Denali Therapeutics Announces Advancement and Expansion of Its LRRK2 Inhibitor Clinical Program for Parkinson’s Disease
December 20 2017 - 4:50PM
Denali Therapeutics Inc. (NASDAQ:DNLI), a biopharmaceutical company
developing a broad portfolio of therapeutic candidates for
neurodegenerative diseases, today announced that its small molecule
inhibitor of leucine-rich repeat kinase 2 (LRRK2), DNL201,
achieved, on average, greater than 90% inhibition of LRRK2 kinase
activity observed at peak and greater than 50% inhibition at trough
drug levels at the highest multiple dose tested in a healthy
volunteer Phase 1 study. Based on a full review of the clinical
data from this ongoing study, and additional preclinical data, the
FDA has removed the previously imposed partial clinical hold.
LRRK2 inhibition was measured by two independent blood-based
biomarker assays of LRRK2 activity: phosphorylation of LRRK2 at
Serine 935 and phosphorylation of the LRRK2 substrate Rab10. Both
markers reflect the function of LRRK2 kinase activity and Rab
phosphorylation is linked to lysosomal dysfunction associated with
Parkinson’s disease. In addition, robust central nervous system
penetration of DNL201 has been achieved as demonstrated by
measurement of DNL201 in the cerebrospinal fluid (CSF). These data,
in combination with pharmacokinetics/pharmacodynamics (PK/PD)
modeling, indicate robust and sustained target engagement of LRRK2
in brain.
Denali also announced that it has commenced dosing of its second
small molecule inhibitor of LRRK2, DNL151, in healthy volunteers in
the Netherlands. Denali now has two distinct small molecules
targeting LRRK2 inhibition in human clinical testing for
Parkinson’s disease.
Denali plans to select either DNL201 or DNL151 to move into
studies in Parkinson’s disease patients carrying a LRRK2 mutation
after completion of Phase 1 healthy volunteer studies for both
molecules. In the ongoing studies in healthy volunteers, Denali is
investigating safety and tolerability, PK and PD in blood and CSF,
and characterizing a biomarker to estimate target engagement in
brain.
“Mutations in LRRK2 are a major risk factor for Parkinson’s
disease. Targeting this degenogene represents a promising approach
to develop disease modifying medicines for patients suffering from
this terrible disease,” said Ryan Watts, Ph.D., CEO. “By restoring
LRRK2 activity to normal levels, we believe we can reverse
lysosomal dysfunction, which could potentially benefit both
patients with LRRK2 mutations, as well as idiopathic Parkinson’s
disease patients who exhibit lysosomal dysfunction,” said Dr.
Watts.
“Our robust biomarker assay allows us to establish and monitor
LRRK2 target and pathway engagement, and assess the exposures
required to reach desired target inhibition. We have demonstrated
significant inhibition of LRRK2 kinase activity with DNL201, which
gives us confidence to proceed with further clinical testing,” said
Carole Ho, M.D., Chief Medical Officer.
About Denali
Denali is a biopharmaceutical company developing a broad
portfolio of therapeutic candidates for neurodegenerative diseases.
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 express or implied in this press
release include, but are not limited to, plans to progress either
DNL201 or DNL151 into studies in Parkinson’s disease patients
following completion of Phase 1 healthy volunteer studies for both
molecules, results of targeting mutations of LRRK2 to develop
disease modifying medicines for Parkinson’s disease patients, the
effects of restoring LRRK2 activity to normal levels and potential
benefits to both patients with LRRK2 mutations and idiopathic
Parkinson’s disease who exhibit lysosomal dysfunction, and Denali’s
plans to conduct further clinical testing in this area. 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 its product
candidates; Denali’s dependence on successful development of its
BBB platform technology and product candidates currently in its
core program; Denali’s ability to conduct or complete clinical
trials on expected timelines; the uncertainty that any of Denali’s
product candidates will receive regulatory approval necessary to be
commercialized; Denali’s ability to continue to create a pipeline
of product candidates or develop commercially successful products;
and other risks, including those described in Denali’s Prospectus
filed with the SEC on December 8, 2017. The forward-looking
statements in this press release are based on information available
to Denali as of the date hereof. Denali disclaims any
obligation to update any forward-looking statements, except as
required by law.
Contacts:
Lizzie Hyland(646)
495-2706lhyland@gpg.com
or
Morgan Warners(202)
295-0124mwarners@gpg.com
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