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

Publication Details

Neurology and Therapy

March 2024

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Author(s)

Marco Luigetti¹ ², Dianna Quan³, John L Berk⁴, Isabel Conceição⁵, Yohei Misumi⁶, Chi-Chao Chao⁷, Shaun Bender⁸, Emre Aldinc⁸, John Vest⁸, David Adams⁹

Affiliations

¹Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy; ²Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy; ³Department of Neurology, University of Colorado Anschutz, Aurora, CO, USA; ⁴Boston Medical Center, Boston, MA, USA; ⁵Department of Neurology, CHULN, Hospital Santa Maria and Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; ⁶Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; ⁷Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan; ⁸Alnylam Pharmaceuticals, Cambridge, MA, USA; ⁹Neurology 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.