Three hemophilia organizations, the World Federation of Hemophilia, the European Haemophilia Consortium and the National Hemophilia Foundation issued a joint statement reporting that Sanofi Genzyme had placed a global dosing hold on its “full clinical development program for fitusiran due to the identification of new adverse events.”
Fitusiran is a once-once monthly, subcutaneously dosed non-factor-replacement therapy that leverages small interfering RNA (siRNA) to target and decrease antithrombin. This promotes sufficient thrombin creation to restore hemostasis and prevent bleeding in patients with hemophilia A or B.
Sanofi has indicated that as of October 30, they had “voluntarily paused dosing and enrollment in the ongoing fitusiran clinical studies to allow investigation of reports of non-fatal thrombotic events in patients in the trials. This decision is in alignment with the independent external Data Monitoring Committee.”
The statement goes on to say that the company is “currently engaging with regulatory authorities and assessing relevant trial data. During this pause in dosing and enrollment, all other trial-related activities will continue.”
Sanofi notes that patients in the trials often have other health issues and comorbidities which could be complicated by the ongoing COVID-19 pandemic.
On June 19, 2020, Sanofi had released positive long-term efficacy and safety data for the drug from interim analysis of the Phase II extension trial in hemophilia A and B patients, with or without inhibitors. At that time, they indicated the data only reinforced its potential and to lower annualized blood rates (ABRs) over a period of up to 57 months.
“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, Sanofi, at the time. “We are continuing to advance our portfolio of factor and non-factor therapies that could offer people with hemophilia a broad range of therapeutic options to fit their individual needs.”
The Phase II OLE trial evaluated the long-term efficacy and safety of the drug in moderate or severe hemophilia A and B, with or without inhibitors, who had been in the previous fitusiran trial. It evaluated 34 enrolled patients and they were followed for up to 4.7 years.
Back in 2018, Phase II and Phase III trials of the drug were placed on hold after a thrombotic event in the Phase II trial. The event was a cerebral venous sinus thrombosis (cerebral edema) that was potentially linked to fitusiran and resulted in the death of the patient. At that time, the drug was in development by Alnylam Pharmaceuticals, which changed the protocol guidelines and added educational materials on decreases doses of replacement factor to treat bleeding in the trial participants.
Alnylam and Sanofi were partnered on the drug in 2014, then in 2018, they restructured the agreement and Sanofi took full rights to fitusiran. Alnylam kept global development and commercial rights to its RNAi therapeutics programs for ATTR amyloidosis, including patisiran and ALN-TTRsc02, with Sanofi to receive royalties on any of those projects.