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Background and Objective <p>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).</p> Methods <p>Patients received vutrisiran 25&#xa0;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.</p> Results <p>Observed median (95% confidence interval [CI]) serum TTR knockdown with vutrisiran was 64.2% (61.6–67.8) at Week 3 (<i>n</i>&#xa0;=&#xa0;114), with steady-state trough knockdown 86.2% (84.1–92.6) (<i>n</i>&#xa0;=&#xa0;118) in HELIOS-A, and 69.0% (66.0–72.0) at Week 6 (<i>n</i>&#xa0;=&#xa0;294), with steady-state trough knockdown 82.5% (80.5–84.9) (<i>n</i>&#xa0;=&#xa0;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, <i>TTR</i> genotype, <i>N</i>-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).</p> Conclusions <p>Vutrisiran led to rapid, sustained, and consistent TTR knockdown in HELIOS-A and HELIOS-B, supporting fixed-dose vutrisiran 25&#xa0;mg Q3M across patients with ATTRv-PN and ATTR-CM.</p> Graphical abstract <p></p>

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Vutrisiran-Mediated Knockdown of Transthyretin in Patients with ATTR Amyloidosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月27日

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  • Marianna Fontana,
  • Vincent Algalarrondo,
  • Pablo Garcia-Pavia,
  • Mathew S. Maurer,
  • Julian D. Gillmore,
  • Francesco Cappelli,
  • Kiranmai Kolachana,
  • Xiuqing Gao,
  • Satyawan Jadhav,
  • Nitin Mehrotra,
  • Gabriel Robbie,
  • Prajakta Badri

摘要

Background and Objective

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.

Graphical abstract