Denali Therapeutics Inc. (Nasdaq: DNLI), a biopharmaceutical
company developing a broad portfolio of product candidates
engineered to cross the blood-brain barrier (BBB) for the treatment
of neurodegenerative diseases and lysosomal storage diseases, today
announced program progress and expected milestones for 2024, which
Chief Executive Officer, Ryan Watts, Ph.D., will highlight during a
corporate presentation at the 42nd Annual J.P. Morgan Healthcare
Conference on Tuesday, January 9th, at 10:30 a.m. Pacific Time.
“In 2024, we expect enrollment to be completed in our
late-stage clinical trials for MPS II and ALS, and we are
establishing commercial readiness,” said Ryan Watts, Ph.D., Chief
Executive Officer of Denali. “In addition, we are excited to
announce initiation of clinical development for our second Enzyme
Transport Vehicle (TV)-enabled program, DNL126 in MPS IIIA, and
that our first two Oligonucleotide TV-enabled programs are in
IND-enabling studies targeting tau in Alzheimer’s disease
(OTV:MAPT) and alpha-synuclein in Parkinson’s disease (OTV:SNCA).
Based on clinical validation and momentum with the TV platform, we
have prioritized advancing additional TV programs for common
neurodegenerative diseases.”
Denali’s 2024 Outlook
Expected progress and key milestones in 2024 across Denali’s
therapeutic portfolio are summarized below.
LATE-STAGE AND MID-STAGE CLINICAL PROGRAMS
Tividenofusp alfa
(DNL310): MPS II (Hunter
syndrome)
Tividenofusp alfa (DNL310) is an investigational,
intravenously administered, Enzyme Transport Vehicle (ETV)-enabled,
iduronate-2-sulfatase (IDS) replacement therapy designed to cross
the BBB and address the behavioral, cognitive, and physical
manifestations of MPS II (Hunter syndrome).
Interim Phase 1/2 study data up to two years of treatment have
demonstrated that once weekly intravenous dosing with DNL310 was
generally well-tolerated and led to rapid and sustained
normalization of cerebral spinal fluid (CSF) heparan sulfate to
normal healthy levels, improvement in lysosomal function
biomarkers, and robust and statistically significant reduction of
neurofilament light (NfL), a marker of neuronal damage. In
addition, positive clinical outcome changes in adaptive behavior,
cognition, and auditory function were observed.
The global Phase 2/3 COMPASS study continues to recruit up to 54
participants with neuronopathic and non-neuronopathic MPS II. Upon
completion of the ongoing Phase 1/2 study, and together with data
from COMPASS, this combined data package is intended to support
registration.
2024 expected progress and milestones:
- Complete enrollment of global Phase 2/3 COMPASS study in MPS
II
- Presentation of additional interim Phase 1/2 data
at WORLDSymposium™ (February 4-9) and at the Society
for the Study of Inborn Errors of Metabolism (SSIEM) Annual
Symposium (September 3-6)
DNL343 (eIF2B Activator): ALS
DNL343 is an investigational small molecule activator of the
eukaryotic initiation factor 2B (eIF2B) designed to inhibit the
cellular integrated stress response (ISR) and prevent or slow
disease progression by interfering with stress granule formation
and TDP-43 aggregation, which is a hallmark pathology present in
virtually all individuals with ALS. Previously announced results of
a Phase 1b study in participants with ALS demonstrated that
once-daily oral dosing with DNL343 for 28 days was generally
well-tolerated and was associated with extensive distribution in
the cerebrospinal fluid as well as robust inhibition of ISR
biomarkers. Recruitment is ongoing in Regimen G (DNL343) of the
Phase 2/3 HEALEY ALS Platform Trial.
2024 expected progress and milestones:
- Complete enrollment of participants in
Regimen G (DNL343) in Phase 2/3 HEALEY ALS Platform Trial
SAR443820/DNL788 (CNS-Penetrant RIPK1
Inhibitor): ALS, MS
SAR443820/DNL788 is an investigational, CNS-penetrant, small
molecule inhibitor of RIPK1, a critical signaling protein in a
canonical inflammatory and cell death pathway. Increased RIPK1
activity in the CNS is hypothesized to drive neuroinflammation and
cell necroptosis and to contribute to neurodegeneration. Denali and
Sanofi are co-developing SAR443820. Sanofi has completed enrollment
of two Phase 2 studies: 305 participants have enrolled in the
HIMALAYA ALS study and 174 participants have enrolled in the K2
multiple sclerosis (MS) study.
2024 expected progress and milestones:
- Sanofi to announce topline results from the Phase 2 HIMALAYA
study in ALS in the first half of 2024
- Continue K2 Phase 2 study in MS
BIIB122/DNL151 (LRRK2 Inhibitor): Parkinson’s
disease
BIIB122/DNL151 is an investigational small molecule inhibitor of
LRRK2, one of the most common genetic drivers of Parkinson’s
disease. Targeting LRRK2 has the potential to impact the underlying
biology and slow the progression of Parkinson’s disease. Denali and
Biogen are co-developing BIIB122. Biogen is conducting the global
Phase 2b LUMA study of BIIB122 in early-stage Parkinson’s disease
with and without LRRK2 mutations.
