FDA to Review Vutrisiran for Polyneuropathy of Hereditary ATTR Amyloidosis

The Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for vutrisiran for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults.

Polyneuropathy of hATTR is caused by the buildup of abnormal amyloid protein in peripheral nerves, the heart, and other organs. Vutrisiran is an investigational, subcutaneously-administered RNAi therapeutic designed to block the production of wild-type and mutant transthyretin protein. 

The NDA submission is supported by data from the global, randomized, open-label phase 3 HELIOS-A study (ClinicalTrials.gov Identifier: NCT03759379), which evaluated the efficacy and safety of vutrisiran in 164 adults with hATTR amyloidosis. Patients were randomly assigned 3:1 to receive vutrisiran (n=122) 25mg subcutaneously once every 3 months or patisiran (n=42) 0.3mg/kg intravenously once every 3 weeks for 18 months. The study used the placebo arm of the phase 3 APOLLO study (ClinicalTrials.gov Identifier: NCT01960348) as an external comparator for the primary and most secondary endpoints.

The primary endpoint was the change from baseline in the modified Neuropathy Impairment Score (mNIS+7) at 9 months. Key secondary endpoints included changes in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and gait speed assessed by the timed 10-meter walk test (10-MWT).

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Results showed that vutrisiran met the primary endpoint achieving a 2.24 point mean decrease in mNIS+7 score at 9 months compared with a 14.76 point mean increase for the external placebo arm (mean difference, 17.0 point; P <.001). These findings in the vutrisiran arm were consistent with that observed in the patisiran arm. 

Treatment with vutrisiran resulted in a 3.3 point mean decrease in Norfolk QoL-DN score at 9 months compared with a 12.9 point mean increase for the external placebo arm (mean difference, 16.2 point; P <.001). Patients treated with vutrisiran remained stable in gait speed, while patients in the external placebo arm worsened in gait speed (P <.001).

Vutrisiran was associated with an 83% reduction in mean steady-state serum transthyretin levels. Improvements in other exploratory endpoints were also observed, including the cardiac endpoint of NT-proBNP, change in modified body mass index and the Rasch-built overall disability scale.

Regarding safety, treatment-emergent adverse events included diarrhea, pain in extremity, fall, and urinary tract infections. Dyslipidemia and urinary tract infection were reported as serious drug-related adverse events related to vutrisiran.

A Prescription Drug User Fee Act (PDUFA) target date of April 14, 2022 has been set for the application. “If approved, once-quarterly, subcutaneously administered vutrisiran may represent a new treatment option that potentially reverses polyneuropathy manifestations of disease,” said Rena Denoncourt, Vice President, TTR Franchise Lead.

The FDA previously granted Orphan Drug and Fast Track designations to vutrisiran for the treatment of polyneuropathy of hATTR amyloidosis in adults.


Alnylam announces U.S. Food and Drug Administration acceptance of New Drug Application for investigational vutrisiran for the treatment of the polyneuropathy of hereditary ATTR amyloidosis. [press release]. Cambridge, MA: Alnylam Pharmaceuticals, Inc.; June 24, 2021. Alnylam presents positive results from HELIOS-A phase 3 study of investigational vutrisiran. [press release]. Cambridge, MA: Alnylam Pharmaceuticals, Inc.; April 19, 2021.

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