Denali Therapeutics Inc. (Denali) is a biopharmaceutical company that discovers and develops therapeutics to defeat neurodegenerative diseases and lysosomal storage diseases.
The company has invented, developed, and validated a proprietary technology called the TransportVehicle (TV) to address the blood-brain barrier (BBB) challenge. The TV has a modular design enabling the delivery of large molecules, i.e., enzymes, oligonucleotides, and antibodies, to all tissues of the body, including the br...
Denali Therapeutics Inc. (Denali) is a biopharmaceutical company that discovers and develops therapeutics to defeat neurodegenerative diseases and lysosomal storage diseases.
The company has invented, developed, and validated a proprietary technology called the TransportVehicle (TV) to address the blood-brain barrier (BBB) challenge. The TV has a modular design enabling the delivery of large molecules, i.e., enzymes, oligonucleotides, and antibodies, to all tissues of the body, including the brain, by crossing the BBB after systemic administration. Over the last few decades, large molecule biotherapeutics have enabled medical breakthroughs in treating a wide array of serious diseases, but with very limited success in central nervous system (CNS) diseases. Now, with the invention and validation of its TV technology, the company is leading the field in delivering on the potential of biotherapeutics to transform the lives of individuals with neurodegenerative, lysosomal, and other serious diseases.
The company is building a broad portfolio of therapeutic candidates by investing in its TV franchises, i.e., Enzyme TV (ETV), Oligonucleotide TV (OTV), and Antibody TV (ATV), to advance programs for rare diseases, such as lysosomal storage diseases, and common diseases, such as Alzheimer's disease and Parkinson's disease. Its most advanced TV-enabled program is tividenofusp alfa (DNL310, ETV:IDS) for the potential treatment of mucopolysaccharidosis II (MPS II, or Hunter syndrome). The company plans to submit a biologics license application (BLA) for tividenofusp alfa under the FDA's accelerated approval pathway in early 2025, and it is preparing for a potential commercial launch in late 2025 or early 2026. The company's TV-enabled clinical development portfolio also includes DNL126 (ETV:SGSH) for MPS IIIA (Sanfilippo syndrome) and DNL593 (PTV:PGRN) for frontotemporal dementia-granulin (FTD-GRN). Its small molecule clinical development portfolio includes BIIB122/DNL151 (small molecule LRRK2 inhibitor) for Parkinson’s disease and DNL343 (small molecule eIF2B activator) for amyotrophic lateral sclerosis (ALS).
Strategy
The key elements of the company’s strategy are to discover and develop a new class of barrier-crossing therapeutics; accelerate and expand a broad portfolio of tv-based product candidates; and launch initial products targeting rare lysosomal storage diseases.
The company expects its first potential product launches to be with tividenofusp alfa for MPS II, followed by DNL126 for MPS IIIA. MPS II and MPS IIIA belong to a group of lysosomal storage diseases, which are caused by genetic mutations that lead to single-enzyme deficiencies. Lysosomal storage diseases afflict more than 30,000 individuals worldwide.
The company is engaged in prelaunch activities for tividenofusp alfa, including continued dialogue with prescribers and payers, building a suite of patient support services and capabilities to enable broad access, and establishing a right-sized team in commercial and medical affairs to support tividenofusp alfa and additional ETV launches. The company includes PTV:PGRN as one of its ETV franchise programs, as it has a similar mechanism of action in increasing levels of deficient or missing protein to improve lysosomal function. The company has an active collaboration with Takeda Pharmaceutical Company Limited (Takeda) for the development and commercialization of TAK-594/DNL593 (PTV:PGRN) for FTD-GRN. The company intends to leverage certain efficiencies of scale to support the commercialization of additional product candidates to create an enzyme replacement franchise enabled by its ETV platform. The company's next ETV programs advancing to the clinic are DNL952 (ETV:GAA) for Pompe disease and DNL111 (ETV:Gcase) for Parkinson's disease. The company intends to commercialize these product candidates, if approved, in key markets and/or leverage partnerships to ensure optimal access for patients.
