Sanofi’s fitusiran is called “the dream hemophilia treatment” because it can be used in all hemophilia A or B patients regardless of whether they have inhibitors. In addition, the investigational drug recently proved its prophylaxis effect in a phase 3 study.

However, fitusiran reported two thromboembolic events in the trial. As a result, Sanofi is conducting further research with lower doses or less frequent dosing regimens to address this issue.

The drug’s uncertain safety profile will delay the market release of fitusiran inevitably, observers said.

Researchers presented the results of the phase 3 ATLAS-PPX study at the International Society on Thrombosis and Haemostasias (ISTH) 2022 Congress on Sunday.

Fitusiran is a small interference RNA (siRNA) therapeutic targeting antithrombin. It promotes thrombin generation to rebalance hemostasis and prevent bleeds. Thus, it can be used with or without inhibitors in hemophilia A or B.

The ATLAS-PPX study evaluated the efficacy and safety of fitusiran in 80 adults and adolescents aged 12 or more with severe hemophilia A or B, with or without inhibitors.

The participants received a pre-study prophylaxis regimen with a factor or bypassing agent (BPA) for six months and switched to once-monthly fitusiran 80mg for seven months.

The primary endpoint was annualized bleeding rate (ABR).

The results showed that the overall median ABR was 0.0 for fitusiran prophylaxis, compared to a median ABR of 4.4 with prior prophylaxis.

Fitusiran prophylaxis lowered bleeding by 61 percent compared to factor or BPA prophylaxis, Sanofi said.

Only 16.9 percent of the patients treated with conventional prophylaxis experienced zero bleeds, compared to 63.1 percent with fitusiran.

Median ABR for treated bleeds was 0.0 with fitusiran prophylaxis for patients with and without inhibitors, compared to 6.5 and 4.4 for patients with and without inhibitors, respectively, on prior prophylaxis.

Gili Kenet, the investigator and professor of hematology at the Israeli National Hemophilia Center at Sheba Medical Center, said there was a continued need for new therapies that provide consistent protection while reducing the treatment burden for hemophilia patients.

“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,” she said.

However, due to blood clotting issues, Kenet was skeptical about fitusiran’s safety.

The trial reported thromboembolic events in two participants (3 percent). This was consistent with the previously identified risk of fitusiran. In addition, one of the two patients discontinued treatment.

Kenet said the patient, who discontinued treatment, should not have enrolled for the trial because the patient had a history of deep vein thrombosis.

She also said she would reconsider using fitusiran in elderly patients and those with cardiovascular risks.

Fitusiran has been suffering safety issues since the early-stage clinical trials.

In 2017, a phase 1 trial was suspended after a participant's death due to cerebral hemorrhage.

Sanofi revised the clinical trial and resumed it in late 2017.

In October 2020, a non-fatal thrombosis symptom was found in a phase 3 study, and Sanofi voluntarily put the trial on hold. Later, Sanofi worked with the FDA to analyze data and resumed the fitusiran trial.

Sanofi said it was investigating fitusiran’s safety and efficacy under a revised protocol which includes lower doses (50mg) and a less frequent dosing regimen (once every two months), maintaining an antithrombin target range of 15-35 percent in all ongoing studies.

The company pushed back the expected timing of fitusiran market release by two years to 2024.