Impact of Baseline Neuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study

Marco Luigetti; Dianna Quan; John L Berk; Isabel Conceição; Yohei Misumi; Chi-Chao Chao; Shaun Bender; Emre Aldinc; John Vest; David Adams

doi:10.1007/s40120-024-00595-9

Impact of Baseline Neuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study

Neurol Ther. 2024 Jun;13(3):625-639. doi: 10.1007/s40120-024-00595-9. Epub 2024 Mar 21.

Authors

Marco Luigetti^{1

2}, Dianna Quan³, John L Berk⁴, Isabel Conceição⁵, Yohei Misumi⁶, Chi-Chao Chao⁷, Shaun Bender⁸, Emre Aldinc⁸, John Vest⁸, David Adams⁹

Affiliations

¹ Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy. mluigetti@gmail.com.
² Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy. mluigetti@gmail.com.
³ Department of Neurology, University of Colorado Anschutz, Aurora, CO, USA.
⁴ Boston Medical Center, Boston, MA, USA.
⁵ Department of Neurology, CHULN, Hospital Santa Maria and Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
⁶ Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁷ Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
⁸ Alnylam Pharmaceuticals, Cambridge, MA, USA.
⁹ Neurology Department, Université Paris-Saclay, U1195, INSERM, AP-HP, CHU Bicêtre, Le Kremlin Bicêtre, France.

Abstract

Introduction: Hereditary transthyretin (ATTRv, v for variant) amyloidosis is a rare, progressive, fatal disease with multisystem manifestations, caused by pathogenic variants in the transthyretin (TTR) gene. Vutrisiran, an RNA interference therapeutic that results in rapid TTR knockdown, improved neuropathy and quality of life (QOL) versus external placebo in patients with ATTRv amyloidosis with polyneuropathy in the phase 3 HELIOS-A study (NCT03759379). This post hoc analysis evaluates the impact of baseline neuropathy severity on response to vutrisiran treatment.

Methods: Patients were randomized (3:1) to vutrisiran (n = 122; 25 mg subcutaneous injection once every 3 months) or patisiran (n = 42; 0.3 mg/kg intravenous infusion once every 3 weeks), which served as a reference group. In this post hoc analysis, patients were grouped into quartiles of increasing baseline Neuropathy Impairment Score (NIS): Quartile (Q)1 ≥ 5.0 to ≤ 20.5; Q2 > 20.5 to ≤ 44.1; Q3 > 44.1 to ≤ 73.1; Q4 > 73.1 to ≤ 127.0. Mean change from baseline to Month 18 was summarized by quartile for a range of efficacy endpoints.

Results: Across all baseline NIS quartiles, vutrisiran demonstrated benefit versus external placebo in measures of neuropathy severity (modified NIS + 7), QOL (Norfolk Quality of Life-Diabetic Neuropathy), disability (Rasch-built Overall Disability Scale), gait speed (10-m walk test), and nutritional status (modified body mass index). Overall, patients in lower versus higher NIS quartiles (less severe neuropathy) at baseline maintained better scores at Month 18. The external placebo group progressively worsened in all measures at Month 18.

Conclusions: Vutrisiran demonstrated benefit in neurologic function and other key efficacy measures versus external placebo across all four baseline neuropathy severity quartiles. Patients initiating vutrisiran earlier in their disease course retained the highest neurologic function level after 18 months, highlighting the importance of early diagnosis and treatment.

Trial registration number: ClinicalTrials.gov: NCT03759379.

Keywords: ATTRv amyloidosis; Baseline NIS quartiles; Disability; Neuropathy severity; Nutritional status; Polyneuropathy; Quality of life; RNA interference; Vutrisiran.

Associated data

ClinicalTrials.gov/NCT03759379