Alnylam's Nucresiran Shows Strong TTR Reduction With A Single Dose In Interim Phase 1 Data

Alnylam Pharmaceuticals, Inc., a pioneer in RNAi therapeutics, unveiled fresh findings from its Phase 1 study of nucresiran (previously ALN-TTRsc04), a next-generation RNAi therapeutic targeting transthyretin (ATTR) amyloidosis. These insights were shared during an oral presentation at the 2024 American Heart Association Scientific Sessions held in Chicago.

The findings revealed that a single 300 mg or higher dose of nucresiran resulted in a swift and consistent reduction in serum TTR levels, with average reductions exceeding 90% from baseline by Day 15 and maintained through at least Day 180. At these doses, peak mean TTR reductions surpassed 96% by Day 29. Even at Day 360, a single 300 mg dose continued to deliver a significant reduction in serum TTR levels, with an average drop of over 70%. Data for the 600 mg and 900 mg cohorts at Day 360 are still pending. To date, nucresiran has demonstrated a favourable tolerability profile across all dose levels.

Pushkal Garg, M.D., Chief Medical Officer, Alnylam, said in a statement, “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. Furthermore, we are encouraged by the potential of nucresiran to reduce interpatient variability in TTR lowering.”

He further added, “Nucresiran utilizes our IKARIA platform, which has now demonstrated the potential to achieve durability supportive of biannual or annual dosing, representing a potential new paradigm in the treatment of ATTR amyloidosis. Importantly, nucresiran has been well tolerated at all dose levels tested to date. We look forward to sharing Phase 3 development plans in the first quarter of 2025.”

The Phase 1 dose-finding study, which is still underway, assessed the safety, pharmacodynamics, and pharmacokinetics of single doses of nucresiran in healthy participants. As initially highlighted during Alnylam’s R&D Day in December 2023, a single administration of nucresiran achieved a rapid and long-lasting reduction in serum TTR levels.

For participants who received a 300 mg dose, mean serum TTR reductions were 90.3% by Day 15, 96.5% by Day 29, and 92.6% by Day 180, with levels remaining 71.12% lower at Day 360. In the 600 mg cohort, mean reductions reached 95.0% by Day 15, 97.8% by Day 29, and 96.0% by Day 180. Similarly, for the 900 mg cohort, reductions averaged 91.7% at Day 15, 96.7% at Day 29, and 94.2% at Day 180. Data for Day 360 TTR reductions in the 600 mg and 900 mg cohorts are not yet available.

TTR reduction showed minimal variability among participants. At Day 29, reductions ranged from 96.0% to 96.7% in the 300 mg group, 96.6% to 98.6% in the 600 mg group, and 96.0% to 97.3% in the 900 mg group. Nucresiran demonstrated strong tolerability across all doses tested. Most adverse events were mild, with none attributed to the treatment. No injection site reactions or significant safety concerns, including liver-related signals, were reported.