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 and lysosomal storage diseases, today
announced that the U.S. Food and Drug Administration (FDA) has
selected DNL126 for participation in the Support for clinical
Trials Advancing Rare disease Therapeutics (START) Pilot Program.
DNL126 is an investigational enzyme replacement therapy designed to
cross the BBB for the potential treatment of MPS IIIA (Sanfilippo
syndrome type A).
The FDA announced the START Pilot Program on September 29, 2023,
with the stated purpose to further accelerate the pace of
development of novel drug and biological products that are intended
to address an unmet medical need as a treatment for a rare disease.
Selected participants of the START Pilot Program are provided
opportunities to obtain frequent advice and engage in more rapid ad
hoc communication with FDA review staff to address product-specific
development issues. The START pilot and metrics are milestone
driven and agreed upon by the FDA and sponsor. Initial selection
for START planned to include up to six eligible programs (three
each) from the FDA’s Center for Biologics Evaluation and Research's
(CBER) Office of Therapeutic Products and Center for Drug
Evaluation and Research's (CDER) Office of New Drugs.1
“We are thrilled to be selected by the FDA for participation in
START and see this as another important opportunity to work
together to solve challenges unique to rare disease drug
development,” said Carole Ho, M.D., Chief Medical Officer of
Denali. “It is an exciting time to be part of the collective effort
of making new treatments available to individuals and families
living with rare diseases. We look forward to continued
collaboration with CDER to determine the most efficient development
path for DNL126 in MPS IIIA, a devastating and progressive disease
for which treatments are urgently needed.”
Denali is conducting a Phase 1/2 study of DNL126 for children
with MPS IIIA, which has generated high interest from the MPS IIIA
community for whom there are no approved treatment options. As a
selected START participant, Denali anticipates the increased level
of engagement will facilitate alignment on the most efficient
development path to ultimately support a marketing application for
DNL126 in MPS IIIA.
Denali is also developing tividenofusp alfa (DNL310) as a
potential treatment for people living with MPS II (Hunter syndrome)
and expects to complete enrollment of the Phase 2/3 COMPASS study
this year. Given the advanced development stage of the program,
Denali did not apply to START for tividenofusp alfa. The FDA
granted Fast Track designation to tividenofusp alfa, which also
facilitates increased communication and engagement with the FDA
specific to this program.
About MPS IIIA (Sanfilippo syndrome Type A)MPS
III, also called Sanfilippo syndrome, is a rare, genetic lysosomal
storage disease that causes neurodegeneration. There are four main
types of MPS III, depending on the enzyme affected. Type A is
caused by genetic defects that result in 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. A natural history study of
biomarkers and adaptive behavior in MPS IIIA is ongoing and more
information can be found here.
About DNL126 (ETV:SGSH)DNL126 (ETV:SGSH) is an
investigational, intravenously administered, Enzyme Transport
Vehicle (ETV)-enabled N-sulfoglucosamine sulfohydrolase (SGSH)
replacement therapy designed to cross the BBB via receptor-mediated
transcytosis into the brain and to enable broad delivery of SGSH
into cells and tissues throughout the body with the goal of
addressing the behavioral, cognitive, and physical manifestations
of MPS IIIA.
About the Phase 1/2 study of DNL126Denali is
conducting a multicenter, open-label, Phase 1/2 study to assess the
safety, tolerability, pharmacokinetics, pharmacodynamics, and
exploratory clinical efficacy of DNL126 in participants with MPS
IIIA. The core study period is approximately 6 months and is
followed by an open-label extension for approximately 18 months.
More information about the Phase 1/2 study can be found here.
About tividenofusp alfa (DNL310)Tividenofusp
alfa (DNL310) is a fusion protein composed of iduronate 2-sulfatase
(IDS) fused to Denali’s proprietary Enzyme Transport Vehicle (ETV),
which is engineered to cross the BBB via receptor-mediated
transcytosis into the brain and to enable broad delivery of IDS
into cells and tissues throughout the body with the goal of
addressing the behavioral, cognitive, and physical manifestations
of MPS II. In March 2021, the U.S. Food and Drug
Administration granted Fast Track designation to DNL310 for
the treatment of patients with MPS II. In May 2022,
the European Medicines Agency granted DNL310 Priority
Medicines designation. DNL310 is an investigational product
candidate and has not been approved by any Health Authority.
About the Phase 2/3 COMPASS study of tividenofusp
alfaBased on supportive clinical and preclinical data to
date, Denali is enrolling the Phase 2/3 COMPASS study in North
America, South America, and Europe. The Phase 2/3 COMPASS
study is expected to enroll 54 participants with MPS II with and
without neuronopathic disease. The participants are randomized 2:1
to receive either tividenofusp alfa (DNL310) or idursulfase,
respectively. Cohort A includes children ages 2 to 6 with
neuronopathic disease; cohort B includes children ages 6 to 17
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.
More information about the COMPASS study can be
found here.
About Denali’s Transport Vehicle PlatformThe
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 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 Denali's plans, timelines, and expectations related to
DNL126, including the ongoing Phase 1/2 study; expectations with
respect to the START program, including interactions with the FDA,
overall development plans, and pathway for approval; plans,
timelines, and expectations related to tividenofusp alfa (DNL310),
including the ongoing COMPASS study and the timing and pathway for
approval; and statements made by Denali’s Chief Medical 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: Denali’s dependence on
successful development of its BBB platform technology and
TV-enabled product candidates; Denali’s ability to initiate and
enroll patients in its current and future clinical trials; Denali’s
ability to conduct or complete clinical trials 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 to differ from preclinical,
early clinical, preliminary or expected results; the risk of
significant adverse events, toxicities, or other undesirable side
effects; the risk that results from early clinical biomarker
studies will not translate to clinical benefit in late clinical
studies; the risk that product candidates may not receive
regulatory approval necessary to be commercialized; 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; 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 additional
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, 2024, and
May 7, 2024, 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.
Reference:
- U.S. Food and Drug Administration (September 29, 2023): FDA
Launches Pilot Program to Help Further Accelerate Development of
Rare Disease Therapies.
https://www.fda.gov/news-events/press-announcements/fda-launches-pilot-program-help-further-accelerate-development-rare-disease-therapies
(Accessed June 3, 2024)
Investor and Media Contact:Laura Hansen, PhD
Vice President, Investor Relations (650) 452-2747
hansen@dnli.com
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