Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy (HELIOS-B)

Authors, Journal, Affiliations, Type, DOI

• Fontana M, Berk JL, Gillmore JD, Witteles RM, Grogan M, Drachman B, Damy T, Garcia-Pavia P, Taubel J, Solomon SD, et al. (HELIOS-B Trial Investigators)
• N Engl J Med 2025;392:33–44
• Multi-institutional (87 sites, 26 countries); corresponding author at National Amyloidosis Centre, University College London
• Phase 3, international, multicenter, double-blind, randomized, placebo-controlled trial
• DOI: https://doi.org/10.1056/NEJMoa2409134
• Funded by Alnylam Pharmaceuticals

Overview

HELIOS-B is a landmark phase 3 double-blind RCT (n=655) evaluating vutrisiran — a subcutaneous siRNA therapeutic (25 mg every 12 weeks) that silences hepatic TTR mRNA — in patients with variant or wild-type ATTR-CM. Vutrisiran significantly reduced the composite primary endpoint of all-cause death and recurrent cardiovascular events (HR 0.72; 95% CI 0.56–0.93; P=0.01) and reduced all-cause mortality through 42 months (HR 0.65; 95% CI 0.46–0.90; P=0.01). Functional capacity (6-minute walk test) and quality of life (KCCQ-OS) were better preserved with vutrisiran. Benefits were consistent across the overall population (including patients on background tafamidis) and in the monotherapy population (not on tafamidis), suggesting additive benefit beyond TTR stabilization.

Keywords

Transthyretin amyloidosis, cardiomyopathy, vutrisiran, RNA interference, siRNA, tafamidis, ATTR-CM, wild-type ATTR, variant ATTR, HELIOS-B, NT-proBNP, 6-minute walk test, KCCQ, heart failure

Key Takeaways

Background and Rationale

• ATTR-CM is progressive and fatal with a median survival of 2–6 years after diagnosis; tafamidis (TTR tetramer stabilizer) was the only approved therapy and while it reduces mortality, quality of life and functional capacity continued to decline.
• Vutrisiran is a GalNAc-conjugated siRNA with phosphonothioate linkages and increased 2'-O-methyl nucleotide content, targeting hepatic TTR mRNA (both WT and variant) via the asialoglycoprotein receptor — allows once-every-3-months dosing.
• Prior HELIOS-A trial (vutrisiran in hereditary ATTR polyneuropathy) suggested exploratory cardiac benefit (NT-proBNP, echocardiographic, and scintigraphy measures), supporting the HELIOS-B hypothesis.

Study Design

• Phase 3, double-blind, placebo-controlled RCT; 1:1 randomization; vutrisiran 25 mg SC vs placebo every 12 weeks for up to 36 months.
• Stratified by: tafamidis use at baseline (yes/no), ATTR type (variant/wild-type), NYHA class/age.
• Key inclusion criteria: age 18–85; confirmed ATTR-CM (biopsy or validated scintigraphy criteria); IVS wall thickness >12 mm; history of HF; NT-proBNP 300–8500 pg/mL (or 600–8500 with AF); 6MWT ≥150 m.
• Key exclusion criteria: NYHA class IV; NYHA III with NAC ATTR stage 3; eGFR <30 mL/min/1.73m²; polyneuropathy disability score ≥IIIa.
• Monotherapy population: patients not on tafamidis at baseline (60% of each group; 196 vutrisiran, 199 placebo).
• All patients instructed to take recommended daily allowance of vitamin A (TTR is a retinol carrier).
• Open-label extension available after double-blind period.

Patient Characteristics

• n=655; median age 77 years; 93% male; 88% wild-type ATTR; 78% NYHA class II; 40% on tafamidis at baseline.
• Among variant ATTR patients (n=76), 13 different pathogenic TTR variants identified; V122I most common (64%).
• Among monotherapy population, ~22% initiated tafamidis during the trial; ~33% of overall population started SGLT2 inhibitor during trial.
• Generally less severe disease at baseline than ATTR-ACT cohort (better 6MWT, KCCQ, NT-proBNP, troponin, NYHA).

Primary Endpoint: Death from Any Cause and Recurrent CV Events

• Overall population: HR 0.72 (95% CI 0.56–0.93; P=0.01) — vutrisiran vs placebo. 125 (38%) vs 159 (48%) with ≥1 primary endpoint event.
• Monotherapy population: HR 0.67 (95% CI 0.49–0.93; P=0.02). 76 (39%) vs 105 (53%) with ≥1 primary endpoint event.
• Benefit consistent across both components (death and CV hospitalizations/urgent visits).
• Time-to-first-event analysis: HR 0.72 (95% CI 0.57–0.91; P=0.006) overall; HR 0.64 (95% CI 0.48–0.87; P=0.004) monotherapy.
• Kaplan-Meier curves diverged after approximately 6 months.
• Benefit broadly consistent across all prespecified subgroups (age, tafamidis use, ATTR type, NYHA class, NT-proBNP level).

