Sutimlimab (BIVV009 and TNT009) is a first-in-class humanized monoclonal antibody. Bioverativ, a subsidiary of Sanofi, is developing it to treat hemolysis in patients with cold agglutinin disease (CAD).

The U.S. Food and Drug Administration granted sutimlimab priority review in May 2020. A decision for approval is expected on or by Nov. 13, 2020.

What is CAD?

In CAD, autoantibodies called cold agglutinins bind to red blood cells (RBCs) in cold temperatures, causing them to clump. The binding of antibodies activates the classical complement pathway, a part of the immune system. This pathway normally plays a role in increasing the immune response against threats. In CAD, this system is activated by mistake, triggering the lysis, or disintegration, of RBCs. The excessive lysis of RBCs results in hemolytic anemia, which is responsible for the majority of the symptoms of CAD.

How does sutimlimab work?

Sutimlimab is a monoclonal antibody that binds to C1s, a protein that is part of the classical complement pathway. In this way, the treatment may block all of the downstream steps in the C1s-mediated complement pathway, and potentially reduce RBC lysis. The treatment may, therefore, be able to prevent hemolytic anemia in CAD patients.

The advantage of sutimlimab is that it blocks only one of the three arms of the complement pathway, and does not affect the other two pathways — the lectin and alternative pathways. Therefore, sutimlimab ensures that the complement pathway is not totally ineffective.

Sutimlimab in clinical trials

A prospective, double-blind, randomized, placebo-controlled Phase 1 study (NCT02502903) is ongoing and still recruiting participants in Austria. Its aim is to determine the safety, tolerability, and activity of sutimlimab in healthy volunteers and patients with complement-mediated disorders including CAD. Researchers are conducting the study in four parts. Part A is an ascending dose study and part B is a multiple-dose study in healthy volunteers. Part C is a multiple ascending dose study in patients with complement-mediated disorders including CAD, and part D is a multiple-dose study in CAD patients.

Researchers published the results of part A in the journal Transplantation in October 2017. The study showed that single doses of BIVV009 (3 to 100 mg per kg of body weight) were safe and that participants tolerated the treatment well. The results also showed that the treatment significantly inhibited complement pathway activation in a dose-dependent manner.

Data from 10 CAD patients also appeared in the journal Blood in February 2019. Participants received a test dose of 10 mg per kg of sutimlimab. They then received a full dose of 60 mg per kg one to four days later. Finally, they received three additional weekly doses of 60 mg per kg. All patients tolerated these doses well. 

The starting hemoglobin levels in the patients’ blood were below 11 g/deciliter (dL). However, it rapidly increased in 7 of 10 patients by about 1.6 g/dL of blood at the end of the first week of treatment. It further increased by an average of 3.9 g/dL within six weeks after the start of treatment. Hemoglobin is the protein in red blood cells that carries oxygen. The accepted normal range of hemoglobin in the blood is 12 to 15.5 g/dL for women, and 13.5 to 17.5 g/dL for men. The study’s results suggest that the treatment resolved anemia.

Researchers also observed significant improvements in other markers of hemolysis. The high blood serum levels of bilirubin, a breakdown product of hemoglobin and a marker for hemolysis in the liver, rapidly normalized within 24 hours of treatment with sutimlimab in most patients. Moreover, low blood serum levels of haptoglobin, a liver-generated protein that binds to free hemoglobin in the blood, normalized in four patients within a week of treatment with sutimlimab. All these parameters suggested that BIVV009 significantly resolved hemolytic anemia.

During treatment with sutimlimab, none of the patients required any blood transfusions, including 6 of the 10 patients who had undergone transfusion just before the start of treatment. When researchers stopped treatment with sutimlimab, hemolytic anemia recurred within three to four weeks in all 10 patients. However, sutimlimab treatment did not change the agglutination of RBCs on blood smears or the symptoms of acrocyanosis.

Six of the responders were recruited into a program where they would be treated long-term with sutimlimab as part of a trial to identify the optimal dose of sutimlimab that can prevent hemolysis.

Re-exposure to sutimlimab immediately caused a rapid and complete inhibition of hemolysis in all six patients. These patients remained transfusion-free while undergoing treatment for up to 18 months. Two of the six patients had to drop out of the program for personal reasons and became transfusion-dependent.

The study showed that patients tolerated sutimlimab well, and the treatment did not cause significant adverse events. Researchers expect to complete the study in March 2021.

A Phase 3, open-label, multi-center study (NCT03347396) called CARDINAL is underway to assess the efficacy and safety of sutimlimab in 20 patients with primary CAD who have a recent history of blood transfusion. This trial has two parts: part A aims to determine whether sutimlimab administration can increase hemoglobin levels to greater than or equal to 12 g/dL, the accepted normal range of blood hemoglobin level, so that blood transfusions would not be needed. Part B aims to study the long-term safety and tolerability of sutimlimab by evaluating the number of participants with treatment-related adverse events and serious adverse events.

Secondary outcomes that researchers will analyze include mean changes in the levels of bilirubin and lactate dehydrogenase, changes in the FACIT (functional assessment of chronic illness therapy, a 13-item questionnaire that assesses fatigue), fatigue scale scores, the number of necessary blood transfusions, and the number of blood units transfused after the first five weeks of sutimlimab administration. The expected completion date of the study is September 2020.

The results from the first part of the study indicate that of 24 patients, 13 met the goal of increased hemoglobin levels. More than 70% of patients did not require blood transfusions past week 5 of the study. They also showed increases in FACIT scores. 

Researchers reported no serious adverse events during the trial.

A Phase 3, randomized, double-blind, placebo-controlled study (NCT03347422) called CADENZA is also underway to assess the safety and efficacy of sutimlimab in 40 CAD patients without a recent history of blood transfusion. The primary outcomes of the study include the number of patients who respond to treatment based on at least a 1.5-point increase in hemoglobin levels above baseline that would prevent any requirement for blood transfusion between weeks 5 and 26 post-treatment. The study will also evaluate the number of adverse events and serious adverse events during the period of evaluation (approximately one year).

Secondary outcome measures include changes in the FACIT-fatigue scale scores and lactate dehydrogenase levels from baseline. The study also aims to analyze the percentage of participants with symptomatic anemia during treatment with sutimlimab. The symptoms of anemia include fatigue, weakness, shortness of breath, palpitations, fast heartbeat, lightheadedness, and/or chest pain. Researchers expect to complete this study in December 2021.

 

Last updated: May 27, 2020

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