Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

Abstract

Background

The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy.

Methods

HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months.

Results

HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10⁻¹²), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths.

Conclusions

Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile.

ClinicalTrials.gov

NCT03759379

Keywords:

• ATTRv amyloidosis
• hATTR amyloidosis
• patisiran
• RNA interference
• vutrisiran

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Acknowledgments

The authors would like to thank the patients and their families for their participation in the HELIOS-A study. In addition, they would like to thank Rebecca Shilling for her contribution to the study and manuscript content, Emre Aldinc for his contribution to the manuscript content, Rick Blakesley for his support in data analysis, and the members of the HELIOS-A Collaborators group for their work on the study (The HELIOS-A Collaborators list is available here). Editorial assistance was provided by Ed Childs of Adelphi Communication Ltd, and funded by Alnylam Pharmaceuticals.

Disclosure statement

Prof. Adams reports consultancy for Alnylam Pharmaceuticals, Eidos, and Pfizer Inc. Prof. Tournev reports speakers bureau/lecturer fees from Ewopharma, Genesis Pharma, Pfizer Inc., Roche, and Sanofi. Also, advisory board/committee and consultancy fees from Alnylam, Novartis, Pfizer, and Roche and research grants from Pfizer, Roche, and Sanofi. Dr. Taylor has received honoraria from Pfizer Inc. Dr. Coelho reports no financial disclosures. Institution was paid per protocol for the participation in the trials sponsored by Alnylam. Prof. Planté-Bordeneuve reports no financial disclosures. Dr. Berk reports consultancy for Akcea Therapeutics, Corino Therapeutics, Intellia Therapeutics, and Ionis Pharmaceuticals. Also, research funding from Pfizer Inc., and consultancy and research funding from Alnylam Pharmaceuticals, Eidos Therapeutics, and Ionis Pharmaceuticals. Dr. González-Duarte has received honoraria from Alnylam Pharmaceuticals and Pfizer Inc. Prof. Gillmore reports consultancy for Alnylam Pharmaceuticals. Dr. Low reports no financial disclosures. Prof. Sekijima reports honoraria and research funding from Alnylam Pharmaceuticals and Pfizer Inc. Dr. Obici reports speakers bureau fees from Akcea Therapeutics, Alnylam Pharmaceuticals, Pfizer Inc., and SOBI. Drs. Chen, Badri, and Arum report being employees of Alnylam Pharmaceuticals. Dr. Vest reports being an employee of Alnylam Pharmaceuticals, and reports ownership of equity in Alnylam Pharmaceuticals. Prof. Polydefkis reports consultancy for Akcea, Alnylam Pharmaceuticals, Biogen-Idec, Pfizer Inc., and Vertex Pharmaceuticals.

Data availability statement

De-identified individual participant data that support these results will be made available in a secure-access environment 12 months after study completion and when the product and indication have been approved for no less than 12 months in the US and the EU. Access will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.

Additional information

Funding

This study was funded by Alnylam Pharmaceuticals Inc. The funder collaborated with authors during study design, data collection, data analysis, data interpretation, and writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.