Switch to Fitusiran Reduced Bleed Rates in Hem A and B
Most people with hemophilia A or B who switched from an approved prophylactic (preventive) therapy regimen to once-monthly treatment with fitusiran in the ATLAS-PPX clinical trial had no bleeds over seven months on the investigational therapy, new data show.
Fitusiran also reduced bleeding rates regardless of the presence of inhibitors — neutralizing antibodies that may lower the efficacy of standard replacement therapies.
“These positive data support fitusiran’s potential to transform prophylaxis treatment for people with hemophilia A or B, with or without inhibitors, with a median annual bleed rate of zero across all patient populations,” Dietmar Berger, MD, PhD, said in a press release. Berger is global head of development and chief medical officer at Sanofi, which is developing fitusiran alongside Alnylam Pharmaceuticals.
Study findings were shared earlier this month at the International Society on Thrombosis and Haemostasis (ISTH) 2022 Congress. The presentation was titled “A Phase 3 study (ATLAS-PPX) to evaluate efficacy and safety of fitusiran, an siRNA therapeutic, in people with haemophilia A or B who have switched from prior factor or bypassing agent prophylaxis.”
The open-label Phase 3 ATLAS-PPX trial (NCT03549871) enrolled 80 male participants, ages 12 and older, with severe hemophilia A or B. All participants had been using approved prophylactic therapies, either with a factor replacement therapy or a bypassing agent.
For the first six months of the study, participants continued on their standard prophylactic regimen. Then, all of the participants switched to treatment with fitusiran, given at a dose of 80 mg via under-the-skin injections once monthly for a total of seven months.
The study’s main goal was to compare bleeding rates during standard prophylaxis or fitusiran treatment.
A total of 65 participants — 50 with hemophilia A and 15 with hemophilia B — were included in the analysis of bleeding rates. Among them, 19 had inhibitors.
While on prior prophylaxis, the median annual bleeding rate was 4.4 bleeds/year. By comparison, while participants were on fitusiran, the median annual bleeding rate was zero, with nearly two-thirds (63.1%) of participants remaining bleed-free during the seven months of fitusiran treatment. Over six months on prior treatment, less than 1 in 5 (16.9%) participants were bleed-free. These results were broadly similar in patients with or without inhibitors.
Lower overall bleeding rate
Statistical analyses demonstrated that, compared to prior prophylactic therapy, fitusiran significantly reduced the overall bleeding rate by 61.1%. Rates of spontaneous bleeds and joint bleeds also were significantly reduced with fitusiran.
Participants also reported improvements in health-related life quality after switching to the experimental medication, with an improvement of more than four points on a standardized measure called Haem-A-QOL.
“These phase 3 results are encouraging and support fitusiran’s potential to provide people with hemophilia A or B, regardless of inhibitor status, with a meaningful reduction in bleeding episodes,” said trial investigator Gili Kenet, MD. Kenet is professor of hematology and director of the Israeli National Hemophilia Center at Sheba Medical Center and head of the Amalia Biron Thrombosis Research Institute of Tel Aviv University in Israel.
According to researchers, safety data from the trial were “generally consistent with previously identified risks of fitusiran.” The most common side effects attributed to the medication were increased alanine aminotransferase (a marker of liver damage), upper respiratory tract infection, and the common cold. Clotting events were reported in two participants on fitusiran.
Fitusiran is designed to promote blood clotting by lowering the levels of a protein called antithrombin, which normally prevents clotting. In Sanofi’s ongoing studies, the company is exploring the experimental treatment’s safety and efficacy under an amended protocol, with lower and less-frequent doses that aim to maintain antithrombin levels at around 15–35% of the normal range.
“We are excited to continue to explore fitusiran under an amended protocol that focuses on dose optimization, including lower doses and less frequent dosing regimens, with the potential for as few as six injections per year,” Berger said.
In addition to data from ATLAS-PPX, Sanofi presented findings from two other open-label Phase 3 trials — ATLAS-INH (NCT03417102) and ATLAS-A/B (NCT03417245) — showing that prophylactic treatment with fitusiran was able to lower the consumption of bypassing agents and clotting factor concentrates by more than 90% in patients with hemophilia A and B, with and without inhibitors.
An exploratory analysis of data from ATLAS-INH also demonstrated that fitusiran was able of lowering antithrombin activity levels by more than 80% in less than a month. This was accompanied by an increase in the production of thrombin, an enzyme that promotes blood clotting. Importantly, these effects were sustained over the course of the study, leading to a reduction of more than 90% in annual bleeding rates in patients receiving fitusiran prophylaxis, compared with those treated with bypassing agents on an on-demand basis.