2024 expected progress and milestones:
- Continue Phase 2b LUMA study in
early-stage Parkinson’s disease
Eclitasertib (SAR443122/DNL758) (Peripheral RIPK1
Inhibitor): Ulcerative colitis (UC)
Eclitasertib (SAR443122/DNL758), is an investigational,
peripherally restricted, small molecule inhibitor of RIPK1. Sanofi
is solely responsible for the development and commercialization of
peripherally restricted RIPK1 inhibitors.
2024 expected progress and milestones:
- Continue Phase 2
UC study
EARLY-STAGE CLINICAL AND PRECLINICAL
PROGRAMS
TAK-594/DNL593 (PTV:PGRN): Frontotemporal
Dementia-Granulin (FTD-GRN)
DNL593 is an investigational, intravenously administered,
Protein Transport Vehicle (PTV)-enabled progranulin (PGRN)
replacement therapy designed to restore normal levels of PGRN in
the brain without interfering with normal PGRN transport and
processing. DNL593 is being co-developed with Takeda. Results from
Part A of a Phase 1/2 study (n=38) demonstrated that single doses
of DNL593 were generally well-tolerated in healthy subjects and
resulted in substantial increases in CSF PGRN levels. These data
suggest brain delivery of DNL593 was achieved and has the potential
to address PGRN deficiency in FTD-GRN.
Denali today also announced that enrollment and dosing have been
voluntarily paused in Part B (n=9 dosed to date) of the DNL593
Phase 1/2 study in participants with FTD-GRN to implement protocol
modifications. The pause is based on infusion-related reactions
(IRRs) reported in two study participants, one Grade 2 and one
Grade 3 in severity and both deemed serious adverse events. Both
study participants’ IRRs resolved with infusion discontinuation and
standard treatment measures within the same day. DNL593 has been
otherwise well-tolerated in the study, with all other adverse
events reported as mild in severity. The protocol modification will
allow for premedication and other measures aimed at reducing the
risk of IRRs.
2024 expected progress and milestones:
- Continue Part B of the Phase 1/2 study
in FTD-GRN
DNL126 (ETV:SGSH): MPS IIIA (Sanfilippo syndrome Type
A)
DNL126 (ETV:SGSH) is an investigational, intravenously
administered, ETV-enabled N-sulfoglucosamine sulfohydrolase (SGSH)
replacement therapy designed to cross the BBB and address the
behavioral, cognitive, and physical manifestations of MPS IIIA
(Sanfilippo syndrome Type A). Recruiting activities are ongoing for
the Phase 1/2 study of DNL126 in MPS IIIA.
2024 expected progress and milestones:
- Biomarker proof of concept and safety
data from the Phase 1/2 study by the end of 2024
Oligonucleotide Transport Vehicle (OTV)
platform
Denali’s OTV platform is designed to enable peripheral
administration of oligonucleotide therapeutics such as antisense
oligonucleotides (ASOs) to address a wide range of
neurodegenerative and other neurological diseases. Denali has
submitted a manuscript for publication, which can be found on
bioRxiv here. Denali has selected five ASO targets for further
development and today announced that OTV:MAPT targeting tau for
Alzheimer’s disease and OTV:SNCA targeting alpha-synuclein for
Parkinson’s disease are the first programs in the Investigational
New Drug (IND)-enabling stage of development.
2024 expected progress and milestones:
- IND-enabling studies with OTV:MAPT and
OTV:SNCA
Antibody Transport Vehicle Amyloid beta (ATV:Abeta)
program
ATV:Abeta is an investigational, ATV-enabled anti-amyloid-beta
therapy designed to increase brain exposure and target engagement
of antibody therapeutics directed against amyloid-beta, which may
enable improved plaque clearance and reduced amyloid-related
imaging abnormalities (ARIA). Accumulation of amyloid-beta plaque
in the brain is a defining feature of Alzheimer’s disease. Biogen
exercised its option to license Denali’s ATV:Abeta program and is
responsible for all development and commercial activities and
associated expenses.
2024 expected progress and milestones:
DISCOVERY PROGRAMS
Denali continues to use deep scientific expertise in
neurodegeneration biology and the blood-brain barrier to discover
and develop medicines and platforms with the focus on programs
enabled by the Transport Vehicle and targeting common
neurodegenerative disease, including Alzheimer’s and Parkinson’s,
and lysosomal storage diseases.
CORPORATE UPDATES
Based on clinical validation and prioritization of Denali’s
TV-enabled platforms for brain delivery of large molecules, Denali
today also announced its intention to spin out its preclinical
small molecule portfolio with the formation of a new company
(“NewCo”), which will be independently funded. A team of proven
small molecule CNS drug developers with a track record of invention
at Denali will assume leadership of the NewCo. Denali will maintain
ownership of and continue to advance its current portfolio of
clinical stage small molecule programs.
