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FDA Extends Review of Vutrisiran for ATTR Amyloidosis 3 Months, Now Expected in July 2022

Alnylam’s investigational subcutaneous RNAi therapy is in development for both wild-type and hereditary transthyretin-mediated amyloidosis, with data from the phase 3 HELIOS-A trial demonstrating its potential in treating associated polyneuropathy.

Vutrisiran, an investigational subcutaneous RNA interface (RNAi) therapy in development for the treatment of transthyretin-mediated (ATTR) amyloidosis—both hereditary (hATTR) and wild-type—has had its FDA review period extended 3 months. The Alnylam product’s new drug application (NDA) now has a target review date of July 14, 2022.1

Importantly, there are no additional clinical data requests from the FDA. In a statement, Alnylam announced that this extension on the review period has been offered to allow for the appraisal of new information related to a secondary packaging and labeling facility that had recently been inspected and needed classification for the FDA to complete its review, with no issues directly related to vutrisiran. Alnylam noted that it had identified a new facility for those processes and submitted an amendment to the NDA as a result.

“We are committed to working with the FDA and the new facility to bring this important treatment option as quickly as possible to patients living with the polyneuropathy of hATTR amyloidosis, an inherited, progressively debilitating, and fatal disease,” Pushkal Garg, MD, chief medical officer, and executive vice president, Development and Medical Affairs, Alnylam, said in a statement.1 “We are confident in our regulatory application and the body of data supporting the efficacy and safety of vutrisiran.”

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The Alnylam product was granted fast track designation by the FDA for the treatment of polyneuropathy related to hATTR amyloidosis in April 2020, shortly after completing enrollment for its phase 3 HELIOS-A study (NCT03759379). The original data announcement displaying vutrisiran’s potential for hATTR amyloidosis from that trial were announced in January 2021.2 A year later, new 18-month data on the RNAi therapy were announced, demonstrating that it met the secondary end points measured in HELIOS-A.3

Those 18-month data showed a statistically significant improvement in neuropathy impairment, as well as quality of life, gait speed, nutritional status, and overall disability for those treated with vutrisiran compared with the comparator drug, patisiran (Onpratto; Alnylam). Additional findings suggested that vutrisiran was not inferior to patisiran in reducing serum TTR, with a mean baseline reduction of 88%.3

HELIOS-A included 164 participants with hATTR amyloidosis and polyneuropathy, who were randomized 3:1 to either 25-mg vutrisiran (n = 122) or 0.3-mg/kg patirisan (n = 42), as well as an external placebo group (n = 77). After 18 months of treatment, those treated with vutrisiran experienced a mean 0.46-point decrease in modified Neuropathy Impairment Score compared with 28.09 increase in the placebo group. As well, those treated with vutrisiran reported a mean 1.2-point decrease in Norfolk Quality of Life–Diabetic Neuropathy scores compared with a mean 19.8-point increase for those on placebo.

In March 2021, shortly after the topline results of the HELIOS-A study were announced, NeurologyLive® convened a panel of experts in the care of hATTR amyloidosis, including John L. Berk, MD; P. James B. Dyck, MD; Michael J. Polydefkis, MD; Thomas H. Brannagan III, MD; and Ronald Witteles, MD. The group provided commentary on the second-generation TTR gene silencer’s efficacy at 9 months, providing their perspectives on what it might bring to the landscape. Check out more of that conversation below.

REFERENCES
1. Alnylam Announces 3-Month Extension of Review Period for New Drug Application for Vutrisiran. News release. Alnylam. April 4, 2022. Accessed April 13, 2022. https://www.businesswire.com/news/home/20220404005293/en/Alnylam-Announces-3-Month-Extension-of-Review-Period-for-New-Drug-Application-for-Vutrisiran
2. Alnylam reports positive topline results from HELIOS-A phase 3 study of vutrisiran in patients with hATTR amyloidosis with polyneuropathy. News release. Alnylam Pharmaceuticals. January 7, 2021. Accessed April 13, 2022. https://www.businesswire.com/news/home/20210107005224/en/Alnylam-Reports-Positive-Topline-Results-from-HELIOS-A-Phase-3-Study-of-Vutrisiran-in-Patients-with-hATTR-Amyloidosis-with-Polyneuropathy
3. Alnylam presents positive 18-month results from HELIOS-A phase 3 study of investigational vutrisiran in patients with hATTR amyloidosis with polyneuropathy. News release. Alnylam Pharmaceuticals. January 21, 2022. Accessed April 13, 2022. https://www.businesswire.com/news/home/20220121005075/en/Alnylam-Presents-Positive-18-Month-Results-from-HELIOS-A-Phase-3-Study-of-Investigational-Vutrisiran-in-Patients-with-hATTR-Amyloidosis-with-Polyneuropathy