Denali Therapeutics Announces Significant Program Progress and Expected Key Milestones in 2021 for Its Broad Therapeutic Portfolio in Neurodegeneration
- Late-breaker presentation on 12-week data from Cohort A in Phase 1/2 study of DNL310 (ETV:IDS) in Hunter syndrome (MPS II) to be held at WORLD Symposium on February 12th
- Following previously announced data on CSF GAG reduction with DNL310 and achievement of biomarker proof-of-concept, Phase 1/2 study is expanded with the addition of a third cohort (Cohort C) to further explore clinical endpoints
- Announcing five new enzyme replacement therapy programs in Transport Vehicle (TV) portfolio; expanding manufacturing capabilities and building out commercial capabilities
- Phase 1b study of LRRK2 inhibitor, DNL151 (BIIB122), in Parkinson’s disease is complete; target engagement and pathway engagement goals were met and data will be presented at an upcoming medical congress; late-stage clinical development to begin by year-end 2021 in collaboration with Biogen
- Phase 1 healthy subject data on EIF2B activator, DNL343, expected to be available in 1H 2021; Phase 1b study in ALS patients planned to begin in 2H 2021
- Phase 1 study of CNS-penetrant RIPK1 inhibitor, DNL788 (SAR443820), initiated by Sanofi in Q4 2020; Phase 2 study of peripherally-restricted RIPK1 inhibitor, DNL758 (SAR443122), in cutaneous lupus erythematosus to begin in early 2021
- IND-enabling studies for PTV:PRGN and ATV:TREM2 to trigger two milestone payments from Takeda in Q1 2021
SOUTH SAN FRANCISCO, Calif., Jan. 08, 2021 (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 neurodegenerative diseases, today announced program progress and expected milestones for 2021, which Chief Executive Officer, Ryan Watts, Ph.D., will highlight during a corporate presentation at the 39th Annual J.P. Morgan Healthcare Conference on Tuesday, January 12, at 10 a.m. Eastern Time.
“We begin the year with exciting momentum building off multiple achievements in 2020 including first-in-human biomarker proof-of-concept for our proprietary Transport Vehicle (TV) technology to deliver biotherapeutics to the brain and progression of our LRRK2 program to late-stage clinical development in collaboration with Biogen,” said Dr. Watts. “We expect 2021 to be a year of significant growth for Denali on our path to becoming a fully integrated discovery, development and commercial organization. Our near-term focus is to advance our first product candidates towards late-stage clinical development; continue to develop our TV portfolio, including five new Enzyme TV (ETV) programs; expand manufacturing capabilities; and continue to build out commercial capabilities to serve patients and deliver the full potential of our pipeline.”
Denali’s 2021 Outlook
Denali’s therapeutic portfolio includes small molecules designed to cross the BBB and biotherapeutics that are enabled to cross the BBB using Denali’s TV technology. Expected progress and key milestones in 2021 across Denali’s therapeutic portfolio are summarized below.
Expanding Phase 1/2 study of ETV:IDS (DNL310) in Hunter syndrome (MPS II)
Denali’s lead TV-enabled program is ETV:IDS (DNL310) for the potential treatment of Hunter syndrome (MPS II). In November 2020, Denali announced positive biomarker proof-of-concept data from five patients enrolled in Cohort A, who received four weekly intravenous doses of DNL310, showing a statistically significant reduction in levels of glycosaminoglycans (GAGs) as measured in the cerebrospinal fluid (CSF), with normal healthy levels being achieved in four of five patients.
The ongoing Phase 1/2 study is progressing as per plan, with dose escalation in Cohort A completed and patient enrollment initiated in Cohort B. New data from Cohort A after 12 weeks of treatment will be presented in a late-breaker presentation at the WORLD Symposium on February 12th. Based on strong proof-of-concept data, Denali is expanding its DNL310 development program by adding a third cohort (Cohort C, ~12 patients) to the ongoing Phase 1/2 study, which will enable further exploration of clinical endpoints related to neuronopathic manifestations in patients. Denali plans to initiate a Phase 2/3 study in 1H 2022.
Expanding Denali’s TV portfolio and announcing five new ETV programs for lysosomal storage diseases
More than 30,000 patients suffer from lysosomal storage diseases world-wide, with approximately two-thirds having CNS manifestations that are not addressed by currently available enzyme replacement therapies. Following achievement of human biomarker proof of concept with ETV:IDS (DNL310) for Hunter syndrome, Denali is expanding the development of its current ETV programs including DNL310 (as described above) and ETV:SGSH for MPS IIIA. In addition, Denali is announcing five new brain-penetrant enzyme replacement therapy programs in its ETV portfolio including: (1) ETV:GBA for Gaucher disease and Parkinson’s disease; (2) ETV:GAA for Pompe disease; (3) ETV:IDUA for MPS I; (4) ETV:NAGLU for MPS IIIB; and (5) ETV:ARSA for MLD. Activities are underway to expand manufacturing capabilities and continue to build out commercial capabilities.
