Alnylam Pharmaceuticals, Inc. announced additional positive interim results for the ongoing single ascending dose portion 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). The data were presented today in a late-breaker session at the 16th Clinical Trials on Alzheimer?s Disease (CTAD) conference, being held October 24-27, 2023, in Boston, MA. ALN-APP is the first clinical-stage program using Alnylam's proprietary C16-siRNA conjugate platform for central nervous system (CNS) delivery and the first investigational RNAi therapeutic to demonstrate gene silencing in the human brain.

ALN-APP is being developed in collaboration with Regeneron. 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, blinded single doses of ALN-APP, which are administered by intrathecal injection, have been well tolerated.

All adverse events were mild or moderate in severity. Cerebral spinal fluid (CSF) safety biomarkers, routine labs, and the exploratory biomarker neurofilament light chain (NfL) all continue to show no concerning trends. Patients treated with a single dose of 75mg ALN-APP experienced rapid and sustained reduction in CSF of both soluble APPa (sAPPa) and soluble APPß (sAPPß), biomarkers of target engagement, with maximum reductions of 84% and 90%, respectively.

These effects were highly durable, with mean reductions in sAPPa and sAPPß of 33% and 39%, respectively, at 10 months after a single 75mg dose. Available data on exploratory disease-related biomarkers showed robust reductions in CSF of Aß42 and Aß40, the soluble forms of the amyloidogenic peptides that aggregate into amyloid deposits in AD and CAA. At two months after a single dose of 75mg ALN-APP, mean reductions in CSF Aß42 and Aß40 were 49% and 71%, respectively.

Further exploration of single doses of ALN-APP is ongoing in Part A. In addition, the first patient has now been dosed in Part B, the multiple-dose part of the study. Part B was previously initiated in Canada and has also now received all required approvals to proceed in the UK and the Netherlands. The multiple dose part of the study remains on partial clinical hold in the U.S. due to findings observed in non-clinical chronic toxicology studies.

Successful human translation of the C16-siRNA conjugate platform is unlocking a broader portfolio of CNS programs. In addition to ALN-APP, Alnylam and Regeneron have named 10 targets in the CNS as part of their exclusive collaboration established in 2019 to discover RNAi therapeutics for CNS and ocular diseases. About the Phase 1 Study of ALN-APP: The Phase 1 study is a multicenter, 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 (Part A) and multiple dose phase (Part B) in patients with EOAD.

The planned enrollment for this study is up to 60 patients. 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 (Aß). Reducing APP protein production is expected to reduce the secretion of Aß 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 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.