N Engl J Med. 2026 Aug 28. doi: 10.1056/NEJMoa2608510. Online ahead of print.
ABSTRACT
BACKGROUND: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease caused by deposition of misfolded transthyretin (TTR). Eplontersen, an antisense oligonucleotide, reduces the production of hepatic TTR. The effect of eplontersen on ATTR-CM is unclear.
METHODS: In this phase 3, international, double-blind trial, we randomly assigned, in a 1:1 ratio, patients with ATTR-CM to receive subcutaneous eplontersen (45 mg) or placebo every 4 weeks for 140 weeks, in addition to standard treatment. The primary end point was a cumulative composite of death from cardiovascular causes and recurrent cardiovascular clinical events up to week 140. The effect of death from noncardiovascular causes on the primary analysis was assessed with a cumulative composite of death from any cause and cardiovascular events up to week 140.
RESULTS: A total of 1432 patients underwent randomization and received at least one dose of the assigned intervention (715 patients in the eplontersen group and 717 in the placebo group). The mean age of the patients was 76.4 years, and 90.6% were men. A total of 381 primary end-point events occurred in 210 patients (29.4%) receiving eplontersen, and 392 events occurred in 231 patients (32.2%) receiving placebo (rate ratio, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P = 0.28). Death from cardiovascular causes, as a component of the primary end point, occurred in 74 patients in the eplontersen group and in 70 in the placebo group; there were 307 cardiovascular clinical events in the eplontersen group and 322 in the placebo group. The rate ratio for the composite of death from any cause and cardiovascular events was 0.86 (95% CI, 0.71 to 1.04). Serious adverse events occurred in 413 patients (57.8%) in the eplontersen group and in 426 (59.4%) in the placebo group.
CONCLUSIONS: Among patients with ATTR-CM, eplontersen therapy did not lead to a lower risk of a composite of death from cardiovascular causes and recurrent cardiovascular events than placebo up to 140 weeks. (Funded by Ionis Pharmaceuticals and AstraZeneca; CARDIO-TTRansform ClinicalTrials.gov number, NCT04136171.).
PMID:42663301 | DOI:10.1056/NEJMoa2608510