Secondary Endpoints: Mortality

• All-cause mortality through 42 months, overall population: HR 0.65 (95% CI 0.46–0.90; P=0.01). 60 (18%) vs 85 (26%) deaths.
• All-cause mortality through 42 months, monotherapy population: HR 0.66 (95% CI 0.44–0.97; P=0.045).
• 42-month timepoint chosen to capture more events and improve precision; mortality benefit not expected in first 6 months (consistent with ATTR-ACT tafamidis data showing delayed effect).

Secondary Endpoints: Functional Capacity and Quality of Life

• 6-minute walk test at 30 months (overall): LS mean change −45.4 m (vutrisiran) vs −71.9 m (placebo); difference +26.5 m (95% CI 13.4–39.6; P<0.001).
• KCCQ-OS at 30 months (overall): LS mean change −9.7 points (vutrisiran) vs −15.5 points (placebo); difference +5.8 points (95% CI 2.4–9.2; P<0.001) — exceeds 5-point MCID threshold.
• NYHA class improvement or no change at 30 months: 68% vutrisiran vs 61% placebo; LS mean difference 8.7 percentage points (95% CI 1.3–16.1; P=0.02).
• Similar benefits in monotherapy population for all secondary endpoints.
• Median changes over time showed relative stability in vutrisiran group (vs decline in placebo).

Pharmacodynamics

• Mean trough serum TTR reduction: 81.0% (95% CI 79.0–83.0) at 30 months — rapid and sustained.

Safety

• Adverse events in 99% (vutrisiran) vs 98% (placebo) — essentially identical rates.
• Serious adverse events: 62% (vutrisiran) vs 67% (placebo).
• Discontinuation: 3% (vutrisiran) vs 4% (placebo).
• No clinically relevant changes in laboratory measures, vital signs, or ECG in either group.
• No new safety signals identified (consistent with HELIOS-A safety profile).

Discussion and Context

• HELIOS-B extends TTR-lowering RNAi benefit (initially shown in polyneuropathy in HELIOS-A) to cardiomyopathy, both wild-type and variant ATTR.
• The trial included healthier patients at baseline than ATTR-ACT, yet still showed HR 0.65 for all-cause mortality — suggesting potential benefit even in earlier disease stages.
• Concurrent SGLT2 inhibitor use (33%) and tafamidis use (40%) did not attenuate vutrisiran benefit.
• The LWYY model limitation (treats death and CV events equally) addressed by consistent win-ratio and time-to-first-event sensitivity analyses.

Limitations of the document

• Tafamidis was an allowed background therapy but not randomized — no head-to-head comparison of vutrisiran monotherapy vs tafamidis alone possible.
• Trial not powered for statistical significance within tafamidis-on subgroup alone (40% of patients).
• 93% male and predominantly White — limits generalizability to women and diverse populations.
• Low proportion of variant ATTR (12%) reflecting global preponderance of wild-type.
• Industry-funded (Alnylam Pharmaceuticals) with sponsor involvement in design and analysis.
• Median follow-up up to 36 months double-blind; 42-month mortality endpoint includes open-label extension crossover (placebo → vutrisiran).

Key Concepts Mentioned

• concepts/Gene-Silencing-Therapy — vutrisiran as clinical-stage GalNAc-siRNA for TTR mRNA knockdown
• concepts/Cardiac-Amyloidosis-Imaging — scintigraphy used for ATTR-CM diagnosis

Key Entities Mentioned

• entities/ATTR-Amyloidosis — primary disease studied; vutrisiran as new disease-modifying therapy
• entities/Vutrisiran — the therapeutic agent studied in HELIOS-B
• entities/Heart-Failure — primary clinical manifestation and outcome domain
• entities/Sotatercept — N/A (not mentioned, but context of expanding ATTR therapeutic options)

Wiki Pages Updated

• wiki/sources/vutrisiran-attrcm-heliosb-nejm-2025.md — created
• wiki/entities/ATTR-Amyloidosis.md — updated with HELIOS-B results, vutrisiran as second disease-modifying class
• wiki/entities/Vutrisiran.md — created
• wiki/concepts/Gene-Silencing-Therapy.md — updated with HELIOS-B data for vutrisiran in ATTR-CM
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated