SAR445088 well-tolerated, working as expected in Phase 1 CAD trial

Also known as riliprubart, the therapy is the potential successor to Enjaymo

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A single infusion of one of two doses of SAR445088 — Sanofi’s potential successor to Enjaymo (sutimlimab-jome) — was well-tolerated by people with cold agglutinin disease (CAD) in a small Phase 1b clinical trial.

The experimental therapy, also known as riliprubart, appeared to work as expected, with a single dose leading to a sustained reduction in hemolysis, or red blood cell destruction — a hallmark of CAD.

The findings were presented at the 65th annual meeting of the American Society of Hematology (ASH) in the poster “Classical Complement Inhibition by SAR445088 (BIVV020) in Adults with Cold Agglutinin Disease: Safety, Tolerability and Activity Results From the Open-Label, Non-Randomized, Single-Dose Phase 1b Study.”

SAR445088 is an antibody designed to block the activity of the classical complement pathway, a group of immune proteins whose activation contributes to hemolysis at low temperatures.

It works via a similar mechanism to Sanofi’s Enjaymo, the first and only therapy specifically approved for CAD in the U.S. and Europe. SAR445088 targets the activated form of the classic complement C1s protein, instead of both active and inactive C1s, reducing the amount of antibody wasted on non-targets.

This, along with other modifications that make it lasts longer in the body, likely means the second-generation therapy may be given at lower doses and/or less frequently than Enjaymo.

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Rapid improvements with SAR445088

Promising findings in a cellular model of CAD and in healthy volunteers within a prior Phase 1 trial prompted Sanofi to launch a Europe-based Phase 1b trial (NCT04269551) to evaluate the safety and pharmacological properties of SAR445088 in adults with CAD.

The study enrolled 11 women and one man, ages 54-80, who were given a single infusion of SAR445088 at one of two doses (15 or 30 mg/kg).

The therapy was generally well-tolerated, with no serious side effects reported. The most common ones included blood in the urine, headache, rash, joint pain, fatigue, and acrocyanosis, a bluish skin discoloration that occurs when blood vessels are blocked.

At the start of the study, the patients on average had high levels of bilirubin, a hemolysis marker, and low levels of hemoglobin, the protein in red blood cells that carries oxygen throughout the body — both confirming hemolysis.

Both SAR445088 doses led to rapid improvements in these markers within a week. One month after an infusion, average hemoglobin and bilirubin levels were within or near normal ranges, and these were sustained for more than two months after that.

Other biomarker data indicated SAR445088 led to a marked reduction in classic complement activation to around normal levels, suggesting the therapy is working as designed.

The higher dose generally led to stronger improvements.

Based on available pharmacological data, researchers estimated SAR445088’s half-life is about eight to 15 weeks. A half-life is the time it takes for the amount of a therapy in the body to reduce by half. A longer half-life means the medication lasts longer.

The half-life of Enjaymo, which is administered once weekly for the first two weeks and every other week thereafter, is only about three weeks.

“The mechanism of action of riliprubart resulted in a prolonged half-life, potentially offering patients with CAD a favorable dosing schedule,” the researchers wrote.

Another Phase 1 trial (NCT04802057) is assessing SAR445088’s long-term safety and pharmacological properties in nine adults with CAD who may or may not have received the therapy in previous trials. Participants are receiving the therapy for up to six years, with the study slated to end in 2028.

CARDINAL, CADENZA results

In a separate poster at ASH, scientists presented a combined safety analysis from the two Phase 3 trials whose data supported Enjaymo’s approval: CARDINAL (NCT03347396), which included CAD patients who’d had a blood transfusion in the prior six months, and CADENZA (NCT03347422), which enrolled patients without a history of recent transfusions.

The poster, titled “Combined Safety Data for Sutimlimab in Cold Agglutinin Disease: A Post-Hoc Analysis of the Phase 3 Cardinal and Cadenza Studies,” included data on 66 patients, ages 46-88.

Less than half of them (45.5%) had an adverse event deemed possibly related to Enjaymo. These included headache, acrocyanosis, high blood pressure, injection-site reactions, nausea, and fever. Four patients had serious adverse events possibly related to Enjaymo, including eye bleeding, high blood pressure, viral infection, and a severe blood clot in the brain.

The results showed Enjaymo was “generally well tolerated, with the type and frequency of [adverse events] consistent with an older and medically complex population,” the scientists wrote.