Eplontersen misses primary endpoint in CARDIO-TTRansform

The phase III CARDIO-TTRansform trial did not meet its primary efficacy endpoint in patients with transthyretin amyloidosis with cardiomyopathy.

Eplontersen did not significantly reduce cardiovascular mortality and recurrent cardiovascular events compared with placebo in the overall CARDIO-TTRansform population, according to late-breaking results presented at ESC Congress 2026 in Munich, Germany.^1,2

CARDIO-TTRansform was a double-blind phase III trial involving 1,432 patients with wild-type or hereditary transthyretin amyloidosis with cardiomyopathy (ATTR-CM) across 130 centers in 20 countries. Participants receiving available standard of care were randomized 1:1 to eplontersen 45 mg or placebo, administered by subcutaneous injection every 4 weeks. The mean age was 72 years and 9.4% of participants were women.^1,2

Eplontersen is an RNA-targeted therapy designed to reduce production of transthyretin (TTR) by the liver. Although treatment produced the expected suppression of circulating serum TTR, this did not translate into a statistically significant reduction in the primary composite endpoint of cardiovascular mortality and recurrent cardiovascular events through 140 weeks.^1,2

There were 381 primary endpoint events among 210 patients receiving eplontersen compared with 392 events among 231 patients receiving placebo, corresponding to a rate ratio of 0.89 (95% CI 0.73–1.09; p=0.277).^1,2

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Background tafamidis use may have influenced the results

An important feature of CARDIO-TTRansform was the high use of concomitant TTR stabilizer therapy. At baseline, 57% of participants were receiving a stabilizer.¹

In a prespecified subgroup analysis, no additional benefit for the primary endpoint was observed among patients receiving stabilizer therapy at baseline. In contrast, fewer primary endpoint events occurred with eplontersen among patients who were not receiving a stabilizer at baseline, with the result reaching nominal statistical significance.¹

Speaking during the Ask the Trialist session following the Hot Line presentation, investigator Dr. Mathew Maurer, Columbia University Irving Medical Center, New York, highlighted background tafamidis use as an important consideration when interpreting the neutral overall result.²

“I think that is a great question and probably the main takeaway,” Dr. Maurer said, explaining that stabilizer use increased substantially during follow-up as tafamidis became more widely available in participating countries.

“Stabilizer use, as we showed, was 57% at baseline… such that somewhere about 80% of the subjects by the end of the trial were on a concomitant TTR stabilizer.”

Dr. Maurer noted that almost all stabilizer use in the trial involved tafamidis, and that patients starting stabilizer therapy during follow-up were distributed similarly between the treatment groups. He said the increase largely reflected changing access to treatment, particularly in the UK and Spain, rather than differences in disease severity between the groups.²

“In a background use of stabilizers, the trial overall was neutral,” he said, adding that the investigators believed this was “the main reason for the neutral result overall.”²

Among patients who were not receiving a stabilizer at baseline, fewer primary endpoint events occurred with eplontersen, although Dr. Maurer emphasized that this was a subgroup analysis and should therefore be interpreted cautiously.²

He also said that effects on secondary outcomes, including 6-minute walk distance and quality of life, appeared to be driven substantially by patients who were not receiving a stabilizer at baseline.²

Eplontersen was generally well tolerated, with a safety profile consistent with previous findings.¹

The findings highlight an emerging challenge for ATTR-CM trials as effective therapies become increasingly established in clinical practice: determining whether adding a TTR-lowering therapy to background stabilizer treatment provides additional clinical benefit.

Further analyses examining CARDIO-TTRansform according to tafamidis and stabilizer use are being presented during ESC Congress 2026.

References

1. European Society of Cardiology. Eplontersen trial did not meet its primary endpoint in transthyretin-mediated amyloid cardiomyopathy. ESC Congress 2026 press release. August 28, 2026.
2. Maurer M. CARDIO-TTRansform: efficacy and safety of eplontersen in patients with transthyretin amyloid cardiomyopathy. Hot Line 1 presentation and Ask the Trialist discussion. ESC Congress 2026; August 28, 2026; Munich, Germany.