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 diseases, today
announced program progress and expected milestones for 2023, which
Chief Executive Officer, Ryan Watts, Ph.D., will highlight during a
corporate presentation at the 41st Annual J.P. Morgan Healthcare
Conference on Tuesday, January 10th, at 10:30 a.m. Pacific Time.
“We are excited to kick off 2023 with a broad and diversified
therapeutic portfolio of seven programs in clinical development,
anticipated progression and expansion of our TV blood-brain barrier
platform technology, and a highly productive discovery organization
working to capture and translate the potential of new scientific
insights in neurodegeneration biology," said Dr. Watts. “With four
programs expected to be in late-stage development this year, we
continue to build commercial capabilities and expand our global
footprint to ultimately deliver effective medicines to people
living with neurodegenerative and lysosomal storage diseases."
Denali’s 2023 Outlook
Denali’s therapeutic portfolio includes small molecules designed
to cross the BBB and biotherapeutics that are enabled to cross the
BBB using Denali’s TV technology. Expected progress and key
milestones in 2023 across Denali’s therapeutic portfolio are
summarized below.
TV-ENABLED PROGRAMS
DNL310 (ETV:IDS): MPS II (Hunter syndrome)
DNL310 is an investigational, Enzyme Transport Vehicle
(ETV)-enabled, brain-penetrant iduronate-2-sulfatase (IDS)
replacement therapy designed to address the cognitive, behavioral,
and physical manifestations of MPS II (Hunter syndrome). Delivery
of the IDS enzyme to the brain addresses a significant unmet
therapeutic need as current enzyme replacement therapy does not
address neurocognitive manifestations of the disease.
As previously reported, interim Phase 1/2 study data up to one
year of treatment continued to show that once weekly intravenous
dosing with DNL310 led to rapid and sustained normalization to
healthy levels of heparan sulfate in cerebrospinal fluid (CSF) and
improvements in biomarkers of lysosomal function consistent with
durable central nervous system activity. The safety profile, with
up to 85 weeks of dosing, continued to be consistent with approved
enzyme replacement therapies. In addition, one-year exploratory
outcomes data from clinician and caregiver global impression scales
of change suggested that the majority of study participants
improved or stabilized compared to baseline.
The Phase 2/3 COMPASS study continues to recruit up to 54
participants with MPS II with and without neuronopathic disease.
Upon completion of the ongoing Phase 1/2 study, and together with
data from the global COMPASS study, this combined data package is
intended to support registration.
2023 expected progress and milestones:
- Presentation of additional interim
Phase 1/2 data at WorldSymposium (February 22-26) and at the
Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual
Symposium (August 29-September 1).
- Continued recruitment of participants
with MPS II in the global Phase 2/3 COMPASS study.
TAK-594/DNL593 (PTV:PGRN): Frontotemporal
dementia-granulin (FTD-GRN)
TAK-594/DNL593 (PTV:PGRN) is an investigational, Protein
Transport Vehicle (PTV)-enabled, brain-penetrant progranulin (PGRN)
replacement therapy for people with FTD-GRN. As previously
reported, interim results from Part A of the Phase 1/2 study
evaluating DNL593 in healthy subjects demonstrated that single
doses of DNL593 resulted in substantial increases in CSF PGRN
levels suggesting brain delivery of DNL593 was achieved and has the
potential to address PGRN deficiency, which drives FTD-GRN disease
progression. Single doses of DNL593 were generally well tolerated,
based on blinded safety analysis. These data support dosing in
participants with FTD-GRN in Part B (ascending multiple doses) of
the study. Denali has a strategic collaboration with Takeda to
jointly develop and commercialize PGRN delivering PTV-based
molecules.
2023 expected progress and milestones:
- Final data from Phase 1/2 Part A
healthy volunteer study in mid 2023.
- Continued recruitment of participants
with FTD-GRN in Part B of the Phase 1/2 study.
TAK-920/DNL919 (ATV:TREM2): Alzheimer’s disease
(AD)
TAK-920/DNL919 (ATV:TREM2) is an investigational, Antibody
Transport Vehicle (ATV)-enabled, brain-penetrant TREM2 agonist
intended to improve microglial function as a potential treatment
for AD. TREM2 is a receptor expressed on microglia, the resident
immune cells of the brain. Loss-of-function TREM2 genetic mutations
are strongly associated with an increased risk for AD. Animal model
data demonstrate enhanced brain uptake and improved pharmacodynamic
response with DNL919 as compared to a non-ATV TREM2 antibody. A
Phase 1 single ascending dose study in healthy volunteers is
ongoing in the Netherlands. Denali has a strategic collaboration
with Takeda to jointly develop and commercialize TREM2 targeting
ATV-based molecules.
