Denali Therapeutics Announces Phase 1/2 Study Single Dose Healthy Volunteer Data with TAK-594/DNL593 (PTV:PGRN) and Progression to Enrolling Participants with FTD-GRN
November 01 2022 - 7:00AM
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 interim
results from Part A of a Phase 1/2 study evaluating TAK-594/DNL593
(PTV:PGRN) in healthy subjects. Progranulin (PGRN) levels measured
in cerebrospinal fluid (CSF) increased in a dose-dependent manner
compared to baseline and placebo, consistent with brain delivery of
DNL593 and exceeding levels believed to be necessary to rescue
deficits associated with progranulin deficiency, based on
preclinical models.1 Single doses of DNL593 were generally well
tolerated, based on blinded safety analysis. These data support
dosing in participants with frontotemporal dementia and a mutation
in the granulin gene (FTD-GRN) in Part B of the study. DNL593 is an
investigational, brain-penetrant progranulin replacement therapy
being co-developed by Denali and Takeda. These data were presented
at the FTD Prevention Initiative meeting in Paris, France. A copy
of the presentation is available on Denali’s website on the
Investor & Media Relations section under the Events page.
“These data show that single doses of DNL593 result in
substantial increases in CSF progranulin levels suggesting brain
delivery of DNL593 was achieved and has the potential to address
progranulin deficiency, which drives disease progression in people
living with FTD-GRN,” said Carole Ho, M.D., Chief Medical Officer
at Denali. “Together with the safety profile to date, these results
support initiation of dosing in participants with FTD-GRN and
underscore the potential of our Protein Transport Vehicle (PTV)
platform to deliver biotherapeutics across the blood-brain barrier.
As the study progresses, we look forward to learning more about how
DNL593 may impact patients with this devastating neurogenerative
disease who have no approved treatment options.”
As previously announced, this Phase 1/2 study is a multicenter,
randomized, placebo-controlled study evaluating the safety,
tolerability, pharmacokinetics and pharmacodynamics of DNL593. The
study is divided into three parts: In Part A, 35 participants in
five cohorts received either single ascending doses of DNL593 or
placebo; Part B will evaluate participants with FTD-GRN over 25
weeks; Part C is an optional 18-month open-label extension period
available for all participants who complete part B. More
information about the study (NCT05262023) is available here.
About FTDFTD is the most common form of
dementia in people under 60 years of age. While the progression of
symptoms varies by individual, FTD brings an inevitable decline in
function together with changes in personality and social behaviors,
and sometimes language and/or motor dysfunction. Mutations in the
granulin (GRN) gene, which encodes the progranulin (PGRN) protein,
generally result in reduced levels of PGRN and are amongst the most
common genetic causes of FTD. There are currently no approved
medicines to stop or slow the progression of FTD or FTD-GRN.
About TAK-594/DNL593 (PTV:PGRN)TAK-594/DNL593
is an investigational, intravenously administered, brain-penetrant
progranulin (PGRN) replacement therapy enabled by Denali’s Protein
Transport Vehicle (PTV) technology. PGRN is known to promote
lysosomal function, in addition to having neurotrophic and
anti-inflammatory effects. Data from in vitro and in vivo models
providing preclinical proof of concept for DNL593 were published in
the September 2, 2021, issue of the scientific journal Cell.1 The
studies demonstrated that DNL593 enhanced brain uptake of
peripherally administered PGRN by multiple cell types in the brain,
including neurons and microglia, and improved lysosomal function.
In addition, DNL593 rescued both neurodegeneration and microglial
dysfunction in PGRN-deficient mice. These preclinical data support
the potential for DNL593 to increase PGRN levels in the brain and
impact disease progression in individuals with FTD-GRN.
Denali and Takeda are collaborating to co-develop and
co-commercialize DNL593. Denali may receive future milestone
payments from Takeda upon achievement of certain clinical and
regulatory milestone events as well as certain sales-based
milestones. Subject to the terms of the collaboration agreement,
Denali will share the development and commercialization costs
equally with Takeda, and, if applicable, profits on a worldwide
basis.
DNL593 is an investigational therapeutic that has not been
approved by any regulatory authority for any commercial use.
About Denali’s Transport Vehicle PlatformThe
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 receptor, which are expressed at the
blood-brain barrier and are designed to 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
DNL593 and the DNL593 ongoing Phase 1/2 study, including the
initiation of dosing in participants with FTD-GRN; expectations
regarding Denali’s TV technology platform including its Protein
Transport Vehicle (PTV) technology; the therapeutic and commercial
potential of DNL593 and Denali’s TV platform; Denali's progress,
business plans, business strategy, product candidates, planned
preclinical studies and clinical trials and expected milestones and
associated payments; the potential benefits of, likelihood of
success of, and expectations related to Denali’s collaboration with
Takeda; and statements made by 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: Denali’s early stages of
clinical drug development; Denali’s ability to complete the
development and, if approved, commercialization of DNL593 on
expected timelines; Denali’s ability to initiate and enroll
patients in Part B and Part C of the Phase 1/2 study of DNL593 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 DNL593
to differ from preclinical, early clinical, preliminary or expected
results; Denali's ability to continue dose escalation in the Phase
1/2 study of DNL593; the risk of significant adverse events,
toxicities or other undesirable side effects related to DNL593; the
risk that results from early clinical biomarker studies will not
translate to clinical benefit in late clinical studies; the risk
that DNL593 may not receive regulatory approval for FTD-GRN
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 DNL593;
implementation of Denali’s strategic plans for its business,
product candidates and blood-brain barrier platform technology,
including DNL593; 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
Report 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.
Reference:1. Logan T. et al. “Rescue of
lysosomal storage disorder caused by Grn loss of function with a
brain penetrant progranulin biologic” Cell 2021 Sep
2;184(18):4651-4688.
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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