In parallel, the company is advancing TV-enabled programs for common neurodegenerative diseases, such as Alzheimer’s disease and Parkinson's disease, which afflict over 40 million individuals worldwide. Its most advanced programs in the investigational new drug (IND)-enabling stage of development are DNL628 (OTV:MAPT), DNL921 (ATV:Abeta), and DNL422 (OTV:SNCA). Along with amyloid plaques, tau tangles are a pathological hallmark of Alzheimer's disease. The company is targeting both of these pathologies with its ATV and OTV platforms, respectively, aiming to deliver the next generation of anti-amyloid therapeutics and a potential first-in-class anti-tau therapeutic. Preclinical studies with ATV:Abeta have demonstrated potential for better efficacy and safety compared to a standard antibody, with superior plaque reduction and very low rates of amyloid-related imaging abnormalities (ARIA). Likewise, preclinical studies with OTV:MAPT have demonstrated robust and sustained reductions of tau protein. Toxic protein accumulation is also a hallmark in Parkinson's disease, and the company has demonstrated robust reductions of alpha-synuclein with OTV:SNCA in preclinical studies.
In addition to its development programs for neurodegenerative and lysosomal storage diseases, the company has a robust discovery effort to further expand its portfolio and capture the full potential of its TV platform to enhance the delivery of biotherapeutics to all tissues in the body. The company is pursuing opportunities of unmet need in multiple disease areas, including oncology, inflammation, neuromuscular disease, and metabolic disease. For example, it has engineered a bispecific ATV:HER2 antibody and has demonstrated preclinically improved peripheral anti-tumor activity, as well as enhanced brain uptake of the bispecific ATV:HER2 compared to a non-ATV HER2 antibody. The data support the potential for ATV:HER2 to treat HER2-positive peripheral tumors and brain metastases, and further validate the potential for TV applications in oncology.
The company's therapeutic portfolio also includes two late-stage clinical programs for small molecule drug candidates that do not use the TV platform but are engineered with optimized chemical and physical properties to cross the blood-brain barrier (BBB). Denali has an active collaboration with Biogen Inc.’s subsidiaries, Biogen MA Inc. (BIMA) and Biogen International GmbH (BIG) (BIMA and BIG, collectively, Biogen) for the development and commercialization of BIIB122/DNL151 (small molecule LRRK2 inhibitor) for Parkinson's disease. Biogen is conducting the global Phase 2b LUMA study, which is evaluating the ability of BIIB122 to slow disease progression compared to placebo in approximately 640 participants with early-stage Parkinson's disease; completion of enrollment is expected in 2025. In addition, Denali is conducting the complementary Phase 2a BEACON study in LRRK2-associated Parkinson's disease, with the intention to generate biomarker and safety data to inform how LRRK2 inhibition may impact this disease. The company's small molecule eIF2B activator, DNL343, is being evaluated in Regimen G of the Phase 2/3 HEALEY ALS Platform Trial for amyotrophic lateral sclerosis (ALS), led by the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) in collaboration with the Northeast ALS Consortium (NEALS). Following previously reported topline results indicating that the primary and key secondary endpoints were not met, further analyses are anticipated later in 2025, including neurofilament light (NfL) and other fluid biomarkers, data from pre-specified subgroups, as well as extended findings from the active treatment extension period.
Collaborations and partnering are central components of the company's strategy to build, develop, and commercialize its portfolio of product candidates. The company has numerous arrangements with biopharmaceutical companies, technology companies, academic institutions, foundations, and patient-focused data companies. Notable active arrangements include those with Biogen and Takeda, as described above, and Genzyme Corporation, a wholly owned subsidiary of Sanofi S.A. (Sanofi), for the development and commercialization of SAR443122/DNL758 (peripherally restricted small molecule RIPK1 inhibitor) in ulcerative colitis. The company holds significant development and commercialization rights to all of its CNS programs, including the programs that are subject to its collaboration agreements with Biogen and Takeda, where it shares responsibility for clinical development and shares commercialization rights in the United States and China. The company's costs of developing programs associated with these collaborations are largely covered through upfront payments, expected incoming milestones, and cost sharing. The company is also eligible to receive royalty payments for SAR443122/DNL758 from Sanofi. The company may seek additional strategic partnering opportunities as it strives to capture the full value of its portfolio and platforms.
