Sutimlimab Protects Blood Cells Over Time to Improve Life Quality, Trials Report

Sutimlimab continues to lessen the need for blood transfusions, prevent red blood cell destruction, ease fatigue, and limit inflammation in patients with primary cold agglutinin disease (CAD), according to data from two Phase 3 trials.

These findings will be presented by Sanofi, the investigational therapy’s developer, at the 26th Annual European Hematology Association (EHA) Virtual Congress set for June 9–17.

“The data being presented at EHA 2021 demonstrate Sanofi’s commitment to providing first-in-class and potentially transformative treatments for people with immune-mediated rare blood disorders, where significant unmet needs persist,” Karin Knobe, Sanofi’s head of development for rare blood disorders, said in a press release.

Sutimlimab is designed to prevent hemolysis — the destruction of red blood cells, characteristic of CAD — by selectively blocking the activity of the C1 protein. C1 plays a key role in the complement pathway, a part of the immune system that is overactive in CAD.

The investigational therapy is being evaluated in two Phase 3 studies: a randomized and placebo-controlled trial, called CADENZA (NCT03347422), in patients without a recent history of a blood transfusion; and an open-label study called CARDINAL (NCT03347396) in those who had at least one transfusion within six months of trial enrollment.

Both studies are divided into two parts: a Part A that aims to evaluate the therapy’s ability to increase hemoglobin levels and reduce the need for blood transfusions, and Part B to assess the treatment’s long-term safety and tolerability. Of note, hemoglobin is the protein responsible for transporting oxygen in red blood cells.

Previous data from Part A of CARDINAL showed that 13 of 24 enrolled adults saw their hemoglobin levels rise over the course of 26 weeks, without requiring any blood transfusions in that period of time.

New data from CARDINAL now announced by Sanofi showed sutimlimab sustainably maintained hemoglobin and bilirubin — a marker of hemolysis — within a normal, healthy range over one year of treatment. Patients also reported an easing of fatigue and better overall quality of life, as measured by the FACIT-Fatigue score, without any new safety concerns.

These findings are to be presented in the poster “Inhibition of Complement C1s With Sutimlimab in Patients With Cold Agglutinin Disease (CAD): 1-Year Interim Results of the Phase 3 CARDINAL Study Long-Term Follow-Up.”

As stated in the abstract, improvements reported within the first five weeks of treatment among the 24 patients who enrolled in Part A — including a rise in hemoglobin levels, normalization of bilirubin, and improvements in quality of life — were sustained among the 22 who completed the first 26 weeks of treatment and entered Part B. In Part B, 86.4% remained transfusion-free from week 26 through to week 53.

All study participants experienced at least one treatment-related adverse side effect, one of which — a viral infection — was deemed serious.

“These results of the ongoing CARDINAL Part B long-term study demonstrate that continued upstream inhibition of the classical complement pathway with sutimlimab provides sustained and durable treatment effects in chronic CAD,” the researchers wrote.

A separate analysis of CARDINAL’s Part A data — summarized in the poster “Inflammation and Fatigue in Patients With Cold Agglutinin Disease (CAD): Analysis From the Phase 3 CARDINAL Study” — showed sutimlimab use led to a rapid and steady decrease in the levels of certain inflammation markers, which occurred alongside “clinically meaningful improvements in fatigue.”

Pivotal data from CADENZA are in the oral presentation “C1s-Targeted Inhibition of Classical Complement Pathway by Sutimlimab in Cold Agglutinin Disease (CAD): Efficacy and Safety Results From the Randomized, Placebo (PBO)-Controlled Phase 3 CADENZA Study,” and show sutimlimab’s superiority over a placebo at rapidly halting hemolysis, markedly increasing hemoglobin levels, and improving life quality.

“We are excited to share pivotal data from the placebo-controlled CADENZA Phase 3 study of sutimlimab in people with CAD with no recent history of transfusion,” Knobe said.

Researchers found that 16 (73%) patients randomized to sutimlimab saw their hemoglobin levels rise by at least 1.5 g/dL without a need for blood transfusions or certain CAD therapies over the course of 26 weeks of treatment in Part A. In contrast, three (15%) of those given a placebo achieved the same outcome.

Among sutimlimab-treated patients, hemoglobin levels began to rise, bilirubin levels to normalize, and quality of life to improve within the first week of treatment.  All these rapid improvements were also sustained through to weeks 23–26. These changes were not seen among those given a placebo.

In total, five patients — one in the sutimlimab group and four in the placebo — required blood transfusions from weeks five to 26. Serious side effects were reported in three sutimlimab-treated patients and one on placebo, including cerebral venous thrombosis (a blood clot in the brain) that an investigator considered related to the treatment.

Some serious infections were reported, although none were meningococcal. No cases of serious allergic reactions to treatment were reported, and no adverse side effects suggested the development or worsening of autoimmune disease, or the occurrence of lupus.

All placebo group patients and 86% of those in the sutimlimab group completed the first part of CADENZA and entered Part B.

In Part B, three patients stopped sutimlimab’s use due to side effects. High blood pressure, Raynaud’s phenomenon (poor blood flow to the extremities), and acrocyanosis (bluish skin discoloration) was reported more often in sutimlimab-treated individuals than in those on placebo in this phase of the trial. No deaths were reported.

Sutimlimab-treated patients in both studies reported lesser fatigue, along with other quality-of-life improvements. Declines in fatigue occurred rapidly, were sustained throughout treatment, and considered clinically meaningful.

Patient-reported outcomes from CARDINAL and CADENZA will be presented in two separate oral presentations. One is titled “Sustained Improvements in Patient-Reported Outcomes With Sutimlimab in Patients With Cold Agglutinin Disease: 1-Year Follow-Up Interim Results From the CARDINAL Study,” and the other “Sutimlimab, a Targeted Complement C1s Inhibitor, Improves Quality of Life (QOL) in Patients With Cold Agglutinin Disease (CAD): Results From the Randomized, Placebo-Controlled Phase 3 Cadenza Study.”

Data from a combined (both trial) analysis of patient-reported outcomes will also be presented in the poster “Clinically Important Change in FACIT-Fatigue Score for Patients With Cold Agglutinin Disease: An Analysis Using the Phase 3 CARDINAL and CADENZA Studies.”

Sutimlimab is under review by the U.S. Food and Drug Administration (FDA) for approval. A decision date has not been announced; the FDA notified the company in November of “certain deficiencies” at a third-party manufacturing facility that needed to be corrected. No concerns were evident in the FDA letter regarding sutimlimab’s safety and effectiveness.