Alnylam Pharmaceuticals announced positive interim results from its Phase 1 clinical trial of nucresiran (ALN-TTRsc04), a next-generation RNAi therapeutic being developed for transthyretin (ATTR) amyloidosis. The data, presented at the American Heart Association Scientific Sessions 2024, showcased rapid and sustained knockdown of serum TTR levels in healthy subjects.
Rapid and Sustained TTR Reduction
The Phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of single ascending doses of nucresiran in healthy adult subjects. Key findings revealed that a single dose of nucresiran at 300 mg or higher led to a rapid reduction of serum TTR, with low inter-patient variability. Specifically, mean reductions of greater than 90% from baseline were achieved by Day 15 and sustained through at least Day 180. Peak reductions of mean TTR levels exceeded 96% by Day 29. Furthermore, at Day 360, serum TTR levels remained substantially reduced, with a mean reduction of greater than 70% observed after a single 300 mg dose.
"We are very excited by these new Phase 1 data with nucresiran, our next-generation TTR-targeting RNAi therapeutic, which demonstrated that a single dose of ≥300 mg achieved rapid knockdown of TTR greater than 90% from Day 15 that was sustained to at least six months," said Pushkal Garg, M.D., Chief Medical Officer, Alnylam.
Potential for Infrequent Dosing
The observed durability of TTR knockdown suggests the potential for biannual or annual subcutaneous dosing, which could represent a significant advancement in the treatment paradigm for ATTR amyloidosis. Nucresiran utilizes Alnylam's IKARIA platform, designed to achieve deeper and more durable TTR knockdown with less frequent administration.
Safety and Tolerability
Across all tested doses, nucresiran was well-tolerated. The majority of adverse events were mild, and none were considered treatment-related. Notably, no injection site reactions or liver-related safety signals were identified.
Study Design and Demographics
The Phase 1 trial was a randomized, double-blind, placebo-controlled, single ascending dose study. It enrolled 48 healthy adult subjects who were randomized 3:1 to receive a single dose of nucresiran (5, 25, 100, 300, 600, or 900 mg) or placebo. The primary endpoint was safety, while secondary endpoints included changes from baseline in serum TTR over time and characterization of nucresiran pharmacokinetics.
About ATTR Amyloidosis
ATTR amyloidosis is a progressive and often fatal disease caused by the misfolding and aggregation of transthyretin (TTR) protein. These amyloid deposits accumulate in various organs and tissues, leading to polyneuropathy, cardiomyopathy, and other debilitating manifestations. There are two main forms of ATTR: hereditary ATTR (hATTR), caused by TTR gene variants, and wild-type ATTR (wtATTR), which occurs without a gene variant. The disease affects an estimated 50,000 people worldwide with hATTR and 200,000-300,000 with wtATTR.
Alnylam anticipates sharing Phase 3 development plans for nucresiran in the first quarter of 2025.
