AstraZeneca and Ionis' Wainua Fails Phase 3 CARDIO-TTRansform Trial in ATTR-CM
On July 9, 2026, Ionis Pharmaceuticals and its partner AstraZeneca announced that their landmark Phase 3 CARDIO-TTRansform trial evaluating Wainua (eplontersen) in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) failed to meet its primary efficacy endpoint. The trial did not show a statistically significant reduction in the composite outcome of cardiovascular (CV) mortality and recurrent CV clinical events up to Week 140 compared with placebo.
The trial, which is the largest enrolled ATTR-CM study to date with 1,432 randomized participants, evaluated eplontersen against a contemporary standard of care backdrop. Crucially:
- 57% of patients in each arm received a stabilizer treatment (such as Pfizer's tafamidis) at baseline.
- An additional 24% of patients in each arm initiated stabilizer therapy during the course of the 140-week trial.
- In this stabilizer-heavy contemporary cohort, adding the RNA-targeted silencer eplontersen did not provide a statistically significant benefit.12
However, a prespecified subgroup analysis of patients treated with eplontersen monotherapy (those not taking a stabilizer at baseline) showed a nominally significant hazard ratio of 0.71 on the composite primary endpoint compared to placebo. No treatment effect was observed in patients who were on stabilizer therapy at baseline. Eplontersen was well tolerated and achieved large, sustained reductions in serum transthyretin (TTR).
Dr. Brett P. Monia, Chief Executive Officer of Ionis, stated:
"Although we are disappointed that the study did not meet the primary endpoint, these results have the potential to guide the treatment landscape for ATTR-CM and contribute to advancing future care for patients."
Dr. Mathew Maurer, primary investigator and professor of cardiology at Columbia University Irving Medical Center, added:
"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."
The full dataset and subgroup analyses are scheduled to be presented to the scientific community at the European Society of Cardiology (ESC) Congress in late August 2026.
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An instance of Ubiquitous background standard-of-care therapies neutralize the observable clinical efficacy of next-generation drug candidates. — The clinical benefit of the next-generation silencer was completely neutralized when layered on top of existing standard-of-care stabilizer treatments. ↩︎
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An instance of Clearing a disease's signature biological biomarker does not guarantee functional clinical improvement. — Despite achieving large, sustained reductions in the disease's target serum TTR protein, the drug failed to show real-world clinical or survival benefit over the existing standard of care. ↩︎