Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical
company developing a broad portfolio of product candidates
engineered to cross the blood-brain barrier (BBB) for
neurodegenerative diseases, today announced additional positive
interim data from a Phase 1/2 study evaluating ETV:IDS (DNL310), an
investigational brain-penetrant enzyme replacement therapy intended
to treat both central nervous system (CNS) and peripheral
manifestations of Hunter syndrome (MPS II). The interim results
being presented today at MPS 2021, the 16th International Symposium
on MPS and Related Diseases, include safety data up to Weeks 43 and
25 from Cohorts A and B, respectively, 6-month biomarker data from
Cohort A and up to 3-month biomarker data from Cohort B. Denali
Management will host a webinar today for analysts and investors
beginning at approximately 11:30 a.m. Eastern Time.
“The longer-term safety data and 6-month biomarker data on
DNL310 from Cohort A continue to demonstrate durability of effect
with CNS impact, improved peripheral activity after switching from
standard of care, and a safety profile consistent with standard of
care enzyme replacement therapy,” said Carole Ho, M.D., Denali’s
Chief Medical Officer. “We are also encouraged by initial
indications of improved clinical symptoms and function reported by
investigators and parents in all five patients enrolled in Cohort
A. In addition, this is the first time we are sharing data from
Cohort B, which is designed to inform dose selection, and
exploratory biomarker data demonstrate activity of DNL310 across
all dose regimens. Based on these data, we are accelerating our
efforts to initiate a pivotal Phase 2/3 study of DNL310 in the
first half of 2022 and to begin enrolling Cohort C in the Phase 1/2
study to further investigate clinical endpoints.”
This interim analysis of the Phase 1/2 study included data on
five patients enrolled in Cohort A and 12 patients enrolled in
Cohort B. All patients have neuronopathic MPS II disease except for
one patient with non-neuronopathic MPS II disease in Cohort B. The
median age of patients is 6 years in both cohorts, with the
youngest patients aged 5 and 2 in Cohorts A and B, respectively.
All patients received weekly intravenous doses of DNL310 after
switching from idursulfase enzyme replacement therapy on Day 1 of
the study. Data being presented include safety data up to Weeks 43
and 25 from Cohorts A and B, respectively; 6-month and up to
3-month biomarker data from Cohorts A and B, respectively; and
exploratory clinical Global Impression of Change data from Cohort A
up to Week 24.
Results across Cohorts A and B showed that, following the switch
from idursulfase to DNL310, the levels of heparan sulfate in
cerebrospinal fluid (CSF) normalized in all patients analyzed
(n=15), with rapid response observed in most patients (n=12) by
Week 7, which is consistent with crossing of the BBB by DNL310 and
activity in tissues of the CNS. Rapid normalization of CSF heparan
sulfate at low dose regimens suggest that BBB crossing with
Denali’s Transport Vehicle (TV) was robust and efficient.
Furthermore, the observed decline in urine and serum heparan
sulfate was consistent with improved peripheral activity with
DNL310.
Exploratory clinical data suggest improved clinical symptoms and
function for all five patients enrolled in Cohort A as reported by
investigators and parents. Based on Global Impression of Change
scales [Clinician Global Impression of Change (CGI-C) and Parent
Global Impression of Change (PGI-C)], which are standardized
assessment scales used to measure change, the data showed clinical
improvement in overall MPS II symptoms, cognitive abilities,
behavior, and physical abilities.
Exploratory lysosomal lipid data showed reductions, which are
consistent with improved lysosomal function: 10 of 15 patients
across Cohorts A and B had normal GM3 ganglioside levels, including
patients on low dose regimens and with shorter duration of
treatment. In addition, reductions in levels of bis(monoacyl
glycerol)-phosphate (BMP) and a potential reduction in levels of
glucosylceramide (GlcCer) were observed in Cohort A at Week 24.
High within patient variability in levels of neurofilament
(Nf-L), an exploratory biomarker of neuronal structure, was
observed pre- and post-treatment. Data from an ongoing
observational natural history study conducted by Denali showed a
marked increase in mean levels of serum Nf-L over a 4.5- to 6-month
period in patients (n=3) who subsequently enrolled in Cohort A of
the Phase 1/2 study. During the 6-month treatment period of the
Phase 1/2 study, mean levels of serum and CSF Nf-L in Cohort A
(n=5) showed a modest increase. Denali believes that the utility of
Nf-L as a treatment response biomarker in MPS II will require
further investigation.
The safety profile of DNL310 remained consistent with standard
of care enzyme replacement therapy. DNL310 was generally well
tolerated with the most common treatment-emergent adverse events
being infusion-related reactions (IRRs). IRRs occurred in 12 of 17
(71%) patients: the majority had mild (n=5) or moderate (n=6) IRRs,
and 1 patient had severe IRRs. A total of 3 serious adverse events
(SAEs) were reported: 1 previously reported SAE for a patient
enrolled in Cohort A based on a mild IRR, and 2 SAEs in a patient
enrolled in Cohort B based on severe IRRs. The SAEs resolved, and
both patients are continuing in the study. All other
treatment-emergent adverse events were mild or moderate.
