Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical
company developing a broad portfolio of product candidates
engineered to cross the blood-brain barrier (BBB) for
neurodegenerative diseases, today announced positive Phase 1
clinical results and regulatory progress for two investigational
small molecule therapeutics in development for the treatment of
amyotrophic lateral sclerosis (ALS) at the 2021 Annual Northeast
ALS (NEALS) Meeting being held virtually, October 6-7.
“Effective treatment options are a critical
unmet medical need for people living with ALS,” said Carole Ho,
M.D., Denali’s Chief Medical Officer. “DNL343 and SAR443820 are
designed to modulate distinct biological pathways implicated in
ALS, including the integrated stress response and inflammation,
respectively. We are pleased that the data generated preclinically
and in Phase 1 studies support clinical investigation of both
molecules as potential treatments for individuals with ALS.”
“We’re very encouraged by the initial results of
the Phase 1 study of SAR443820 for the treatment of ALS,” said
Nazem Atassi, M.D., Sanofi’s Global Head of Early Neurodevelopment.
“ALS is a devastating disease for patients and their families, with
no available cure or effective treatment for slowing its
progression. We look forward to launching the Phase 2 HIMALAYA
trial in adults with ALS in early 2022 and to achieving our
ultimate goal of helping people living with ALS.”
Highlights from eIF2B activator DNL343
clinical and preclinical data presented at NEALS
Denali presented positive results from a Phase 1
study in healthy volunteers (n=95) in which safety,
pharmacokinetics (PK) and pharmacodynamics (PD) of single and
multiple ascending doses of DNL343 were evaluated. The results
demonstrated that DNL343 was generally well tolerated for up to 14
days of dosing, with robust distribution in the central nervous
system (CNS) and predictable dose-related increases in DNL343
exposure with a PK profile supporting once daily dosing. Biomarker
assessments were also made as related to the cellular integrated
stress response (ISR). The ISR is a biological pathway implicated
in ALS and other diseases. After healthy volunteers were treated
with DNL343, samples of their blood cells were subjected to stress
ex vivo, and robust changes in biomarkers of the ISR were observed,
confirming pathway engagement.
Denali also presented preclinical data in a
mouse model of vanishing white matter (VWM) disease, a genetic and
progressive disorder that causes severe neurological symptoms after
exposure to certain stressors. eIF2B activity is reduced in the VMW
disease model leading to chronic activation of the ISR, making this
a relevant model for demonstrating target engagement and ISR
modulation by DNL343. After treatment with DNL343, body weight and
motor function were normalized in these mice. Furthermore, ISR gene
expression and stress response protein levels were reduced in both
peripheral tissues as well as the brain. A similar PK/PD
relationship was observed in mice and in humans, supporting DNL343
dose selection in the ongoing Phase 1b study in participants with
ALS.
The Phase 1b study (NCT05006352) is a
multicenter, randomized, placebo-controlled, double-blind, 28-day
study followed by an 18-month open-label extension, designed to
evaluate the safety, PK and PD of DNL343 in approximately 30
participants with ALS. Dosing in this study began in the third
quarter of 2021.
Highlights from RIPK1 inhibitor
SAR443820 clinical trial design presentation at NEALS and Fast
Track Designation
Denali’s partner Sanofi presented plans for a
Phase 2 study of RIPK1 inhibitor SAR443820 in participants with ALS
based on positive results of a Phase 1 study in healthy volunteers.
In that study, robust target engagement was demonstrated at doses
that were generally well tolerated. The Phase 2 study, named
HIMALAYA, is a multi-center, randomized,
double-blind, placebo-controlled study, followed by an open-label
long-term extension, to evaluate the efficacy and safety of
SAR443820 in adult participants with ALS. This Phase 2 study is
expected to commence in the first quarter of 2022.
The U.S. FDA has granted Fast Track designation
to SAR443820 for the treatment of ALS. Fast Track is an FDA process
designed to facilitate the development and expedite the review of
drugs to treat serious conditions and fill an unmet medical need.
Fast Track designation may allow for early and frequent
communication with the FDA regarding the development of SAR443820
for the treatment of ALS. This designation also enables rolling
review of the marketing application.
About the eIF2B activator
DNL343
Modulation of eIF2B activity with DNL343 is a
novel and targeted investigational approach with first-in-class
potential for the treatment of ALS. eIF2B is an intracellular
protein complex that regulates protein synthesis and is required
for neuronal health and function. When neurons experience stress,
as occurs in ALS, eIF2B activity is suppressed. This leads to
impaired protein synthesis and results in the formation of "stress
granules," which are thought to be a precursor of TDP-43
aggregation, a hallmark pathology in ALS. DNL343 is designed to
activate eIF2B and thereby restore protein synthesis, disperse
TDP-43 aggregates, and improve neuronal survival. DNL343 is an
investigational therapeutic and has not been approved by any
regulatory authority for any commercial use.
