CARDIO-TTRansform trial investigating eplontersen fails to meet primary efficacy endpoint

The CARDIO-TTRansform trial investigating eplontersen in patients with transthyretin-mediated amyloid cardiomyopathy did not meet its primary efficacy endpoint, according to results presented in a Hot Line session today at ESC Congress 2026.

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease characterized by misfolded transthyretin (TTR) amyloid deposits in the heart muscle. The deposits can lead to a reduction in cardiac function, worsening symptoms of heart failure and recurrent cardiovascular events.

ATTR-CM is an under-recognized cause of heart failure. With an estimated 300,000 to 500,000 people living with ATTR-CM worldwide, greater awareness, earlier diagnosis and appropriate targeted treatment are critical to improving outcomes and quality of life for patients," he said.

Doctor Mathew Maurer, presenter, Columbia University Irving Medical Center, New York, USA

Eplontersen is a once-monthly RNA-targeted silencer designed to reduce TTR production by the liver. Eplontersen is approved for the treatment of hereditary/variant TTR amyloid polyneuropathy. The CARDIO-TTRansform trial investigated the efficacy and safety of eplontersen in patients with ATTR-CM.

This was a double-blind phase III trial conducted in 130 centres in 20 countries worldwide. A total of 1,432 patients with wild-type or hereditary ATTR-CM were enrolled who were receiving available standard of care. Participants were randomized (1:1) to receive eplontersen 45 mg or placebo by subcutaneous injection every four weeks. The mean age of the study population was 72 years and 9.4% were women.

The primary endpoint was a composite of cardiovascular mortality and recurrent cardiovascular events. There were 381 primary endpoint events in 210 patients receiving eplontersen compared with 392 events in 231 patients receiving placebo (rate ratio 0.89; 95% confidence interval 0.73 to 1.09; p=0.277).

Eplontersen produced suppression of circulating serum TTR, consistent with the expected pharmacodynamic effect of TTR gene silencing, as assessed by a prespecified exploratory endpoint through Week 140.

The majority of participants (57%) were receiving stabilizer therapy at baseline. In a prespecified subgroup analysis, the observed treatment effect differed according to baseline stabilizer use. Among patients not receiving stabilizer therapy at baseline, fewer primary composite endpoint events were observed with eplontersen monotherapy than with placebo, with the result reaching nominal statistical significance. Among patients receiving stabilizer therapy at baseline, no additional treatment benefit was observed for the primary endpoint.

Eplontersen was generally well tolerated, with a safety profile consistent with previous results.

"In CARDIO-TTRansform, the largest ATTR-CM trial to date, eplontersen achieved reductions in circulating serum TTR, although the trial did not demonstrate a significant reduction in the primary endpoint in the overall population," concluded Doctor Maurer. "Baseline stabilizer use appeared to influence the primary results. No additional benefit was observed in patients receiving background stabilizer therapy, while fewer primary endpoint events were observed with eplontersen in patients not receiving a stabilizer. These findings will inform clinical practice and the evaluation of TTR-lowering treatment strategies in ATTR-CM."