Single Doses of ALN-APP Demonstrated Dose-Dependent, Rapid and Sustained Reduction of sAPPα and sAPPβ in Cerebrospinal Fluid, with Up to 90% at Highest Dose to Date

Encouraging Clinical Safety and Tolerability Profile Observed with Single Dosing to Date

Results Provide First Demonstration of Gene Silencing by RNAi Therapeutics in the Human Brain Using Alnylam’s Proprietary C16 Platform

CAMBRIDGE, MA & TARRYTOWN, NY, USA I April 26, 2023 I Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) and Regeneron Pharmaceuticals, Inc. (Nasdaq: REGN) announced today positive interim results from the ongoing single ascending dose part of the Phase 1 study of ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy (CAA).

Twenty patients have been enrolled in three single-dose cohorts in Part A of the ongoing Phase 1 study in patients with early-onset Alzheimer’s disease. In this study to date, single doses of ALN-APP, which are administered by intrathecal injection, have been well tolerated. All adverse events were mild or moderate in severity, with available cerebrospinal fluid data for white blood cells and protein appearing similar to placebo. Early data for neurofilament light chain from a subset of cohorts (2 of 3 studied) looked comparable to placebo. Patients treated with ALN-APP experienced dose-dependent, rapid and sustained reduction in cerebrospinal fluid of both soluble APPα (sAPPα) and APPβ (sAPPβ), biomarkers of target engagement, with maximum reduction of 84% and 90%, respectively. Median decreases of both biomarkers of greater than 70% was sustained for at least three months at the highest dose tested. Detailed interim results from this study are planned to be reported at an upcoming scientific conference.

“ALN-APP, via its upstream targeting mechanism, has the potential to address the underlying cause of two devastating CNS diseases, Alzheimer’s disease and CAA, which affect many millions of people and their families around the world. Thus, we are excited by these interim clinical data for ALN-APP, which demonstrate rapid, substantial and sustained target protein reduction and encouraging safety and tolerability to date,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “We look forward to continuing to advance ALN-APP through the Phase 1 study, which will inform our future development plans in both Alzheimer’s disease and CAA.”

These early results establish the first human translation of Alnylam’s proprietary C16-siRNA conjugate platform for central nervous system (CNS) delivery and are the first clinical demonstration of gene silencing in the human brain using an RNAi therapeutic.

“Establishing human proof of concept with ALN-APP is a major step in our efforts to expand our organic product engine to extrahepatic tissues like the CNS, a critical goal in our Alnylam P5x25 strategy,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “This further reinforces our belief that RNAi therapeutics have the potential to become a new class of medicines for silencing genes implicated in causing CNS diseases. Given these encouraging interim data, we are accelerating our efforts with Regeneron to bring forward additional genetically validated development candidates for other neurologic diseases, many of which have few or no therapeutic options for patients.”

“When we entered into this collaboration, the idea that you could profoundly silence disease-causing genes in the brain was simply a bold dream. The current data suggest that this dream is closer to becoming a reality, offering hope for the many patients suffering from incurable neurological diseases,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron. “This approach to preventing production of amyloid precursor protein – as opposed to trying to clear amyloid plaques after they have already formed – provides a new way to potentially combat the scourge of Alzheimer’s disease, which has devastated so many families and proven historically difficult to treat.”

Further exploration of single-doses of ALN-APP is ongoing in Part A of the Phase 1 study (Canada, Netherlands, United Kingdom and United States) to evaluate longer term safety and duration of action and to identify the multi-dose regimen for Part B. Part B will include patients from Part A, and has received regulatory approval to proceed in Canada where the majority of the Part A clinical trial patients have been enrolled. Additional pre-clinical data, as well as the emerging clinical data announced today, will be shared with the FDA, which has placed a partial clinical hold on Part B in the U.S. due to findings observed in prior non-clinical chronic toxicology studies.

In addition to ALN-APP, Alnylam and Regeneron have named ten targets in the CNS as part of their exclusive collaboration established in 2019 to discover RNAi therapeutics for eye and CNS diseases.

Conference Call Information 
Alnylam management will discuss the interim results from the Phase 1 study of ALN-APP via conference call on Wednesday, April 26, 2023 at 4:30 pm ET. To access the call, please register online at Participants are requested to register a minimum of 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months.

A live audio webcast of the call will be available on the Investors section of the Company’s website at An archived webcast will be available on the Alnylam website approximately two hours after the event.

About the Phase 1 Study of ALN-APP 
The Phase 1 study is a multi-center, randomized, double-blind, placebo-controlled trial designed to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of ALN-APP in patients with early-onset Alzheimer’s disease (EOAD). The study is being conducted in two parts: single ascending dose phase and multiple dose phase in patients with EOAD. The planned enrollment for this study is up to 60 patients.

The interim readout of the Phase 1 study of ALN-APP is focused on assessing safety, tolerability and levels of target engagement biomarkers, sAPPα and sAPPβ.

About ALN-APP 
ALN-APP is an investigational, intrathecally administered RNAi therapeutic targeting amyloid precursor protein (APP) in development 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 proprietary C16-siRNA conjugate technology, which enables enhanced delivery to cells in the CNS. This program is being developed in collaboration with Regeneron Pharmaceuticals. The safety and efficacy of ALN-APP have not been evaluated by the FDA, EMA, or any other health authority.

About 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 Cerebral Amyloid Angiopathy 
Cerebral amyloid angiopathy (CAA) is the second most-common cause of hemorrhagic stroke. CAA is defined by progressive deposition of amyloid beta (Aβ) into the walls of small arteries, arterioles, and capillaries in the brain, causing impaired vascular reactivity, focal tissue damage, and increased risk for intracerebral hemorrhage. CAA has also been shown to be an independent contributor to cognitive impairment. There are currently no available treatment options for CAA.

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 20 years ago, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), AMVUTTRA® (vutrisiran) and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. 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 and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

About Regeneron 
Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for nearly 35 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to nine FDA-approved treatments and numerous product candidates in development, almost all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, pain, hematologic conditions, infectious diseases and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune®, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.

For more information, please visit or follow @Regeneron on Twitter.

SOURCE: Alnylam Pharmaceuticals