Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical
company developing a broad portfolio of product candidates
engineered to cross the blood-brain barrier for the treatment of
neurodegenerative diseases and lysosomal storage diseases, today
announced new interim data from the ongoing open-label, single-arm
Phase 1/2 study of DNL310 (ETV:IDS) in children with MPS II (Hunter
syndrome). DNL310 is an investigational enzyme replacement therapy
designed to cross the BBB and address the behavioral, cognitive,
and physical manifestations of MPS II. The interim data from the
Phase 1/2 study of DNL310 were highlighted in an oral presentation
at the Society for the Study of Inborn Errors of Metabolism (SSIEM)
Annual Symposium 2023 in Jerusalem, Israel. A PDF of the Phase 1/2
presentation is available on Denali’s website on the Events page of
the Investor section.
"It is encouraging to see normalization of heparan sulfate in
CSF as well as reductions in lysosomal lipid biomarkers and
neurofilament light over two years, even in patients with high
pre-existing anti-drug antibodies," said Barbara Burton, MD,
Attending Physician, Genetics, Genomics and Metabolism at the Ann
& Robert H. Lurie Children’s Hospital of Chicago, who presented
the Phase 1/2 data at SSIEM. "The treatment effect seen on these
biomarkers of neurocognitive decline, along with one-year data
demonstrating positive changes in adaptive behavior, cognition, and
auditory function, continue to support the potential of DNL310 to
offer meaningful benefit for people living with MPS II. I look
forward to learning more as recruitment continues in the global
Phase 2/3 COMPASS study."
The interim Phase 1/2 data presented at SSIEM included new
biomarker and safety data from additional participants receiving up
to two years of treatment with DNL310 as well as previously
presented clinical outcomes data for participants receiving one
year of treatment. A summary of key results includes:
- Achievement of normal levels of CSF heparan sulfate, sustained
over time, including in participants with high pre-existing
anti-drug antibodies
- Sustained normal levels of CSF lysosomal lipids in most
participants consistent with improved lysosomal function
- Robust reduction in serum neurofilament light (NfL), a marker
of neuronal damage, reached statistical significance after 61 weeks
and a 64% reduction after two years of treatment with DNL310
- Improvements in mean cognitive Bayley Scales of Infant and
Toddler Development III (BSID-III) and Vineland Adaptive Behavior
Scales II (VABS-II) raw scores, and auditory brainstem response
(ABR) thresholds at week 49 of DNL310 treatment, suggest positive
effects on cognition, adaptive behavior, and hearing
- DNL310 continues to be generally well tolerated
- The interim safety profile, clinical outcomes data, and
biomarker effects, including normalization of CSF heparan sulfate
and reduction in NfL, continue to support development of DNL310 in
MPS II
"We are excited to share sustained effects on key disease
biomarkers in MPS II with DNL310 treatment, now out to two years,"
said Carole Ho, MD, Chief Medical Officer of Denali. "Importantly,
the robust reduction in serum levels of NfL suggests improvement in
neuronal health, which is not addressed by current enzyme
replacement therapies. We are encouraged to see positive changes
across multiple clinical outcomes measures in the ongoing Phase 1/2
study. We look forward to continued partnership with the MPS
community as we enroll the global Phase 2/3 COMPASS study in MPS II
and plan for expanding the enzyme transport vehicle, including
initiating clinical studies in other lysosomal storage
diseases."
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. Symptoms often begin emerging around
age two and include physical complications, including organ
dysfunction, joint stiffness, hearing loss and impaired growth, and
neurocognitive symptoms with impaired development. The disease is
characterized by a buildup of glycosaminoglycans (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 blood-brain barrier, 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 DNL310
DNL310 is an investigational fusion protein composed of IDS
fused to Denali’s proprietary Enzyme Transport Vehicle (ETV), which
is engineered to cross the blood-brain barrier via
receptor-mediated transcytosis into the brain. Preclinical studies
demonstrate that DNL310 delivers IDS to lysosomes, where it is
needed to break down GAGs. DNL310 is engineered for broad delivery
of IDS into cells and tissues throughout the body, including the
brain, 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
Based on supportive clinical and preclinical data to date,
Denali is conducting the Phase 2/3 COMPASS study, which is expected
to enroll 54 participants with MPS II with and without
neuronopathic disease. The participants will be randomized 2:1 to
receive either DNL310 or idursulfase, respectively. Cohort A will
include children ages 2 to 6 with neuronopathic disease; cohort B
will include 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 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 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
regarding the therapeutic potential of Denali’s Transport Vehicle
platform and DNL310; and statements made by Drs. Barbara Burton 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 early stages of clinical drug development; 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 possibility that results from early clinical biomarker
studies will not translate to clinical benefit in late clinical
studies; the likelihood of regulatory approval of DNL310 necessary
for commercialization; 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 August 8, 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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