Denali Therapeutics Announces DNL343 Interim Phase 1b Data in ALS and Entry into the HEALEY ALS Platform Trial
December 05 2022 - 6:00AM
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 and lysosomal storage disorders, today
announced interim results from a Phase 1b study of its eIF2B
agonist, DNL343, in participants with amyotrophic lateral sclerosis
(ALS). Once-daily oral dosing with DNL343 for 28 days was generally
well tolerated and demonstrated extensive BBB penetration as well
as robust inhibition of biomarkers associated with the integrated
stress response (ISR) in blood samples from study participants. By
inhibiting the ISR pathway, DNL343 is intended to prevent or slow
disease progression associated with stress granule formation and
TDP-43 aggregation, a hallmark pathology present in nearly all
individuals with ALS. The Phase 1b results will be presented at the
33rd International Symposium on ALS/MND, which is being held
virtually December 6-9, 2022. A copy of the poster presentation is
available on Denali’s website on the Investor & Media Relations
section under the Events page. Denali also announced initiation of
the design phase of a Phase 2/3 study for entry into the HEALEY ALS
Platform Trial led by the Sean M. Healey & AMG Center for ALS
at Massachusetts General Hospital (MGH) in collaboration with the
Northeast ALS Consortium.
“These initial Phase 1b results with DNL343 in ALS are
consistent with our previously reported Phase 1 healthy volunteer
data and are an important milestone for the program,” said Carole
Ho, M.D., Chief Medical Officer at Denali. “The data continue to
support late-stage development plans for DNL343, and we are excited
to be collaborating with the HEALEY ALS Platform Trial team in our
unified effort to advance potential treatment options for people
living with ALS.”
“ALS is a devastating progressive disorder with very few
treatment options,” said Merit Cudkowicz, M.D., M.Sc., principal
investigator and sponsor of the HEALEY ALS Platform Trial, director
of the Sean M. Healey & AMG Center for ALS, chief of the
Department of Neurology at MGH, and the Julieanne Dorn Professor of
Neurology at Harvard Medical School. “Given the strong collective
data from the DNL343 program to date, we are looking forward to
working with Denali to develop DNL343 for the HEALEY ALS Platform
Trial, bringing us closer to our goal of finding more effective
treatments for ALS through collaboration.”
About the Phase 1b study in ALSAs previously
announced, the Phase 1b study is a multicenter, randomized,
placebo-controlled, double-blind, 28-day study followed by an
18-month open-label extension, designed to evaluate the safety,
pharmacokinetics, and pharmacodynamics of DNL343 in participants
with ALS. Enrollment in the study is complete with 29 participants.
An interim analysis was performed after 20 participants randomized
to receive DNL343 or placebo had completed the double-blind period
of the study. The open-label extension is ongoing. Further
information on the study can be accessed at ClinicalTrials.gov.
In the interim analysis, DNL343 demonstrated dose-dependent
increases in plasma concentrations and a long plasma half-life,
supporting once-daily dosing. The mean ratio of drug in
cerebrospinal fluid compared to unbound drug in plasma ranged from
1.02–1.23, suggesting that DNL343 effectively crosses the
blood-brain barrier and is extensively distributed to the central
nervous system. Robust inhibition of ISR was noted, as measured by
attenuation of the ISR pathway biomarkers (ATF4 and CHAC1) in blood
samples. DNL343 was generally well tolerated in participants with
ALS in this study.
About the HEALEY ALS PLATFORM TrialThe HEALEY
ALS Platform Trial is a large-scale collaborative effort made
possible by contributions from patients and families, clinical
trial sites, industry partners and research collaborators to
evaluate multiple investigational therapies simultaneously with the
goal of accelerating the development of potential new treatments
for ALS. Therapeutic candidates that enter the platform trial are
chosen by a group of expert ALS scientists and members of the
Healey & AMG Center.
About the eIF2B activator DNL343Modulation 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, activation of the ISR pathway leads to
suppression of eIF2B activity, resulting in impaired protein
synthesis and formation of stress granules. Stress granules are
thought to be a precursor of TDP-43 aggregation, which is 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 Denali TherapeuticsDenali Therapeutics is
a biopharmaceutical company developing a broad portfolio of product
candidates engineered to cross the BBB for neurodegenerative
diseases and lysosomal storage disorders. 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
StatementsThis 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,
including the ongoing Phase 1b study and the initiation of the
design phase of the Phase 2/3 study; the potential benefits of,
likelihood of success of, and expectations related to Denali's
collaboration with the HEALEY ALS Platform Trial; expectations
regarding Denali’s product candidates and the therapeutic and
commercial potential of DNL343; and statements made by Denali’s
Chief Medical Officer and the HEALEY ALS Platform Trial's principal
investigator. 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:
Denali’s transition to a late stage clinical drug development
company; Denali’s and its partners’ ability to initiate, enroll
patients in, conduct, and complete its ongoing and future clinical
trials, including the ongoing Phase 1b study and upcoming Phase 2/3
study of DNL343, on expected timelines; Denali’s reliance on third
parties for the manufacture and supply of its product candidates
for clinical trials; the potential for clinical trial results of
DNL343 to differ from preclinical, preliminary or expected results,
including the initial Phase 1b results for DNL343; the risk of
adverse events; risks related to Denali’s collaborations; the risk
that results from early clinical biomarker studies will not
translate to clinical benefit in late clinical studies; the risk
that DNL343 may not in the future receive regulatory approval as a
treatment for ALS or other indications for which it is being
developed; Denali’s and its partners’ ability to complete the
development and, if approved, commercialization of its product
candidates; 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 BBB platform
technology; and other risks. In light of these risks,
uncertainties, and assumptions, the forward-looking statements in
this press release are inherently uncertain and may not occur, and
actual results could differ materially and adversely from those
anticipated or implied in the forward-looking statements.
Accordingly, you should not rely upon forward-looking statements as
predictions of future events. Information regarding additional
risks and uncertainties may be found in Denali’s most recent
Quarterly Report on Form 10-Q filed with the Securities and
Exchange Commission (SEC) on November 3, 2022, Denali’s Annual
Report on Form 10-K filed with the SEC on February 28, 2022, 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 Contact: Laura Hansen,
Ph.D. (650) 452-2747 hansen@dnli.com
Media Contact:Angela Salerno-Robin(212)
445-8219asalerno-robin@dna-comms.com
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