Structure of RNA
Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.
Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.
As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.
Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.
Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.
“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.
“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. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”
About the patient
Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.
Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 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, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.
Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.
The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.
For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.
All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.
As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.
The company also notified study investigators and global regulatory authorities.
About fitusiran
Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.
Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.
The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.
