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 results from the ongoing open-label,
single-arm Phase 1/2 study of DNL310 (ETV:IDS) in children with MPS
II (Hunter syndrome), including data from additional participants
and up to 104 weeks of treatment. DNL310 is an investigational
brain-penetrant enzyme replacement therapy designed to address the
behavioral, cognitive, and physical manifestations of MPS II. The
interim Phase 1/2 data are being presented at the 19th Annual
WORLDSymposium™ in Orlando, Florida, February 22-26, 2023.
“We continue to see sustained reductions in CSF heparan sulfate
to normal levels in most individuals not previously seen with any
other therapy. Furthermore, over 49 weeks, DNL310 treatment is
associated with positive changes across measures of adaptive
behavior and cognition, global impression, and improvements in
measures of hearing function,” said Joseph Muenzer, M.D., Ph.D.,
Bryson Distinguished Professor in Pediatric Genetics, University of
North Carolina at Chapel Hill. “As the study progresses and
enrollment continues for the global Phase 2/3 COMPASS study, I am
excited to learn more about the potential of DNL310 to offer
meaningful benefit for the entire MPS II patient population."
“We are excited to share new interim analyses from the Phase 1/2
study, including data that suggests hearing improves within a year
with DNL310 treatment in participants previously treated with
idursulfase,” said Carole Ho, M.D., Chief Medical Officer at
Denali. “The consistency of the strong biomarker data and positive
trends in behavior, cognition, global impression data, and hearing,
with a safety profile consistent with standard of care, suggest
robust central nervous system and peripheral activity of
DNL310. These data support continued recruitment in the Phase
2/3 COMPASS study. Additionally, we aim to apply our learnings more
broadly to address high unmet need for individuals living with
other MPS diseases.”
The oral presentation to be given on February 24, 2023, at the
WORLDSymposium™ will include data as of the September 2022
data cut off from the 28 participants enrolled in the Phase 1/2
study of DNL310. All but one participant has neuronopathic MPS II,
and the median age at enrollment was 5 years (range 2 to 12).
Participants received weekly intravenous doses of DNL310 starting
on day 1 of the study, with no wash-out period for those switching
from idursulfase. Key interim results are summarized below:
- Exploratory clinical outcomes data from Vineland Adaptive
Behavior Scales (VABS)-II and Bayley Scales of Infant and Toddler
Development (BSID)-III assessments were reported for the first time
and positive mean changes in raw scores over one year with DNL310
treatment relating to adaptive behavior and cognitive skill gains
were observed, respectively. These raw score results are consistent
with previously reported one-year findings from the Clinician
Global Impression Scales of Change and Caregiver Global Impression
Scales of Change, showing that most participants demonstrated
improvement or stabilization across all domains at week 49 of study
treatment.
- Hearing, as assessed by auditory brainstem response (ABR)
testing, numerically improved over time after initiation of DNL310
across all frequencies. At week 49, ABR thresholds showed
statistically significant improvements across three of the four
frequencies, with a trend toward greater improvement at higher
frequencies.
- The data continue to demonstrate that DNL310 enables rapid and
sustained normalization of heparan sulfate in cerebrospinal fluid
(CSF) with mean reductions from baseline of 91% and 90% at weeks 24
and 49, respectively. Normalization of CSF heparan sulfate was
observed even in participants with high levels of preexisting
anti-iduronate-2-sulfatase antibodies.
- Sustained reduction of lysosomal lipid biomarkers in CSF was
also observed, which is consistent with improved lysosomal
function. At week 24, the mean decline in levels of gangliosides
GM2, GM3, and glucosylsphingosine lipids were 64%, 54%, and 57%,
respectively, which was sustained at week 49 (63%, 49%, and 48%,
respectively).
- After switching from idursulfase to DNL310, a mean decline from
baseline of 85% and 89% was observed for heparan sulfate and
dermatan sulfate biomarkers in the urine, respectively, at week 49,
suggesting DNL310 has added peripheral activity over approved
enzyme replacement therapy.
- The safety profile of DNL310 remains consistent with standard
of care, now with data up to two years of treatment with DNL310.
The most frequent treatment-emergent adverse events were infusion
related reactions, which decreased in frequency and severity with
continued dosing.
- An independent data monitoring committee met in October 2022
and recommended that the study may continue without
modifications.
A PDF of the Phase 1/2 poster will be available on Denali’s
website on the Events page of the Investor section
today.
A second oral presentation to be given on Saturday, February 25,
2023, will highlight preclinical data on DNL126 (ETV:SGSH),
Denali's second most advanced ETV-enabled program. DNL126 is an
investigational, brain-penetrant N-sulfoglucosamine sulfohydrolase
(SGSH) replacement therapy designed to address the behavioral,
cognitive, and physical manifestations of MPS IIIA (Sanfilippo
syndrome Type A). Denali plans to submit an IND application for
DNL126 in the first half of 2023. A PDF of the oral presentation
will be available on Saturday, February 25, 2023, at 8:00 a.m.
Eastern Time on the Events page of the Investor section of Denali’s
website.
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 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.
Families interested in learning more about Denali’s efforts
related to the discovery and development of therapeutics for the
potential treatment of Hunter syndrome are invited to
visit EngageHunter.com, the Denali Hunter syndrome community
engagement website.
About
the EngageHunter.com Website
EngageHunter.com — the Denali Hunter syndrome community
engagement website — is an online destination for emerging
information on Denali’s scientific advances in Hunter syndrome
research and Denali’s clinical trials. Visitors who register on the
Engage Hunter website will receive updates on Denali’s research and
future Denali investigational
studies. EngageHunter.com is intended
for U.S. audiences.
About MPS IIIA (Sanfilippo Syndrome)
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 (NCT05523206) of biomarkers and adaptive behavior in
MPS IIIA is ongoing and more information 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.
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 expectation that it is a potentially
registrational trial; plans, timelines, and expectations related to
DNL126, including the expectation and timing of potential
regulatory submissions; expectations regarding Denali’s TV
technology platform, the therapeutic potential of DNL310 and
DNL126, and Denali’s TV platform; and statements made by Dr. Joseph
Muenzer and 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: risks to Denali’s business and operations caused
directly or indirectly by the COVID-19 pandemic; 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 risk that results from early clinical biomarker
studies will not translate to clinical benefit in late clinical
studies; the risk that DNL310 and DNL126 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, 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 Contact:
Laura Hansen, Ph.D. Vice President, Investor
Relations (650) 452-2747 hansen@dnli.com
Media Contact:
Angela Salerno-Robin(212)
445-8219asalerno-robin@dna-comms.com
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