Gene Silencers Cut ATTR-CM Events, Mostly in Patients Off Stabilizers

Transthyretin (TTR) gene-silencing therapies reduced death and recurrent cardiovascular (CV) events in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), but the benefit was concentrated among patients not already taking a TTR stabilizer, according to a meta-analysis published in JAMA.¹

The analysis pooled the 2 pivotal phase 3 outcomes trials of gene silencers in ATTR-CM: HELIOS-B (NCT04153149), which evaluated vutrisiran, and CARDIO-TTRansform (NCT04136171), which evaluated eplontersen. Together, the trials enrolled 2086 patients (1432 in CARDIO-TTRansform and 654 in HELIOS-B), with a median age of 77 years; 1902 participants were men. HELIOS-B met its primary end point, whereas CARDIO-TTRansform did not, and differences in design, eligibility, end point definitions, and background stabilizer use have made the 2 trials difficult to compare directly, the authors noted.

When CARDIO-TTRansform was presented at the European Society of Cardiology Congress 2026 in August, investigators reported 381 primary end point events among patients receiving eplontersen vs 392 among those receiving placebo (risk ratio [RR], 0.89; 95% CI, 0.73-1.09).² Most participants in that trial (57%) were already taking a stabilizer at baseline.

Gene Silencers Reduced Death and CV Events by 19%

Across both trials, gene silencers reduced the composite of all-cause death and recurrent CV events by 19% compared with placebo (RR, 0.81; 95% CI, 0.69-0.94; P = .006), with no evidence of heterogeneity between trials.¹ Treatment also lowered the risk of all-cause death (HR, 0.74; 95% CI, 0.61-0.91) and time to first all-cause death or CV event (HR, 0.77; 95% CI, 0.67-0.89).

Gene silencers also preserved functional capacity and health status. Patients receiving active treatment had a placebo-corrected 6-minute walk distance difference of 22.2 m (95% CI, 14.3-30.0) and a 4.5-point advantage on the Kansas City Cardiomyopathy Questionnaire–Overall Summary Score (95% CI, 2.7-6.2). By the end of the double-blind period, trough serum TTR levels had fallen by a mean of 81.0% with vutrisiran and 71.9% with eplontersen.

Safety was analyzed descriptively because the trials ascertained events differently, but rates of serious adverse events and treatment discontinuation were similar between the gene silencer and placebo groups, and no new safety signals emerged in either trial.

No Clear Added Benefit for Patients Already Taking Tafamidis

The effect on the primary end point differed significantly by baseline stabilizer use. Among patients not taking a stabilizer, gene silencers reduced the primary end point (RR, 0.69; 95% CI, 0.57-0.85), whereas no significant benefit was seen among patients already taking one (RR, 0.97; 95% CI, 0.77-1.23; P for heterogeneity = .03). Treatment effects on walk distance and health status were similarly attenuated in the stabilizer group. All baseline stabilizer use was tafamidis, which was more common in CARDIO-TTRansform than in HELIOS-B (57% vs 40%).

Because stabilizers and silencers act within the same disease pathway, the authors suggested that the TTR reductions achieved with current silencers may be redundant or insufficient to add benefit for patients already on a stabilizer. They also noted that HELIOS-B had suggested a possible incremental benefit in its relatively small stabilizer subgroup, but the larger CARDIO-TTRansform trial was neutral in that subgroup and carried more statistical weight in the pooled analysis.

The results are not definitive proof that gene silencers cannot add benefit to stabilizer therapy, the investigators cautioned. Limitations included reliance on trial-level rather than patient-level data, the fact that neither trial was powered to test combination therapy, tafamidis being the only stabilizer available at enrollment, and differences in background heart failure therapy between trials. Trials of next-generation therapies that achieve deeper TTR suppression, in which nearly all patients are expected to be receiving a stabilizer, will test whether greater lowering translates into added clinical benefit.

“The findings from this meta-analysis support TTR gene silencing for ATTR-CM,” wrote the researchers of the study. “The attenuated benefit observed for patients receiving concomitant TTR stabilizer therapy may reflect residual differences in case mix, disease duration, or magnitude of TTR suppression or a true ceiling on additional benefit of gene silencing in the setting of background TTR stabilization.”

References

1. Gillmore JD, Hamatani Y, Fontana M, et al. Gene silencer therapy in transthyretin amyloid cardiomyopathy: a meta-analysis of outcomes trials. JAMA. Published online August 30, 2026. doi:10.1001/jama.2026.17246
2. Eplontersen trial did not meet its primary endpoint in transthyretin-mediated amyloid cardiomyopathy. News release. European Society of Cardiology. August 28, 2026. Accessed October 15, 2026. https://www.escardio.org/news/press/press-releases/eplontersen-trial-did-not-meet-its-primary-endpoint-in-transthyretin-mediated-amyloid-cardiomyopathy/