LONDON — Vutrisiran, a gene-silencing drug, led to impressive reductions in all-cause death and recurrent cardiovascular events in patients with transthyretin-mediated amyloidosis with cardiomyopathy (ATTR-CM) in the HELIOS-B trial, suggesting that patients with this fatal disease will soon have a second drug class to slow progression.
Transthyretin amyloidosis results from misfolded transthyretin protein that accumulates as amyloid fibrils in multiple organs, including the heart, where it can cause cardiomyopathy, progressive heart failure, and death. Tafamidis, the first drug approved to treat this condition, is a transthyretin stabilizer that prevents the protein from misfolding.
Tafamidis has been available since 2019, but vutrisiran has a different mechanism of action. It is an RNA interference therapeutic that inhibits hepatic TTR messenger RNA, resulting in rapid knockdown of the pathogenic protein before amyloid-causing monomers can form.
“Until now we have only had tafamidis. Vutrisiran is an important therapy, as it has a completely different mechanism of action, which gives us another option for the high proportion of patients who progress on tafamidis,” said Marianna Fontana, MD, from the National Amyloidosis Centre at University College London, UK. She was lead investigator of the HELIOS-B trial and presented the full results here at the European Society of Cardiology (ESC) 2024 Congress, which were simultaneously published in the New England Journal of Medicine.
HELIOS-B Trial
In the HELIOS-B trial, 655 patients with ATTR-CM were randomized to receive vutrisiran 25 mg administered by subcutaneous injection or placebo every 12 weeks for up to 36 months. At baseline, 40% of the study participants were already taking tafamidis.
The primary endpoint — a composite of death from any cause and recurrent cardiovascular events (cardiovascular hospitalizations or urgent visits for heart failure) — was 28% lower in the vutrisiran group than in the placebo group (hazard ratio [HR], 0.72).
The “consistent efficacy of vutrisiran was seen across all patient subgroups, including patients on baseline tafamidis and those not receiving tafamidis,” Fontana explained.
The drug led to a 33% reduction in the primary endpoint in patients who received vutrisiran as monotherapy (HR, 0.67) and a 21% reduction in those also taking tafamidis (HR, 0.79).
In addition, there was a significant reduction in death in the overall population (HR, 0.69; P = .04).
Vutrisiran maintained functional capacity, health status, quality of life, and NT-proBNP levels, all measures of disease progression, she reported.
Better Effects in Earlier Disease
In patients with early disease, the effects on all endpoints were particularly large, highlighting the need to begin the most effective treatment as early as possible, she said.
“Vutrisiran achieved statistical significance on primary and all secondary endpoints in both overall and monotherapy populations and demonstrated profound and unequivocal benefits on cardiovascular outcomes (including death) and disease progression in a contemporary patient population,” Fontana said.
Although not yet approved by regulators, the “data support vutrisiran as the new standard of care for patients with ATTR-CM, as first line for newly diagnosed patients, and as a switch or add-on therapy in patients progressing on a stabilizer,” she pointed out.
This is the first drug in the gene-silencing class developed to treat ATTR-CM. “Until now, we only had one drug: a transthyretin stabilizer. And we didn’t know what to do when patients progress on that,” Fontana said.
“For me, vutrisiran is a treatment option for first line, but it’s also a drug we can use as an addition to tafamidis or to switch to in patients progressing on tafamidis. These data are very consistent across all subgroups and allow clinicians to choose this drug for all three different settings,” she explained.
The drug appears to work best when given as early as possible in the disease course. And one of the advantages of silencing agents such as vutrisiran is that transthyretin levels can be measured in patients to see how well it is working.
“We can see the TTR levels coming down. That is very helpful, as it shows that the drug is doing exactly what it is supposed to do,” Fontana said.
ATTR-CM More Common Than Previously Thought
ATTR-CM is much more common than previously thought, said Sarah Cuddy, MD, from Brigham and Women’s Hospital in Boston, Massachusetts, during the ESC Hotline session.
“About 10 to 15 years ago, we thought this was an incredibly rare disease. But advances in imaging have changed our understanding,” she explained.
ATTR-CM can now be diagnosed noninvasively, and at-risk populations can be screened. The latest studies suggest that the disease affects around 6% to 28% of patients with heart failure, preserved ejection fraction, and left ventricular hypertrophy, and 13% to 16% of patients referred for transcatheter aortic valve implantation.
“These are a lot of the patients we are seeing in our clinics,” Cuddy said.
Tafamidis first showed a reduction in all-cause mortality and cardiovascular hospitalizations in the ATTR-ACT trial, which enrolled just 440 patients. And in the past year, another TTR stabilizer, acoramidis, has shown efficacy for a similar endpoint.
“These trials are impressive in that they have only a few hundred patients enrolled but are still able to show clear reductions in hard endpoints,” she said. “Now we have HELIOS-B, the first trial with a gene-silencing drug in ATTR-CM, and this also shows positivity for efficacy in primary hard cardiovascular endpoints like death and CV hospitalizations.”
Survival rates for patients with ATTR-CM have improved since tafamidis was introduced. “In the tafamidis trial, the placebo group had a 30-month survival of 57%, and now we’ve shifted this to over 80% in just 6 years,” Cuddy reported. “This is such a win for this disease.”
Questions Remain
There are still many issues to be addressed, such as how the stabilizers compare to the silencers and whether combination therapy is better than monotherapy.
“HELIOS-B is a trial of just 600 patients, so we are getting down into very small numbers in subgroups, and the trial was not powered to look at the tafamidis subgroup alone,” Cuddy explained. “I think there are limited conclusions we can draw from this. And patients already on a therapy are [part of] a very different population than a treatment-naive group. We may be pushing it comparing these survival charts.”
“The compelling data we have seen today shows that early treatment really makes a huge difference to these patients. It really is up to us to detect this disease earlier so we can initiate therapy earlier,” she emphasized.
Several other types of drugs are in development for this condition, including gene-editing and monoclonal antibodies. “Amyloid is such an exciting space right now, and I anticipate that this will continue to be hugely exciting in the years to come,” Cuddy said.
HELIOS-B is a “very positive trial in every respect,” said Christopher Kramer, MD, chief of cardiology at the University of Virginia in Charlottesville and vice president of the American College of Cardiology.
“It’s unusual to see such a positive trial. There were improvements in mortality, heart failure hospitalization, quality of life, and exercise duration. It looks as though vutrisiran is going to be an exciting and much needed new therapy for patients with ATTR-CM,” he said.
