Vutrisiran Reduces Cardiovascular Risk, Improves Quality of Life in ATTR-CM

The HELIOS-B trial has returned promising results, indicating use of vutrisiran (Amvuttra), a novel RNA interference therapy, could provide significant benefit on both outcomes and quality of life for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM).

Presented at the European Society of Cardiology (ESC) Congress 2024, results indicate use of vutrisiran was associated with reduced all-cause mortality and recurrent cardiovascular events as well as benefits in multiple markers of disease progression, with these effects statistically significant regardless of use as monotherapy or with background tafamidis (Vyndamax).

“We investigated whether a novel RNA interference therapeutic, vutrisiran, which targets transthyretin production, could improve clinical outcomes in patients with ATTR-CM and the results were very promising,” said principal investigator Marianna Fontana, MD, PhD, professor of Cardiology and honorary consultant cardiologist at the National Amyloidosis Centre in the Division of Medicine at University College London.

According to recent estimates, ATTR-CM impacts an estimated 300,000 to 500,000 individuals. In the US, estimates indicate 100,000 people live with ATTR-CM but only 1 to 2% have received a diagnosis. Despite the US Food and Drug Administration approval of tafamidis in 2019, ATTR-CM continues to represent a major area of unmet need in cardiology.

Vutrisiran received approval from the FDA for treatment of hereditary ATTR amyloidosis with polyneuropathy based on the phase 3 HELIOS-A trial. HELIOS-B was born out of subanalyses from HELIOS-A demonstrating benefit on cardiovascular manifestations of the HELIOS-A trial.

An international, phase 3, multicenter, double-blind, randomized, placebo-controlled trial, patients in HELIOS-B underwent a 45-day screening period prior to randomization. After the screening period, patients were randomized in a 1:1 ratio to vutrisiran 25 mg or placebo administered subcutaneously once every 3 months for up to 36 months.

Overall, 655 patients from 87 sites in 26 countries were recruited, completed the screening period, and underwent randomization. This cohort had a mean age of 76.5 years, 92.5% were male, 77.6% had NYHA class II heart failure, and 40% were taking tafamidis at baseline.

The trial’s primary endpoint was difference in risk of a composite outcomes consisting of all-cause mortality and recurrent cardiovascular events during the double-blind period, with a specific interest in examining risk among the overall population and those receiving monotherapy vs those on tafamidis at baseline. The trial’s secondary outcomes included changes from baseline to month 30 in 6-MWT distance, from baseline to month 30 in KCCQ-OS, from baseline to month 30 in NYHA class, and all-cause mortality through 42 months.

Results of the trial indicated vutrisiran achieved statistical significance on all primary and secondary endpoints. For the primary composite endpoints, vutrisiran was associated with a 28% (Hazard Ratio [HR], 0.72; 95% Confidence Interval [CI], 0.56 to 0.93; P = .01) relative risk reduction among the overall population and a 33% (HR, 0.67; 95% CI, 0.49 to 0.93; P = .016) relative risk reduction among the monotherapy population, and a 21% (HR, 0.79; 95% CI, 0.51 to 1.21) relative risk reduction among those with background tafamidis use.

Analysis of secondary outcomes suggested vutrisiran use was associated reduced all-cause mortality over 42 months among both the overall (HR 0.64; 95% CI, 0.46 to 0.90; P = .01) and monotherapy populations (HR, 0.65; 95% CI, 0.44 to 0.97; P = .045). Additionally, use of vutrisiran was associated with benefit relative to placebo for 6-MWT (least-squares mean difference, 26.5 meters; 95% CI, 13.4 to 39.6; P <.001) and KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P <.001).

When assessing safety outcomes, results demonstrated the incidence of adverse events was similar among those receiving vutrisiran and those receiving placebo. Investigators pointed out serious adverse events occurred among 62% of the vutrisiran group and 67% of the placebo group.

“Vutrisiran was highly effective and well tolerated in this contemporary population representative of patients that we see in our clinics, with consistent benefits regardless of background tafamidis therapy,” Fontana explained. “Our findings indicate that vutrisiran has the potential to become the new standard of care. This trial is also important as it is the first to show the benefit of gene silencers in any type of cardiomyopathy.”