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

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 x 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