News|Articles|September 4, 2026

Vutrisiran Effects Consistent With, Without Tafamidis in ATTR-CM

Listen

0:00 / 0:00

Key Takeaways

In HELIOS-B (n=654), baseline tafamidis use (40%) did not significantly modify vutrisiran’s effect on mortality plus recurrent cardiovascular events (Pinteraction=.55), despite numerically smaller effects with tafamidis.
Six-Minute Walk Test decline was attenuated with vutrisiran regardless of tafamidis, whereas KCCQ-OSS placebo-corrected differences at month 30 were modest with tafamidis (+1.8) and larger without (+8.7).
Safety profiles were generally comparable for vutrisiran+tafamidis versus tafamidis alone and for vutrisiran monotherapy versus placebo; HELIOS-B was not powered to confirm combination benefit.
Real-world French data indicated extracardiac manifestations often precede ATTR-CM recognition by years and accumulate over time, supporting a prolonged prediagnostic, multisystem disease trajectory.
Post hoc and pooled analyses suggested reduced intrinsic-capacity decline, fewer overall adverse events versus placebo, sex-consistent efficacy across 4 phase 3 datasets, and less left atrial strain deterioration with vutrisiran.

Late-breaking HELIOS-B subgroup data show mortality and CV benefits held regardless of baseline tafamidis use, per results at ESC Congress 2026.

New data presented at the European Society of Cardiology (ESC) Congress 2026 and simultaneously published in the Journal of the American College of Cardiology show that vutrisiran (Amvuttra; Alnylam), an RNA interference (RNAi) therapeutic, provided consistent clinical benefit in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) whether or not they were also taking the TTR stabilizer tafamidis at baseline.¹

“These data add to the deep and consistent evidence base supporting RNAi-mediated TTR silencing in ATTR-CM,” said Teresa Trenkwalder, MD, senior physician at TUM University Hospital German Heart Center, in a statement. “Across patient populations, treatment settings, and manifestations of disease, the analyses of vutrisiran demonstrate the clinical benefit that can be achieved by reducing TTR production at its source.”

Consistent Treatment Effects Across Baseline Tafamidis Use

The prespecified subgroup analysis included 654 randomized and treated patients from the phase 3 HELIOS-B trial (NCT04153149), of whom 259 (40%) were receiving tafamidis at baseline.² For the trial's primary composite end point of all-cause mortality and recurrent cardiovascular events through 36 months, the treatment effect of vutrisiran vs placebo was directionally consistent among patients receiving tafamidis at baseline (rate ratio [RR], 0.79; 95% CI, 0.51-1.21) and those not receiving tafamidis (RR, 0.67; 95% CI, 0.49-0.93), with no statistically significant interaction by baseline tafamidis use (P for interaction = .55).

Similar patterns were observed for the individual components of the primary end point, although treatment-effect estimates were numerically smaller among patients receiving tafamidis. Vutrisiran also attenuated declines in functional capacity, as measured by the Six-Minute Walk Test, in both baseline-tafamidis subgroups, with no significant interaction between treatment effect and tafamidis use.

Effects on health status, measured by the Kansas City Cardiomyopathy Questionnaire-overall summary score differed significantly by baseline tafamidis status over time. At month 30, the placebo-corrected difference favored vutrisiran by 1.8 points among patients receiving tafamidis and by 8.7 points among those not receiving tafamidis.

Safety findings were generally similar between vutrisiran plus tafamidis and tafamidis alone, as well as between vutrisiran monotherapy and placebo. The authors emphasized that HELIOS-B was not powered specifically to establish benefit in the baseline-tafamidis subgroup and concluded that further study is needed to clarify the effects of combining TTR silencing with TTR stabilization.

Broader Analyses Examine Multisystemic and Cross-Sex Effects

Additional analyses presented at ESC 2026 extended the evaluation of ATTR-CM beyond traditional cardiac outcomes. Real-world data from the French National Health Data System show that patients with ATTR-CM had a greater burden of extracardiac manifestations than matched controls, with manifestations across multiple organ systems appearing years before ATTR-CM identification and accumulating over time.¹ These findings support the concept of ATTR-CM as part of a multisystem disease process with a potentially prolonged prediagnostic phase.

A post hoc HELIOS-B analysis of intrinsic capacity, a composite measure encompassing domains of healthy aging, found that vutrisiran was associated with 25% less decline in intrinsic capacity and a 52% lower risk of decline compared with placebo.

A separate post hoc safety analysis found fewer adverse events overall with vutrisiran than with placebo, including reported reductions of 42% in gastrointestinal disorders, 41% in nervous system disorders, and 46% in eye disorders. A pooled analysis of 1402 patients across 4 phase 3 studies of vutrisiran and patisiran found consistent treatment effects between women and men despite differences in baseline disease presentation.

These findings add to a growing body of HELIOS-B secondary analyses examining cardiac structure and function. A separate analysis published in JAMA Cardiology found that left atrial reservoir and contractile strain were severely impaired in patients with ATTR-CM and were independently associated with adverse clinical outcomes, including all-cause mortality or recurrent cardiovascular events and incident atrial fibrillation or flutter.³Patients randomized to vutrisiran showed less deterioration in left atrial strain than those receiving the placebo.

The findings also arrive as diagnosed ATTR-CM prevalence continues to increase in the US.⁴ A recent analysis of large US insurance databases found rising incidence and prevalence over the study periods, accompanied by an increasing burden of comorbidities before ATTR-CM diagnosis.

Alnylam estimates that more than 500,000 people worldwide live with ATTR amyloidosis and that approximately 80% remain undiagnosed.

Taken together, the ESC 2026 findings expand the HELIOS-B evidence base across baseline treatment settings, disease manifestations, and patient populations. The baseline-tafamidis analysis found no evidence that treatment effects differed significantly according to tafamidis use, but additional studies will be needed to determine the clinical benefit of combining TTR silencing with TTR stabilization in ATTR-CM.¹

References

Alnylam presents new data at ESC Congress 2026 reinforcing strength in RNAi-powered TTR silencing across ATTR-CM patient populations and treatment settings. News release. Alnylam Pharmaceuticals, Inc. August 30, 2026. Accessed September 1, 2026. https://investors.alnylam.com/press-release?id=30006
Hamatani Y, Claggett B, Cuddy S, et al. Effect of vutrisiran according to baseline tafamidis use in transthyretin amyloidosis with cardiomyopathy: insights from HELIOS-B. JACC. 2026:S0735-1097(26)07208-6. doi:10.1016/j.jacc.2026.07.022
Jering KS, Manafi A, Claggett BL, et al. Left atrial structure and function, clinical outcomes, and efficacy of vutrisiran in transthyretin amyloidosis with cardiomyopathy: a secondary analysis of the HELIOS-B randomized clinical trial. JAMA Cardiol. 2026:e262992. doi:10.1001/jamacardio.2026.2992
Steinzor P. ATTR-CM incidence and prevalence rose sharply in the US. AJMC^®. June 23, 2026. Accessed September 1, 2026. https://www.ajmc.com/view/attr-cm-incidence-prevalence-rose-sharply-in-the-us