AstraZeneca and Ionis reported that the Phase III CARDIO-TTRansform trial of Wainua (eplontersen) in ATTR-CM did not meet its primary endpoint of reducing cardiovascular mortality and recurrent cardiovascular events through Week 140, while maintaining a consistent safety profile.
Written By: Anamika Koshti, Pharm D
Reviewed By: Pharmacally Editorial Team
AstraZeneca and Ionis announced on July 9, 2026, that the Phase III CARDIO-TTRansform trial (NCT04136171) of Wainua (eplontersen) in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) did not meet its primary efficacy endpoint. The composite of cardiovascular (CV) mortality and recurrent CV clinical events through Week 140 showed no statistically significant difference between Wainua and placebo.
Wainua was generally well tolerated, with a safety profile consistent with prior studies and no new safety signals reported. Full results will be presented at the European Society of Cardiology (ESC) Congress in August 2026.
Understanding ATTR-CM
ATTR-CM is a systemic, progressive, and ultimately fatal disease in which the transthyretin (TTR) protein misfolds into amyloid fibrils that accumulate in the heart, disrupting its structure and impairing its ability to pump blood. It can occur as an inherited form (hereditary ATTRv) or develop with age (wild-type ATTRwt), affecting an estimated 300,000 to 500,000 people worldwide. Patients commonly present with non-specific symptoms such as shortness of breath, swelling, palpitations, dizziness, weakness, and fatigue, often leading to delayed diagnosis.
CARDIO-TTRansform Trial
CARDIO-TTRansform is the largest ATTR-CM trial conducted to date. The global, randomised, double-blind, placebo-controlled Phase III study enrolled 1,432 participants across 130 sites in 20 countries, randomised 1:1 to receive eplontersen 45 mg or placebo every four weeks in addition to available standard of care. Notably, 57% of participants in each arm were receiving a TTR stabiliser at baseline, while another 24% initiated stabiliser therapy during the study. The primary endpoint was the composite of CV mortality and recurrent CV clinical events through Week 140. Secondary endpoints included changes in the 6-minute walk test, Kansas City Cardiomyopathy Questionnaire Overall Summary Score, recurrent CV clinical events, all-cause mortality, CV mortality, and outcomes in patients receiving baseline stabiliser therapy.
Trial Results
In this contemporary treatment population with widespread stabiliser use, adding Wainua to standard of care did not significantly reduce the primary composite endpoint. No treatment effect was observed in patients already receiving stabiliser therapy at baseline. In a prespecified subgroup analysis, patients receiving Wainua without baseline stabiliser therapy experienced fewer primary composite events than placebo, reaching nominal statistical significance. However, this exploratory finding was not adjusted for multiplicity and should be interpreted cautiously pending further analysis.
Clinical implications
Sharon Barr, Executive Vice President, BioPharmaceuticals R&D at AstraZeneca, said the study was designed to evaluate the role of Wainua as a gene-silencing therapy on top of today’s standard of care. Although the trial did not meet its primary objective, she noted that the findings contribute to scientific understanding of treatment strategies for ATTR-CM, a progressive disease affecting hundreds of thousands of patients worldwide.
Path Forward
AstraZeneca and Ionis are conducting a comprehensive analysis of the complete dataset to better understand the findings, which will be presented at the ESC Congress in August 2026. The prespecified monotherapy subgroup signal may provide additional insight into the potential interaction between gene-silencing therapy and TTR stabilisers. The negative primary result does not affect Wainua’s approved indication for hATTR-PN.
About Wainua (Eplontersen)
Wainua is a once-monthly RNA-targeted silencer administered by subcutaneous injection. It suppresses TTR production at its source in the liver, reducing the amount of TTR protein available to form amyloid deposits. The therapy is approved in more than 20 countries for hereditary ATTR polyneuropathy (hATTR-PN), where it has demonstrated sustained TTR reduction. CARDIO-TTRansform evaluated whether this mechanism could also improve cardiovascular outcomes in ATTR-CM.
What This Means for Patients
The findings indicate that adding Wainua to current standard-of-care stabiliser therapy did not improve major cardiovascular outcomes in this trial. At the same time, the extensive use of background stabiliser therapy reflects the evolving treatment landscape for ATTR-CM and may be an important consideration when interpreting these results and designing future studies. Patients and clinicians will look to the full ESC 2026 dataset to determine whether specific patient groups, including those not receiving stabiliser therapy, may derive greater benefit from treatment.
Reference
About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.