medwireNews: Vutrisiran reduces all-cause mortality and recurrent cardiovascular (CV) events in patients with transthyretin amyloid (ATTR) cardiomyopathy, including those already on stabilizing medication, show findings from the HELIOS-B trial.
The results were presented by Marianna Fontana (University College London, UK) at the ESC Congress 2024 in London, UK, and simultaneously published in The New England Journal of Medicine.
She highlighted that the effect of the RNA interference therapeutic, which silences the TTR gene, was measured across a total of 10 clinical endpoints – two primary endpoints and eight secondary endpoints – all of which were met in the overall population and in patients already taking the oral treatment tafamidis at baseline.
The double-blind study involved 655 patients with wild-type or any TTR variant who were randomly assigned to receive subcutaneous vutrisiran 25 mg or placebo every 3 months for up to 36 months. This was followed by an open-label extension phase where all patients received the vutrisiran regimen for up to 60 months.
The 326 participants given vutrisiran had a median age of 77 years and 91.7% were men, while the 328 placebo-treated patients had a median age of 76 years and 93.3% were men.
Fontana pointed out that “while there was a wide range of disease severity in the HELIOS-B trial, overall, the HELIOS-B trial population had a milder form of disease compared to previous trials, reflecting a contemporary population of patients with ATTR cardiomyopathy.”
There was also a high use of background medications including tafamidis in around 40% of patients in each treatment arm and SGLT2 inhibitors in around 3%, therefore “raising the bar for vutrisiran to show a treatment effect,” she commented.
The composite primary endpoint of all-cause mortality and recurrent CV events, measured during the double-blind period, was reduced by a significant 28% with vutrisiran compared with placebo in the overall population.
The presenter highlighted that “both components contributed equally to the composite endpoint,” with a significant 31% reduction in all-cause mortality and a 27% reduction in recurrent CV events.
All-cause mortality continued to be measured through 42 months as a secondary endpoint, with a 35% reduction seen in patients receiving vutrisiran compared with those given placebo.
The treatment benefits were consistent across all prespecified subgroups for both the composite primary and secondary all-cause mortality outcomes. Fontana highlighted that there was a trend toward greater benefits in patients with earlier disease, so patients younger than 75 years or those with baseline N-terminal pro-B natriuretic peptide levels of 2000 ng/L or below, with a 46% and 48% reduction, respectively, in the composite primary endpoint and a 45% and 65% reduction in all-cause mortality through 42 months.
Vutrisiran was also found to be effective in patients irrespective of whether they were also taking tafamidis. Among those who were not, there was a significant 33% reduction in the composite primary endpoint and a 35% reduction in all-cause mortality through 42 months.
And although not powered to show a statistically significant difference in the patients who were taking tafamidis at baseline, Fontana pointed out that the “results show the added benefit of vutrisiran on top of tafamidis treatment.”
Treatment with vutrisiran had a positive effect on multiple measures of disease progression, measured as secondary endpoints. These included the 6-minute walk test and the Kansas City Cardiomyopathy Questionnaire, with respective least squares mean increases at 30 months of 26.46 minutes and 5.80 points with vutrisiran versus placebo in the overall population. The percentage of patients whose New York Heart Association Class remained stable or improved at this timepoint was also significantly increased with vutrisiran treatment, with an 8.7 percentage point difference in favor of vutrisiran.
The drug was “well tolerated,” the presenter reported. Most of the adverse events (AEs) were mild to moderate, and the vutrisiran and placebo groups had similar rates of serious AEs (61.7 vs 67.1%) and severe AEs (48.5 vs 59.1%). She added that “cardiac AEs were similar or lower with vutrisiran compared with placebo.”
Fontana concluded that “overall, the results from the HELIOS-B trial show that, if approved, vutrisiran has the potential to become a standard of care for newly diagnosed patients, but also for those progressing on stabilizers.”
Giving a discussant review of the study, Sarah Cuddy (Brigham and Women’s Hospital, Boston, Massachusetts, USA) highlighted how far treatment of ATTR cardiomyopathy has come in the past 6 years, with benefits in hard endpoints such as cardiovascular events and death now being demonstrated.
“I think that the compelling data that we have today, that we have seen from what’s been presented, is that early treatment really makes a huge difference with these patients, so it is on us to detect this disease earlier in order to initiate therapy earlier.”
She acknowledged that small numbers in some of the subgroups “limit the kind of conclusions that we can draw,” such as whether gene silencers are better than stabilizers or whether a combination of the two has “additive value.”
Nevertheless, she concluded that gene silencers add to the “number of tools we can use for therapy,” and highlighted that the amyloid space “will continue to be hugely exciting in the years to come,” with ongoing studies in gene editing and monoclonal antibodies.
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ESC Congress 2024; London, UK: 30 August–2 September
N Engl J Med 2024; doi:10.1056/NEJMoa2409134