2023 expected progress and milestones:
- Data from the Phase 1 single ascending
dose study in healthy volunteers by year-end 2023.
DNL126 (ETV:SGSH): MPS IIIA (Sanfilippo syndrome Type
A)
DNL126 (ETV:SGSH) is Denali’s second most advanced ETV program
following DNL310 (ETV:IDS). DNL126 is in development for the
potential treatment of MPS IIIA (Sanfilippo syndrome Type A), a
rare lysosomal storage disease that causes neurodegeneration. MPS
IIIA is caused by genetic defects that result in a reduction in the
activity of N-sulfoglucosamine sulfohydrolase (SGSH), an enzyme
responsible for degrading heparan sulfate in the lysosome. There
are no approved treatments for MPS IIIA. Preclinical data
demonstrated that intravenous DNL126 treatment reduced heparan
sulfate in a dose-dependent manner in brain and CSF in an MPS IIIA
mouse model.
2023 expected progress and milestones:
- Preclinical data at WORLDSymposium
(February 22-26).
- Submission of an investigational new
drug (IND) application in the first half and Phase 1/2 recruitment
activities in the second half of 2023.
Oligonucleotide Transport Vehicle (OTV)
platform
Oligonucleotides, such as antisense oligonucleotides (ASOs), are
a novel class of biotherapeutics with the potential to address the
root cause of many diseases through modulation of gene expression.
This class, however, has been limited in its potential for
treatment of neurodegenerative diseases, primarily due to the
challenge of delivering effective amounts of drug to relevant brain
regions. Direct injection into the CSF (e.g., intrathecal
injection) or certain brain regions has not achieved the robust
biodistribution into deep brain tissue, which may be necessary for
effective therapeutic activity.
As previously reported, nonhuman primate data with Denali’s OTV
demonstrated that intravenous delivery of an ASO enabled by OTV
technology resulted in broad brain biodistribution of the ASO and
knockdown of target gene expression in all brain cell types, which
was superior to intrathecal administration of the ASO. These data
support the potential of the OTV platform to enable peripheral
administration of oligonucleotide therapeutics and to address a
wide range of neurodegenerative and other neurological diseases.
Denali has selected five ASO targets for further development with a
near-term focus on advancing two OTV candidates towards clinical
development.
SMALL MOLECULE PROGRAMS
BIIB122/DNL151 (LRRK2 inhibitor): Parkinson’s disease
(idiopathic and LRKK2-positive)
BIIB122/DNL151 is a small molecule inhibitor of LRRK2, which may
have the ability to restore impaired lysosomal function, which is
implicated in Parkinson's disease (PD) pathology and disease
progression. BIIB122/DNL151 is the most clinically advanced small
molecule inhibitor of LRRK2 currently in clinical testing for
PD.
Results from Phase 1 and Phase 1b trials of BIIB122 in healthy
volunteers and patients with PD, respectively, showed robust target
and pathway engagement as measured by pS935 LRRK2 and pT73
Rab10, respectively. In addition, a dose-dependent reduction in
urine of the lysosomal lipid 22:6-bis[monoacylglycerol] phosphate
(BMP), a biomarker of lysosomal function, was achieved with BIIB122
treatment, providing evidence supporting improvement of lysosomal
function. BIIB122 was generally well tolerated across a broad range
of doses for up to 28 days, the longest treatment duration in both
studies.
Denali has a strategic collaboration with Biogen to jointly
develop and commercialize small molecule inhibitors of LRRK2.
Biogen is conducting two global late-stage clinical trials of
BIIB122: the Phase 2b LUMA study, which commenced in May 2022 in
approximately 640 participants with early-stage PD; and the Phase 3
LIGHTHOUSE study, which commenced in September 2022 in
approximately 400 participants with PD with a confirmed LRRK2
pathogenic variant. Both studies are evaluating the efficacy and
safety of BIIB122 as compared to placebo.
2023 expected progress and milestones:
- Continued recruitment of participants
with PD in the Phase 2b LUMA and Phase 3 LIGHTHOUSE studies.
SAR443820/DNL788 (CNS-penetrant RIPK1 inhibitor): ALS,
MS, AD
SAR443820/DNL788 is a small molecule inhibitor of RIPK1, a
critical signaling protein in a canonical inflammatory and cell
death pathway. Increased RIPK1 activity in the brain drives
neuroinflammation and cell necroptosis and contributes to
neurodegeneration. RIPK1 inhibition has been shown to have
beneficial effects in preclinical models of amyotrophic lateral
sclerosis (ALS), multiple sclerosis (MS), Alzheimer's disease (AD),
and other diseases.
