Eplontersen misses primary endpoint in phase 3 CARDIO-TTRansform trial for ATTR cardiomyopathy

Eplontersen monotherapy subgroup shows possible signal despite overall trial miss

Ionis Pharmaceuticals (Carlsbad, CA, USA) and AstraZeneca (Cambridge, UK) have announced that the phase 3 CARDIO-TTRansform trial (NCT04136171) of eplontersen (Wainua®; Ionis Pharmaceuticals and AstraZeneca) did not meet its primary efficacy endpoint in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).^1,2

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ATTR-CM is a systemic, progressive disease in which misfolded transthyretin (TTR) protein accumulates as amyloid fibrils in the heart, disrupting cardiac structure and function. It is an underrecognized cause of heart failure (HF) and can be hereditary (ATTRv) or wild-type (ATTRwt). Patients often present with nonspecific symptoms, including shortness of breath, swelling, palpitations, dizziness, weakness and fatigue, which can contribute to delayed diagnosis. An estimated 300,000 to 500,000 people are living with ATTR-CM worldwide.^1,2

Eplontersen is a once-monthly RNA-targeted silencer that reduces serum TTR production at its source in the liver. It is administered by subcutaneous injection and is approved as Wainua for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, also known as hATTR-PN or ATTRv-PN, in more than 20 countries.^1,2

CARDIO-TTRansform is a global, randomized, double-blind, placebo-controlled phase 3 trial evaluating eplontersen in adults with wild-type or hereditary ATTR-CM receiving available standard of care. The trial enrolled 1,432 participants across 130 sites in 20 countries, making it the largest enrolled ATTR-CM trial to date, according to the companies. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo by subcutaneous injection every 4 weeks. At baseline, 57% of patients in each arm were receiving a TTR stabilizer, and a further 24% in each arm initiated a stabilizer during the trial.^1,2

The primary endpoint, a composite of cardiovascular mortality and recurrent cardiovascular clinical events through Week 140, was not met in the overall population. In this contemporary standard-of-care population, adding eplontersen did not provide a statistically significant benefit versus placebo.^1,2

In a prespecified subgroup analysis of patients treated with eplontersen monotherapy, without background stabilizer therapy, a nominally significant hazard ratio of 0.71 was observed for the composite outcome compared with placebo. In patients who were receiving stabilizer therapy at baseline, no treatment effect was observed. In the overall population, multiple secondary, imaging and biomarker analyses favored eplontersen, and large, sustained reductions in circulating TTR were reported, consistent with the silencer class.¹

According to the companies, eplontersen was generally well tolerated, with a safety profile consistent with previous studies and no new safety signal reported.^1,2

“Over the last decade, multiple advances and increased awareness of ATTR-CM have driven earlier diagnosis, improved management and better outcomes for patients,” said Mathew Maurer, primary investigator and Arnold and Arlene Goldstein professor of cardiology at Columbia University Irving Medical Center (New York, NY, USA) in a press release. “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.”¹

Ionis and AstraZeneca said they will continue to analyze the full data set, with results to be shared with the scientific community at the European Society of Cardiology (ESC) Congress in August 2026. The companies’ updates suggest that background stabilizer therapy may be an important consideration when interpreting the trial and designing future ATTR-CM studies.^1,2

References

1. Ionis Pharmaceuticals, Inc. Update on CARDIO-TTRansform Phase 3 trial of eplontersen in adults with transthyretin-mediated amyloid cardiomyopathy [Press release]. July 9, 2026.
2. AstraZeneca. Update on CARDIO-TTRansform Phase III trial for Wainua (eplontersen) in adults with transthyretin-mediated amyloid cardiomyopathy [Press release]. July 9, 2026.
3. ClinicalTrials.gov. CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM). ClinicalTrials.gov Identifier: NCT04136171.