Sanofi and Alnylam Pause Fitusiran Development Again Due to New Adverse Events in Hemophilia Trials

Compiled by Keke

Three International Hemophilia Organizations Announce That Sanofi Has Suspended the Development of Its “RNA-Silencing” Hemophilia Therapy Fitusiran, Co-Developed with Alnylam, Due to New Side Effects Identified in Clinical Trials

According to a joint statement issued on November 6 by the World Federation of Hemophilia, the European Haemophilia Consortium, and the National Hemophilia Foundation (USA), Sanofi has voluntarily paused its global study temporarily after “identifying new adverse events.”

Fitusiran is a once-monthly, subcutaneously administered investigational non-factor replacement therapy that utilizes an interference mechanism known as small interfering RNA (siRNA), sometimes referred to as silencing RNA, to target and reduce antithrombin (AT). This promotes sufficient thrombin generation in patients with hemophilia A or B to restore hemostasis and prevent bleeding. Developed by Alnylam Pharmaceuticals using its ESC-GalNAc conjugate technology, the therapy offers enhanced potency and durability via subcutaneous administration. Furthermore, it holds potential for the treatment of other rare bleeding disorders.

For safety reasons, this is not the first time Sanofi has paused research on fitusiran. In 2017, after a patient with hemophilia A died from a thrombotic event or blood clot in a Phase 2 study, the development of fitusiran faced a clinical hold by the U.S. Food and Drug Administration (FDA). Alnylam suspended patient dosing in the trial and devised a strategy to enhance safety monitoring and reduce the risk of fatal thrombosis affecting more patients.

However, in mid-December 2017, Sanofi and Alnylam announced that the U.S. FDA had approved protocol amendments for the fitusiran study and other updated clinical data, allowing the resumption of clinical studies of fitusiran in patients with hemophilia, including the Phase 2 open-label extension study and the Phase 3 ATLAS program.

In 2018, Sanofi acquired the global patent rights to fitusiran after restructuring its development agreement with Alnylam Pharmaceuticals. Under the previous agreement, marketing rights for fitusiran and Onpattro (patisiran), a drug now approved for the treatment of amyloidosis, were allocated by geographic region. Subsequently, Genzyme, a subsidiary of Sanofi, has focused on developing fitusiran for the treatment of hemophilia A and B.

Phase 1 clinical studies demonstrated that fitusiran reduces antithrombin (AT) levels and increases thrombin generation in patients with hemophilia A and B without inhibitors. Subsequent Phase 2 studies showed similarly encouraging safety and tolerability profiles for fitusiran during concomitant administration of replacement factors or bypassing agents, with no thromboembolic events reported.

In August 2019, the clinical trial application for fitusiran received implicit approval from the Center for Drug Evaluation (CDE) for the treatment of adult patients and adolescent patients aged 12 years and older with hemophilia A or B, with or without inhibitory antibodies, to prevent or reduce the frequency of bleeding episodes.

In June this year, Sanofi released its latest report at the World Federation of Hemophilia Network Summit, sharing interim analysis results from a Phase 2 open-label extension (OLE) study evaluating the efficacy and safety of fitusiran. The study included 34 patients with moderate-to-severe hemophilia A or B who had previously participated in fitusiran clinical trials. These patients received fixed monthly doses of either 50 mg or 80 mg of fitusiran, with follow-up periods extending up to 4.7 years and a median exposure duration of 2.6 years. Results showed that antithrombin levels remained consistently reduced (approximately 75% lower than baseline), regardless of inhibitor status, leading to median peak thrombin levels falling within the lower range observed in healthy volunteers. The overall mean annualized bleeding rate (ABR) was reduced to 0.84. Among patients who had previously received prophylactic treatment, the mean ABR was 2.0, whereas for those who had previously required on-demand treatment, the mean ABR was 12.0. These findings reinforce the potential of fitusiran to sustainably restore hemostatic balance and reduce ABR over nearly five years.

However, fitusiran, plagued by misfortune, has once again encountered safety concerns in its research nearing success. Reportedly, the latest study was suspended due to new adverse events, but Sanofi has not yet disclosed specific details of these events. If fitusiran is successfully approved in the future, safety will remain a continuous concern for both Sanofi and external stakeholders.

References:

1.Sanofi, Alnylam's hemophilia med fitusiran is on hold—again

2.Sanofi announces positive long-term efficacy and safety data for fitusiran from interim analysis of Phase 2 extension study in people with hemophilia A and B, with or without inhibitors

3.Global Dosing Hold in Fitusiran Trials Initiated by Sanofi Genzyme to Investigate New Adverse Events