Denali has a strategic collaboration with Sanofi to jointly
develop and commercialize small molecules that inhibit RIPK1. In
2022, Sanofi commenced dosing in the HIMALAYA global Phase 2 study
of SAR443820 and expects to enroll approximately 260 participants
with ALS. A Phase 2 study in MS is also planned. Denali is leading
preclinical research on SAR443820 as a potential treatment for
AD.
2023 expected progress and milestones:
- Initiation of Phase 2 study in MS in
early 2023.
- Completion of recruitment of
participants with ALS in the Phase 2 HIMALAYA study.
DNL343 (eIF2B activator): ALS
DNL343 is a small molecule activator of the eukaryotic
initiation factor 2B (eIF2B) with first-in-class potential for the
treatment of ALS and other indications. DNL343 is designed to
inhibit the cellular integrated stress response (ISR) to prevent or
slow disease progression that is associated with stress granule
formation and TDP-43 aggregation, a hallmark pathology present in
nearly all individuals with ALS.
Denali is conducting a Phase 1b 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.
As previously reported, an interim analysis was performed after 20
participants randomized to receive DNL343 or placebo had completed
the double-blind period of the study. The interim results
demonstrated that 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 ISR pathway in blood samples from study participants. The
interim data continue to support late-stage development of DNL343;
as previously announced, the design phase of the Phase 2/3 study of
DNL343 is underway 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.
2023 expected progress and milestones:
- Final data from the 28-day
double-blind, placebo-controlled portion of the Phase 1b study in
mid 2023.
- Initiation of Phase 2/3 study in the
HEALEY ALS Platform Trial in mid 2023.
OTHER CLINICAL PROGRAMS
SAR443122/DNL758 (peripherally-restricted RIPK1
inhibitor): CLE and UC
Denali’s collaboration with Sanofi also includes the
peripherally-restricted RIPK1 inhibitor SAR443122/DNL758
(eclitasertib), which is currently being evaluated in a Phase 2
trial in patients with cutaneous lupus erythematosus (CLE). Today
Denali announced that Sanofi has initiated a Phase 2 trial of
SAR443122 in patients with ulcerative colitis (UC). Sanofi is
solely responsible for the development and commercialization of
peripherally restricted RIPK1 inhibitors.
2023 expected progress and milestones:
- Primary completion of Phase 2 CLE
study in June 2023.
- Continued recruitment of participants
with ulcerative colitis in the Phase 2 study.
DISCOVERY PROGRAMS
Denali continues to advance a broad preclinical portfolio
including programs enabled by the Enzyme Transport Vehicle, the
Antibody Transport Vehicle, and the Oligonucleotide Transport
Vehicle, and several small molecules engineered to cross the BBB
and intended as potential treatments for patients with
neurodegenerative diseases and lysosomal storage diseases.
Today Denali announced that new research will be presented at
the upcoming inaugural Keystone Symposium on 'Drug Delivery to the
Brain: Challenges and Progress', which is being held January 23-26,
2023, in Breckenridge, Colorado, including expansion of the TV
technology to utilize an additional BBB transporter and potential
TV applications in oncology.
Webcast and slide deck for Denali’s corporate
presentation at the J.P. Morgan Healthcare Conference
A webcast of Dr. Watts’ presentation during the J.P. Morgan
Conference as well as a PDF of the related slide deck will be
available on the Events page under the Investor section of the
Denali’s website at
https://www.denalitherapeutics.com/investors/events. An archived
replay of the presentation will be available for approximately 30
days following the event.
About Denali’s TV Platform
The blood-brain barrier is essential in maintaining the brain’s
microenvironment and protecting it from harmful substances and
pathogens circulating in the bloodstream. Historically, the
blood-brain barrier has posed significant challenges to drug
development for central nervous system diseases by preventing most
drugs from reaching the brain in therapeutically relevant
concentrations. Denali’s Transport Vehicle platform is a
proprietary technology designed to effectively deliver large
therapeutic molecules such as antibodies, enzymes, proteins, and
oligonucleotides across the blood-brain barrier after intravenous
administration. The Transport Vehicle technology is based on
engineered Fc domains that bind to specific natural transport
receptors, such as transferrin receptor, which are expressed at the
blood-brain barrier and are designed to deliver the Transport
Vehicle and its therapeutic cargo to the brain through
receptor-mediated transcytosis. In animal models, antibodies and
enzymes engineered with the Transport Vehicle technology
demonstrate more than 10- to 30-fold greater brain exposure than
similar antibodies and enzymes without this technology. Improved
exposure and broad distribution in the brain may increase
therapeutic efficacy by enabling widespread achievement of
therapeutically relevant concentrations of product candidates.
