**Alnylam Pharmaceuticals, Renowned RNAi Therapy Leader, Unveils Promising Phase 1 Outcomes for Nucresiran**
Alnylam Pharmaceuticals, a front-runner in the field of RNA interference (RNAi) therapeutics, disclosed the latest findings from its phase 1 research on nucresiran (previously known as ALN-TTRsc04), an advanced RNAi solution targeting transthyretin (ATTR) amyloidosis. The outcomes were showcased during an oral presentation at the 2024 American Heart Association Scientific Sessions held in Chicago.
The evidence demonstrated that a single 300 mg dose or more of nucresiran precipitated a swift and substantial reduction in serum TTR levels, displaying minimal variation among patients. Average declines exceeding 90% from initial levels were documented by Day 15 and persisted beyond Day 180. At these dosages, maximum average TTR reductions greater than 96% were attained by Day 29. Additionally, TTR serum levels sustained a significant reduction by Day 360, with over 70% average reduction observed following a 300 mg dose. Data for the 600 mg and 900 mg doses at Day 360 remain pending. Thus far, all dose levels of nucresiran have exhibited favorable tolerability.
“These recent phase 1 findings with nucresiran, our pioneering RNAi therapeutic focused on TTR, are exhilarating,” remarked Pushkal Garg, M.D., Chief Medical Officer at Alnylam. “A single administration of 300 mg realized a swift TTR knockdown exceeding 90% from Day 15 that sustained for a minimum of six months. Moreover, nucresiran’s potential to diminish interpatient variability in TTR suppression is encouraging. Leveraging our IKARIA platform, nucresiran achieves sustained effects that could support semi-annual or annual dosing, suggesting a novel treatment approach for ATTR amyloidosis. Notably, every tested dose level of nucresiran has been well tolerated. We are eagerly anticipating the disclosure of our phase 3 plans in early 2025.”
The ongoing phase 1 assessment focuses on the safety, along with the pharmacodynamics and pharmacokinetics, of singular nucresiran doses in healthy participants. Previously discussed at Alnylam’s R&D Day in December 2023, a sole dose of nucresiran prompted a durable, rapid reduction of serum TTR.
Subjects receiving a single 300 mg dose saw average serum TTR reductions of 90.3% on Day 15, 96.5% on Day 29, and 92.6% by Day 180. By Day 360, the average reduction hit 71.12%. In those given a 600 mg dose, average serum TTR decline reached 95.0% at Day 15, 97.8% at Day 29, and 96.0% by Day 180. The 900 mg cohort experienced reductions of 91.7% at Day 15, 96.7% at Day 29, and 94.2% by Day 180. Day 360 knockdown data remain unavailable for both 600 mg and 900 mg groups.
Inter-patient variability in TTR knockdown has been minimal; by Day 29, reductions in the 300 mg group ranged from 96.0 – 96.7%, 96.6 – 98.6% in the 600 mg group, and 96.0 – 97.3% in the 900 mg cohort.
Nucresiran showcased favorable tolerability at all dose levels throughout the trial. Most adverse effects were mild and unrelated to the treatment, with no injection site reactions or safety signals observed, including hepatic concerns.
Phase 1 trial methodology incorporates a randomized, double-blind, placebo-controlled format to assess the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) responses of nucresiran in healthy adults. The trial involved 48 adults, randomized 3:1 to receive ascending doses of 5, 25, 100, 300, 600, or 900 mg of nucresiran or placebo. The key goal is safety, with secondary objectives assessing changes in serum TTR over time and the characterization of nucresiran’s PK in plasma and urine.
Nucresiran is under investigation to rapidly address both mutant and wild-type transthyretin (TTR), tackling the core of transthyretin (ATTR) amyloidosis via Alnylam’s proprietary IKARIA platform. It suggests enhanced therapeutic durability with less frequent dosing. Its safety and effectiveness have yet to be validated by regulatory authorities.
Transthyretin amyloidosis (ATTR) is an under-identified condition characterized by rapid progression and life-threatening impairments, resulting from misfolded TTR proteins accumulating in various body regions like nerves and gastrointestinal tracts. Patients might experience polyneuropathy or cardiomyopathy symptoms. ATTR manifests as hereditary (hATTR) involving a TTR gene mutation or wild-type (wtATTR) without genetic variants, affecting millions globally.
RNAi illustrates a natural gene-silencing mechanism emerging as a critical and fast-evolving area in biology and pharmaceuticals. Its discovery was honored with the Nobel Prize in Physiology or Medicine in 2006 as a transformative scientific breakthrough. By exploiting natural RNAi activities, RNAi therapeutics, powered by small interfering RNA (siRNA), effectively silence genetic templates for disease-related proteins, pioneering transformative treatments.
Alnylam pioneers RNAi translation into novel medications, ushering in transformative solutions for diverse conditions with unmet needs through this groundbreaking scientific platform.