Rare Daily Staff

Alnylam Pharmaceuticals said it has halted dosing in ongoing trials following the death of a 78-year-old man with hemophilia A in a mid-stage open label extension study of the RNAi therapeutic.

The company said it has suspended dosing in all ongoing trials of fitusiran as it reviews the circumstances of the death and develops a risk mitigation strategy. Alnylam recently began a late-stage study of the drug in patients with hemophilia A and B, but had not yet dosed any patients. The company said it will resume the studies as soon as possible upon agreements with global regulatory authorities and the implementation of enhanced patient safety monitoring.

News of the clinical trial suspension sent shares in Alnylam downward. It closed at $72.53 per share on September 7, the day of the announcement. It was down $13.49, nearly a 16 percent decline.

The news was not only a blow to Alnylam, but also Sanofi Genzyme, which in 2014 entered into an alliance with the Cambridge, Massachusetts-based RNAi company for the development of RNAi therapeutics. As part of that agreement Sanofi Genzyme invested $700 million in Alnylam. In November 2016, Sanofi Genzyme exercised its right to co-develop and co-commercialize fitusiran in the United States, Canada, and Western Europe. That expanded on the company’s previous decision to exercise opt-in rights to develop and commercialize fitusiran in the rest of the world.

Hemophilia is a hereditary bleeding disorder caused by a genetic mutation that results in inadequate levels of thrombin, an enzyme that causes clotting. Fitusiran is an experimental RNAi therapy that is administered once-monthly. It targets antithrombin, a protein that inactivates certain enzymes involved in coagulation. Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding in patients with hemophilia A or B.

Currently the standard treatment for people with hemophilia involves replacement of the deficient clotting factor. The can restore the ability to generate adequate thrombin. However, about one third of the people with severe hemophilia A will develop a neutralizing antibody to their replacement factor and may become unable to benefit from it. Some hemophilia B patients develop a similar problem, but at a lower rate.

Approximately nine days prior to being admitted to a hospital, the man who died during the study developed exercise-induced right hip pain that was treated with a total of three doses of factor VIII concentrate on three separate days. Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, based on a CT scan, a physician diagnosed the patient as having a subarachnoid hemorrhage. He was treated with factor VIII. The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

His medical condition worsened during a 14-day hospitalization, despite the administration of factor VIII and the patient died from subsequent cerebral edema. Alnylam initiated further investigation of the patient’s death, including review of his CT scans by three independent neuro-radiologists, who all confirmed on September 1, 2017, that the initiating event was a cerebral venous sinus thrombosis, and not a subarachnoid hemorrhage.

As a result of the new information, Alnylam said it suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related fitusiran, and to develop a risk mitigation plan. Alnylam also postponed a scheduled webinar about fitusiran that had been scheduled for September 12.

September 7, 2017