Alnylam Pharmaceuticals announced positive interim results from its Phase 1 study 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 transthyretin (TTR) levels following a single dose, suggesting the potential for biannual or annual dosing. This could represent a significant advancement in the treatment of ATTR amyloidosis, a debilitating and often fatal disease.
Rapid and Sustained TTR Reduction
The Phase 1 trial results demonstrated that a single dose of nucresiran at 300 mg or higher led to a rapid reduction in serum TTR levels, with mean reductions exceeding 90% from baseline by Day 15. This effect was sustained for at least six months (Day 180). Furthermore, peak reductions in mean TTR levels surpassed 96% by Day 29 at these doses. Data from the 360-day mark showed a mean TTR reduction of greater than 70% after a single 300 mg dose. These results highlight the potential for nucresiran to provide a durable therapeutic effect with infrequent dosing.
Low Inter-Patient Variability
An important aspect of the study was the low inter-patient variability observed in TTR reduction. At Day 29, TTR reduction ranged from 96.0% to 96.7% in the 300 mg cohort, 96.6% to 98.6% in the 600 mg cohort, and 96.0% to 97.3% in the 900 mg cohort. This consistency suggests that nucresiran could offer a more predictable therapeutic response across a diverse patient population.
Safety and Tolerability
Nucresiran was well tolerated at all tested doses in the Phase 1 study. The majority of adverse events were mild, and none were considered related to the treatment. Notably, there were no injection site reactions or liver-related safety signals identified. This encouraging safety profile supports further development of nucresiran as a potential treatment for ATTR amyloidosis.
IKARIA Platform and Future Development
Nucresiran utilizes Alnylam's IKARIA platform, which is designed to achieve deeper and more durable knockdown of TTR, potentially enabling less frequent dosing. Alnylam plans to share Phase 3 development plans for nucresiran in the first quarter of 2025. The company's Chief Medical Officer, Pushkal Garg, M.D., expressed excitement about the Phase 1 data, emphasizing the potential of nucresiran to reduce interpatient variability and offer a new treatment paradigm for ATTR amyloidosis with biannual or annual dosing.
Study Design
The Phase 1 trial was a randomized, double-blind, placebo-controlled, single ascending dose study involving 48 healthy adult subjects. Participants were randomized in a 3:1 ratio 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 in serum TTR levels over time and characterization of nucresiran pharmacokinetics.
About ATTR Amyloidosis
Transthyretin amyloidosis (ATTR) is a progressive disease caused by misfolded TTR proteins that accumulate as amyloid deposits in various organs and tissues. It manifests in two forms: hereditary ATTR (hATTR), caused by TTR gene variants, and wild-type ATTR (wtATTR), occurring without a gene variant. ATTR affects an estimated 50,000 people worldwide with hATTR and 200,000-300,000 with wtATTR.
