Denali Therapeutics Reports Positive Three-Month Data from Phase 1/2 Study with ETV:IDS (DNL310) in Patients with Hunter Synd...
February 12 2021 - 6:30AM
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 results from the ongoing Phase 1/2 study
evaluating ETV:IDS (DNL310) as a potential
brain-penetrant enzyme replacement therapy for treating both
central nervous system (CNS) and peripheral manifestations
of Hunter syndrome (MPS II). The data will be presented
later today during a late-breaker session at WORLDSymposium™.
Denali management will host an analyst webinar
today beginning at 8:00 a.m. Eastern Time to discuss
both interim clinical and new preclinical data that will be
presented at the conference.
An interim analysis included data on a total of five patients
enrolled in Cohort A in the Phase 1/2 study, who all received three
months of weekly intravenous doses of DNL310 after switching from
idursulfase enzyme replacement therapy on Day 1 of the study. Key
results included:
- Normal levels of heparan sulfate, a glycosaminoglycan (GAG), in
cerebrospinal fluid (CSF) that were seen after four weeks of dosing
in four of five patients were sustained after three months of
dosing (mean 85% reduction across Cohort A; p<0.001); heparan
sulfate levels were further significantly reduced and approached
normal levels in the fifth patient (from 25% to 73% reduction from
one to three months, respectively).
- Reductions in downstream exploratory CSF biomarkers, GM3 and
BMP (lysosomal lipids), of 39% and 15%, respectively,
were observed after eight weeks of dosing with DNL310, consistent
with improvement in lysosomal function.
- Reductions in urine heparan sulfate and dermatan
sulfate following a switch from idursulfase, of
76% and 82%, respectively, were observed
after eight weeks of dosing of DNL310, supporting
potential for improved peripheral effects relative to standard of
care.
- DNL310 was generally well tolerated with no dose reductions and
all five patients continue in the study. The most frequently
observed adverse events were mild or moderate infusion-related
reactions in three of five patients, which is consistent
with other enzyme replacement therapies
(ERTs).
- Based on three-month clinical data, doses of DNL310 from 3
mg/kg to 30 mg/kg are generally well tolerated and provide
flexibility for dose selection in clinical studies.
“We are encouraged by these new Phase 1/2 data, which continue
to support the overall safety profile and biomarker effects of
DNL310 as an investigational treatment in Hunter syndrome,” said
Carole Ho, M.D., Denali’s Chief Medical Officer. “Importantly, at
dose levels resulting in robust and durable biomarker response,
DNL310 appears generally well tolerated and consistent
with standard of care ERT. We are pleased to observe
that early biomarker effects initially seen after four weeks
of treatment with DNL310 were sustained after three
months of dosing. We are also encouraged by the findings
related to exploratory lipid biomarkers which indicate,
for the first time, improvement in lysosomal function. Taken
together, these data support our previously announced decision
to expand and advance clinical studies with DNL310 as a
potential treatment for both body and brain in patients with Hunter
syndrome.”
Denali also presented preclinical research at WORLDSymposium™ on
a mouse model of Hunter syndrome showing that ETV:IDS treatment
reduces CSF GAGs and that these reductions are correlated with GAG
reductions in the brain. Furthermore, reduction in CSF GAG levels
was associated with subsequent improvements in lysosomal function,
neurodegeneration biomarkers, neurobehavioral outcomes
and correction of skeletal disease manifestations in the
mouse model.
“The magnitude and durability of biomarker response and
tolerability seen with DNL310 provide strong support for the
potential application of our Transport Vehicle (TV) technology to
deliver enzymes and other therapeutic modalities to the brain,”
said Ryan Watts, Ph.D., Denali’s Chief Executive Officer. “Compared
to other investigational BBB transport technologies, we have
engineered specific molecular properties into our TV technology for
better brain uptake and biodistribution of the therapeutic cargo to
relevant cell types. The DNL310 Phase 1/2 results also support the
potential for systemic administration of TV-enabled therapeutics to
address peripheral disease. Taken together, these data increase our
confidence that DNL310 may ultimately prove to be an impactful
therapy for Hunter syndrome patients and their families and that we
can apply our TV technology more broadly to defeat degeneration and
address other diseases with brain manifestations.”
About the DNL310 Development Program for the Potential
Treatment of Hunter syndrome (MPS II)Hunter syndrome (MPS
II) is a rare neurodegenerative lysosomal storage disorder caused
by a mutation 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 GAGs, 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 BBB. 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. Denali previously announced human
biomarker proof-of-concept for its TV technology from Cohort A
(n=5) of an ongoing Phase 1/2 study of DNL310 in patients with
Hunter syndrome. The study is currently enrolling Cohort B, and a
Cohort C is planned to further explore clinical endpoints. DNL310
is an investigational drug and is not approved by any health
authority.
About Denali’s TV Platform The 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 are delivered to the brain
through receptor-mediated transcytosis. Denali research has shown
that in animal models, antibodies and enzymes engineered with the
TV technology have demonstrated 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).
Webinar Information Denali will host a
webinar today, Friday, February 12, at 8:00 a.m. Eastern
Time to discuss the DNL310 Phase 1/2 data. A registration link
will be available on the Events page under the Investor section of
Denali’s website at
https://www.denalitherapeutics.com/investors/events or by clicking
here. An archived replay of the webinar will be available for at
least 30 days following the event.
About Denali Therapeutics Denali
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 progress and business plans; plans, timelines and
expectations related to DNL310, the DNL310 development program,
Denali’s TV technology platform, other programs enabled by Denali’s
TV platform, and the ongoing Phase 1/2 study, and planned future
studies, of DNL310; 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: any and all risks to Denali’s
business and operations caused directly or indirectly by the
evolving COVID-19 pandemic; risk of the occurrence of any event,
change or other circumstance that could give rise to the
termination of Denali’s agreements with its partners; Denali’s
early stages of clinical drug development; Denali’s and its
partners’ ability to complete the development and, if approved,
commercialization of its product candidates; 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; Denali’s dependence on successful development of its
blood-brain barrier platform technology and TV-enabled product
candidates; Denali’s and its partners' ability to conduct or
complete clinical trials on expected timelines; 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, and that DNL310 may not
receive regulatory approval as a treatment of Hunter syndrome
necessary to be commercialized; risk of the occurrence of any
event, change or other circumstance that could give rise to the
termination of Denali’s agreements with its partners; Denali’s
ability to continue to create a pipeline of product candidates or
develop commercially successful products; Denali’s ability to
obtain, maintain, or protect intellectual property rights related
to its product candidates; implementation of Denali’s strategic
plans for its business, product candidates and blood-brain barrier
platform technology; and other risks. 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, 2020, and
November 5, 2020, 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)
452-2747 hansen@dnli.com Media
Contacts: Lizzie Hyland (646)
495-2706 lhyland@gpg.com or Morgan
Warners (202) 295-0124 mwarners@gpg.com
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