– First Clinical Study of a Central Nervous
System-Administered RNAi Therapeutic Showed Rapid and Robust Target
Engagement with Sustained Effect Over 6 Months with a Single Dose
–
– ALN-APP Continues to Demonstrate an
Encouraging Clinical Safety and Tolerability Profile –
– Multiple-dose Portion of Study, Part B, Being
Initiated in Approved Regions –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) announced today
updated 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 results were presented at the 2023
Alzheimer’s Association International Conference (AAIC) being held
July 16-20, 2023 in Amsterdam, The Netherlands. 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 Pharmaceuticals, Inc.
Twenty patients with early-onset Alzheimer’s disease have been
enrolled in three single-dose cohorts in Part A of the ongoing
Phase 1 study. 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.
Cerebrospinal fluid (CSF) white blood cell count and total protein
levels showed no remarkable elevations from baseline. Routine
laboratory assessments (hematology, serum chemistry, liver
function, urinalysis, coagulation) as well as preliminary data for
the exploratory biomarker neurofilament light chain (NfL) did not
reveal any significant abnormalities. Patients treated with a
single dose of 75mg ALN-APP experienced a rapid and sustained
reduction in cerebrospinal fluid of both soluble APPα (sAPPα) and
soluble APPβ (sAPPβ), biomarkers of target engagement, with maximum
reductions of 84% and 90%, respectively. Mean reductions in sAPPα
of greater than 55% and sAPPβ greater than 65% were sustained at 6
months after a single dose. Additional results can be seen in the
presentation on Capella.
“We’ve known for decades that mutations that increase APP
production, or alter its proteolysis, cause early-onset Alzheimer’s
disease, early-onset CAA or both,” said Dr. Sharon Cohen, MD,
FRCPC, Neurologist and Medical Director, Toronto Memory Program.
“These Phase 1 results show that a single dose of ALN-APP can
rapidly reduce APP production and that this effect is sustained at
6 months. Given the critical need for new and better treatments for
AD and CAA, these results are promising, and the approach warrants
further study.”
Further exploration of single doses of ALN-APP is ongoing in
Part A. In addition, the safety review committee has recommended
initiation of Part B, the multiple-dose part of the study. Part B
will enroll patients from Part A and has already received
regulatory approval to proceed in Canada, where the majority of the
Part A clinical trial patients were enrolled. The multiple dose
part of the study remains on partial clinical hold in the U.S. due
to findings observed in prior non-clinical chronic toxicology
studies.
“The rapid, robust, and sustained target engagement that we have
achieved with a single dose of ALN-APP and the encouraging interim
safety data to date illustrate the potential of RNAi therapeutics
to set a new standard for silencing disease-causing genes in the
CNS and target diseases like AD and CAA upstream of existing
therapies,” said Tim Mooney, Director, ALN-APP Program Leader at
Alnylam. “We are excited to initiate the multiple dose part of the
Phase 1 study and learn more about the potential of this new
approach for these devastating diseases.”
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 eye and CNS
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.
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 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 Pharmaceuticals
(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 in
2002, 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), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO®
(lumasiran), 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 www.alnylam.com and
engage with us on Twitter at @Alnylam, on LinkedIn, or on
Instagram.
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 Alnylam to identify new potential drug
development candidates and advance its research and development
programs, including ALN-APP, Alnylam’s ability to obtain approval
for new commercial products or additional indications for its
existing products, and Alnylam’s projected commercial and financial
performance, should be considered forward-looking statements.
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: Alnylam’s ability 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 Alnylam’s product candidates, including patisiran and
vutrisiran; actions or advice of regulatory agencies and Alnylam’s
ability to obtain and maintain regulatory approval for its product
candidates, including patisiran and vutrisiran, as well as
favorable pricing and reimbursement; successfully launching,
marketing and selling Alnylam’s approved products globally; 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; delays,
interruptions or failures in the manufacture and supply of
Alnylam’s product candidates or its marketed products; delays or
interruptions in the supply of resources needed to advance
Alnylam’s research and development programs, including as may arise
from recent disruptions in the supply of non-human primates;
obtaining, maintaining and protecting intellectual property;
Alnylam’s ability to successfully expand the indication for
ONPATTRO or AMVUTTRA 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 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 2022 Annual Report on Form 10-K filed with the Securities
and Exchange Commission (SEC), as may be updated from time to time
in Alnylam’s subsequent Quarterly Reports on Form 10-Q 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 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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version on businesswire.com: https://www.businesswire.com/news/home/20230716241827/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media) 617-682-4340
Josh Brodsky (Investors) 617-551-8276
Alnylam Pharmaceuticals (NASDAQ:ALNY)
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