Manufacturing Deficiencies Delay FDA Decision on Sutimlimab for Adults

The U.S. Food and Drug Administration (FDA) has issued a complete response to Sanofi’s application requesting that its investigational therapy sutimlimab be approved for treating hemolysis — the breakdown of red blood cells — in adults with cold agglutinin disease (CAD), the company announced in a press release.

While the complete response letter did not report any issues regarding clinical data on the therapy’s safety and effectiveness, which were provided in Sanofi’s biologics license application, it referred to “certain deficiencies” detected by the agency during a pre-license inspection of a third-party manufacturing facility, the company said. No information has been given about the name or location of that facility.

Sanofi said that it remains in close contact with both the FDA and the cited manufacturing facility to resolve these deficiencies in a “timely manner.” A satisfactory resolution of the unidentified deficiencies is needed for sutimlimab to gain approval in the U.S.

A decision on the therapy’s approval had been expected by Nov. 13, after the FDA granted priority review to the application in May. It is now unclear when a final decision will be made.

However, if approved, sutimlimab would become the first treatment for hemolysis for adults with CAD.

Sutimlimab, formerly known as BIVV009 and TNT009, is an antibody that selectively blocks the activity of C1, a protein with a central role in the classical complement pathway, which is overly activated in CAD patients.

This abnormal activation causes hemolysis, or the premature breakdown of the red blood cells that transport oxygen throughout the body using the hemoglobin protein. Such hemolysis, in turn, ultimately leads to hemolytic anemia, an anemia caused by the rupture of red blood cells, which is responsible for most CAD symptoms.

By blocking C1, the therapy — developed by Bioverativ, a Sanofi company — is expected to prevent hemolytic anemia and lessen the disease burden in people with CAD.

Sutimlimab has received breakthrough therapy designation in the U.S., and orphan drug designation in both the U.S. and Europe, for the treatment of hemolysis in CAD patients. These designations are meant to speed up the therapy’s clinical development and review by providing regulatory support, financial benefits, and marketing exclusivity for a period of time upon approval — specifically, seven years in the U.S. and 10 years in Europe.

Sanofi’s application is based on positive data from the first part of the ongoing, open-label, CARDINAL Phase 3 study (NCT03347396), which is evaluating the safety and effectiveness of sutimlimab in 24 adults with primary CAD.

Participants, who had received at least one blood transfusion in the prior six months, received weight-based doses of sutimlimab every week for the first two weeks, then every other week for another 24 weeks (about six months). The therapy was administered directly into the bloodstream.

CARDINAL’s main goal was to assess whether the therapy could increase hemoglobin levels by at least 2 g/dL from the study’s start, or normalize these levels to at least 12 g/dL, while preventing the need for additional blood transfusions.

The results from the first part showed that 13 participants (54.2%) met this goal and that hemoglobin levels were raised by a mean of 2.6 g/dL (from 8.6 to 11.2 g/dL) at the trial’s end.

In addition, more than two-thirds (70.8%) of patients did not require blood transfusions from week five onward, and there were clinically meaningful improvements in patient-reported quality of life measures, including less fatigue, reduced mental and physical deficits, and increased mobility and the ability to perform daily activities.

Improvements in quality of live assessments correlated with a near-complete blocking of the body’s complement system and with the resolution of hemolysis, the researchers noted.

Seven participants experienced serious adverse events (side effects) and one died of liver cancer during the trial, but none of these events were deemed related to sutimlimab. Two patients withdrew from the trial prior to its completion, for reasons unrelated to the therapy.

All 22 participants who completed the trial’s first part have enrolled in its second part, which aims to evaluate sutimlimab’s safety and tolerability over one year.

Sanofi also is conducting a placebo-controlled Phase 3 trial, called Cadenza (NCT03347422), to test sutimlimab against a placebo in about 40 adults with primary CAD who did not undergo a recent blood transfusion. Top-line results are expected by December 2021.