AstraZeneca, Ionis data spark debate about RNA drugs’ impact on deadly heart disease

An article from AstraZeneca, Ionis data spark debate about RNA drugs’ impact on deadly heart disease Results published in NEJM raised questions about the benefits “silencer” medications provide on top of standard therapies for TTR cardiomyopathy and amplified investor pressure on Alnylam. Published Aug. 28, 2026 Jonathan Gardner Senior Reporter Share Copy link Email LinkedIn X/Twitter Facebook Print License Add us on Google Two years ago, Alnylam Pharmaceuticals presented study data showing that people with a deadly heart condition would live longer, and better avoid hospital stays, if they received a drug combination involving nucleic acid-based medicine it had developed.

That finding suggested there are additive benefits to using Alnylam’s medication, known as Amvuttra, on top of standard medications. The results added billions of dollars to Alnylam’s market value, and led to the drug’s approval in that heart condition, called transthyretin-mediated amyloidosis cardiomyopathy. New study results published in the New England Journal of Medicine and presented at a medical meeting on Friday, however, raise questions about the impact drugs like Amvuttra have.

In that trial, partners AstraZeneca and Ionis Pharmaceuticals found that a similar kind of medication didn’t have the same benefits. Since their top-line release in July, the data sparked questions about why eplontersen might have fallen short and whether Alnylam’s drug is as impactful as testing indicated. Called Waiuna and known scientifically as eplontersen, Ionis and AstraZeneca’s drug is already approved for a rarer form of transthyretin amyloidosis that affects the nerves.

The companies had hoped to make the drug more widely available by initiating the “CARDIO-TTRansform” study, a large study testing the treatment in people with TTR cardiomyopathy. The trial enrolled more than 1,400 volunteers already on standard of care medications. Half were randomized to take eplontersen, with the other half receiving a placebo.

After 140 weeks, investigators didn’t detect a statistically significant reduction in the risk of a cardiovascular event or death. Data revealed Friday show that 29% in the group taking eplontersen experienced such events, versus 32% of those given a placebo. The result surprised investors and analysts and called into question how helpful it might be to use these “silencing” medications — which stop mutated genes from producing misfolded TTR proteins — on top of drugs that “stabilize” TTR proteins instead.

Those treatments, Pfizer’s Vyndamax and BridgeBio’s Attruby, were considered the standard of care before Amvuttra’s approval last year. The shifting treatment landscape was evident in AstraZeneca and Ionis’ trial, which aimed to enroll a more contemporary study population. In Alnylam’s “HELIOS-B” study, 53% of enrollees were on stabilizers, compared to 81% of those in CARDIO-TTRansform.

Study data published Friday revealed that more cardiovascular events or deaths occurred in people randomized to receive eplontersen than those who took a placebo. “The negative outcome raises the possibility that the incremental benefit of combining a silencer with a [stabilizer] is smaller than previously assumed as seen in HELIOS-B, rather than the study having been designed poorly,” wrote Jefferies analyst Michael Leuchten, who covers AstraZeneca, in a note to clients. “This result makes it hard for us to see a path towards filing/approval,” added Stifel analyst Paul Matteis, who covers Ionis.

In NEJM, investigators outlined several reasons why eplontersen might’ve failed. Management of heart failure “evolved” during the trial, with “increasing” use of stabilizers as well as other therapies, they wrote. What’s more, the trial’s “broad inclusion criteria captured patients across the full spectrum” of disease.

“In such patients, treatments that reduce new amyloid production, such as eplontersen, may be less likely to be beneficial, as was observed in this trial,” they added. Alnylam’s shares fell as much as 5% in morning trading Friday and are down around 30% since AstraZeneca and Ionis announced the results. AstraZeneca and Ionis’ stock prices ticked down about 1% and 2%, respectively.

The trial’s findings may not change the commercial outlook for Amvuttra, Matteis wrote. Amvuttra’s use in combination with stabilizers is “fairly minimal,” whereas the “primary driver of growth for [Alnylam] is further penetrating the monotherapy population.” The company recorded $1.9 billion in revenue from Amvuttra in the first six months of 2026, accounting for 86% of its revenue. The bigger question for Alnylam, according to analysts, is how the results might impact development of a next-generation product for TTR amyloidosis called nucresiran.

Its pivotal trial allows for use of stabilizers and heart failure medications which, investors fear, could lead to a negative outcome. Matteis suggested that Alnylam could tweak nucresiran’s study design to heighten its chances of success. There are “multiple potential pivots,” such as “biasing further enrollment towards monotherapy” or making nucresiran monotherapy’s impact the study’s “primary outcome,” Matteis wrote.

“The fact that the CARDIO-TTransform data are so negative for the combo (they are unequivocal) could further embolden [Alnylam] to make changes sooner.” A new type of drug called a transthyretin “depleter,” which binds to and removes amyloid deposits, may have better luck, Leuchten noted. AstraZeneca, Novo Nordisk and startup Attralus have put such drugs into clinical trials. Recommended Reading AstraZeneca, Ionis drug fails big heart disease study in major setback By Ben Fidler • July 9, 2026 Full study data back Alnylam heart drug’s benefit, but leave doctors with tough choices By Ben Fidler • Aug.

30, 2024 Add us on Google Share Copy link Email LinkedIn X/Twitter Facebook Print License Filed Under: Pharma, Biotech, Clinical Trials