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 new data presentations highlighting the broad potential
of its BBB-crossing enzyme replacement therapies in development for
the treatment of mucopolysaccharidoses (MPS). New clinical data on
tividenofusp alfa (DNL310) in MPS II (Hunter syndrome) and mouse
model data on DNL126 (ETV:SGSH) in MPS IIIA (Sanfilippo syndrome
type A) are being presented this week at the 20th Annual
WORLDSymposium™ in San Diego, California.
“It is exciting to see new clinical outcomes data, now up to two
years of treatment with tividenofusp alfa,” said Joseph Muenzer,
M.D., Ph.D., Bryson Distinguished Professor in Pediatric Genetics,
University of North Carolina at Chapel Hill, who presented the
Phase 1/2 data on tividenofusp alfa in MPS II. “The robust and
sustained biomarker reductions, including NfL, and the effects on
measures of behavior, cognition, hearing, liver volumes and growth
indicate positive treatment effects in brain and somatic tissues.
Denali’s BBB-crossing enzyme replacement approach has the potential
to prevent cognitive and behavioral manifestations in MPS IIIA.
Together with Denali and the MPS community, I am passionately
advocating for the fastest path to approval to enable new treatment
options for people living with MPS diseases.”
In addition, new data on somatic outcomes from the same study of
tividenofusp alfa will be presented for the first time by Barbara
Burton, M.D., Professor of Pediatrics, Genetics, Genomics and
Metabolism at Feinberg School of Medicine in Chicago. The Phase 1/2
results demonstrate normalization of enlarged liver and spleen
volumes and maintenance of normal growth compared to healthy boys
in almost all participants. New two-year peripheral biomarker data
demonstrate high magnitude and sustained reduction of urine heparan
sulfate and dermatan sulfate, including in participants who
switched from standard-of-care enzyme replacement therapy to
tividenofusp alfa, suggesting enhanced peripheral activity.
Tividenofusp alfa treatment continued to be generally well
tolerated.
New MPS IIIA mouse model data on DNL126 will also be presented
at the conference showing improvements in lysosomal and microglial
morphology, neurodegeneration, and cognitive function. Treatment
with DNL126 resulted in lowered heparan sulfate accumulation in the
brain and in cerebrospinal fluid and improved cognitive function in
adult MPS IIIA mice. A correlation between the levels of heparan
sulfate and cognitive behavioral performance was observed. Denali
also announced that dosing has begun in the Phase 1/2 study of
DNL126 for the potential treatment of MPS IIIA.
“Our goal is to bring effective new medicines to MPS families as
soon as possible,” said Carole Ho, M.D., Chief Medical Officer of
Denali. “We are excited to present additional Phase 1/2 data
demonstrating the potential for tividenofusp alfa to treat both
brain and physical symptoms of MPS II disease, and we look forward
to continued collaboration with the MPS community to complete
enrollment in our global Phase 2/3 COMPASS study this year. We are
also pleased to share that dosing has begun in the Phase 1/2 study
of DNL126 for the potential treatment of MPS IIIA. We are driven by
the urgent need of patients and families and will work with the
community of scientists, physicians, advocates, and the FDA to find
the fastest path to approval.”
About MPS II (Hunter syndrome)MPS II, also
called Hunter syndrome, is a rare genetic disease that affects over
2,000 individuals, primarily males, world-wide, and leads to
behavioral, cognitive, and physical symptoms ultimately resulting
in shortened lifespan. MPS II is caused by mutations in the
iduronate-2-sulfatase (IDS) gene, which leads to a deficiency of
the IDS enzyme responsible for the breakdown of the
glycosaminoglycans (GAGs) heparan and dermatan sulfate in
lysosomes. Symptoms often begin emerging around age two and include
physical complications, including organ dysfunction, joint
stiffness, hearing loss and impaired growth leading to short
stature, and neurocognitive symptoms with impaired development. The
disease is characterized by a buildup of GAGs in lysosomes — the
part of the cell that breaks down materials including GAGs. The
current standard of care enzyme replacement therapy partially
treats the physical symptoms but does not cross the BBB, and as a
result, cognitive and behavioral symptoms experienced by the
majority of patients with MPS II are not addressed. Therapies that
address behavioral, cognitive, and physical manifestations of the
disease are one of the greatest unmet needs for this community.
About tividenofusp alfa (DNL310)Tividenofusp
alfa (DNL310) is a fusion protein composed of 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 studyBased 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. The
Phase 2/3 COMPASS study is being conducted globally in North
America, South America, and Europe. 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 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, ETV-enabled
N-sulfoglucosamine sulfohydrolase (SGSH) replacement therapy
designed to cross the BBB for the potential treatment of MPS IIIA.
A Phase 1/2 study of DNL126 in MPS IIIA is ongoing; more
information 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 TherapeuticsDenali
Therapeutics is a biopharmaceutical company developing a broad
portfolio of product candidates engineered to cross the blood-brain
barrier for neurodegenerative diseases and lysosomal storage
diseases. Denali pursues new treatments by rigorously assessing
genetically validated targets, engineering delivery across the
blood-brain barrier, 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
DNL310, the ongoing Phase 2/3 COMPASS study, and the open-label,
single-arm Phase 1/2 study, including the continued recruitment of
participants for the Phase 2/3 COMPASS study and the timing and
availability of data for both studies; the potential for data from
the ongoing DNL310 studies to support registration; expectations
related to DNL126, the ongoing natural history study, and the
ongoing Phase 1/2 study; expectations regarding the therapeutic
potential of Denali’s Transport Vehicle platform and DNL310; and
statements made by Drs. Joseph Muenzer and Carole Ho. 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 27, 2023, and
November 7, 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 Relations (650)
452-2747 hansen@dnli.com
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