Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced the presentation of new results from its Phase 1 study of nucresiran (formerly ALN-TTRsc04), a next-generation RNAi therapeutic in development for the treatment of transthyretin (ATTR) amyloidosis. The data were presented in an oral session at the American Heart Association Scientific Sessions 2024 in Chicago.

These new results demonstrated that a single dose of nucresiran at 300 mg or higher led to rapid knockdown of serum TTR with low inter-patient variability, with mean reductions of greater than 90% from baseline achieved at Day 15 and sustained through at least Day 180. At these doses, peak reduction of mean TTR levels of greater than 96% were achieved by Day 29. Furthermore, serum TTR levels remained substantially reduced at Day 360 with a mean reduction of greater than 70% after a single 300 mg dose. Day 360 results are not yet available for the 600 mg and 900 mg dose cohorts. All doses of nucresiran have been well tolerated to date.

“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. “Furthermore, we are encouraged by the potential of nucresiran to reduce interpatient variability in TTR lowering. 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 ongoing Phase 1 dose-finding study evaluated the safety, as well as pharmacodynamics and pharmacokinetics, of single doses of nucresiran in healthy subjects. As previously presented at Alnylam’s R&D Day in December 2023, a single dose of nucresiran led to rapid knockdown of serum TTR that was highly durable.

In subjects receiving a single 300 mg dose of nucresiran, mean serum TTR reduction of 90.3% was observed at Day 15, 96.5% at Day 29, and 92.6% at Day 180. At Day 360, mean serum TTR Reduction was 71.12%. In subjects receiving a single 600 mg dose, mean serum TTR reduction of 95.0% was observed at Day 15, 97.8% at Day 29, and 96.0% at Day 180. In subjects receiving a single 900 mg dose, mean serum TTR reduction of 91.7% was observed at Day 15, 96.7% at Day 29, and 94.2% at Day 180. As of the data cutoff date, TTR knockdown levels at Day 360 were not available for either the 600 mg or 900 mg cohort.

There has been low inter-patient variability in the TTR reduction observed; 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.

In the study, nucresiran has been well tolerated at all tested doses. The majority of adverse events across doses have been mild and none have been considered to be related to treatment. There have been no injection site reactions and no safety signals identified, including no liver-related signals.