimab, which Sanofi gained through its $11.6 billion acquisition of Bioverativ, has been granted Breakthrough Therapy designation by the FDA and Orphan Drug Status by the FDA, European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency in Japan.

Karin Knobe, head of development, Rare and Rare Blood Disorders, Sanofi

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