About Denali Therapeutics
Denali 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 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
Denali's business strategy, business plans, expected progress and
key milestones for Denali’s therapeutic portfolio in 2023;
expectations relating to the potential for Denali’s product
candidates to treat various neurodegenerative and lysosomal storage
diseases including MPS II (Hunter Syndrome), ALS, PD, AD, FTD-GRN,
MPS IIIA (Sanfilippo syndrome Type A) and related peripheral
inflammatory diseases; planned preclinical studies and clinical
trials relating to the pipeline of product candidates; expectations
regarding the timing of results and data from such studies and
trials; timelines, plans, and expectations relating to Denali’s
Transport Vehicle (TV) platform, including its Antibody Transport
Vehicle (ATV), Protein Transport Vehicle (PTV), Oligonucleotide TV
(OTV) and Enzyme Transport Vehicle (ETV) technologies; plans,
timelines and expectations relating to the Phase 1/2 and Phase 2/3
trials and enrollment of the Phase 2/3 trial of DNL310, as well as
subsequent registration; plans, timelines, and expectations
relating to the development of DNL593, including the Phase 1/2 Part
A and Part B trials; plans, timelines and expectations relating to
the development of DNL919, including the Phase 1 healthy volunteer
trial; plans, timelines, and expectations relating to DNL126 and
its potential to treat MPS IIIA, as well as the Phase 1/2 trials
and planned regulatory filings; plans, timelines and expectations
relating to the Biogen-led development of LRRK2 inhibitor DNL151,
including the global Phase 2b trial and global Phase 3 trial;
plans, timelines and expectations relating to the Sanofi-led
development of DNL788, including Phase 2 trials in ALS and MS and
preclinical exploration of potential treatment of AD; plans,
timelines and expectations regarding the Phase 1b and Phase 2/3
trials of DNL343; plans, timelines and expectations relating to the
Sanofi-led development of DNL758, including Phase 2 trials in CLE
and ulcerative colitis; plans, timelines and expectations relating
to expansion of the TV technology to utilize an additional BBB
transporter and potential TV applications in oncology; plans and
expectations with respect to Denali’s collaborations with Biogen,
Sanofi and Takeda; and statements made by Denali’s Chief Executive
Officer. 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; risk of the occurrence of any event,
change or other circumstance that could give rise to the
termination of Denali’s agreements with its collaborators; Denali’s
early stages of clinical drug development; Denali’s and its
collaborators’ ability to complete the development and, if
approved, commercialization of its product candidates; Denali’s and
its collaborators’ ability to enroll patients in its ongoing and
future clinical trials; Denali’s reliance on third parties for the
manufacture and supply of its product candidates for clinical
trials; Denali’s dependence on successful development of its
blood-brain barrier platform technology and its programs and
product candidates; Denali’s and its collaborators’ ability to
conduct or complete clinical trials on expected timelines; the risk
of significant adverse events, toxicities or other undesirable side
effects; the risk that preclinical profiles of Denali’s product
candidates may not translate in clinical trials, including risks
related to the predictive ability of nonhuman data; the potential
for clinical trials of Denali’s product candidates to differ from
preclinical, early clinical, preliminary or expected results; the
uncertainty that product candidates will receive regulatory
approval necessary to be commercialized; Denali’s ability to
continue to create a pipeline of product candidates or develop
commercially successful products; Denali's ability to attract,
motivate and retain qualified managerial, scientific and medical
personnel; developments relating to Denali’s competitors and its
industry, including competing product candidates and therapies;
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; Denali’s ability to
obtain additional capital to finance its operations, as needed;
Denali’s ability to accurately forecast future financial results in
the current environment; general economic and market conditions;
and other risks and uncertainties. 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 risks and
uncertainties may be found in Denali’s Annual and Quarterly Reports
filed on Forms 10-K and 10-Q filed with the Securities and Exchange
Commission (SEC) on February 28, 2022 and November 3, 2022,
respectively, and Denali’s future reports to be filed with the SEC.
Denali does not undertake any obligation to update or revise any
forward-looking statements, to conform these statements to actual
results or to make changes in Denali’s expectations, except as
required by law.
Investor Relations Contact:
Laura Hansen, Ph.D.Vice President, Investor Relations (650)
452-2747hansen@dnli.com
Media Contact:
dna Communications Angela Salerno-RobinSenior Vice President,
Media Relations, Healthcare(212)
445-8219Asalerno-robin@dna-comms.com
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