The company is guided by the core Denali Values of trust, growth, grit, and unity, and these values form the foundation of its Environmental, Social & Governance (ESG) practices. The company's working culture seeks to develop quality leaders, foster diversity and inclusion, and emphasize continuous growth. The company embraces differences and acknowledges the valuable perspectives that a diverse and inclusive workforce brings to problem-solving and invention. The company strives to manage its operations in a way that is sustainable and reduces its impact on the environment, including through a Green Alternative program that provides researchers with information on suitable alternative chemicals that have a lower environmental impact for common solvents. Additionally, several waste streams have been segregated on-site for proper disposal or recycling, such as containers, food waste, plastics, styrofoam, and glass chemical containers, to maximize recycling and composting. The company also maintains an ongoing commitment to corporate governance principles, with oversight of ESG matters by Denali's Board of Directors, and a strong performance orientation in its compensation program.
Approach to Crossing Biological Barriers and Defeating Neurodegeneration
The company invented, developed, and continues to optimize a proprietary technology called the TransportVehicle (TV) to deliver its large molecule biotherapeutic candidates to the brain after systemic administration. Clinical and preclinical studies with several of the company's TV-enabled product candidates have demonstrated high concentrations and broad distribution in all explored regions of the CNS and in key CNS cell types, and have shown improved pharmacodynamic effects compared to standard biotherapeutics.
The company's TV technology is modular and enables several classes of biotherapeutics to more effectively cross the blood-brain barrier (BBB), including enzymes, antibodies, oligonucleotides, and other proteins. The TV technology is engineered to engage specific BBB transport receptors, such as the transferrin receptor (TfR) and CD98 heavy chain (CD98hc), which are highly expressed in brain capillaries and facilitate the transport of proteins into the brain in a process called receptor-mediated transcytosis.
The company's TV technology is differentiated from other BBB technologies through its engineering approach, which may provide superior therapeutic efficacy, safety, and tolerability through higher stability, exposure, and biodistribution, as well as the potential for lower immunogenicity of drug candidates in the brain. Compared to conventional approaches that use the Fab portion (the arms) of a full-length antibody to bind to the targeted BBB receptor (e.g., TfR), the company uses an Fc domain (the legs).
The company has engineered the BBB receptor binding site into one of the Fc's (monovalent binding) and can optimize binding affinity (how tightly the Fc binds its BBB receptor target) to enhance brain delivery and limit receptor degradation. The company can also modify the amino acid sequences in the Fc to enable conditional effector function, which is important for the optimal activity of certain molecules, such as ATV:Abeta, that require immune cell activity for therapeutic effect. By toggling effector function on or off, the loss of reticulocytes (immature red blood cells) can be avoided, potentially limiting anemia, which is a known liability associated with targeting the transferrin receptor.
The company's pipeline of TV-enabled programs includes three clinical-stage programs and more than ten programs in preclinical development. The company achieved proof of concept with safety, pharmacokinetic, and pharmacodynamic data from Phase 1/2 clinical studies in patients and healthy volunteers, as well as data from several preclinical studies in mouse and nonhuman primate models. Preclinical studies demonstrated robust and sustained pharmacodynamic effects in the brain after intravenous dosing of TV-enabled antibodies, enzymes, proteins, and oligonucleotides, while standard antibodies, enzymes, proteins, and oligonucleotides had no or minimal pharmacodynamic effects. These data show that TV-enabled product candidates have the potential to achieve therapeutically relevant concentrations in the brain after systemic administration, making them potentially superior to traditional biologic therapeutics in targeting neurodegenerative diseases.
The company's most advanced TV-enabled program is tividenofusp alfa (ETV:IDS), for which it plans to submit a Biologics License Application (BLA) for the treatment of MPS II using the FDA's accelerated approval pathway in early 2025, and, pending approval, launch in late 2025 or early 2026. In addition, the company will seek alignment with the FDA on an accelerated approval path for its second ETV clinical program, DNL126 (ETV:SGSH), for the treatment of MPS IIIA. Together, the company expects these two programs to be the foundation of a broad franchise of TV-enabled enzyme replacement therapies for lysosomal storage diseases, which affect more than 30,000 people worldwide.
