Eplontersen Misses Primary Endpoint in Phase 3 ATTR-CM Trial

On July 9, 2026, AstraZeneca and Ionis reported that the phase 3 CARDIO-TTRansform trial of eplontersen (Wainua) did not meet its primary efficacy endpoint in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).¹

“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,” Sharon Barr, executive vice president of BioPharmaceuticals R&D, said in a statement. “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.”¹

CARDIO-TTRansform Missed Primary ATTR-CM Endpoint

In the overall study population, adding eplontersen to contemporary standard of care did not produce a statistically significant benefit on the composite of cardiovascular mortality and recurrent cardiovascular events compared with placebo, the companies reported. The trial included substantial use of transthyretin stabilizer therapy, with 57% of patients in each arm receiving a stabilizer at baseline and an additional 24% in each arm initiating a stabilizer during the trial.¹

Among patients treated with eplontersen monotherapy vs placebo, fewer primary composite events were observed, and the result was nominally significant, according to the companies. In patients receiving stabilizer therapy at baseline, no treatment effect was observed.¹

ATTR-CM can be hereditary or wild-type and is characterized by cardiac deposition of amyloid fibrils composed of misfolded transthyretin protein. The condition can present with nonspecific signs and symptoms, including dyspnea, edema, palpitations, dizziness, weakness, and fatigue. The companies cited an estimated 300,000 to 500,000 people living with ATTR-CM worldwide, while noting the condition remains underrecognized as a cause of heart failure.¹

Eplontersen Trial Design and Reported Safety

CARDIO-TTRansform was a global, multicenter, 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 1432 participants across 130 sites in 20 countries. Participants were randomly assigned in a 1:1 ratio to receive eplontersen 45 mg or placebo by subcutaneous injection every 4 weeks.¹

The primary endpoint was the composite of cardiovascular mortality and recurrent cardiovascular clinical events through week 140. Listed secondary endpoints included change from baseline in 6-minute walk test distance and Kansas City Cardiomyopathy Questionnaire overall summary score at week 140; total recurrent cardiovascular clinical events through week 140; all-cause mortality through weeks 140 and 160; the primary endpoint in patients receiving a TTR stabilizer at baseline; and cardiovascular mortality through weeks 140 and 160. The team also noted that eplontersen was generally well tolerated, with a safety profile described as consistent with previous results.¹

Regulatory Context and Next Steps for Eplontersen

Eplontersen is an RNA-targeted therapy designed to reduce the production of serum transthyretin at its source in the liver. In the United States, it is administered once monthly and can be self-administered using an autoinjector or given as a prefilled syringe by a health care professional, according to the companies.¹

Eplontersen is approved for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults in more than 20 countries, including in the European Union under the name Wainzua. The CARDIO-TTRansform results described in the announcement concern ATTR-CM and do not indicate a positive phase 3 outcome for that cardiomyopathy indication.¹

AstraZeneca and Ionis stated they will analyze the full data set to better characterize the findings. The companies plan to share results with the scientific community at the European Society of Cardiology (ESC) Congress in August 2026. Key unanswered issues include the magnitude of treatment effect in the overall study population, subgroup analyses by baseline stabilizer use, functional and quality-of-life outcomes, and complete safety data.¹

References

1. AstraZeneca. Update on CARDIO-TTRansform Phase III trial for Wainua (eplontersen) in adults with transthyretin-mediated amyloid cardiomyopathy. Published July 9, 2026. Accessed July 9, 2026. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2026/update-cardio-ttransform-phase-iii-trial.html