BIVV009 (sutimlimab), previously called TNT009, is a first-in-class humanized monoclonal antibody, which directly binds and inhibits C1s, an upstream complement pathway protein.

It is being developed by Bioverativ, a subsidiary of Sanofi, for the treatment of cold agglutinin disease (CAD).

How BIVV009 works

In CAD, autoantibodies called cold agglutinins bind to and cause the clumping of red blood cells (RBCs) when exposed to cold temperatures. This activates the classical complement pathway, which further triggers the lysis, or disintegration, of the RBCs. The excessive lysis of the RBCs in CAD results in hemolytic anemia, which is responsible for the majority of the symptoms characteristic of the disease.

BIVV009 is a monoclonal antibody that binds to C1s, an active upstream protein that is part of the classical complement pathway. This way it blocks the activation of the downstream steps of this pathway that are required for the RBC lysis preventing hemolytic anemia.

The advantage of BIVV009 is that it only blocks one of the three arms of the complement pathway, namely the classical pathway. The other two pathways — the lectin and alternative pathways — are not affected. Therefore, BIVV009 ensures that the complement pathway, which is an important component of the immune system in fighting infections and blood clotting, is not rendered totally ineffective.

BIVV009 in clinical trials

A prospective, double-blind, randomized, placebo-controlled study (NCT02502903) is ongoing to determine the safety, tolerability, and activity of BIVV009 in 122 healthy volunteers and patients with complement-mediated disorders including CAD. This study is being conducted in four parts. Part A is an ascending dose study in healthy volunteers; 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.

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

Data from 10 CAD patients were also published in the Blood journal. The patients received a test dose of 10 mg per kg of BIVV009 followed by a full dose of 60 mg per kg of the treatment one to four days later and three additional weekly doses of 60 mg per kg. These doses were well-tolerated by all patients.

The starting hemoglobin levels of the patients were below 11 g/dL but rapidly increased in 7 of 10 patients by about 1.6 g/dL of blood at the end of the first week of treatment and 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 g/dL. These results suggest that the underlying anemia was resolved by the treatment.

Significant improvements were also observed for 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 BIVV009 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 BIVV009. All these parameters suggested that BIVV009 significantly resolved hemolytic anemia.

However, BIVV009 treatment did not change the agglutination of RBCs on blood smears or the symptoms of acrocyanosis. During treatment with BIVV009, none of the patients required any blood transfusions, including 6 of the 10 patients who had undergone transfusion just before the treatment had started. When treatment with BIVV009 was stopped, hemolytic anemia recurred within three to four weeks in all 10 patients.

Six of the responders were then enrolled in a program where they would be treated long-term with BIVV009 as part of a trial to identify the optimal dose of BIVV009 to prevent hemolysis.

Re-exposure to BIVV009 immediately caused a rapid and complete inhibition of hemolysis in all six patients, and they remained transfusion-free while undergoing treatment for up to 18 months. Two of the six patients had to drop off this program for personal reasons and became transfusion-dependent.

The study also showed that BIVV009 was well-tolerated and there were no significant treatment-related adverse events. The study is expected to be completed in 2021.

A Phase 3, open-label, multi-center study (NCT03347396) called Cardinal is underway to assess the efficacy and safety of BIVV009 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 BVV009 administration can increase hemoglobin levels to greater than or equal to 12 g per dL, the accepted normal range of blood hemoglobin level, and render unnecessary the requirement for blood transfusion in the CAD patients. Part B aims to study the long-term safety and tolerability of BVV009 by evaluating the number of participants with treatment-related adverse events and serious adverse events.

Secondary outcomes that will be analyzed include mean changes in the levels of bilirubin and lactate dehydrogenase, changes in the FACIT (functional assessment of chronic illness therapy)-fatigue scale scores, the number of blood transfusions required and the number of blood units transfused after the first five weeks of BIVV009 administration. FACIT is a 13-item questionnaire that assesses self-reported fatigue and its impact on daily activities and function. This study is expected to be completed in June.

A Phase 3, randomized, double-blind, placebo-controlled study (NCT03347422) called Cadenza is also being conducted to assess the efficacy and safety of BIVV009 in 40 CAD patients without a recent history of blood transfusion. The primary outcomes of the study include estimating 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 being analyzed 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 BIVV009. The symptoms of anemia include fatigue, weakness, shortness of breath, palpitations, fast heartbeat, lightheadedness, and/or chest pain. This study is expected to be completed in August 2020.

Other details

The U.S. Food and Drug Administration (FDA) granted BIVV009 breakthrough therapy and orphan drug designation in 2016.


Last updated: Aug. 11, 2019


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