CARDIO-TTRansform: Eplontersen Fails to Meet Primary Endpoint in ATTR-CM due to Background Stabilizers
The Phase III CARDIO-TTRansform clinical trial evaluating the monthly subcutaneous RNA-targeted gene silencer eplontersen (Wainua) in transthyretin amyloid cardiomyopathy (ATTR-CM) failed to meet its primary composite endpoint of cardiovascular mortality and recurrent cardiovascular events.
Presented at a Hot Line session of the European Society of Cardiology (ESC) Congress 2026 on August 28 and published in The New England Journal of Medicine, the trial is the largest ATTR-CM study conducted to date, enrolling 1,432 patients across 130 centers in 20 countries. Despite demonstrating robust suppression of circulating serum transthyretin (TTR), eplontersen was unable to show a statistically significant clinical benefit in the overall trial population.
Key Findings and Subgroup Analysis
- Primary Endpoint Miss: There were 381 primary composite events in 210 patients in the eplontersen group compared to 392 events in 231 patients in the placebo group (rate ratio 0.89; 95% confidence interval 0.73 to 1.09; p=0.277) over 140 weeks.
- The Stabilizer Confound: The trial's failure was heavily driven by the background use of stabilizers (such as Pfizer's tafamidis).1 At baseline, 57% of participants in each arm were receiving stabilizer therapy, and an additional 24% initiated stabilizer therapy during the trial.
- Subgroup Divergence:
- On Stabilizers: No additional treatment benefit was observed when eplontersen was added to background stabilizer therapy.
- No Stabilizers (Monotherapy): Among patients who were not taking stabilizers at baseline, eplontersen monotherapy demonstrated fewer primary composite events compared to placebo, reaching nominal statistical significance.
Market Implications
The failure of CARDIO-TTRansform raises broader questions about whether injectable gene silencers provide any incremental benefit over oral stabilizers like tafamidis or BridgeBio's new stabilizer acoramidis. It also highlights potential headwinds for other silencers in development or on the market, such as Alnylam's vutrisiran (Amvuttra), as clinicians weigh the convenience of oral stabilizers against injectable silencers.
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An instance of Ubiquitous background standard-of-care therapies neutralize the observable clinical efficacy of next-generation drug candidates. — The heavy baseline and mid-trial utilization of standard-of-care stabilizers in both arms neutralized the observable clinical benefit of the next-generation therapy. ↩︎