Wainua Misses Primary Endpoint in ATTR-CM Phase III Trial

AstraZeneca and Ionis Pharmaceuticals have announced that their Phase III CARDIO-TTRansform trial evaluating Wainua (eplontersen) in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) did not meet its primary efficacy endpoint.

The study assessed whether Wainua could reduce a composite outcome of cardiovascular mortality and recurrent cardiovascular clinical events over a period of up to 140 weeks, compared with placebo. While the treatment was generally well tolerated and demonstrated a safety profile consistent with previous findings, the trial did not show a statistically significant benefit for the overall study population.

CARDIO-TTRansform enrolled patients receiving contemporary standard-of-care treatment for ATTR-CM, a progressive and potentially fatal disease caused by the accumulation of abnormal transthyretin amyloid proteins in the heart. The condition can lead to heart failure, arrhythmias, hospitalisations and cardiovascular death.

The trial was designed as a multicentre, randomised, double-blind, placebo-controlled Phase III study. More than half of participants in both treatment arms, 57%, were already receiving a transthyretin stabiliser at baseline. A further 24% of patients in each arm started stabiliser therapy during the study.

According to the companies, adding Wainua to existing standard of care did not produce a statistically significant improvement in the composite endpoint of cardiovascular mortality and recurrent cardiovascular events. No treatment effect was observed among patients who were receiving stabiliser therapy at baseline.

However, a prespecified subgroup analysis showed that patients treated with Wainua as monotherapy experienced fewer primary composite events compared with placebo. The result was described as nominally significant, suggesting that further analysis will be required to determine the potential clinical relevance of the finding.

Sharon Barr, Executive Vice President of BioPharmaceuticals R&D at AstraZeneca, said the trial was designed to explore the potential role of a gene-silencing therapy alongside current treatment approaches.

“The CARDIO-TTRansform trial was designed to examine the role of Wainua, a gene silencer treatment, on top of today’s standard of care in reducing recurring cardiovascular events and mortality,” Barr said. “Although the trial did not meet its primary objective, we believe the results support greater scientific understanding of treatment approaches for the hundreds of thousands of patients worldwide suffering from this progressive and often fatal condition.”

Wainua is an antisense oligonucleotide therapy designed to reduce production of transthyretin, the protein responsible for amyloid buildup in ATTR diseases. The therapy is already being studied across transthyretin amyloidosis indications, including hereditary transthyretin-mediated polyneuropathy.

AstraZeneca and Ionis said they will conduct a detailed analysis of the full CARDIO-TTRansform dataset. The companies plan to present the results to the scientific community at the European Society of Cardiology Congress in August 2026.