Experimental heart drug misses trial goal but protects some participants

The injectable therapy eplontersen failed to show a significant benefit over a placebo at reducing cardiovascular events and related deaths in a Phase 3 clinical trial of adults with transthyretin amyloid cardiomyopathy (ATTR-CM).

While the trial, called CARDIO-TTRansform (NCT04136171), missed its primary goal in the overall patient group, the therapy was associated with a significantly lower risk of heart-related events and death among participants who were not already taking standard-of-care medications called TTR stabilizers.

The trial, which enrolled more than 1,400 patients over more than 2.5 years, tested eplontersen on top of standard care. Because most participants were already receiving approved TTR stabilizers, eplontersen showed no additional effect in that specific subgroup.

The therapy’s developers, Ionis Pharmaceuticals and AstraZeneca, will continue to analyze the full study dataset, and detailed analyses will be presented at a scientific conference next month.

“We believe these findings reflect the rapidly evolving treatment landscape, in which contemporary ATTR-CM patients are widely treated with stabilizers,” Brett P. Monia, PhD, CEO of Ionis, said in a company press release. “Although we are disappointed that the study did not meet the primary [goal], these results have the potential to guide the treatment landscape for ATTR-CM and contribute to advancing future care for patients.”

Recommended Reading

July 17, 2023 News by Marisa Horak, MS

Benefits of eplontersen continue for more than 1.5 years: Trial data

How eplontersen targets ATTR-CM

ATTR-CM is a progressive disease where toxic clumps of a protein called transthyretin (TTR) build up in the heart muscle, leading to severe cardiac damage.

A TTR silencer, eplontersen is designed to reduce TTR protein levels by shutting down the activity of the gene that provides instructions to make this protein. This is expected to prevent further formation and accumulation of toxic protein clumps, ultimately slowing disease progression.

The therapy, given via under-the-skin injections, is approved under the name Wainua (Wainzua in Europe) for hereditary transthyretin amyloidosis with polyneuropathy, a related disease where toxic TTR protein clumps damage the nervous system.

TTR stabilizers are another class of ATTR-CM medications that prevent the TTR protein from forming toxic clumps. Two of these stabilizers are currently approved in the U.S.: Vyndamax (tafamidis) and Attruby (acoramidis).

In CARDIO-TTRansform, a total of 1,432 adults with ATTR-CM were enrolled and randomly assigned to receive either eplontersen or a placebo once monthly for more than 2.5 years, in addition to standard treatments.

More than half (57%) of participants were receiving TTR stabilizers at the study’s start, and another 24% started such medications during the trial.

The primary objective of the study was to determine if eplontersen could outperform a placebo in reducing a combined measure of cardiovascular-related death and recurring cardiovascular events after about 2.5 years.

Secondary goals included the assessment of exercise capacity, heart disease-related quality of life, total recurrent cardiovascular clinical events, rates of death from all causes, and the main goal in the subgroup of patients receiving a TTR stabilizer at the study’s start.

Unraveling the trial results

The developers have now announced that CARDIO-TTRansform did not meet its main goal in either the overall study population or the subgroup of participants already taking TTR stabilizers at the start of the trial.

“Over the last decade, multiple advances and increased awareness of ATTR-CM have driven earlier diagnosis, improved management and better outcomes for patients,” said Mathew Maurer, MD, CARDIO-TTRansform’s primary investigator at Columbia University Irving Medical Center. “These data from the largest enrolled study of a contemporary ATTR-CM patient population provide important clarity for the field that will help inform future treatment decisions in ATTR-CM.”

Monia added: “We extend our sincere gratitude to the patients, families and investigators whose participation helped progress the science of ATTR-CM treatment.”