Design and Rationale of A Phase 3 Study to Evaluate the Efficacy and Safety of Nucresiran (Aln-Ttrsc04) in Patients with Transthyretin Amyloidosis with Cardiomyopathy

Introduction Transthyretin amyloidosis (ATTR) is a progressive and fatal condition caused by deposition of misfolded transthyretin (TTR) as amyloid fibrils in multiple tissues. ATTR is classified as either hereditary (hATTR) or wild-type (wtATTR), depending on the presence or absence of amyloidogenic TTR gene variants, and manifests as either primarily cardiomyopathy (ATTR-CM), polyneuropathy, or a mixed phenotype. RNA interference (RNAi) therapeutics suppress the hepatic production of TTR by targeting wild-type and variant TTR mRNA for degradation. Previous studies showed that rapid TTR knockdown with RNAi therapeutics improves outcomes for ATTR patients regardless of etiology or manifestation. Most recently, vutrisiran was shown to improve outcomes for patients with ATTR-CM across multiple domains in the HELIOS-B study, including reducing cardiovascular events and all-cause mortality, and improving functional capacity and quality of life. Larger reductions in TTR levels correlated with greater clinical benefit in patients with hATTR and polyneuropathy, suggesting that greater TTR knockdown may offer similar benefits in ATTR-CM. Nucresiran (ALN-TTRsc04) is a next-generation RNAi therapeutic designed for the treatment of ATTR. In a Phase 1, ascending-single-dose study in healthy adults (NCT05661916), nucresiran led to rapid and sustained knockdown of TTR. Up to 95% knockdown by Day 15 and >90% mean reductions through Month 6 were achieved with subcutaneously administered doses ≥300 mg that were well tolerated. Hypothesis The efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of nucresiran in patients with ATTR-CM will be evaluated in a global, Phase 3, randomized, placebo-controlled study, the rationale and design of which will be described. Methods The study design, including inclusion and exclusion criteria, will be finalized in Q1 2025. Enrollment of adult patients with ATTR-CM is expected to begin in 2025. Key endpoints will assess mortality and cardiovascular events. Results The nucresiran Phase 3 ATTR-CM study design and rationale will be presented. Conclusions The Phase 3 study will investigate the efficacy, safety, and PK/PD of nucresiran in patients with ATTR-CM. Nucresiran has the potential to provide greater and more sustained TTR knockdown with lower inter-patient variability and less frequent dosing than current TTR-lowering therapies. This abstract will be presented at HFA 2025, May 17-20, 2025, Belgrade, Serbia.