Fitusiran Continues to Prevent Bleeds in Hemophilia A or B, Trial Shows

As a long-term preventive treatment, fitusiran leads to sustained reductions in bleed frequency in people with moderate-to-severe hemophilia A or B regardless of inhibitor status, early results from an extension study show.

The findings were presented at the recent World Federation of Hemophilia Virtual Summit and detailed in a press release.

Fitusiran, also known as ALN-AT3, is an experimental RNA interference (RNAi) agent being developed by Alnylam Pharmaceuticals, in collaboration with Sanofi Genzyme, to treat people with hemophilia A or B, with and without inhibitors — neutralizing antibodies that render replacement therapies useless.

The therapy works by blocking the activity of a protein called antithrombin, which inactivates thrombin and blood clotting.

Fitusiran is based on an Alnylam delivery technology that enables increased potency and durability with subcutaneous (under-the-skin) injection, according to the companies.

Previous data from a Phase 1 trial (NCT02035605) showed that a once-a-month fitusiran injection reduced the levels of antithrombin and restored the balance of clotting elements in adults with hemophilia A or B.

New interim data are from a Phase 1/2 long-term safety and efficacy extension study (NCT02554773) in 34 patients with moderate-to-severe hemophilia A or B who completed the previous Phase 1 trial.

Patients to date have been given monthly injections of fitusiran, at a dose of 50 or 80 mg, for up to 57 months (about 4.7 years).

As of March 10, the analysis cutoff date, results showed that as a preventive monthly treatment, fitusiran lowered the levels of antithrombin by about 75% since the study’s start (baseline measure), and raised median peak thrombin levels to the lower end of normal values seen in healthy individuals.

Fitusiran also reduced the frequency of annual bleeding episodes — assessed by the annualized bleeding rate (ABR) — across several patient subgroups, including those with and without inhibitors. The strongest drops were seen in people with inhibitors (median ABR decreased from 42 to 0.44), followed by patients without inhibitors who were previously receiving on-demand therapy — median ABR decreased from 12 to 1.01.

Treatment was generally well tolerated. Two serious adverse events were reported, including a case of elevated liver enzymes, but no one developed neutralizing antibodies against the medication. One patient died in 2017 from cerebral venous sinus thrombosis, a condition in which a blood clot prevents blood from exiting the brain, resulting in a hemorrhage.

The most common adverse events included elevations in liver enzymes, headache, irritation at the injection site, nasopharyngitis (common cold), upper respiratory tract infection, and diarrhea.

“These new interim data support the potential of fitusiran to have a transformative impact on hemophilia management with the aim to provide patients with consistent bleed protection and only once monthly subcutaneous dosing,” said Dietmar Berger, global head of development at Sanofi.

In addition to this extension study, six clinical trials in the ATLAS clinical program — ATLAS-INH (NCT03417102), ATLAS-A/B (NCT03417245), ATLAS-PPX (NCT03549871), ATLAS-PEDS (NCT03974113), and ATLAS-OLE (NCT03754790) — are assessing the safety and efficacy of fitusiran in patients with severe hemophilia A or B, with and without inhibitors.

Both ATLAS-PPX, in patients ages 12 and older, and ATLAS-PEDS, in children ages 1 to 11, are enrolling participants. For more information, please click the study’s name highlighted in this sentence.

“We continue to investigate the clinical profile of fitusiran in our Phase 3 ATLAS program with results expected in the first half of 2021 and look forward to offering this novel therapy to patients globally,” Berger said.