Eplontersen with and without background transthyretin stabilizers in transthyretin amyloid cardiomyopathy: secondary analysis of a phase 3, randomized controlled trial.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) therapies include both TTR gene silencers and TTR stabilizers. The role of TTR gene silencers added to background TTR stabilizer therapy is unknown, and the effects of silencer treatment in the absence of stabilizer use are unclear. In the CARDIO-TTRansform study, 1,432 patients (n = 135 (9.4%) women and n = 1,297 (90.6%) men) with ATTR-CM were randomized (1:1) and treated with the antisense oligonucleotide eplontersen (45 mg every 4 weeks) that targets TTR or with placebo for up to 140 weeks. At baseline, 57% of the patients were taking TTR stabilizers. In the overall study, treatment with eplontersen did not reduce the primary composite endpoint. Here, in a prespecified analysis, we show that the primary endpoint (a composite of cardiovascular mortality and recurrent cardiovascular events) was modified by baseline stabilizer use (Pinteraction = 0.017). Benefits were observed in those patients not on stabilizers at baseline (rate ratio (RR) = 0.71, 95% confidence interval (CI) 0.54 to 0.93, P = 0.012), whereas no benefits were observed in those on stabilizers at baseline (RR = 1.14, 95% CI 0.85 to 1.53, P = 0.39). The safety profile of eplontersen was favorable, irrespective of baseline stabilizer use. Treatment with eplontersen versus placebo demonstrated a clinically meaningful benefit among patients not receiving background stabilizers but provided no additional clinical benefit in those on background stabilizer therapy. These findings of a strong treatment effect modification may offer insight for therapeutic decision-making in clinical practice. ClinicalTrials.gov registration: NCT04136171 .