DNLI - Denali Therapeutics Announces Key Anticipated 2024 Milestones and Priorities to Further Advance Its Therapeutics Portfolio for Neurodegeneration and Lysosomal Storage Diseases | Benzinga
- Complete enrollment in Denali-led, late-stage programs for MPS II and ALS, and establish commercial readiness
- Advance broad clinical-stage portfolio of seven therapeutic product candidates across neurodegeneration (ALS, Parkinson's disease, MS, FTD-GRN), lysosomal storage disease (MPS II, MPS IIIA), and inflammatory disease (UC)
- Advance OTV:MAPT targeting tau for Alzheimer's disease and OTV:SNCA targeting alpha-synuclein for Parkinson's disease in IND-enabling studies
- Prioritize preclinical portfolio with focus on Transport Vehicle-enabled biotherapeutics
SOUTH SAN FRANCISCO, Calif., Jan. 08, 2024 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ:DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and lysosomal storage diseases, today announced program progress and expected milestones for 2024, which Chief Executive Officer, Ryan Watts, Ph.D., will highlight during a corporate presentation at the 42nd Annual J.P. Morgan Healthcare Conference on Tuesday, January 9th, at 10:30 a.m. Pacific Time.
"In 2024, we expect enrollment to be completed in our late-stage clinical trials for MPS II and ALS, and we are establishing commercial readiness," said Ryan Watts, Ph.D., Chief Executive Officer of Denali. "In addition, we are excited to announce initiation of clinical development for our second Enzyme Transport Vehicle (TV)-enabled program, DNL126 in MPS IIIA, and that our first two Oligonucleotide TV-enabled programs are in IND-enabling studies targeting tau in Alzheimer's disease (OTV:MAPT) and alpha-synuclein in Parkinson's disease (OTV:SNCA). Based on clinical validation and momentum with the TV platform, we have prioritized advancing additional TV programs for common neurodegenerative diseases."
Denali's 2024 Outlook
Expected progress and key milestones in 2024 across Denali's therapeutic portfolio are summarized below.
LATE-STAGE AND MID-STAGE CLINICAL PROGRAMS
Tividenofusp alfa (DNL310): MPS II (Hunter syndrome)
Tividenofusp alfa (DNL310) is an investigational, intravenously administered, Enzyme Transport Vehicle (ETV)-enabled, iduronate-2-sulfatase (IDS) replacement therapy designed to cross the BBB and address the behavioral, cognitive, and physical manifestations of MPS II (Hunter syndrome).
Interim Phase 1/2 study data up to two years of treatment have demonstrated that once weekly intravenous dosing with DNL310 was generally well-tolerated and led to rapid and sustained normalization of cerebral spinal fluid (CSF) heparan sulfate to normal healthy levels, improvement in lysosomal function biomarkers, and robust and statistically significant reduction of neurofilament light (NfL), a marker of neuronal damage. In addition, positive clinical outcome changes in adaptive behavior, cognition, and auditory function were observed.
The global Phase 2/3 COMPASS study continues to recruit up to 54 participants with neuronopathic and non-neuronopathic MPS II. Upon completion of the ongoing Phase 1/2 study, and together with data from COMPASS, this combined data package is intended to support registration.
2024 expected progress and milestones:
- Complete enrollment of global Phase 2/3 COMPASS study in MPS II
- Presentation of additional interim Phase 1/2 data at WORLDSymposium™ (February 4-9) and at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium (September 3-6)?
DNL343 (eIF2B Activator): ALS
DNL343 is an investigational small molecule activator of the eukaryotic initiation factor 2B (eIF2B) designed to inhibit the cellular integrated stress response (ISR) and prevent or slow disease progression by interfering with stress granule formation and TDP-43 aggregation, which is a hallmark pathology present in virtually all individuals with ALS. Previously announced results of a Phase 1b study in participants with ALS demonstrated that once-daily oral dosing with DNL343 for 28 days was generally well-tolerated and was associated with extensive distribution in the cerebrospinal fluid as well as robust inhibition of ISR biomarkers. Recruitment is ongoing in Regimen G (DNL343) of the Phase 2/3 HEALEY ALS Platform Trial.