About the RIPK1 Inhibitor
SAR443820/DNL788
SAR443820/DNL788 is a novel, CNS-penetrant,
small molecule inhibitor of RIPK1, a critical signaling mediator of
necroptotic cell death, cytokine release, and inflammatory
pathways. Denali and Sanofi entered into a broad collaboration in
October 2018 for the global development and commercialization of
RIPK1 inhibitors. This includes CNS-penetrant molecules such as
SAR443820/DNL788, which was evaluated in a Phase 1 study in healthy
volunteers, with potential development for neurological indications
such as ALS, multiple sclerosis (MS) and Alzheimer’s disease (AD).
Sanofi leads Phase 1 and Phase 2 development of SAR443820/DNL788
for ALS and MS and leads co-development of SAR443820/DNL788 with
Denali in Phase 3 clinical trials for ALS, AD and MS.
SAR443820/DNL788 is an investigational therapeutic that has not
been approved by any regulatory authority for any commercial
use.
Denali Webinar for analysts and
investors on October 6, 2021, at 4:30 p.m. ET
Denali plans to host a webinar for analysts and
investors to highlight development programs in ALS and
frontotemporal dementia (FTD) on October 6, 2021, starting at
approximately 4:30 p.m. Eastern Time. During the webinar, Denali
will review the NEALS presentations related to its investigational
small molecule therapeutics DNL343, an eIF2B activator, and
SAR443820, a RIPK1 inhibitor. Denali will also review preclinical
data on DNL593 (PTV:PGRN), its Transport Vehicle (TV)-enabled
biotherapeutic in development for FTD-GRN, which was recently
published in Cell. The webinar will be available on Denali’s
corporate website on the Events page under the Investor section at
https://www.denalitherapeutics.com/investors/events. An archived
replay of the webinar will be available for at least 30 days
following the event. Preregistration for the webinar can be
accessed here.
About Denali
TherapeuticsDenali Therapeutics is a
biopharmaceutical company developing a broad portfolio of product
candidates engineered to cross the blood-brain barrier (BBB) for
neurodegenerative diseases. Denali pursues new treatments by
rigorously assessing genetically validated targets, engineering
delivery across the BBB and guiding development through biomarkers
that demonstrate target and pathway engagement. Denali is based
in South San Francisco. For additional information, please
visit www.denalitherapeutics.com.
Cautionary Note Regarding
Forward-Looking Statements
This press release contains forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995. Forward-looking statements expressed or implied
in this press release include, but are not limited to, statements
regarding plans, timelines and expectations related to DNL343,
SAR443820/DNL788; the DNL343 ongoing Phase 1b study and the planned
Phase 2 study of SAR443820/DNL788; expectations regarding Denali’s
product candidates and the therapeutic potential of DNL343 and
SAR443820/DNL788; statements made by Denali’s Chief Medical
Officer; and statements made by Sanofi’s Global Head of Early
Neurodevelopment. Actual results are subject to risks and
uncertainties and may differ materially from those indicated by
these forward-looking statements as a result of these risks and
uncertainties, including but not limited to, risks related to: any
and all risks to Denali’s business and operations caused directly
or indirectly by the evolving COVID-19 pandemic; Denali’s and its
partners’ ability to enroll patients in its ongoing and future
clinical trials; the potential for clinical trial results of DNL343
or SAR443820/DNL788 to differ from preclinical, preliminary or
expected results; the risk that the expected benefits of Fast Track
designation for SAR443820/DNL788 will not materialize; the risk
that DNL343 or SAR443820/DNL788 may cause serious adverse events;
the risk that DNL343 and SAR443820/DNL788 may not in the future
receive regulatory approval as a treatment for amyotrophic lateral
sclerosis (ALS) or other indications for which they are being
developed; risk of the occurrence of any event, change or other
circumstance that could give rise to the termination of Denali’s
collaboration agreements; Denali’s and its partners’ ability to
complete the development and, if approved, commercialization of its
product candidates; Denali’s reliance on third parties for the
manufacture and supply of its product candidates for clinical
trials; Denali’s and it's partners' ability to conduct or complete
clinical trials on expected timelines; Denali’s ability to obtain,
maintain, or protect intellectual property rights related to its
product candidates; implementation of Denali’s strategic plans for
its business, product candidates and blood-brain barrier platform
technology; and other risks, including those described in Denali’s
most recent Quarterly Report on Form 10-Q filed with the Securities
and Exchange Commission (SEC) on August 4, 2021, Denali’s Annual
Report on Form 10-K filed with the SEC on February 26, 2021, and
Denali’s future reports to be filed with the SEC. The
forward-looking statements in this press release are based on
information available to Denali as of the date hereof. Denali
disclaims any obligation to update any forward-looking statements,
except as required by law.
Investor Relations Contact: |
Media Contacts: |
|
Laura Hansen, Ph.D.Vice
President, Investor Relations(650) 452-2747hansen@dnli.com |
Lizzie Hyland(646)
495-2706lizzie.hyland@fgh.comorMorgan Warners(202)
295-0124morgan.warners@fgh.com |
|
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