Cash, cash equivalents, and marketable securities were
approximately $1.12 billion as of September 30,
2023. Denali anticipates its operating expenses in 2024 will be
less than or equal to those in 2023 based on prioritization of its
portfolio, thereby extending the company’s cash runway into
2027.
Expected 2024 Key Milestones for Denali-Led
Programs
PROGRAM |
MILESTONE |
TIMING |
DNL310(ETV:IDS) |
Additional long-term Phase 1/2 data at WORLD |
Feb 4-9 |
Additional long-term Phase 1/2 data at SSIEM |
Sept 3-6 |
Complete enrollment of global Phase 2/3 COMPASS study in MPS
II |
2024 |
DNL593(PTV:PGRN) |
Continue Part B of Phase 1/2 study in FTD-GRN |
2024 |
DNL126(ETV:SGSH) |
Preclinical data at WORLD |
Feb 4-9 |
Initiate dosing in Phase 1/2 |
Early 2024 |
Biomarker proof of concept and safety data from Phase1/2 study in
MPS IIIA |
Late 2024 |
DNL343(eIF2B activator) |
Complete enrollment of Regimen G in Phase 2/3 HEALEY ALS Platform
Trial |
2024 |
OTV:MAPT |
IND enabling studies |
2024 |
OTV:SNCA |
IND enabling studies |
2024 |
Expected 2024 Key Milestones for Partner-Led
Programs
PROGRAM |
MILESTONE |
STRATEGIC PARTNER |
BIIB122/DNL151(LRRK2 inhibitor) |
Continue Phase 2b LUMA study in early-stage PD |
Biogen |
ATV:Abeta |
IND enabling studies |
Biogen |
SAR443820/DNL788(CNS-penetrant RIPK1
inhibitor) |
Topline results of the Phase 2 HIMALAYA study in ALS (1H 2024) |
Sanofi |
Continue Phase 2 K2 study in MS |
SAR443122/DNL758(Peripherally-restrictedRIPK1
inhibitor) |
Continue Phase 2 UC study |
Sanofi |
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://investors.denalitherapeutics.com/events. An archived replay
of the presentation will be available for approximately 30 days
following the event.
About Denali’s Transport Vehicle 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 receptors, which are expressed at
the blood-brain barrier and 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 blood-brain barrier (BBB) for the treatment of
neurodegenerative diseases and lysosomal storage 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
expectations regarding Denali’s TV technology platform, including
the Enzyme Transport Vehicle (ETV), Antibody Transport Vehicle
(ATV) and Oligonucleotide Transport Vehicle (OTV); statements made
by Denali’s Chief Executive Officer; plans, timelines, and
expectations regarding DNL310 and the ongoing Phase 2/3 COMPASS and
Phase 1/2 studies, including with respect to enrollment and the
timing and availability of data; plans, timelines, and expectations
of both Denali and Takeda regarding DNL593 and the ongoing Phase
1/2 study, including the modification of the study protocol and
impact on the occurrence of IRRs; plans, timelines, and
expectations related to DNL126, including the Phase 1/2 study,
including the timing and availability of data; plans, timelines,
and expectations regarding Denali's OTV platform and related
programs, including the publication of manuscripts, the advancement
of candidates towards clinical development, and the potential for
registration; plans, timelines, and expectations of both Denali and
Biogen regarding the ATV:Abeta program and its registrational
potential; plans, timelines, and expectations of both Denali and
Biogen regarding DNL151 and the ongoing Phase
2b LUMA study; plans, timelines, and expectations of both
Denali and Sanofi regarding DNL788 and the ongoing Phase 2 HIMALAYA
study in ALS and Phase 2 study in MS, including with respect to the
timing and availability of data; plans, timelines, and expectations
regarding DNL343, including enrollment in Regimen G of the Phase
2/3 HEALEY ALS Platform Trial; plans, timelines, and expectations
regarding DNL758, including the ongoing Phase 2 study in patients
with UC; the creation, funding, and leadership of NewCo; Denali's
anticipated operating expenses; and plans and expectations for
Denali's preclinical programs. 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 by adverse
economic conditions; 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 transition to a
late-stage clinical drug development company; 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
that preclinical profiles of Denali’s product candidates may not
translate in clinical trials; the potential for clinical trials to
differ from preclinical, early clinical, preliminary or expected
results; the risk of significant adverse events, toxicities or
other undesirable side effects; 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;
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; and other risks and uncertainties, including
those described in Denali's most recent Annual and Quarterly
Reports on Forms 10-K and 10-Q filed with the Securities and
Exchange Commission (SEC) on February 27,
2023 and November 6, 2023, 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 and Media Contact:
Laura Hansen, Ph.D.Vice President, Investor
Relationshansen@dnli.com
Denali Therapeutics (NASDAQ:DNLI)
Historical Stock Chart
Von Mai 2024 bis Jun 2024
Denali Therapeutics (NASDAQ:DNLI)
Historical Stock Chart
Von Jun 2023 bis Jun 2024