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 final results from
Phase 1 and Phase 1b studies of its small molecule LRRK2 inhibitor,
BIIB122/DNL151, which is being developed in collaboration with
Biogen as a potential treatment of Parkinson’s disease. Safety and
biomarker goals were met in both studies, supporting plans to
advance BIIB122/DNL151 into late-stage clinical development in
Parkinson’s disease by year-end 2021. The results will be presented
at the International Association of Parkinsonism and Related
Disorders Virtual Congress, being held May 1-4.
Results from the Phase 1 study of healthy volunteers (N=184) and
the Phase 1b study of patients with Parkinson’s disease (N=36)
showed achievement of robust target and pathway engagement with
BIIB122/DNL151 treatment as measured by pS935 LRRK2 and pT73 Rab10
(pRab10), respectively. In addition, a dose-dependent reduction in
urine of the lysosomal lipid BMP, a biomarker of lysosomal
function, was achieved with BIIB122/DNL151 treatment, providing
peripheral evidence supporting improvement of lysosomal function.
BIIB122/DNL151 was generally well tolerated across a broad range of
doses for up to 28 days, the longest treatment duration in both
studies.
“The Phase 1/1b results show that treatment with BIIB122/DNL151
achieved robust LRRK2 target engagement and downstream biological
pathway engagement at doses that were generally well tolerated in
healthy volunteers and patients with Parkinson’s disease,” said
Carole Ho, M.D., Chief Medical Officer at Denali. “This rigorous
Phase 1/1b dataset exemplifies Denali’s approach of using
biomarkers to guide drug development for neurodegenerative diseases
and supports our plans with Biogen to advance BIIB122/DNL151 into
late-stage clinical development for the potential treatment of
Parkinson’s disease.”
Mutations in the LRRK2 gene can cause Parkinson’s disease. LRRK2
is a regulator of lysosomal function, which is impaired in
Parkinson’s disease and may contribute to neurodegeneration.
Inhibition of LRRK2 activity may slow the progression of
Parkinson’s disease in patients with and without known genetic
risks based on restoration of lysosomal function.
“LRRK2 is a novel and promising target for the development of
new, potentially disease-modifying therapies that have not yet been
available as treatment options for people living with Parkinson’s
disease,” said Alfred W. Sandrock, Jr., M.D., Ph.D., Executive Vice
President, Research & Development at Biogen. “Denali’s Phase 1
and Phase 1b data support BIIB122/DNL151 as a potential
first-in-class oral therapy that may slow the progression of
Parkinson’s disease. We look forward to continued collaboration
with Denali as we finalize plans for late-stage development.”
Summary of key biomarker results from Phase 1 and Phase
1b studies
A total of 184 healthy volunteers (145 BIIB122/DNL151, 39
placebo) were enrolled in the Phase 1 study and treated with single
or once daily multiple doses ranging from 15 mg to 300 mg for up to
28 days or twice daily doses of up to 400 mg for 14 days. A total
of 36 patients with Parkinson’s disease (26 BIIB122/DNL151, 10
placebo) were enrolled in the Phase 1b study and treated with once
daily multiple doses up to 300 mg for 28 days.
In the Phase 1 and Phase 1b studies, a dose dependent robust
reduction in pS935 of greater than or equal to 50% in whole blood
was observed at doses of BIIB122/DNL151 greater than 70 mg in
healthy volunteers and across all dose levels studied in patients
(80 mg, 130 mg, and 300 mg given once daily for 28 days). This
level of pS935 reduction observed is consistent with the magnitude
of reduction required for normalization of increased LRRK2 kinase
activity observed in Parkinson’s patients with kinase activating
LRRK2 mutations. In addition, across both studies, a robust
reduction in pS935 of greater than or equal to 80% was observed at
doses of BIIB2122/DNL151 greater than or equal to 225 mg.
Further, a dose dependent reduction in phosphorylation of Rab10,
a substrate of LRRK2, was observed across the healthy volunteer
cohorts in Phase 1, and a reduction of greater than or equal to
approximately 50% was observed at all dose levels studied in
patients in Phase 1b. After normalizing for total LRRK2 levels,
pRab10 was elevated by approximately 2-fold in patients with
sporadic Parkinson’s disease and in LRRK2 mutation carriers
compared with healthy volunteers. Thus, the levels of pRab10
reduction observed in the Phase 1b study are consistent with the
magnitude required for normalization of pRab10 levels in patients
with Parkinson’s disease.
