The company had placed a voluntary dosing hold on its full clinical development program for fitusiran at the end of October, after reports of non-fatal thrombotic (blood clot-related) events in trial participants.
Working with the U.S. Food and Drug Administration, the company completed an assessment of the available data so that dosing could resume. Sanofi is also working with regulatory authorities outside the U.S. to resume dosing in other countries as quickly as possible.
To ensure the safety of trial participants, the company will be amending trial protocols, with an adjusted dose and dosing regimen. These amendments are expected to delay global regulatory submission timelines relative to adults and adolescents with hemophilia by about 18 months.
Fitusiran is an experimental RNA interference therapy that works by blocking the activity of antithrombin, a protein that normally helps to prevent clotting. By blocking antithrombin, fitusiran is intended to promote clotting, and in doing so, prevent bleeding, in people with hemophilia. The medication is administered via a subcutaneous (under-the-skin) injection once per month.
Fitusiran is being developed by Sanofi Genzyme and Alnylam Pharmaceuticals as a treatment for hemophilia A and B. It is designed for people with or without inhibitors, which are antibodies that limit the effectiveness of replacement therapies.
In a Phase 1 trial (NCT02035605) completed in 2017, fitusiran lowered antithrombin levels and restored the balance of clotting proteins in adults with hemophilia A or B. Individuals who completed this trial were allowed to enroll in an extension study (NCT02554773).
Clinical trials of fitusiran were suspended in 2017, after a participant in the extension study died from a blood clot that caused bleeding in the brain. The trials resumed at the end of that year, after protocol amendments were made.
Early data from the extension study were announced earlier this year. The investigational medication decreased antithrombin levels and reduced the frequency of bleeding episodes in people with moderate to severe hemophilia A or B.
The most common adverse events reported in the extension study were increases in liver enzymes, headache, irritation at the injection site, common cold, upper respiratory tract infection, and diarrhea. Two serious adverse events were reported, one an instance of abnormally high liver enzymes, but no participant developed inhibitors. Generally, the therapy was safe and well tolerated.
In addition to the extension study, Sanofi is currently funding three Phase 3 trials of fitusiran in adolescents and adults with hemophilia: ATLAS-INH (NCT03417102), ATLAS-A/B (NCT03417245), and ATLAS-PPX (NCT03549871).
ATLAS-PPX is currently recruiting males with severe hemophilia A or B, ages 12 and up. Recruitment is ongoing at centers around the world; more information can be found here.
Sanofi is also funding the extension study ATLAS-OLE (NCT03754790), for male hemophilia patients ages 12 and up who complete one Phase 3 trial of fitusiran.
The ATLAS-PEDS trial (NCT03974113) is testing fitusiran in children (ages 1–11) with hemophilia. Dosing in this study remains paused, pending further evaluation.
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