Fitusiran Dosing in Trials Reduced to Lower Blood-clot Risk

Sanofi has reduced the dosing of its investigational treatment fitusiran in clinical trials to lower the risk of blood clots in people with hemophilia, according to a joint statement representing patient organizations worldwide.

In October 2020, the company placed a voluntary dosing hold on its full clinical development program for fitusiran, after reports of non-fatal vascular thrombotic (blood clot-related) events in trial participants.

The first two cases were associated with doses of clotting factor concentrates or a bypassing agent that exceeded current guidelines to manage breakthrough bleeds. The other three reports, which led to the dosing pause and were all in patients whose treatment adhered to these guidelines, affected the brain or the spinal cord.

Evaluation of these reports suggested that the risk of brain bleeding may be greater with levels of antithrombin — a protein that normally helps prevent clotting — that have been reduced below 10% of normal. As such, clinical studies will now target antithrombin levels between 15% and 35%, to enhance the benefit-risk profile of fitusiran in these patients. For this purpose, fitusiran’s dose will be reduced to 50 mg every other month in adults and adolescents, with further adjustments as needed on a case-by-case basis.

A revised dosing plan has been submitted to health authorities. After clearance from the U.S. Food and Drug Administration, dosing was allowed to resume in the country. A similar decision was reached in Japan, with other locations potentially following suit, according to the statement from the European Hemophilia Consortium, the World Federation of Hemophilia, and the National Hemophilia Foundation.

Fitusiran is an experimental RNA interference therapy being developed by Alnylam Pharmaceuticals and Sanofi Genzyme to treat people with hemophilia A or B, with and without inhibitors — neutralizing antibodies that can render replacement therapies useless.

By blocking antithrombin, fitusiran is designed to enhance blood coagulation, and in doing so, prevent bleeding in hemophilia patients. The therapy is given via a subcutaneous (under-the-skin) injection.

In a previous Phase 1 trial (NCT02035605), treatment with fitusiran reduced the levels of antithrombin and restored the balance of clotting elements in adults with hemophilia A or B. Participants who completed this study were allowed to join an extension study (NCT02554773).

Trials of fitusiran were suspended in 2017, because one patient in the extension study died from a blood clot that caused bleeding in the brain. Protocol amendments enabled the studies to resume later that year.

Results from the extension study show that fitusiran lowered the levels of antithrombin and decreased the frequency of bleeding episodes in patients with moderate to severe hemophilia A or B.

Treatment was generally safe and well-tolerated. Two serious adverse events were reported, including a case of abnormally high liver enzymes, but no participant developed inhibitors.

In addition to this study, Sanofi is assessing the safety and efficacy of fitusiran in several Phase 3 trials: ATLAS-INH (NCT03417102), ATLAS-A/B (NCT03417245), and ATLAS-PPX (NCT03549871), ATLAS-PEDS (NCT03974113), and ATLAS-OLE (NCT03754790).

ATLAS-PPX trial is expected to recruit up to 80 males, 12 and older, with severe hemophilia. Recruiting is ongoing in clinical sites around the world.

In turn, ATLAS-PEDS trial is testing fitusiran in 12 boys, ages 1 to 11, with hemophilia. Clinical sites in the U.S., Canada, India, Italy, and Spain are enrolling.

In addition, Sanofi Genzyme is funding the extension study ATLAS-OLE in nearly 244 hemophilia male patients, 12 and older, who complete a Phase 3 trial of fitusiran. Recruitment is ongoing in the U.S. and elsewhere.