Cardiac biomarker profile in ATTR-CM looks good with vutrisiran

In the treatment of patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM), the use of the small interfering ribonucleic acid (siRNA) vutrisiran helps reduce and maintain the stability of NT-proBNP and troponin I—biomarkers associated with increased mortality in this population, as reported in a late-breaking clinical research presentation in HFSA 2024.

Exploratory analyses of biomarker data from the phase III HELIOS-B trial showed that at month 30, vutrisiran yielded a 32-percent relative reduction in NT-proBNP (geometric mean fold-change ratio, 0.68, 95 percent confidence interval [CI], 0.61–0.76; p<0.000001) and in troponin I (geometric mean fold-change ratio, 0.68, 95 percent CI, 0.62–0.75; p<0.00001) compared with placebo. [Maurer M, et al, HFSA 2024]

The favourable treatment effect of vutrisiran on cardiac biomarkers was observed as early as 6 months (NT-proBNP: p=0.0127; troponin I: p=0.0098), with a progressive improvement over time, noted first study author Dr Mathew Maurer from Columbia University Irving Medical Center, New York, New York, US.

Additionally, vutrisiran consistently improved cardiac biomarkers across various subgroups, as defined by age, ATTR type, NYHA class, and baseline NT-proBNP levels, both in the overall population and in the cohort of patients not receiving stabilizer therapy with tafamidis at baseline (monotherapy population).

Maurer pointed out that the changes in cardiac biomarkers in the monotherapy population and in the subgroup of patients who were receiving tafamidis at baseline further demonstrated the beneficial effect of vutrisiran.

“The relative reduction with vutrisiran vs placebo was 43 percent for NT-proBNP [p<0.000001] and 45 percent for troponin I [p<0.000001] in the monotherapy population at month 30. On top of tafamidis, the relative reduction with the siRNA vs placebo was 18 percent and 10 percent for NT-proBNP [p=0.0045] and troponin I [p=0.0849], respectively,” he said.

Long-term stability

“Vutrisiran maintained the long-term stability of NT-proBNP and troponin I,” Maurer noted, adding that the median change from baseline to month 30 in both biomarkers was minimal and “not really clinically relevant” compared with the larger increases seen with placebo across the overall population, monotherapy population, and the baseline tafamidis subgroup.

Maurer emphasized that elevated baseline levels of NT-proBNP and troponin I were predictive of adverse clinical events, and the favourable effects of vutrisiran on these biomarkers aligned with its positive effects on cardiovascular events and all-cause mortality, which were reported in the main results of HELIOS-B. [N Engl J Med 2024;doi:10.1056/NEJMoa2409134]

HELIOS-B showed that “vutrisiran rapidly knocked down TTR, lowered the risk of all-cause mortality and cardiovascular events compared with placebo, and preserved functional capacity and quality of life in a contemporary population with ATTR-CM, including [individuals with] substantial use of background therapy,” he continued. [N Engl J Med 2024;doi:10.1056/NEJMoa2409134]

The siRNA had “acceptable safety and tolerability profile, as previously established,” Maurer said.

A total of 665 patients with ATTR-CM participated in HELIOS-B. At baseline, approximately 40 percent of patients were receiving tafamidis, 3 percent were receiving SGLT2 inhibitors, and 80 percent had substantial use of diuretics. The patients were randomly assigned to receive vutrisiran 25 mg or placebo subcutaneously every 12 weeks for up to 36 months.