In addition to its MPS II and MPS IIIA programs, the company is conducting a Phase 1/2 study for FTD-GRN with TAK-594/DNL593 (PTV:PGRN), which has a similar mechanism of action in replacing deficient enzyme activity to improve lysosomal function. The company's next two ETV-enabled programs advancing to the clinic are DNL952 (ETV:GAA) for Pompe disease and DNL111 (ETV:Gcase) for Parkinson’s disease and Gaucher disease. DNL622 (ETV:IDUA) is also in the IND-enabling stage for Hurler syndrome (MPS I). The company has built clinical manufacturing capabilities for its TV-enabled programs and continues to expand its commercial capabilities in lysosomal storage diseases. Launching in rare indications first gives the company the opportunity to build and establish its commercial organization so that it is poised for success in larger indications over time.
The company's ETV franchise lays the foundation for value creation to fuel the expansion of its TV portfolio utilizing its ATV and OTV platforms. In preclinical studies, broader brain biodistribution of ATV and OTV-enabled antibodies and oligonucleotides is achieved compared to non-TV-enabled standard antibodies and oligonucleotides. The company has further engineered these platforms to optimize certain pharmacokinetic, pharmacodynamic, and safety properties. For example, its ATV:Abeta construct contains a cisLALA mutation that confers the ability to toggle effector function on or off, such that immune cells are activated only when ATV:Abeta is bound to amyloid beta (Abeta) plaque and not when bound to TfR. This feature addresses a known safety liability of utilizing TfR associated with the depletion of reticulocytes (immature red blood cells) in the bone marrow, where the transferrin receptor is highly expressed. With cisLALA, the ATV:Abeta construct remains immune silent when bound to TfR, thus minimizing the risk of anemia from reticulocyte loss. The company is advancing DNL921 (ATV:Abeta) and DNL628 (OTV:MAPT) targeting Abeta and tau, respectively, for Alzheimer’s disease, as well as DNL422 (OTV:SNCA) targeting alpha-synuclein for Parkinson’s disease.
The company's preclinical studies have established TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.
Biomarker-Driven Development and Approval
As part of its strategy, the company identifies and validates biomarkers that are relevant for both animal models and human trials, and are critical for selecting patients, predicting and measuring target engagement, supporting dose selection, and enabling decisions on the progression of product candidates to the next phase of development. When practicable, the company is developing patient selection biomarkers for its programs to enable the identification of patients with the relevant disease biology and stage of disease likely to benefit from targeted therapy, in order to increase the likelihood of success of clinical trials. Ultimately, the company expects to positively impact market acceptance of these targeted therapies, driven by high and meaningful response rates within the targeted population as defined by the patient selection biomarkers.
The company recognizes the urgency for people living with neurodegenerative and lysosomal storage diseases to have effective treatment options. Biomarkers have successfully been used as primary clinical endpoints to secure a faster path to approval in indications, such as ALS and Alzheimer’s disease. The company is actively engaged in efforts, which include collaboration with its patient communities, advocacy groups, and other drug developers, to press for more regulatory flexibility in using biomarker data as the basis for approval in disease indications where the unmet medical need is high and treatment options are few or non-existent. These efforts are in addition to ongoing discussions with health authorities regarding the potential use of validated biomarkers as primary clinical endpoints to support faster paths to approval for its product candidates. In September 2024, the company announced the outcome of a successful meeting with the Center for Drug Evaluation and Research (CDER) of the FDA, providing a path to filing a BLA for accelerated approval and subsequent conversion to full approval for tividenofusp alfa for the treatment of MPS II. Agreement was reached that CSF heparan sulfate 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. The company intends to submit the BLA under the accelerated approval pathway in early 2025.
Programs
The company is developing a broad portfolio of targeted therapeutic candidates for neurodegenerative and lysosomal storage diseases, with discovery efforts expanding into other serious disease areas. Its programs are at various stages of clinical and preclinical development. In addition to its clinical development portfolio, the company expects to advance one to two new molecule entities (NMEs) into clinical development over the next three years, beginning in 2025.
Clinical Programs
Tividenofusp alfa (DNL310, ETV:IDS) Enzyme Replacement Therapy Program for MPS II (Hunter Syndrome)
MPS II, also called Hunter syndrome, is a rare genetic disease that affects over 2,000 individuals, primarily males, in commercially accessible geographies 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 sulfate 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.
