Alnylam Announces Interim Phase 1 Data of Nucresiran (ALN-TTRsc04) Showing Rapid Knockdown of TTR that is Sustained at Six Months Following a Single Dose

− Single Dose of Nucresiran 300mg or Higher Led to Rapid Knockdown of Mean TTR Levels of Greater than 90% by Day 15 that was Sustained at Six Months −

− At These Doses, Peak Reduction of Mean TTR Levels of Greater than 96% were Achieved by Day 29 −

− Data Support Potential for Biannual or Annual Subcutaneous Dosing, Representing a New Paradigm in the Treatment of ATTR Amyloidosis −

− Encouraging Safety and Tolerability Observed −

− Alnylam Continues to Expect to Share Phase 3 Development Plans in Q1 2025 –

Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today 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.

Phase 1 Study Design

The Phase 1 trial is a randomized, double-blind, placebo-controlled, single ascending dose study designed to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of nucresiran in healthy adult subjects. The study enrolled 48 healthy adult subjects randomized 3:1 to receive a single ascending dose of 5, 25, 100, 300, 600, or 900 mg of nucresiran or placebo. The primary endpoint of the study is safety and secondary endpoints include the change from baseline in serum TTR over time, as well as characterization of plasma and urine pharmacokinetics (PK) of nucresiran.

About Nucresiran

Nucresiran is an investigational RNAi therapeutic in development to deliver rapid knockdown of mutant and wild-type transthyretin (TTR) and address the underlying cause of transthyretin (ATTR) amyloidosis. As part of Alnylam's proprietary IKARIA™ platform, nucresiran has the potential to achieve deeper and more durable rapid knockdown of TTR, allowing for less frequent dosing. The safety and efficacy of nucresiran have not been established or evaluated by the FDA, EMA or any other health authority.

About ATTR

Transthyretin amyloidosis (ATTR) is an underdiagnosed, rapidly progressive, debilitating and fatal disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy or both manifestations of disease. There are two different forms of ATTR – hereditary ATTR (hATTR), which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR), which occurs without a TTR gene variant and impacts an estimated 200,000-300,000 people worldwide.

About RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of today's medicines by potently silencing messenger RNA (mRNA) – the genetic precursors that encode for disease-causing or disease pathway proteins – thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

About Alnylam Pharmaceuticals

Alnylam (NASDAQ:ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its "Alnylam P5x25" strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on X (formerly Twitter) at @Alnylam, or on LinkedIn, Facebook, or Instagram.

Alnylam Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam's expectations, beliefs, goals, plans or prospects including, without limitation, the potential for nucresiran to achieve durability supportive of biannual or annual dosing and to represent a new paradigm in the treatment of ATTR amyloidosis; the potential to reduce interpatient variability in TTR lowering with nucresiran; and the timing of Alnylam's release of Phase 3 development plans for nucresiran should be considered forward-looking statements. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation, risks and uncertainties relating to: Alnylam's ability to successfully execute on its "Alnylam P5x25" strategy; Alnylam's ability to successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam's product candidates; actions or advice of regulatory agencies and Alnylam's ability to obtain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam's approved products globally; and any delays, interruptions or failures in the manufacture and supply of Alnylam's product candidates or its marketed products; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's 2023 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam's subsequent Quarterly Reports on Form 10-Q and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

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