Alnylam Reports Interim Phase 1 Data of Nucresiran Showing Sustained TTR Knockdown at Six Months After Single Dose

Alnylam Pharmaceuticals, Inc., a premier company in RNAi therapeutics, has unveiled promising new data from its Phase 1 study of nucresiran, previously known as ALN-TTRsc04. This next-generation RNAi therapeutic is under development for treating transthyretin (ATTR) amyloidosis and the results were showcased in an oral session at the American Heart Association Scientific Sessions 2024 in Chicago.

The study revealed that a single dose of nucresiran at 300 mg or higher resulted in a swift reduction of serum TTR levels with minimal inter-patient variability. The mean reductions exceeded 90% from baseline by Day 15 and remained significant through at least Day 180. By Day 29, a peak reduction of over 96% in mean TTR levels was observed. Furthermore, serum TTR levels stayed substantially reduced on Day 360, with a mean reduction of over 70% following a single 300 mg dose. Data for the 600 mg and 900 mg dose cohorts at Day 360 are pending. All doses of nucresiran have been well tolerated.

Dr. Pushkal Garg, Chief Medical Officer at Alnylam, expressed excitement over the data, emphasizing the potential of nucresiran to significantly reduce TTR levels with sustained effects over six months. Nucresiran's use of Alnylam's IKARIA platform suggests the possibility of biannual or annual dosing, marking a potential new treatment paradigm for ATTR amyloidosis. The safety profile of nucresiran has been positive across all tested doses, with no significant adverse events reported.

The ongoing Phase 1 study is designed to assess the safety, pharmacodynamics, and pharmacokinetics of single doses of nucresiran in healthy volunteers. Previously shared data from Alnylam’s R&D Day in December 2023 showed similar rapid and durable TTR reductions. For the 300 mg dose cohort, mean serum TTR reductions of 90.3% at Day 15, 96.5% at Day 29, and 92.6% at Day 180 were recorded. On Day 360, the reduction remained at 71.12%. In the 600 mg cohort, reductions of 95.0% at Day 15, 97.8% at Day 29, and 96.0% at Day 180 were noted. The 900 mg cohort showed reductions of 91.7% at Day 15, 96.7% at Day 29, and 94.2% at Day 180. Data for Day 360 for the 600 mg and 900 mg doses are not yet available. The study has shown low inter-patient variability in TTR reduction, with narrow ranges across different doses.

Nucresiran has been well tolerated at all doses, with mostly mild adverse events unrelated to the treatment. The absence of injection site reactions and any significant safety signals, including liver-related issues, highlights the favorable safety profile of nucresiran.

The Phase 1 trial is a randomized, double-blind, placebo-controlled, single ascending dose study aimed at evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of nucresiran in healthy adults. The study included 48 participants randomized to receive varying doses of nucresiran or placebo. The primary endpoint focuses on safety, while secondary endpoints include changes in serum TTR from baseline and the pharmacokinetic profile of nucresiran in plasma and urine.

Nucresiran is an investigational RNAi therapeutic that aims to reduce both mutant and wild-type transthyretin (TTR) proteins, thereby addressing the root cause of transthyretin amyloidosis. It leverages Alnylam’s IKARIA platform to achieve deeper, more durable TTR knockdowns, potentially allowing for less frequent dosing. The safety and efficacy of nucresiran have yet to be established by regulatory authorities.

ATTR amyloidosis is a severe, often underdiagnosed disease caused by misfolded TTR proteins, leading to amyloid deposits in critical organs. It can present as polyneuropathy, cardiomyopathy, or both. The disease manifests in two forms: hereditary ATTR (hATTR), affecting approximately 50,000 people globally, and wild-type ATTR (wtATTR), impacting an estimated 200,000 to 300,000 individuals worldwide.

RNA interference (RNAi) is a natural cellular process of gene silencing, recognized as a major scientific breakthrough and awarded the Nobel Prize in 2006. RNAi therapeutics represent a new class of medicines that potently silence disease-causing genes. Alnylam Pharmaceuticals has been at the forefront of RNAi therapeutic development, translating Nobel Prize-winning science into transformative treatments. The company, headquartered in Cambridge, MA, continues to advance its deep pipeline of investigational medicines aimed at addressing both rare and common diseases.