AstraZeneca and Ionis miss in key ATTR-CM trial

Why it matters: The result weakens AstraZeneca’s attempt to expand eplontersen beyond hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), where the drug is already approved in more than 20 countries, including in the EU as Wainzua.

The context: ATTR-CM is a progressive and often underdiagnosed heart disease caused by misfolded transthyretin (TTR) protein building up in the heart. AstraZeneca estimates that 300,000 to 500,000 people live with the condition worldwide.

How it works: eplontersen is a once-monthly RNA-targeted silencer designed to reduce production of transthyretin at its source in the liver.

• That is different from stabilisers such as tafamidis and acoramidis, which aim to prevent the TTR protein from misfolding and forming amyloid deposits. The question for CARDIO-TTRansform was whether silencing TTR could add meaningful benefit on top of today’s standard of care.

Zoom in: The CARDIO-TTRansform trial enrolled 1,432 patients across 130 sites in 20 countries, making it the largest ATTR-CM trial enrolled to date.

• Patients were randomised to receive eplontersen 45 mg or placebo every four weeks, on top of available standard of care. The primary endpoint measured cardiovascular mortality and recurrent cardiovascular clinical events through week 140.
• The trial missed that endpoint. AstraZeneca and Ionis said adding eplontersen did not provide a statistically significant benefit in a modern treatment setting where many patients were already receiving TTR stabilisers.

By the numbers: A stabiliser was used by 57% of patients in each arm at baseline, while another 24% started one during the study.

• In patients already on stabiliser therapy at baseline, no treatment effect was observed. In a prespecified monotherapy subgroup, eplontersen showed a better result, with a 29% risk reduction.

Yes, but: The companies have not yet provided the full dataset. They said secondary, imaging and biomarker analyses favoured eplontersen, that TTR reductions were large and sustained, and that the drug was well tolerated.

• The full results are expected to be presented at the European Society of Cardiology Congress in August 2026.

Big picture: For AstraZeneca, the trial miss is a commercial and strategic blow rather than a total loss for the drug. Wainua remains approved for hereditary transthyretin amyloidosis with polyneuropathy, but the larger cardiomyopathy opportunity now looks much harder to reach.

• The failure also removes, at least for now, a potential competitor to ATTR-CM drugs from Pfizer, BridgeBio and Alnylam, whose positions in the market look stronger after the miss. Their respective drugs are either blockbusters or on their way to be.
• Shares of Alnylam and BridgeBio have climbed after the news, while AstraZeneca’s and Ionis’ stock prices have seen a sharp decrease.