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 reduction of transthyretin (TTR) levels in healthy subjects.
A single dose of nucresiran at 300 mg or higher led to a mean TTR reduction of greater than 90% from baseline by Day 15, which was sustained through at least Day 180. Peak reduction of mean TTR levels exceeded 96% by Day 29 at these doses. Furthermore, at Day 360, a single 300 mg dose resulted in a mean TTR reduction of greater than 70%.
Key Findings from the Phase 1 Trial
The Phase 1 study enrolled 48 healthy adult subjects who were randomized to receive single ascending doses 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 pharmacokinetic characterization.
Pushkal Garg, M.D., Chief Medical Officer at Alnylam, stated, "We are very excited by these new Phase 1 data with nucresiran… 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."
Consistent TTR Reduction Across Patient Population
Notably, the study demonstrated low inter-patient variability in TTR reduction. For instance, at Day 29, TTR reduction ranged from 96.0 – 96.7% in the 300 mg cohort, 96.6 – 98.6% in the 600 mg cohort, and 96.0 - 97.3% in the 900 mg cohort.
Specifically, subjects receiving a single 300 mg dose of nucresiran experienced a mean serum TTR reduction of 90.3% at Day 15, 96.5% at Day 29, and 92.6% at Day 180. At Day 360, the mean serum TTR reduction was 71.12%.
Safety and Tolerability Profile
Nucresiran was well-tolerated at all tested doses. The majority of adverse events were mild, and none were considered treatment-related. There were no injection site reactions or liver-related safety signals identified.
Implications for ATTR Amyloidosis Treatment
These results suggest that nucresiran, leveraging Alnylam’s IKARIA platform, could potentially allow for less frequent dosing, such as biannual or annual subcutaneous administration, representing a significant advancement in the treatment of ATTR amyloidosis. Alnylam anticipates sharing Phase 3 development plans in the first quarter of 2025.
Transthyretin amyloidosis (ATTR) is a debilitating disease caused by misfolded TTR proteins that accumulate as amyloid deposits in various organs. It affects an estimated 50,000 people worldwide with the hereditary form (hATTR) and 200,000-300,000 with the wild-type form (wtATTR).