The study continues without modification following
recommendation by an independent data monitoring committee on July
9, 2021.
“DNL310 is our lead program enabled by our blood-brain barrier
Transport Vehicle platform, and these data continue to validate the
platform’s potential as we advance additional TV-enabled programs
toward the clinic,” said Ryan Watts, Ph.D., Denali’s Chief
Executive Officer. “Our DNL310 program exemplifies application of
Denali’s core scientific principles to increase likelihood of
success by targeting degenogenes, engineering therapeutics to cross
the blood-brain barrier, and using biomarkers to inform
development. We are encouraged by these interim data and we look
forward to continued collaboration with the community to advance
MPS II research and DNL310 as a potential treatment for affected
individuals and their families.”
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.
Denali Webinar for Analysts and InvestorsDenali
will host a webinar for analysts and investors to present the
interim data from the Phase 1/2 study of DNL310. The webinar will
begin at approximately 11:30 a.m. EDT / 8:30 a.m. PDT on Sunday,
July 25, 2021, and will be available on Denali’s corporate website
on the Events page under the Investor section and can be accessed
by following this link. An archived replay of the webinar will be
available for at least 30 days following the event.
About DNL310 and Hunter Syndrome (MPS II)Hunter
syndrome (MPS II) is a rare neurodegenerative lysosomal storage
disease caused by mutations in the gene that encodes for the enzyme
iduronate-2-sulfatase (IDS). The resultant reduction or loss of IDS
enzyme activity leads to accumulation of glycosaminoglycans, which
causes lysosomal dysfunction and neurodegeneration as well as
progressive damage to multiple organs including bone, cartilage,
heart and lung. Current standard of care enzyme replacement
treatment does not address neuronopathic manifestations of the
disease as it does not sufficiently cross the blood-brain barrier
(BBB). DNL310 is an investigational 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. More information about the ongoing Phase 1/2 study
of DNL310 in patients with Hunter syndrome can be found on
ClinicalTrials.gov by following this link.
About Denali’s TV PlatformThe BBB is essential
in maintaining the brain’s microenvironment and protecting it from
harmful substances and pathogens circulating in the bloodstream.
Historically, the BBB has posed significant challenges to drug
development for CNS diseases by preventing most drugs from reaching
the brain in therapeutically relevant concentrations. Denali’s TV
platform is a proprietary technology designed to effectively
deliver large therapeutic molecules such as antibodies, enzymes,
proteins, and oligonucleotides across the BBB after intravenous
administration. The TV technology is based on engineered Fc
fragments that bind to specific natural transport receptors, such
as transferrin receptor, which are expressed at the BBB and deliver
TV and its therapeutic cargo to the brain through receptor-mediated
transcytosis. In animal models, antibodies and enzymes engineered
to the TV 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. ETV:IDS (DNL310) is Denali’s lead TV-enabled program in
Phase 1/2 development for the potential treatment of Hunter
syndrome (MPS II).
About the EngageHunter.com
WebsiteEngageHunter.com — the Denali Hunter
syndrome (MPS II) 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.
About Denali TherapeuticsDenali Therapeutics is
a biopharmaceutical company developing a broad portfolio of product
candidates engineered to cross the blood-brain barrier (BBB) for
neurodegenerative 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
DNL310, the DNL310 ongoing Phase 1/2 study and expectations
regarding enrollment in Cohort C, plans to accelerate efforts to
initiate the planned Phase 2/3 in the first half of 2022, plans
regarding other planned future studies, expectations regarding
Denali’s TV technology platform, the therapeutic potential of
DNL310 and Denali’s TV platform, and statements made by Denali’s
Chief Medical Officer and Chief Executive 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 early stages of clinical drug
development; Denali’s and its partners’ ability to complete the
development and, if approved, commercialization of DNL310; Denali’s
and its partners’ ability to enroll patients in its ongoing and
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, preliminary or expected results, the risk
that Denali will be able to continue dose escalation in the Phase
1/2 study, whether DNL310 will cause any serious adverse events,
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; and that DNL310 may not receive regulatory
approval as a treatment of Hunter syndrome necessary to be
commercialized. 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 26, 2021, and May 5, 2021,
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 Relations Contact:Laura Hansen,
Ph.D.Vice President, Investor Relations(650)
452-2747hansen@dnli.com
Media Contacts:Lizzie Hyland(646)
495-2706Lizzie.Hyland@FGH.com orMorgan
Warners(202) 295-0124Morgan.Warners@FGH.com
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