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Alnylam Continues Scientific Leadership in Advancement of RNAi Therapeutics at the 17th Annual Meeting of the Oligonucleotides Therapeutics Society

− Reveals Hexadecyl (C16) Lipophilic Conjugate for Potent and Effective Delivery of siRNAs in the CNS –

− Presents Pre-clinical Data with IKARIA Platform Demonstrating Potential to Achieve Over 90% Target Knockdown with an Annual Dosing Regimen –

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today new pre-clinical research results demonstrating continued RNAi therapeutics platform innovation and scientific leadership. The research was presented at the 17th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held virtually from September 26 – 29, 2021. Among the presentations from Alnylam scientists, new pre-clinical data were presented identifying a hexadecyl (C16) moiety as a lipophilic ligand by which conjugation to siRNAs enables the potential for safe, robust, and durable target knockdown in the central nervous system following intrathecal administration. In addition, pre-clinical platform data were presented highlighting the Company’s extended duration platform, called IKARIA™, which has the potential to enable highly potent (i.e., >90 percent) target mRNA silencing with an annual dosing regimen.

“At OTS this year we are pleased to share research illustrating Alnylam’s continued leadership in the advancement of RNAi therapeutics. Here we show that conjugation of lipophilic C16 to siRNAs enables robust and durable target knockdown in the CNS in rats and non-human primates following intrathecal administration. We believe that if these pre-clinical findings are translated in human studies, then RNAi therapeutics could offer a meaningful new treatment option with infrequent dosing for a broad range of CNS diseases,” said Kevin Fitzgerald, Ph.D., Chief Scientific Officer of Alnylam. “In addition, we are highlighting advancements in our siRNA platform with IKARIA, a proprietary design and chemistry approach that confers exquisite target specificity, deeper levels of target mRNA silencing, and potential for an annual dosing regimen. With IKARIA, we believe we can design very long-acting siRNAs with all the proven pharmacological advantages and established human experience of existing RNAi therapeutics, with the potential to deliver meaningful advances for patients.”

New pre-clinical data were presented from Alnylam’s CNS-targeting platform. Various fatty acid ligands were conjugated to SOD1-targeting siRNAs and evaluated in rats. A hexadecyl (C16)-conjugated siRNA was shown to yield robust and durable target knockdown throughout the brain and spinal cord following intrathecal administration. Combining a 5’-vinyl phosphonate (VP) modification with C16 provided the greatest level of potency. This chemistry was therefore selected for further evaluation. In rat studies, single or multiple intrathecal doses of a SOD1-targeting siRNA led to robust, dose-dependent, and durable silencing of SOD1 throughout the brain. Further, in toxicology studies performed in rats and NHPs, no test article-related findings were seen for C16 conjugates, suggesting the potential for a clean safety and tolerability profile.

Additional pre-clinical data were presented with an siRNA targeting amyloid precursor protein (APP). Alnylam is developing ALN-APP as a potential treatment for early onset Alzheimer’s Disease (AD) and cerebral amyloid angiopathy (CAA), with a planned Clinical Trial Application (CTA) filing in late 2021. An APP siRNA was shown in vitro to cause greater intracellular reductions in soluble APP beta (sAPPβ) fragments compared to β-site APP cleaving enzyme (BACE) inhibitors. Moreover, in an experiment using induced pluripotent stem cell (iPSC)-derived neurons, treatment with APP siRNA was able to reduce the size of Rab5+ early endosomes back to wild-type levels within two weeks of treatment compared to control treated cells. This result shows that siRNA-mediated APP lowering corrects an early intracellular phenotype known to be linked to neurotoxicity in AD patients. Finally, in a transgenic mouse model of human sAPP, siRNA-mediated silencing of APP led to phenotypic improvements. Further, in CTA-enabling GLP toxicology studies in rats and NHPs there were no test-article related findings with ALN-APP, revealing an encouraging non-clinical tolerability profile in support of upcoming human studies.

In a separate presentation, initial pre-clinical results were presented on the Company’s IKARIA platform. Using the proprietary IKARIA design and chemistry, RNA sequencing analysis revealed that a transthyretin (TTR)-targeting siRNA delivered to hepatocytes, ALN-TTRsc04, achieved exquisite specificity. The IKARIA-derived ALN-TTRsc04 molecule also demonstrated comparable potency and durability with an analog of vutrisiran in NHP studies. Computational modeling data suggest that a single 300 mg subcutaneous dose of ALN-TTRsc04 may result in trough TTR reduction greater than 90% that is durable for approximately one year. ALN-TTRsc04 is planned to enter clinical development at or around year-end 2022 with an investigational new drug (IND) application filing.

Additional OTS presentations by Alnylam included previously shown results on:

  • Development of lumasiran for the treatment of primary hyperoxaluria type 1
  • Interim results from a Phase 1 study of zilebesiran (ALN-AGT), an investigational RNAi therapeutic in development for the treatment of hypertension.

For the full breadth of results presented by the Company at OTS please visit the Capella section of the Alnylam website.

Finally, Alnylam is also pleased to announce that its publication in Nucleic Acids Research entitled Investigating the pharmacodynamic durability of GalNAc-siRNA conjugates* has been chosen by the Oligonucleotide Therapeutics Society Awards Committee as a winner of the Paper of the Year – Basic Research category. This award is designed to honor the year’s most impactful paper in the field of oligonucleotide therapeutics.

* Brown et al., Nucleic Acids Res. 2020 Dec 2;48(21):11827-11844.

About hATTR Amyloidosis

Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

About IKARIA™ Platform

Alnylam’s IKARIA platform takes advantage of more than two decades of experience in developing RNAi therapeutics. IKARIA enables an extended duration of activity in preclinical studies, with potential for annual dosing in humans, and has design features which provide exquisite specificity, further widening the potential therapeutic index, with enhanced target reduction levels.

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) is leading 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 genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), and OXLUMO® (lumasiran), as well as Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six 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 and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam’s expectations, plans and prospects, including without limitation, the potential of lipophilic C16 conjugated siRNAs to enable robust and durable target knockdown in the CNS in humans, resulting in the possibility of a meaningful new treatment option with infrequent dosing for a broad range of CNS diseases, the potential of its IKARIA platform to enable highly potent target mRNA silencing with an annual dosing regimen, the potential of ALN-APP as a treatment for early onset AD and for CAA, and the expected timing of a CTA filing for ALN-APP, the potential of ALN-TTRsc04 to result in trough TTR reduction greater than 90% that is durable for approximately one year and the expected timing for an IND filing, its aspirations to become a leading biotech company, and the planned achievement of its “Alnylam P5x25” strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. 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: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam’s business, results of operations and financial condition and the effectiveness or timeliness of Alnylam’s efforts to mitigate the impact of the pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches, including C16 and IKARIA, and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to successfully expand the indication for ONPATTRO (or vutrisiran, if approved) in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam’s ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) 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.

This release is not intended to convey conclusions about efficacy or safety as to any investigational uses or dosing regimens of any investigational RNAi therapeutics. There is no guarantee that any investigational therapeutics or dosing regimens for such therapeutics will successfully complete clinical development or gain health authority approval.


Alnylam Pharmaceuticals, Inc.

Christine Regan Lindenboom

(Investors and Media)


Josh Brodsky



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