Advancing the first LRRK2 inhibitor into late-stage clinical development for Parkinson’s disease
In August 2020, Denali and Biogen announced a collaboration to co-develop and co-commercialize Denali’s small molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) for Parkinson’s disease. Denali has evaluated two LRRK2 inhibitors, DNL201 and DNL151 (BIIB122), in more than 300 healthy volunteers and Parkinson’s patients who participated in Phase 1 and Phase 1b studies. As previously announced, DNL151 was selected by Denali and Biogen as the lead molecule to advance into late-stage clinical development with DNL201 as a backup. A Phase 1b study in Parkinson’s patients is complete; target engagement and pathway engagement goals were met. Denali will present data from the Phase 1b study at upcoming medical congresses. Denali is currently completing further dose escalation cohorts in an expanded Phase 1 study to define the full therapeutic window of DNL151. The companies expect to initiate late-stage clinical development of DNL151 in Parkinson’s patients by year-end 2021. Two clinical studies are planned: one in patients who carry LRRK2 mutations and the other in patients who have idiopathic disease.
Initiating the first clinical study of an EIF2B activator in amyotrophic lateral sclerosis (ALS)
Mutations in genes associated with ALS and frontotemporal dementia (FTD) alter RNA homeostasis, which contributes to the aggregation on TDP-43 or other RNA binding proteins observed in a large proportion of patients. Activators of EIF2B have demonstrated benefits in resolving TDP-43 aggregation, restoring protein translation and attenuating neurodegeneration via inhibition of the cellular integrated stress response in numerous in vitro and in vivo models. Denali’s most advanced EIF2B activator, DNL343, is a brain-penetrant small molecule designed to rescue EIF2B function and restore normal RNA metabolism. Results from a Phase 1 study of DNL343 in healthy volunteers are expected to be available in 1H 2021. Denali plans to initiate a Phase 1b study of DNL343 in patients with ALS in 2H 2021.
Advancing RIPK1 inhibitors for neurodegenerative and peripheral inflammatory diseases
Denali has a strategic collaboration with Sanofi for the development of small molecules that inhibit receptor interacting serine/threonine protein kinase 1 (RIPK1). RIPK1 is a critical signaling protein in the tumor necrosis factor (TNF) receptor pathway and is a regulator of inflammation and cell death. In Q4 2020, Sanofi initiated a Phase 1 healthy volunteer study of DNL788 (SAR443820), a potent, selective, and brain-penetrant small molecule RIPK1 inhibitor intended to treat patients with ALS, Alzheimer’s disease, and multiple sclerosis; data is expected to be available in 2H 2021. The collaboration with Sanofi also includes peripherally-restricted RIPK1 inhibitors. Denali previously announced that Sanofi completed enrollment in a Phase 1b clinical trial of DNL758 (SAR443122), a peripherally-restricted small molecule inhibitor of RIPK1, in hospitalized adult patients with severe COVID-19 lung disease. In addition, Sanofi plans to initiate a Phase 2 clinical trial of DNL758 in patients with cutaneous lupus erythematosus in early 2021.
Advancing additional TV-enabled modalities towards clinical development
DNL593 (PTV:PGRN), an intravenously administered recombinant progranulin biotherapeutic enabled by Denali’s Protein Transport Vehicle (PTV), is designed to restore normal levels of progranulin in multiple cell types in the brain for the potential treatment of FTD. In December 2020, Denali initiated IND-enabling studies for DNL593 for which Denali will receive a related milestone payment of
DNL919 (ATV:TREM2), an intravenously administered antibody enabled by Denali’s Antibody Transport Vehicle (ATV), is designed to modulate TREM2 and normalize microglial function for the potential treatment of Alzheimer’s disease. Denali expects to initiate IND-enabling studies for DNL919 in January 2021 and for which Denali will receive a related milestone payment of
Summary Table of 2021 Expected Key Milestones
| Timing | Investigational Drug Candidate | Therapeutic Area | Expected Milestone |
| Q1 | ETV:IDS (DNL310) | Hunter syndrome (MPS II) | Late-breaker presentation on 12-week data from Cohort A in Phase 1/2 study at WORLD Symposium |
| Q1 | PTV:PGRN (DNL593) | frontotemporal dementia (FTD) | Receive milestone payment from Takeda for initiation of IND-enabling studies |
| Q1 | ATV:TREM2 (DNL919) | Alzheimer’s disease | Receive milestone payment from Takeda for initiation of IND-enabling studies |
| 1H |
Denali Therapeutics Inc.
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About DNLIdenali therapeutics inc. (“denali”) is a biotechnology company focused on the discovery and development of therapies for patients with neurodegenerative diseases, including alzheimer’s disease, parkinson’s disease, als and others. denali was founded by scientists, industry experts and investors who share the vision that recent scientific insights into the genetic causes and biological processes underlying neurodegenerative disease, together with new translational medicine tools, offer an unprecedented opportunity to discover and develop effective medicines. denali is rigorously pursuing a science-driven approach to translational medicine and clinical development. founding investors include fidelity biosciences, arch venture partners, flagship ventures and the alaska permanent fund (represented by crestline investors).
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