Denali Therapeutics Inc. (Nasdaq: DNLI), a biopharmaceutical
company developing a broad portfolio of product candidates
engineered to cross the blood-brain barrier for neurodegenerative
diseases and lysosomal storage disorders, today announced new
interim results from a Phase 1/2 trial of DNL310 (ETV:IDS) in MPS
II (Hunter syndrome). DNL310 is an investigational, brain-penetrant
enzyme replacement therapy designed to address the cognitive,
behavioral, and physical manifestations of Hunter syndrome. The
data were presented at the 2022 Society for the Study of Inborn
Errors of Metabolism (SSIEM) Annual Symposium in Freiburg, Germany,
by Joseph Muenzer, M.D., Ph.D., Bryson Distinguished Professor in
Pediatric Genetics, University of North Carolina at Chapel Hill.
“The achievement of healthy normal levels of heparan sulfate in
all participants in the Phase 1/2 study, including those with high
pre-existing anti-iduronate-2 sulfatase antibodies, was also
accompanied in most participants by improvement or stabilization in
clinical symptoms and function as reported by both clinicians and
caregivers,” said Carole Ho, M.D., Chief Medical Officer at Denali.
“These latest interim data continue to differentiate DNL310 and
demonstrate sustained effects on key MPS II disease biomarkers as
well as a safety profile similar to standard of care. We are
actively engaged in enrolling our Phase 2/3 COMPASS study in which
we aim to demonstrate a meaningful impact for children with Hunter
syndrome and their families.”
Dr. Muenzer added: "We have not previously seen reductions in
CSF heparan sulfate to normal levels with any therapy, suggesting
that we may see long-term cognitive stabilization with DNL310 in a
population destined to have CNS decline. Furthermore, normal levels
of CSF heparan sulfate were observed even in participants who
entered the study with high levels of anti-drug antibodies against
idursulfase. I am excited for the Phase 2/3 COMPASS study to
continue to explore the potential of DNL310 as a treatment for the
entire MPS II patient population.”
The presentation at SSIEM included data from 27 participants
enrolled in the Phase 1/2 trial with data available as of the data
cut off on March 22, 2022. All but one participant has
neuronopathic MPS II, and the median age 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. Earlier interim results from the Phase
1/2 study were presented at WORLDSymposium™ 2022 (link to corporate
press release). A copy of the presentation is available on Denali’s
website on the Investor & Media Relations section under the
Events page. Key results are summarized below.
Data continue to show rapid and sustained reduction of
relevant central nervous system (CNS) and peripheral biomarkers to
normal healthy levels
Data from additional participants in the Phase 1/2 study
continue to show rapid and sustained reduction of relevant CNS and
peripheral biomarkers to normal healthy levels. Rapid normalization
of cerebrospinal fluid (CSF) heparan sulfate levels was observed in
most patients after 4 to 6 weekly intravenous doses of DNL310. All
participants approached normal CSF heparan sulfate levels by week
24 and this was sustained in all participants who reached week 49
(89% reduction from baseline), including in two children with
preexisting high levels of anti-iduronate-2-sulfatase
antibodies.
Results also continued to demonstrate normalization of lysosomal
lipid biomarkers in CSF, which is consistent with improved
lysosomal function. At week 24, the mean decline in levels of the
gangliosides GM2 and GM3 was 63% and 52%, respectively, which was
sustained at week 49.
After switching from idursulfase to DNL310, a mean decline from
baseline of 84% and 88% 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.
One-year, exploratory, open-label clinical outcomes data
suggest improvement or stabilization in the majority of Phase 1/2
study participants
One-year exploratory clinical outcomes data from the Phase 1/2
study were presented from Clinician Global Impression Scales of
Change (CGI-C) and Caregiver Global Impression Scales of Change
(CaGI-C) for the first time. These are standardized assessment
scales used to measure change and modified to measure overall MPS
II symptoms and specific domains impacted by Hunter syndrome,
including communication, social skills, daily living skills,
problematic behavior, and physical abilities. For participants with
assessments at week 49, most demonstrated improvement or
stabilization across all domains since entering the Phase 1/2
study.
Safety profile of DNL310, now with up to 85 weeks of
dosing, remains similar to standard of care
The safety profile of DNL310 with up to 85 weeks of dosing
remains similar to standard of care. The most frequent
treatment-emergent adverse events (TEAEs) were infusion related
reactions (IRRs). IRR frequency and severity decreased with
continued dosing, demonstrating tolerance to dosing with DNL310.
There were no treatment withdrawals or study discontinuations due
to TEAEs. The study continues without modification following
recommendation by an independent data monitoring committee in April
2022.
About Hunter Syndrome
Hunter syndrome, also called MPS II, is a rare genetic disease
that affects over 2,000 individuals, primarily males, world-wide,
and leads to physical, cognitive, and behavioral symptoms. Hunter
syndrome 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 Hunter syndrome are not addressed. Therapies that
address cognitive, behavioral, 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. 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. In March 2021, the U.S.
Food and Drug Administration granted Fast Track designation to
DNL310 for the treatment of patients with Hunter syndrome. 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 Hunter syndrome 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 designed to support registration
of DNL310 for the treatment of MPS II. 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 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 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 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 and
the DNL310 ongoing Phase 1/2 study, plans regarding the timing and
structure of, and expectations regarding enrollment in, the Phase
2/3 COMPASS study, including the expectation that it is potentially
a registrational trial, expectations regarding Denali’s Transport
Vehicle technology and platform, the therapeutic potential of
DNL310 and Denali’s Transport Vehicle platform, and statements made
by Denali’s Chief Medical Officer and Dr. Joseph Muenzer. 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 ability to complete the development and,
if approved, commercialization of DNL310 on expected timelines;
Denali’s ability to initiate and enroll patients in the Phase 2/3
COMPASS study of DNL310 and other future clinical trials; Denali’s
reliance on third parties for the manufacture and supply of its
product candidates for clinical trials; the potential for clinical
trial results of DNL310 to differ from preclinical, early clinical,
preliminary or expected results; Denali's ability to continue dose
escalation in the Phase 1/2 study of DNL310; the risk of
significant adverse events, toxicities or other undesirable side
effects related to DNL310; whether DNL310 will impact downstream
biomarkers of neurodegeneration; the risk that results from early
clinical biomarker studies will not translate to clinical benefit
in late clinical studies; the risk that early clinical benefits
will not continue to stabilize or improve with respect to clinical
symptoms and function; the risk that DNL310 may not receive
regulatory approval as a treatment for Hunter syndrome 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 related to DNL310; implementation
of Denali’s strategic plans for its business, product candidates
and blood-brain barrier platform technology, including DNL310; 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 August 8, 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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