Denali Therapeutics Inc. (Nasdaq: DNLI) today announced the outcome
of a recent successful meeting with the Center for Drug Evaluation
and Research (CDER) division of the U.S. Food and Drug
Administration (FDA) providing a path to filing a biologics license
application (BLA) for accelerated approval and subsequent
conversion to full approval for tividenofusp alfa (DNL310) for the
treatment of MPS II (Hunter syndrome). Agreement was reached that
cerebrospinal fluid heparan sulfate (CSF HS) is reasonably likely
to predict clinical benefit and can be used as a surrogate endpoint
to support accelerated approval for tividenofusp alfa in MPS II.
Based on discussions with CDER, Denali will include preclinical and
clinical data on biomarkers (CSF HS and neurofilament light (NfL))
and safety in the BLA for tividenofusp alfa as a treatment of MPS
II and intends to submit the BLA under the accelerated approval
pathway in early 2025.
“We thank CDER for a positive and collaborative discussion and
their guidance on CSF HS as a surrogate biomarker, which we see as
a significant step towards accelerating development of medicines
for individuals and families living with MPS II,” said Carole Ho,
MD, Chief Medical Officer of Denali. “This milestone reflects a
collective effort across the patient community, academia and
industry to communicate the science and advocate for faster paths
to effective treatments addressing these devastating rare diseases.
We are excited by the potential to deliver a new MPS treatment
sooner using the accelerated approval pathway. We also look forward
to plans for conversion to full approval following completion of
the global Phase 2/3 COMPASS study, and we are grateful for the
continued participation and commitment of patients, clinicians, and
study teams involved in the tividenofusp alfa clinical
studies.”
“The Phase 1/2 data show that treatment with tividenofusp alfa
produces robust and durable effects, with normalization of key
disease biomarkers and improvement or stabilization in associated
CNS and somatic clinical endpoints,” said Barbara Burton, MD,
Professor of Pediatrics, Genetics, Genomics and Metabolism at
Feinberg School of Medicine in Chicago, who will present the Phase
1/2 data at the SSIEM conference. “The totality of data support
Denali's plans to file for accelerated approval of tividenofusp
alfa with the potential to address a critical unmet need for
CNS-penetrant therapies in MPS II.”
Highlights of Phase 1/2 Data Being Presented at SSIEM
2024 Denali also announced new interim data from the Phase
1/2 study being presented at the Symposium of the Society for the
Study of Inborn Errors of Metabolism (SSIEM 2024) taking place
September 3-6, 2024, in Porto, Portugal. The presentations include
data from additional study participants (N=37) and longer duration
of treatment with tividenofusp alfa (up to Week 129) as well as new
analyses on biomarkers and clinical outcomes. Highlights are
summarized as follows:
- CSF HS: 90% mean reduction in CSF HS from
baseline at Week 24 with all participants having normal or near
normal levels at Week 24. CSF HS reduction was sustained through
Week 104.
- Urine GAGs: Proportion of participants with
normal total urine glycosaminoglycans (GAGs) (colorimetric method)
increased from 5% of participants at baseline to 77% at Week 24,
and the effect was sustained through Week 129. Importantly, the
majority of patients were on standard of care prior to switching to
tividenofusp alfa, without a protocol defined washout period,
suggesting additional urine GAG reduction with tividenofusp alfa
treatment.
- Serum NfL: Significant and sustained reduction
of serum NfL from baseline with all participants who had reached
Week 129 having normal or near normal levels, suggesting a
reduction of neuronal injury in participants with MPS II. More
rapid NfL reductions were associated with younger age.
- Clinical Outcomes: Improvement or
stabilization in adaptive behavior and cognitive scores, hearing,
liver volume, and growth outcomes were observed.
- Safety: Tividenofusp alfa was generally well
tolerated, with a safety profile that continues to support
development as a treatment for MPS II.
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 responsible for the breakdown of the
glycosaminoglycans (GAGs) heparan and dermatan sulfate in
lysosomes. Symptoms often begin emerging around age two and include
physical complications, including organ dysfunction, joint
stiffness, hearing loss and impaired growth leading to short
stature, and neurocognitive symptoms with impaired development. The
disease is characterized by a buildup of 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 (BBB), 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 the MPS community.
About tividenofusp alfa (DNL310)Tividenofusp
alfa (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 and
to enable broad delivery of IDS into cells and tissues throughout
the body 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 studyBased on
supportive clinical and preclinical data to date, Denali is
enrolling the Phase 2/3 COMPASS study in North America, South
America, Europe, and Australia. The Phase 2/3 COMPASS study is
expected to enroll 54 participants with MPS II with and without
neuronopathic disease. The participants are randomized 2:1 to
receive either tividenofusp alfa (DNL310) or idursulfase,
respectively. Cohort A includes children ages 2 to 6 with
neuronopathic disease; Cohort B includes children ages 6 to 26
without neuronopathic disease. More information about the COMPASS
study can be found here.
About Denali’s Transport Vehicle Platform The
blood-brain barrier (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 central
nervous system diseases by preventing most drugs from reaching the
brain in therapeutically relevant concentrations. Denali’s
Transport Vehicle (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 domains that bind to specific natural transport
receptors, such as transferrin receptor and CD98 heavy chain amino
acid transporter, which are expressed at the BBB and deliver the TV
and its therapeutic cargo to the brain through receptor-mediated
transcytosis. In animal models, antibodies and enzymes engineered
with the TV technology demonstrate more than 10- to 30-fold greater
brain exposure than similar antibodies and enzymes without this
technology. Oligonucleotides engineered with the TV technology
demonstrate more than a 1,000-fold greater brain exposure in
primates than systemically delivered oligonucleotides 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. The TV platform has been clinically validated and three
TV-enabled programs are currently in clinical development.
About Denali TherapeuticsDenali Therapeutics is
a biopharmaceutical company developing a broad portfolio of product
candidates engineered to cross the blood-brain barrier for
neurodegenerative diseases and lysosomal storage 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
StatementsThis 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
tividenofusp alfa (DNL310), including enrollment in the ongoing
Phase 1/2 study and Phase 2/3 COMPASS study and the timing and
availability of data from these studies, interactions with the FDA
and the timing, pathway, and likelihood of regulatory approval,
overall development plans, and statements made by Denali’s Chief
Medical Officer and Dr. Barbara Burton. 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 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 product candidates 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, 2024, and
August 1, 2024, 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 ContactLaura Hansen, Ph.D. Vice
President, Investor Relations (650) 452-2747 hansen@dnli.com
Media ContactRich AllanFGS
Global Rich.Allan@fgsglobal.com503-851-0807
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