Eplontersen Trial Misses Main Goal

What Did the CARDIO-TTRansform Trial Find?

CARDIO-TTRansform was a Phase 3, randomized, double-blind, placebo-controlled trial conducted at 130 centers in 20 countries. It enrolled 1,432 adults with hereditary or wild-type transthyretin amyloid cardiomyopathy, also called ATTR-CM, and evaluated subcutaneous eplontersen 45 mg every four weeks for up to 140 weeks.

According to results presented at the European Society of Cardiology Congress, the rate ratio for the primary composite endpoint was 0.89, with a 95% confidence interval of 0.73 to 1.09 and a p-value of 0.277. This means the difference was not statistically significant. Eplontersen substantially lowered circulating transthyretin and was generally well tolerated, but that biological effect did not translate into a proven reduction in the trial's primary cardiovascular outcome.

Why Might Background TTR Stabilizer Treatment Matter?

ATTR-CM develops when misfolded transthyretin forms amyloid deposits in the heart, progressively making the muscle thicker and less able to pump efficiently. Stabilizer medicines are designed to keep the transthyretin protein from breaking apart and misfolding, while eplontersen is an antisense medicine that reduces production of transthyretin in the liver.

Fifty-seven percent of participants were taking a stabilizer when the trial began, and additional participants started one during follow-up. A prespecified analysis found fewer primary endpoint events with eplontersen among patients who were not taking a stabilizer at baseline, while no added effect was detected among baseline stabilizer users. Because this was a subgroup analysis and stabilizer use was not independently randomized, the apparent monotherapy signal should be treated as suggestive rather than definitive.

What Do the Results Mean for People With ATTR-CM?

The result is important because it tests whether combining two strategies—reducing transthyretin production and stabilizing the remaining protein—provides greater clinical protection. CARDIO-TTRansform did not demonstrate that benefit for cardiovascular death and recurrent events in its overall population, even though several functional, imaging and biomarker measures favored eplontersen.

The trial does not prove that eplontersen is ineffective in every ATTR-CM setting, nor does it change its separate approved use for polyneuropathy caused by hereditary transthyretin-mediated amyloidosis. Further analyses and dedicated trials would be needed to determine whether selected patients who are not receiving stabilizers could benefit. Patients should not start, stop or combine amyloidosis treatments without advice from an experienced cardiology or amyloidosis team.