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Vutrisiran-Mediated Knockdown of Transthyretin in Patients with ATTR Amyloidosis

Publication Details

Clinical Pharmacokinetics

May 2026

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Author(s)

Marianna Fontana¹, Vincent Algalarrondo², Pablo Garcia-Pavia³, Mathew S Maurer⁴, Julian D Gillmore⁵, Francesco Cappelli⁶, Kiranmai Kolachana⁷, Xiuqing Gao⁷, Satyawan Jadhav⁷, Nitin Mehrotra⁷, Gabriel Robbie⁷, Prajakta Badri⁷

Affiliations

¹National Amyloidosis Centre, UCL, Division of Medicine, University College London, Royal Free Hospital, Pond Street, London, NW3 2QG, UK; ²French Reference Centre for Cardiac Amyloidosis Ceramic-Cardio, Department of Cardiology, Bichat University Hospital, AP-HP, Paris, France; ³Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; ⁴Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA; ⁵National Amyloidosis Centre, UCL, Division of Medicine, University College London, Royal Free Hospital, Pond Street, London, NW3 2QG, UK; ⁶Tuscan Regional Amyloidosis Centre and Cardiomyopathy Unit, Careggi University Hospital, University of Florence, Florence, Italy; ⁷Alnylam Pharmaceuticals, Cambridge, MA, USA

Abstract

Background:

We assessed the consistency of serum transthyretin (TTR) knockdown with the RNA interference therapeutic vutrisiran across subpopulations of patients with hereditary TTR amyloidosis (ATTR) with polyneuropathy (ATTRv-PN) in HELIOS-A (NCT03759379) and ATTR with cardiomyopathy (ATTR-CM) in HELIOS-B (NCT04153149).

Methods:

Patients received vutrisiran 25 mg subcutaneously every 3 months (Q3M). Serum TTR was measured during randomized treatment through Month 18 in HELIOS-A (post-dose/peak and pre-dose/trough sampling) and Month 30 in HELIOS-B (trough only, except Week 6). The effects of intrinsic/extrinsic factors on serum TTR knockdown from baseline were assessed. Pharmacokinetic/pharmacodynamic modeling was used to support consistency in TTR knockdown between studies.

Results:

Observed median (95% confidence interval [CI]) serum TTR knockdown with vutrisiran was 64.2% (61.6–67.8) at Week 3 (n = 114), with steady-state trough knockdown 86.2% (84.1–92.6) (n = 118) in HELIOS-A, and 69.0% (66.0–72.0) at Week 6 (n = 294), with steady-state trough knockdown 82.5% (80.5–84.9) (n = 307) in HELIOS-B. There were no meaningful differences in serum TTR percent knockdown across subgroups defined by baseline characteristics, including age, sex, ethnicity/race, weight, TTR genotype, N-terminal pro-B-type natriuretic peptide, and serum TTR concentration (both studies), and ATTRwt/ATTRv, disease stage/severity, troponin I, and tafamidis use (HELIOS-B), or anti-drug antibodies. Model-predicted peak serum TTR knockdown in HELIOS-B was sustained and consistent with observed knockdown in HELIOS-A; predicted median (95% CI) reduction at Month 30 was 87.1% (84.8–89.4).

Conclusions:

Vutrisiran led to rapid, sustained, and consistent TTR knockdown in HELIOS-A and HELIOS-B, supporting fixed-dose vutrisiran 25 mg Q3M across patients with ATTRv-PN and ATTR-CM.