Alnylam Submits CTA Application for ALN-APP, an Investigational RNAi Therapeutic for the Treatment of Alzheimer’s Disease and Cerebral Amyloid Angiopathy

- Company Expects to Initiate a Phase 1 Study in Early-Onset Alzheimer’s Disease in Early 2022, with Initial Human Data at or Around Year-End 2022 -

- ALN-APP Marks the Industry’s First-Ever RNAi Therapeutic Program for CNS Disease and Represents the Start of Alnylam’s Expansion of RNAi Therapeutic Opportunities in Extra-Hepatic Tissues -

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the Company has submitted a Clinical Trial Authorization (CTA) application to The Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom to initiate a Phase 1 study of ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein (APP) for the treatment of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). The Company plans to initiate the Phase 1 study in patients with early-onset AD in early 2022, upon obtaining MHRA approval, and expects to report initial human data at or around year-end 2022.

“Neurodegenerative diseases like early-onset Alzheimer’s disease are devastating to patients and their families and remain an area of profound unmet medical need, requiring a paradigm shift in how we approach treatment of diseases impacting the central nervous system,” said Tim Mooney, Program Leader for the ALN-APP program at Alnylam. “To that end, we are excited to advance the first ever RNAi therapeutic targeting the CNS towards the clinic, with the support of our partners at Regeneron. ALN-APP represents Alnylam’s continued commitment to innovation both in pursuing new genetically validated disease targets and in advancing our platform to target extra-hepatic tissues.”

ALN-APP represents the first-ever RNAi therapeutic targeting CNS diseases. The clinical candidate was designed using Alnylam’s proprietary C16 conjugate technology for the delivery of short interfering RNA (siRNA) to the CNS. As such, ALN-APP represents the start of Alnylam’s expansion of RNAi therapeutic opportunities in extra-hepatic tissues. ALN-APP is being advanced in partnership with Regeneron as part of the companies’ 2019 agreement. Alnylam will lead global development and commercialization of ALN-APP, and Regeneron has exercised its 50-50 co-development and co-commercialization option under the collaboration.

About ALN-APP

ALN-APP is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein (APP) in development in collaboration with Regeneron Pharmaceuticals for the treatment of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Genetic mutations that increase production of APP or alter its cleavage cause early-onset AD, early-onset CAA, or both. ALN-APP is designed to decrease APP mRNA in the central nervous system (CNS), to decrease synthesis of APP protein and all downstream intracellular and extracellular APP-derived cleavage products, including amyloid beta (Aβ). Reducing APP protein production is expected to reduce the secretion of Aβ peptides that aggregate into extracellular amyloid deposits and reduce the intraneuronal APP cleavage products that trigger the formation of neurofibrillary tangles and cause neuronal dysfunction in Alzheimer’s disease. ALN-APP is the first program utilizing Alnylam’s C16 conjugate technology, which enables enhanced delivery to cells in the CNS. The safety and efficacy of ALN-APP have not been evaluated by the FDA, EMA, or any other health authority.

About Early-Onset Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease and the most common form of dementia, affecting over 30 million people worldwide. AD is characterized by progressive memory loss and cognitive decline, with neuropathological accumulation of amyloid plaques, neurofibrillary tangles, and neuroinflammation, ultimately resulting in significant brain atrophy. Disease progression results in progressive loss of independence, increased caregiver burden, institutionalization, and premature death. Early-onset Alzheimer’s disease (EOAD) refers to a subgroup of AD with symptom onset prior to the age of 65, representing approximately 4% to 6% of all AD. EOAD is the leading cause of dementia in younger individuals and is a significant cause of disability and early mortality. Available treatment options include symptomatic treatment and treatment to reduce amyloid deposits in the brain. There are currently no available treatments that have been shown to halt or reverse the progression of the disease.

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), OXLUMO^® (lumasiran), and Leqvio^® (inclisiran) 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 www.alnylam.com 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 future expectations, plans and prospects, including, without limitation, Alnylam’s views with respect to the initiation of the Phase 1 study of ALN-APP in patients with early-onset AD, the potential timing to report initial human data, its continued commitment to innovation both in pursuing new genetically validated disease targets and in advancing its platform to target extra-hepatic tissues, Regeneron’s involvement in the research, development and commercialization of ALN-APP, Alnylam’s aspiration 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; the potential impact of the planned leadership transition at year end on Alnylam’s ability to attract and retain talent and to successfully execute on its “Alnylam P5x25” strategy; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates, including ALN-APP; 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 OXLUMO and ONPATTRO (and 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, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of current 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.

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