Fitusiran Reduced Bleeding Regardless of Inhibitor Status

Marisa Wexler MS avatar

by Marisa Wexler MS |

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Monthly treatment with the investigational medication fitusiran can reduce bleeding in people with hemophilia A and B, with or without inhibitors, according to data from two Phase 3 clinical trials.

“We are encouraged by the data from these initial Phase 3 studies demonstrating fitusiran’s potential as a new therapeutic option for people with hemophilia A or B, regardless of inhibitor status,” Dietmar Berger, MD, PhD, said in a press release. Berger is head of global development at Sanofi, which is developing fitusiran in collaboration with Alnylam Pharmaceuticals.

“These findings underscore fitusiran’s potential to address these challenges and give hope to patients, caregivers, and physicians,” Berger said.

In hemophilia, genetic mutations make the body unable to make certain clotting proteins — factor VIII (FVIII) in the case of hemophilia A, and factor IX (FIX) in the case of hemophilia B.

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Replacement therapies — treatments in which a version of the defective or missing clotting factor is administered — is considered a standard treatment for both forms of the disease. Some patients develop inhibitors, which are antibodies that bind and neutralize delivered clotting factors, rendering replacement therapies ineffective.

“There continues to be a significant need for transformative therapies that offer people with hemophilia consistent protection from bleeds while reducing treatment burden,” Berger said.

Fitusiran is an RNA-based therapy that works by lowering the levels of the protein antithrombin. As its name suggests, antithrombin normally blocks the activity of another protein called thrombin, which is a powerful driver of blood clotting. By reducing antithrombin activity, fitusiran aims to increase clotting ability.

The Phase 3 ATLAS-A/B trial (NCT03417245), sponsored by Sanofi, is one of the clinical studies currently assessing the safety and effectiveness of fitusiran in hemophilia patients.

The trial enrolled 120 male participants, ages 12 and older, at 64 sites around the globe. About three-quarters of the participants had hemophilia A; the rest had hemophilia B. When they entered the trial, participants were being managed with on-demand replacement therapy. None of the patients had inhibitors.

Two thirds of the participants were treated with fitusiran — 80 mg administered as a subcutaneous (under-the-skin) injection once per month — and the rest were given on-demand factor concentrates to control episodic bleeds as needed, for a period of nine months.

Findings from the trial were discussed this month at the American Society of Hematology (ASH) Annual Meeting, in a late-breaking presentation session titled, “Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: First Results from a Phase 3 Study to Evaluate Efficacy and Safety in People with Hemophilia a or B without Inhibitors (ATLAS-A/B)”.

Results showed that the median annualized bleeding rate in the on-demand treatment group was 21.8 bleeds per year. By contrast, the median rate in the fitusiran group was zero.

Half (50.6%) of the patients given fitusiran had no bleeds that required on-demand treatment during the study period, whereas only two patients (5%) receiving on-demand treatment were similarly bleed-free.

Statistical analyses demonstrated that, relative to on-demand treatment, fitusiran reduced the annual bleeding rate by 89.9%. Annual joint bleeding rates decreased similarly by 90.3%.

Fitusiran treatment also significantly improved total and physical health scores, indicating that treatment improved patients’ health-related life quality.

The most common adverse events (side effects) — reported in at least five participants (6.3%) on fitusiran — included the common cold, upper respiratory tract infection, abdominal pain, joint pain, asthma, stomach inflammation, headache, and elevated liver enzymes.

Two participants in the trial discontinued fitusiran because of adverse events — one due to elevated liver enzymes, and one due to cholecystitis (gallbladder inflammation). There were five serious adverse events in the fitusiran group, and nine in the on-demand treatment group. There were no clotting-related or fatal adverse events.

These safety data are “generally consistent with previously identified risks of fitusiran,” the researchers wrote.

“Once-monthly … fitusiran prophylaxis demonstrated a significant reduction in [bleeding rates] in people with severe hemophilia A or B without inhibitors compared with [on demand] treatment,” the researchers wrote, noting that lower bleeding rates were accompanied by meaningful improvements in quality of life.

These findings are overall consistent with those from a similar Phase 3 trial called ATLAS-INH (NCT03417102), which enrolled 57 people with hemophilia A or B with inhibitors.

Data from ATLAS-INH, also reported at ASH, showed that preventive treatment with fitusiran was superior to on-demand treatment with bypassing agents at reducing annualized bleeding rates and improving patients’ quality of life.