Rare Disease Report

Safety Concern Lead Alnylam to Halt Revusiran Program to Treat TTR Amyloidosis w/ Cardiomyopathy

OCTOBER 06, 2016
James Radke, PhD
Alnylam Pharmaceuticals announced it has stopped all clinical studies involving revusiran as a possible treatment for hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM). This includes their Phase 3 pivotal ENDEAVOR study.
This decision follows the recent reports of peripheral neuropathy developing or worsening in some patients enrolled in a Phase 2 open label extension study. During a recent Data Monitoring Committee Meeting, it could not be determined if the new reports of peripheral neuropathy were related to the drug however, the committee did report that the ‘benefit-risk profile for revusiran no longer supported continued dosing.’
While details remain sketchy, the Alnylam also noted that an unblended review of the ongoing phase 3 ENDEAVOR data revealed an imbalance of mortality in the revusiran arm as compared to placebo.
In a press release, John Maraganore, Ph.D., Chief Executive Officer at Alnylam  said:

“Patient safety comes first. We have stopped all dosing and are actively monitoring patients across revusiran studies to ensure their safety. We will also continue to evaluate ENDEAVOUR data to understand the potential cause of these findings.”
Dr Maraganore added:

 “While this outcome is disappointing given the lack of available treatment options for patients suffering from this devastating disease, we remain committed to serving the needs of the ATTR amyloidosis community. We would like to thank patients, caregivers, investigators, and study staff who have been so supportive of the revusiran program."
The decision to discontinue development of revusiran does not affect patisiran, which is currently in Phase 3 development for the treatment of hATTR amyloidosis with polyneuropathy (hATTR-PN), or any other Alnylam investigational RNAi therapeutic program in development.

What is hereditary TTR-mediated amyloidosis (hATTR amyloidosis)

Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier of vitamin A. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.

Two forms of the condition can be separated based on the damaged, either towards neural tissue [familial amyloidotic polyneuropathy (FAP) or hATTR-PN] or cardiac tissue – [familial amyloidotic cardiomyopathy (FAC) or hATTR-CM]. Patients with hATTR-PN have a life expectancy of 5-15 years following symptom onset whereas patients with hATTR-CM live 2.5 – 5 years following symptom onset (if left untreated).

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