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

• Published in: Amyloid Vol. 30; no. 1; pp. 18 - 26
• Main Authors: Adams, David, Tournev, Ivailo L., Taylor, Mark S., Coelho, Teresa, Planté-Bordeneuve, Violaine, Berk, John L., González-Duarte, Alejandra, Gillmore, Julian D., Low, Soon-Chai, Sekijima, Yoshiki, Obici, Laura, Chen, Chongshu, Badri, Prajakta, Arum, Seth M., Vest, John, Polydefkis, Michael
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.01.2023
• Subjects: Amyloid Neuropathies, Familial - complications; Amyloid Neuropathies, Familial - drug therapy; Amyloid Neuropathies, Familial - genetics; ATTRv amyloidosis; hATTR amyloidosis; Humans; patisiran; Polyneuropathies - complications; Polyneuropathies - drug therapy; Polyneuropathies - genetics; Prealbumin - genetics; Quality of Life; RNA interference; vutrisiran; RNA interference; patisiran; ATTRv amyloidosis; hATTR amyloidosis; vutrisiran
• ISSN: 1350-6129; 1744-2818
• DOI: 10.1080/13506129.2022.2091985

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. 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. 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. Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile. NCT03759379