A Phase 3 Global, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ION-682884 (Eplontersen) in Patients With Transthyretin-Mediated Amyloid Cardiomyopathy

doi:10.1056/nejmoa2608510

CARDIO-TTRansform

Paziente / Popolazione Intervento / Esposizione Confronto Esito

In 1,432 patients with transthyretin amyloid cardiomyopathy, eplontersen did not reduce cardiovascular death or recurrent cardiovascular events at 140 weeks compared with placebo.

N

1432pazienti

Disegno

Phase 3 double-blind, placebo-controlled RCT, 1:1, subcutaneous dosing every 4 weeks for up to 140 weeks on top of local standard of care (TTR stabilisers permitted), followed by a 20-week post-treatment period or open-label extension

Esito

Composite of cardiovascular mortality and recurrent cardiovascular clinical events through week 140

Rilevanza

1Definisce la pratica — lo studio su cui poggia la linea guida.

Risultato381 events in 210 patients vs 392 events in 231 (rate ratio 0.89, 95% CI 0.73-1.09; P = 0.28). Serum transthyretin was suppressed through week 140. Without a background stabiliser fewer primary events with eplontersen (nominal significance); with one, no incremental effect.

Fontana M, Masri A, et al. N Engl J Med. 2026; published online 28 August. 10.1056/nejmoa2608510

Discussione e critica

The largest trial ever run in ATTR cardiomyopathy, and a negative one: transthyretin was knocked down as designed, but events did not follow. Fifty-seven percent were already taking a stabiliser, and the prespecified subgroup without one was nominally positive — a hypothesis about non-additive mechanisms, not a finding. The primary analysis counts recurrent events rather than time to first, which is the more generous framing and still did not reach significance.