Alnylam Pharmaceuticals has suspended patient dosing in all ongoing studies of its RNA therapy fitusiran to treat hemophilia A or B, after a patient died of swelling in the brain in a Phase 2 open-label extension trial.
The company will work with the regulatory agencies in reviewing the cause of the death and in making any necessary changes, Alnylam said in a statement on the suspension. It hopes to resume trial dosing by the end of the year.
“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” Akshay Vaishnaw, executive vice president of research and development at Alnylam, said in the release. “We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development.”
Fitusiran, also known as ALN-AT3SC, is designed to specifically lower levels of antithrombin — a protein that inhibits clotting — to improve production of thrombin, a clotting factor. As such, it aims to create a better balance of clotting components that would prevent bleeding events in hemophilia A and B patients.
The OLE study (NCT02554773) involves 33 patients, 27 with hemophilia A and six with hemophilia B, who are being treated with fixed, once monthly 50 mg or 80 mg doses by subcutaneous injection. According to a company release in July, fitusiran showed “encouraging” safety and tolerability at 20 months of treatment “with no thromboembolic events.”
Data from a Phase 1 study (NCT02035605) — whose patients were invited to continue with treatment in the extension trial —demonstrated that once-monthly fitusiran injections lowered antithrombin levels and improved thrombin production.
The death of a patient with hemophilia A was labeled a “thromboembolic event” and is considered to possibly be connected to his treatment. The patient, whose fitusiran dose level or trial site was not identified, complained of a severe headache after a third dosing and was hospitalized. Despite several administrations of factor VIII concentrate, his condition worsened, and he developed a brain hemorrhage and subsequent cerebral edema.
Initial reports by the trial’s investigator considered the cause of death to have been independent of treatment — the results of an unrelated brain hemorrhage — but independent investigators brought in by Alnylam determined that it was a blood clot that led blood vessels in the brain to rupture, leading to the edema.
This trial, and the ATLAS Phase 3 program testing fitusiran in hemophilia patients — which has not yet begun dosing — are on hold while investigations continue and the company develops a “risk mitigation plan” working with all involved regulatory agencies. The ATLAS program comprises three independent trials of fitusiran in patients with hemophilia A and B, with or without alloantibodies, including those on prophylactic therapy.
Alnylam is developing fitusiran and other RNAi therapeutics in collaboration with Sanofi Genzyme.