HELIOS-B: Novel ‘Silencer’ Agent Reduces Death, CV Events in ATTR-CM

Vutrisiran, a subcutaneous therapy that knocks down transport protein levels in the liver, may lower the risk of death and recurrent CV events in patients who have transthyretin amyloidosis with cardiomyopathy (ATTR-CM), according to results of the HELIOS-B trial.

The top-line results were announced in June, when researchers reported that patients on vutrisiran (Amvuttra; Alnylam), a small-interfering RNA (siRNA), were less likely to die or experience CV events compared with placebo with or without concomitant tafamidis (Vyndaqel and Vyndamax; Pfizer). Tafamidis, which reduced all-cause mortality in the ATTR-ACT trial, was the first drug ever approved for ATTR-CM by the US Food and Drug Administration.

In a press conference prior to presentation of the full HELIOS-B study findings today at the European Society of Cardiology (ESC) Congress 2024 in London, lead investigator Marianna Fontana, MD, PhD (University College London, Royal Free Hospital, England), noted that despite recent advances in diagnosis and treatment, ATTR-CM remains a disease that is progressive and fatal and has a high unmet clinical need.

“Overall, the results of the HELIOS-B trial indicate that if approved by regulators, data support vutrisiran as a new standard of care for patients with ATTR cardiomyopathy, as a first-line [treatment] for newly diagnosed patients, and as a switch-on or add-on therapy in patients who are progressing on a stabilizer.”

Approximately 40% of the study population was already taking tafamidis, which, along with the investigational drug acoramidis (BridgeBio), is considered a stabilizer therapy because it reduces circulating levels of TTR. In contrast, vutrisiran is “a first-in-class silencer” of the transport protein, according to Fontana.

The study, simultaneously published in the New England Journal of Medicine, shows that at 42 months’ follow-up, the composite risk of all-cause mortality and recurrent cardiovascular events (primary endpoint) was lower in patients on vutrisiran versus placebo in the overall population (HR 0.72; 95% CI 0.56-0.93) and in those not on background tafamidis (HR 0.67; 95% CI 0.49-0.93). Compared with placebo, the vutrisiran group also had a lower risk of all-cause mortality (HR 0.65; 95% CI 0.46-0.90), a prespecified secondary endpoint.

Vutrisiran is already FDA-approved for the treatment of polyneuropathy associated with hereditary transthyretin-mediated amyloidosis. After the top-line results were announced, Alnylam said they intended to file a supplemental new drug application for vutrisiran for the treatment of ATTR-CM, with additional global regulatory filings expected to follow. A representative for the company confirmed to TCTMD that this is still the plan.

“If approved for this indication, it's going to be a game changer,” said Jose A. Alvarez-Cardona, MD (NYU Langone Health, New York, NY), who was not involved in the study. “We're all hopeful because we have limited treatment options right now for these patients.”

Having another agent in the armamentarium with a different mechanism of action, he added, is important for several reasons. These include that on a practical level, getting an injectable every 3 months might be considerably easier for some, particularly elderly patients who are already taking numerous daily medications.

But cost is the elephant in the room. Tafamidis became the most expensive cardiovascular drug when it hit the market at a list price of $225,000 per year. At this point, it’s unclear how vutrisiran would be priced.

“In light of these results, are the insurance companies now going to limit the options for patients [and say] you have to choose one or the other agent? And if so, how are you going to choose?” Alvarez-Cardona added.

Improvements in Walking and Quality of Life

ATTR-CM can be heredity—resulting from mutations in the TTR gene—or wild type. In the HELIOS-B study, patients with either form and a history of symptomatic heart failure were randomized to vutrisiran 25 mg given subcutaneously every 12 weeks for up to 36 months (n = 326) or placebo (n = 329). The majority had wild-type ATTR-CM and were over age 75.

In addition to a lower risk of the primary endpoint, the vutrisiran group had a lower risk of the individual endpoint of death from any cause (HR 0.65; 95% CI 0.46-0.90). Vutrisiran patients also experienced less of a decline from baseline in 6-minute walk test (difference 26.5 m; P < 0.001) and less of a decline in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire overall summary score (difference 5.8 points).

If approved for this indication, it's going to be a game changer. Jose A. Alvarez-Cardona

There was a trend towards greater benefit of vutrisiran in patients with earlier heart failure, with greater reduction of the primary endpoint compared with placebo in patients with baseline NT-proBNP < 2,000 pg/mL (HR 0.53; 95% CI 0.35-0.79).

To TCTMD, Fontana said the trial results are consistent enough to allow physicians to use vutrisiran as a first-line option, assuming it is approved.

“But it's definitely also a drug that I could use as an add-on on top of tafamidis or switch to in the patients progressing on tafamidis,” she added. “As a physician, the long-term goal for me is to diagnose, early, the patients and start effective treatment such as vutrisiran as soon as possible.”

Alvarez-Cardona said among the remaining questions with regard to using vutrisiran as first-line therapy is whether it has an impact on other aspects of ATTR-CM, such as neurological symptoms and neuropathy, which are common in patients with mixed-phenotype disease, or whether some individuals would require both a stabilizer and a silencer.

“It takes a village to take care of these patients,” he noted. “These results are very reassuring and hopeful, but we still have a lot to learn from the disease and how to manage it.”

Calling the study results “a huge win,” Sarah Cuddy, MD (Brigham and Women's Hospital, Boston, MA), who served as the discussant for the presentation, emphasized that this trial is just one of several major advances in the treatment of ATTR-CM that have occurred in the last few years.

“I think we have a lot of questions,” she added. “Some of our questions are, using this data can we compare the stabilizers to the silencers? Are the silencers better than stabilizers?”

The trial’s small size makes it difficult to evaluate the impact of vutrisiran on various subgroups due to low power, Cuddy said. Additionally, an argument could be made that patients who were already on tafamidis and those who were not are different populations who may not be fully comparable in terms of survival. 

Looking ahead, she noted that gene editing and monoclonal antibody trials in this space add to the many reasons why the treatment of ATTR-CM “will continue to be hugely exciting in the years to come.”