“The future looks brighter after these results.” The discussion that followed the presentation of the study opened with these words by Esther Gonzalez Lopez, cardiologist at the Hospital Universitario Puerta de Hierro Majadahonda in Madrid. HELIOS-B on the efficacy of the siRNA vutrisiran in the treatment of patients with cardiac transthyretin amyloidosis (ATTR-CM), which took place during the first day of the annual meeting of the European Congress of Cardiology (ESC 2024) underway in London.
The results of the study, presented during the first Hotline session of the event and published simultaneously on New England Journal of Medicine (1), highlighted the efficacy of vutrisiran in significantly reducing mortality, cardiovascular events and progression markers in patients affected by this disease.
The HELIOS-B trial was a randomized, double-blind, Phase III study in 655 patients (mean age: 76.5 years) with hereditary or wild-type ATTR-CM recruited from 87 centers in 26 countries. Patients, almost all of whom were male (92.5%), were randomized 1:1 to receive either vutrisiran 25 mg or placebo, administered subcutaneously every 3 months for up to 36 months. More than three-quarters (77.6%) of patients had NYHA class II heart failure and 40% were taking tafamidis at study entry (130 in the experimental group and 130 in the lacebo group).
“We evaluated two prespecified populations: the overall population and the vutrisiran monotherapy population, consisting of patients not receiving tafamidis at baseline,” explained Marianna Fontana of the National Amyloidosis Centre, University College London, who presented the study results in London.
The primary endpoint of the trial was a composite measure of all-cause mortality and recurrent cardiovascular events, assessed – at the time the last patient reached 33 months from enrollment – in the overall population and in the population composed of patients on vutrisiran monotherapy.
Secondary endpoints were all-cause mortality up to 42 months, change from baseline to 30 months in functional capacity (6-minute walk test), quality of life (Kansas City Cardiomyopathy Questionnaire Overall Summary), and NYHA class.
The study met its primary endpoint in both populations considered. Treatment with vutrisiran significantly reduced the risk of all-cause mortality and recurrent cardiovascular events by 28% in the overall population (HR 0.72; 95% CI 0.56–0.93; p=0.012) and by 33% in the monotherapy population (HR 0.67; 95% CI 0.49–0.93; p=0.016).
“In the overall population, considering the double-blind period, a significant nominal difference was observed for both components of the primary endpoint,” Fontana emphasized. “Both components contributed comparably to the composite outcome, with a 31% reduction in all-cause mortality and a 27% reduction in cardiovascular events.”
Furthermore, all-cause mortality was reduced by 36% in the overall population (HR 0.64; 95% CI 0.46–0.90; p=0.01) and by 35% in the monotherapy population (HR 0.65; 95% CI 0.44–0.97; p=0.045) also at 42-month follow-up. Similarly, secondary endpoints of functional capacity, health status and quality of life were also significantly improved with vutrisiran compared to placebo.
In a predefined subgroup analysis, the composite primary endpoint was also reduced by 21% in patients treated with tafamidis (HR 0.79; 95% CI 0.51–1.21). In the same population, all-cause mortality was reduced by 41% (0.59; 95% CI 0.32–1.08). “Even though the study did not have the statistical power necessary to establish an effect in this group of patients,” Fontana commented, “these results suggest an additional benefit of vutrisiran on top of treatment with tafamidis.”
Finally, regarding safety, most of the adverse events that occurred in the vutrisiran-treated group were mild or moderate. Adverse events that led to drug discontinuation were similar in the vutrisiran (3.1%) and placebo (4.0%) groups.
“Vutrisiran – concluded the cardiologist from University College London – achieved all ten endpoints of the HELIOS-B study, primary and secondary, with a reduction in all-cause mortality and cardiovascular events. If approved, this drug has the potential to become the standard of care for newly diagnosed patients and those who progress despite stabilizing therapies.”
Bibliography
1. Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. N Engl J Med 2024; 391:DOI: 10.1056/NEJMoa2409134.