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The Phase 3 CARDIO-TTRansform trial of eplontersen in transthyretin amyloid cardiomyopathy (ATTR-CM) did not meet its primary efficacy endpoint, according to an August 28, 2026, press release from the European Society of Cardiology summarizing results presented in a Hot Line session at ESC Congress 2026 in Munich. Mathew Maurer, MD, of Columbia University Irving Medical Center presented the findings.
ATTR-CM is a progressive, fatal disease in which misfolded transthyretin protein deposits in the heart muscle, reducing cardiac function and driving worsening heart failure and recurrent cardiovascular events. An estimated 300,000 to 500,000 people live with the condition worldwide, and it remains an underrecognized cause of heart failure. Eplontersen, a once-monthly RNA-targeted silencer that reduces transthyretin production in the liver, is already approved for hereditary transthyretin amyloid polyneuropathy.
The double-blind trial enrolled 1,432 patients with wild-type or hereditary ATTR-CM across 130 centers in 20 countries, all receiving available standard of care, and randomized them one-to-one to subcutaneous eplontersen 45 mg or placebo every 4 weeks. Mean age was 72 years, and 9.4% of participants were women. Over 140 weeks, the composite of cardiovascular mortality and recurrent cardiovascular events did not differ significantly between arms, with a rate ratio of 0.89 (95% CI, 0.73-1.09; P=.277), despite robust suppression of circulating transthyretin, consistent with the drug's mechanism.
The investigators reported that the primary results appeared to be influenced by baseline use of stabilizer therapy. No clear benefit emerged among patients receiving a background stabilizer, the majority of the study population, while fewer primary endpoint events occurred with eplontersen among patients not receiving one. Maurer noted that eplontersen achieved its intended reductions in circulating transthyretin even though the trial did not demonstrate a significant reduction in the primary endpoint in the overall population, and the presenters concluded that an unmet need persists for new treatments to improve prognosis in ATTR-CM.
