Oct 25, 2023 Press Release for Alnylam
Alnylam Reports Additional Positive Interim Phase 1 Results for ALN-APP, in Development for Alzheimer’s Disease and Cerebral Amyloid Angiopathy
Oct 25, 2023
– Single Doses of ALN-APP Achieve Sustained Pharmacodynamic Activity up to 10
– Observed Marked Reductions in Aβ42 and Aβ40, Amyloid Fragments Implicated in Alzheimer’s Disease and Cerebral Amyloid Angiopathy –
– First Patient Dosed in Multiple-dose Part B Portion of Study, with the Study Proceeding in
“Today’s results showcase the exciting emerging profile of ALN-APP. This novel approach appears generally well-tolerated and is able to target the amyloid pathway successfully, robustly lowering target engagement biomarkers sAPPα and sAPPβ and maintaining a significant effect up to 10 months after administration,” said Dr.
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 APPα (sAPPα) and soluble APPβ (sAPPβ), biomarkers of target engagement, with maximum reductions of 84% and 90%, respectively. These effects were highly durable, with mean reductions in sAPPα and sAPPβ 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 Aβ42 and Aβ40, 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 Aβ42 and Aβ40 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
“These additional interim data further illustrate the potential for RNAi therapeutics to set a new standard for silencing disease-causing genes in the CNS, providing evidence that a single dose of ALN-APP can achieve deep target engagement, a long duration of action, and an encouraging early safety profile,” said
Successful human translation of the C16-siRNA conjugate platform is unlocking a broader portfolio of CNS programs. In addition to ALN-APP,
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.
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 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
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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, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, the potential for
This press release discusses investigational RNAi therapeutics and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics. There is no guarantee that any investigational therapeutics will successfully complete clinical development or gain health authority approval.
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