AstraZeneca's ATTR-CM trial failure raises broader questions about silencer drugs

AstraZeneca (AZN) has laid out in detail the surprise failure of a closely watched heart disease trial, revealing how its experimental drug offered no additional benefit to patients who were largely already taking a rival class of medicine — the latest twist in a multi-billion dollar market.

The study found that patients with a progressive condition known as ATTR-CM who received AstraZeneca's drug — a so-called silencer — saw no improvements if they were already taking a stabilizer, an effect so pronounced that it sank the entire Phase 3 trial. Most participants were already on a stabilizer at the outset.

The miss has had ramifications beyond AstraZeneca and its development partner Ionis Pharmaceuticals (IONS), unsettling other companies active in the ATTR-CM space, including Alnylam Pharmaceuticals (ALNY), which markets a rival silencer, and BridgeBio (BBIO), maker of a newer stabilizer. Analysts have argued the outcome bolsters the case that stabilizers — which are oral drugs — may be superior to injectable silencers.

AstraZeneca and Ionis announced the failure of the CARDIO-TTRansform trial last month, disclosing that their drug Wainua, also known as eplontersen, did not outperform placebo in reducing cardiovascular deaths or emergencies across the overall patient population. Full data were presented at the European Society of Cardiology's annual meeting in Munich and published simultaneously in the New England Journal of Medicine.

"It is disappointing," said Mina Makar, a senior vice president overseeing AstraZeneca's cardiovascular work, adding that the hope had been that a silencer could protect patients whose disease continued to worsen even while on a stabilizer. "We really felt we could help these patients, because they need something more than a stabilizer alone."

In the overall trial, there were 74 cardiovascular deaths and 307 cardiovascular events among 210 patients who received Wainua as a monthly injection, compared with 70 deaths and 322 events among 231 placebo patients — a difference that was not statistically significant, even as the drug demonstrably reduced TTR production.

The high prevalence of stabilizer use among participants was identified as the primary culprit. When the trial began, 57% of participants were already taking a stabilizer, largely Pfizer's (PFE) Vyndamax; a further 24% initiated a stabilizer during the study, bringing the total to more than 80% — a higher proportion than observed in prior silencer studies.

"Our analysis suggests that that is the main reason why the trial was neutral," said Mathew Maurer, a cardiologist at Columbia University who presented the data.

ATTR-CM, or transthyretin-mediated amyloid cardiomyopathy, is a progressive condition in which the TTR protein misfolds and accumulates in heart muscle, impairing cardiac function and ultimately leading to fatal heart failure. Silencers are designed to suppress TTR production, while stabilizers aim to prevent misfolding. BridgeBio's stabilizer Attruby won approval in late 2024, while Pfizer's Vyndamax is an older incumbent in the class. Though once considered rare, ATTR-CM is now estimated to affect between 400,000 and 500,000 people globally, making it a fiercely contested commercial opportunity.

Rather than benefiting Alnylam by removing a potential competitor, the AstraZeneca setback appeared to stoke wider doubts about the silencer class. Alnylam's own silencer, Amvuttra, which cut the risk of cardiovascular death and events by 33% and 28% respectively in its pivotal HELIOS-B trial, has faced investor concern after its sales failed to meet expectations following last year's launch. Questions have also surfaced about the company's next-generation candidate nucresiran, currently in Phase 3, though Alnylam has reiterated its confidence in the drug, describing it as a more potent silencer.