Eplontersen Misses Primary Cardiovascular Endpoint in ATTR-CM

Key Takeaways

• In an international trial of patients with ATTR-CM, primary-endpoint events affected 29.4% receiving eplontersen versus 32.2% receiving placebo, but the cumulative composite did not differ significantly.
• Cardiovascular deaths were numerically higher with eplontersen, while recurrent cardiovascular clinical events were fewer; neither component established benefit or harm.
• Serious adverse events occurred in 57.8% of eplontersen recipients versus 59.4% of placebo recipients, without a demonstrated safety advantage.

Progressive transthyretin amyloidosis with cardiomyopathy (ATTR-CM) involves deposition of misfolded transthyretin (TTR) and a continuing burden of cardiovascular illness. Eplontersen, an antisense oligonucleotide, reduces hepatic TTR production. For patients receiving standard treatment, whether adding eplontersen changes cardiovascular outcomes remained uncertain, prompting a comparison with placebo.

Investigators in the CARDIO-TTRansform international phase 3, double-blind, randomized trial assigned 1,432 patients with ATTR-CM equally to subcutaneous eplontersen or placebo, each alongside standard treatment. The eplontersen group received 45 mg every four weeks; the placebo group received injections on the same schedule. Treatment continued for 140 weeks. Participants were predominantly men and were, on average, in their late seventies. The primary endpoint was a cumulative composite of cardiovascular death and recurrent cardiovascular clinical events. Investigators also assessed a separate cumulative composite of death from any cause and cardiovascular events.

For the primary cumulative-event comparison, the rate ratio was 0.89 (95% confidence interval, 0.73 to 1.09; P=0.28). The interval included no difference, and eplontersen did not demonstrate a lower risk of the combined cardiovascular outcome. Because clinical events could recur, the proportion of patients experiencing an endpoint event is not itself a cumulative-event rate.

Cardiovascular mortality and recurrent clinical events did not move uniformly across the treatment groups. For the separate composite of death from any cause and cardiovascular events, the rate ratio was 0.86 (95% confidence interval, 0.71 to 1.04), an interval that also included no difference. Serious adverse events occurred in 413 eplontersen recipients and 426 placebo recipients; these descriptive totals do not establish a between-group safety difference.

The investigators concluded that adding eplontersen to standard treatment did not reduce the composite risk of cardiovascular death and recurrent cardiovascular clinical events compared with placebo over the assessed period. That conclusion applies to the combined endpoint, not to an independently demonstrated effect on either component.