Finally, in both healthy volunteers and patients with
Parkinson’s disease, treatment with BIIB122/DNL151 was associated
with a dose-dependent reduction in urine lysosomal lipid
22:6-bis[monoacylglycerol] phosphate (BMP), a marker of peripheral
lysosomal function, as measured from baseline to steady-state.
Summary of BIIB122/DNL151 safety and tolerability
profile in Phase 1 and Phase 1b studies
BIIB122/DNL151 was generally well tolerated in healthy
volunteers and patients with Parkinson’s disease. No serious
adverse events were observed. The majority of healthy volunteers
and patients with treatment-emergent adverse events (TEAEs)
experienced mild to moderate TEAEs. Two healthy volunteers in the
Phase 1 study who received 250 mg twice daily and 400 mg twice
daily, respectively, discontinued with symptoms including nausea
and headache considered related to study drug. Two patients in the
Phase 1b study discontinued on the first study day: one who
received 130 mg once daily experienced severe asymptomatic
hypotension, considered by the investigator as being unrelated to
study drug (pre-existing hypotension), and another patient who
received 300 mg once daily experienced mild hypotension and
orthostatic hypotension with mild dizziness. In all
discontinuations, symptoms resolved with discontinuation of
therapy. There were no clinically meaningful changes in pulmonary
or renal function in either study.
About LRRK2 and BIIB122/DNL151
Mutations in leucine-rich repeat kinase 2 (LRRK2), a regulator
of lysosomal function, are one of the most common genetic risk
factors in Parkinson’s disease. Specific LRRK2 mutations increase
kinase activity, resulting in phosphorylation of Rab GTPases
(phosphorylated Rab [pRab]) and subsequent lysosomal dysfunction,
and associated Parkinson’s disease pathogenic changes. Both
increased LRRK2 activity and pRab have also been observed in people
with Parkinson’s disease independent of LRRK2 mutation status.
LRRK2 inhibition can restore lysosomal function and reduce toxicity
in models of Parkinson’s disease. BIIB122/DNL151 is a potent,
selective, central nervous system–penetrant LRRK2 kinase inhibitor
under investigation for treatment of Parkinson’s disease. Denali
and Biogen plan to advance BIIB122/DNL151 into two late-stage
studies in Parkinson’s disease: one in Parkinson's patients who
carry LRRK2 mutations and the other in Parkinson's patients
independent of mutation status. BIIB122/DNL151 has not been
approved by any Health Authority.
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
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 progress and business plans; plans, timelines
and expectations related to BIIB122/DNL151 of both Denali and
Biogen, including with respect to initiation of late-stage clinical
development; the potential of BIIB122/DNL151 to be a treatment for
Parkinson’s disease and a first-in-class oral therapy; the
potential benefits and likelihood of success of, activity under,
and expectations related to Denali’s collaboration with Biogen; and
statements made by Denali’s Chief Medical Officer and Biogen’s
Executive Vice President, Research & Development. 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 Biogen; Denali’s early
stages of clinical drug development; Denali’s and Biogen’s ability
to advance and complete the development of BIIB122/DNL151; Denali’s
and Biogen’s ability to initiate, enroll patients in, conduct and
complete the planned clinical trials of BIIB122/DNL151 on expected
timelines; 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 its current programs and product
candidates; the potential for the planned clinical trials of
BIIB122/DNL151 to differ from preclinical, early clinical,
preliminary or expected results; the risk of significant adverse
events, toxicities or other undesirable side effects; the
uncertainty that product candidates will receive regulatory
approval necessary to be commercialized; 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, including those described in
Denali’s most recent Annual Report on Form 10-K filed with the
Securities and Exchange Commission (SEC) on February 26, 2021 and
Denali’s future reports to be filed with the SEC. 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.
Investor Relations Contact:Laura Hansen,
Ph.D.Vice President, Investor Relations(650)
452-2747hansen@dnli.comMedia Contacts:Lizzie
Hyland(646) 495-2706lhyland@gpg.comorMorgan Warners(202)
295-0124mwarners@gpg.com
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