HELIOS-B shines on vutrisiran for ATTR-CM

In the phase III HELIOS-B trial, vutrisiran reduced death and cardiovascular (CV) events in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM).

“HELIOS-B met all 10 primary and secondary endpoints in the overall and monotherapy population (ie, patients not on tafamidis at baseline),” said principal investigator Professor Marianna Fontana from the University College London, Royal Free Hospital, London, UK, at ESC 2024.

There were statistically significant reductions in the primary composite endpoint of all-cause mortality and recurrent CV events with vutrisiran vs placebo, both in the overall (hazard ratio [HR], 0.718; p=0.0118) and monotherapy cohorts (HR, 0.672; p=0.0162).

The effects were nominally significant when looking at each component of the primary composite endpoint (HR, 0.694; p=0.0389 [all-cause mortality] and relative rate ratio, 0.733; p=0.0010 [recurrent CV events]). [Fontana, M, et al, ESC 2024]

Secondary endpoints

The significant treatment effects with vutrisiran were seen across all secondary endpoints in the overall population: all-cause mortality through month 42 (HR, 0.645; p=0.0098), 6-MWT* change at month 30 (least-squares mean [LSM] difference, 26.46; p=0.00008), KCCQ-OS** change at month 30 (LSM difference, 5.8; p=0.0008), and NYHA*** class (adjusted difference in percentage of stable or improved patients, 8.7 percent; p=0.0217).

A similar trend favouring vutrisiran was observed in the monotherapy cohort (HR, 0.655; p=0.0454 [all-cause death], LSM difference, 32.09; p=0.00005 [6-MWT], LSM difference, 8.69; p=0.0003 [KCCQ-OS]), and adjusted difference, 12.5 percent; p=0.0121 [NYHA class]).

The 6MWT, KCCQ-OS, and NYHA class findings suggest that vutrisiran maintains functional capacity, health status, and quality of life (QoL) relative to placebo, noted Montana.

Subgroup analysis

The benefits were consistent across all prespecified subgroups, with greater benefits in patients with earlier disease such as those aged <75 years (HR, 0.545 [primary outcome] and HR, 0.552 [secondary outcome of all-cause death]) and those with baseline NT-proBNP^# ≤2,000 ng/L (HRs, 0.525 and 0.348, respectively).

“[The] particularly large effects seen in patients with early disease [highlight] the need to begin the most effective treatment as early as possible,” Fontana noted.

“Early treatment makes a huge difference in these patients … It is on us [clinicians] to detect this disease earlier to initiate therapy earlier,” said discussant Dr Sarah Cuddy from Brigham and Women's Hospital, Boston, Massachusetts, US, at ESC 2024.

Vutrisiran provided added benefit for those receiving baseline tafamidis, as evidenced by the favourable HRs for both the primary outcome (HR, 0.785) and secondary outcome of all-cause death (HR, 0.588).

NT-proBNP, safety

Vutrisiran also maintained relative stability of NT-proBNP – a well-established cardiac biomarker prognostic of mortality in ATTR-CM – as opposed to the placebo arm which showed a steady rise in NT-proBNP level, as reflected by the adjusted geometric mean fold-change ratio in both overall (0.68) and monotherapy (0.57) populations.

“The majority of adverse events (AEs) were mild or moderate, [with none] seen ≥3 percent more frequently with vutrisiran compared with placebo,” Montana said, adding that the cardiac AEs were similar or lower with the former vs the latter.

Very promising results

ATTR-CM leads to progressive heart failure (HF), arrhythmias, functional status and QoL decline, increased hospitalizations, and reduced survival. [Heart Fail Rev 2015;20:163-178; Amyloid 2015;22:123-131; Am Heart J 2012;164:222-228.e1; Eur Heart J 2012;33:1120-1127]

“Despite recent advances in the diagnosis and treatment … ATTR-CM remains a fatal, progressive condition with a high unmet clinical need … We investigated whether [vutrisiran] could improve clinical outcomes in patients with ATTR-CM and the results were very promising,” Fontana said.

A total of 655 participants (median age 76.5 years, 92.5 percent men) who had ATTR (wild-type or any TTR variant) with confirmed CM and history of symptomatic HF were randomized 1:1 to SC vutrisiran 25 mg or placebo Q3M for up to 36 months. About three-quarters had NYHA class II and two-thirds were at ATTR disease stage 1.

At baseline, ~40 percent of participants were on tafamidis, about 80 percent were on diuretics, and roughly 3 percent were on SGLT2^## inhibitors.

New standard of care?

“[Taken together,] vutrisiran demonstrated profound and unequivocal benefits on CV outcomes (including mortality) and disease progression in a contemporary population representative of patients we see in our clinics – those who were also receiving multiple effective therapies, including tafamidis, SGLT2 inhibitors, and diuretics,” noted Fontana during the press conference.

There were also consistent benefits on multiple clinical measures of disease progression, as well as NT-proBNP. Subgroup findings aligned with the primary results, and the safety and tolerability profile of vutrisiran was deemed acceptable, she added.

“If approved, vutrisiran has the potential to become a standard of care as first-line [therapy] for newly diagnosed patients, and as a switch or add-on therapy in those progressing on stabilizing therapies,” Montana concluded. “This trial is also important as it is the first to show the benefit of gene silencers in any type of CM.”