2024 expected progress and milestones:
- Complete enrollment of participants in Regimen G (DNL343) in Phase 2/3 HEALEY ALS Platform Trial
SAR443820/DNL788 (CNS-Penetrant RIPK1 Inhibitor): ALS, MS
SAR443820/DNL788 is an investigational, CNS-penetrant, small molecule inhibitor of RIPK1, a critical signaling protein in a canonical inflammatory and cell death pathway. Increased RIPK1 activity in the CNS is hypothesized to drive neuroinflammation and cell necroptosis and to contribute to neurodegeneration. Denali and Sanofi are co-developing SAR443820. Sanofi has completed enrollment of two Phase 2 studies: 305 participants have enrolled in the HIMALAYA ALS study and 174 participants have enrolled in the K2 multiple sclerosis (MS) study.
2024 expected progress and milestones:
- Sanofi to announce topline results from the Phase 2 HIMALAYA study in ALS in the first half of 2024
- Continue K2 Phase 2 study in MS
BIIB122/DNL151 (LRRK2 Inhibitor): Parkinson's disease
BIIB122/DNL151 is an investigational small molecule inhibitor of LRRK2, one of the most common genetic drivers of Parkinson's disease. Targeting LRRK2 has the potential to impact the underlying biology and slow the progression of Parkinson's disease. Denali and Biogen are co-developing BIIB122. Biogen is conducting the global Phase 2b LUMA study of BIIB122 in early-stage Parkinson's disease with and without LRRK2 mutations.
2024 expected progress and milestones:
- Continue Phase 2b LUMA study in early-stage Parkinson's disease
Eclitasertib (SAR443122/DNL758) (Peripheral RIPK1 Inhibitor): Ulcerative colitis (UC)
Eclitasertib (SAR443122/DNL758), is an investigational, peripherally restricted, small molecule inhibitor of RIPK1. Sanofi is solely responsible for the development and commercialization of peripherally restricted RIPK1 inhibitors.
2024 expected progress and milestones:
- Continue Phase 2 UC study
EARLY-STAGE CLINICAL AND PRECLINICAL PROGRAMS
TAK-594/DNL593 (PTV:PGRN): Frontotemporal Dementia-Granulin (FTD-GRN)
DNL593 is an investigational, intravenously administered, Protein Transport Vehicle (PTV)-enabled progranulin (PGRN) replacement therapy designed to restore normal levels of PGRN in the brain without interfering with normal PGRN transport and processing. DNL593 is being co-developed with Takeda. Results from Part A of a Phase 1/2 study (n=38) demonstrated that single doses of DNL593 were generally well-tolerated in healthy subjects and resulted in substantial increases in CSF PGRN levels. These data suggest brain delivery of DNL593 was achieved and has the potential to address PGRN deficiency in FTD-GRN.
Denali today also announced that enrollment and dosing have been voluntarily paused in Part B (n=9 dosed to date) of the DNL593 Phase 1/2 study in participants with FTD-GRN to implement protocol modifications. The pause is based on infusion-related reactions (IRRs) reported in two study participants, one Grade 2 and one Grade 3 in severity and both deemed serious adverse events. Both study participants' IRRs resolved with infusion discontinuation and standard treatment measures within the same day. DNL593 has been otherwise well-tolerated in the study, with all other adverse events reported as mild in severity. The protocol modification will allow for premedication and other measures aimed at reducing the risk of IRRs.
2024 expected progress and milestones:
- Continue Part B of the Phase 1/2 study in FTD-GRN
DNL126 (ETV:SGSH): MPS IIIA (Sanfilippo syndrome Type A)
DNL126 (ETV:SGSH) is an investigational, intravenously administered, ETV-enabled N-sulfoglucosamine sulfohydrolase (SGSH) replacement therapy designed to cross the BBB and address the behavioral, cognitive, and physical manifestations of MPS IIIA (Sanfilippo syndrome Type A). Recruiting activities are ongoing for the Phase 1/2 study of DNL126 in MPS IIIA.
2024 expected progress and milestones:
- Biomarker proof of concept and safety ...