In September 2024, the company announced a successful Type C meeting with CDER, providing a path to filing a BLA for accelerated approval and subsequent conversion to full approval for tividenofusp alfa based on the Phase 2/3 COMPASS study for the treatment of MPS II. An agreement was reached that a reduction in CSF heparan sulfate 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. The BLA is intended to be submitted under the accelerated approval pathway in early 2025 and will include preclinical and clinical data on biomarkers (CSF and urine heparan sulfate and neurofilament light (NfL)), safety data, and clinical data, including liver volume, hearing thresholds, cognition, and adaptive behavior.
The company is engaged in prelaunch activities, including continued dialogue with prescribers and payers, building a suite of patient support services and capabilities to enable broad access. It is building a right-sized team in commercial and medical affairs to support tividenofusp alfa and additional ETV product launches. The ongoing open-label extension of the Phase 1/2 study will generate long-term safety data. The company is also conducting the global Phase 2/3 COMPASS study, which will support global approval.
The company has previously reported interim analyses from the Phase 1/2 study and most recently reported the primary analysis of efficacy and safety at the 2025 WORLDSymposium in February 2025. The Phase 1/2 study is a multicenter, multiregional, open-label, single-arm study to assess the safety, pharmacokinetics, and pharmacodynamics of tividenofusp alfa administered once weekly by intravenous infusion. The primary analysis included data from 47 participants who completed the 24-week treatment period and additional long-term follow-up. Long-term data demonstrated that robust reductions and normalization in key biomarkers from baseline were maintained over time, with continued improvement in hearing, cognition, and adaptive behavior. In addition, long-term safety data with a median follow-up of two years, and out to more than four years, demonstrated that tividenofusp alfa was generally well tolerated.
DNL126 (ETV:SGSH) Program for MPS IIIA (Sanfilippo Syndrome A)
In January 2024, the company commenced dosing participants with MPS IIIA in a multicenter, open-label, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory clinical efficacy of DNL126. The core study period is 25 weeks (approximately 6 months) and is followed by a 72-week (approximately 18 months) open-label extension.
In February 2024, the company presented preclinical data at the 2024 WORLDSymposium demonstrating that DNL126 improved lysosomal and microglial morphology, neurodegeneration, and cognitive function in adult MPS IIIA mice. Peripheral treatment with ETV:SGSH lowered substrate accumulation (heparan sulfate) in the brain and in CSF, which was correlated with improved cognitive behavioral performance in adult MPS IIIA mice.
In June 2024, the company announced that DNL126 was selected for the FDA's Support for Clinical Trials Advancing Rare Disease Therapeutics (START) program to accelerate the development of rare disease therapeutics. Collaborative engagement has commenced to support progress toward a pre-BLA meeting.
In June 2024, the company announced that DNL126 was selected for the FDA's Support for Clinical Trials Advancing Rare Disease Therapeutics (START) program to accelerate the development of rare disease therapeutics. Collaborative engagement has commenced to support progress toward a pre-BLA meeting.
Based on the preliminary Phase 1/2 results and a positive regulatory environment, the company expanded the Phase 1/2 study and it continues to assess development plans for DNL126 including an accelerated approval path.
TAK-594/DNL593 (PTV:PGRN) Program for FTD-GRN
In January 2024, Denali announced that enrollment and dosing were voluntarily paused in Part B of the Phase 1/2 study to implement protocol modifications. The pause was based on 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 within the same day with infusion discontinuation and standard treatment measures. TAK-594/DNL593 was otherwise well-tolerated in the study, with all other adverse events reported as mild in severity. In August 2024, the company announced that the protocol amendment for the Phase 1/2 study was finalized, allowing for premedication and other measures aimed at reducing the risk of IRRs, and prescreening of participants for Cohort B2 had begun. In January 2025, it announced that dosing is ongoing in the study.
BIIB122/DNL151 LRRK2 Inhibitor Program for Parkinson's disease
Results from Phase 1 and Phase 1b trials of BIIB122/DNL151 in healthy volunteers and patients with Parkinson's disease, respectively, showed robust target and pathway engagement as measured by pS935 LRRK2 and pT73 Rab10 (pRab10), respectively. Furthermore, a reduction in total LRRK2 in the CSF demonstrated central target engagement, and a dose-dependent reduction in urine of the lysosomal lipid 22:6-bis[monoacylglycerol] phosphate (BMP), a biomarker of lysosomal function, suggested an improvement in 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.
In February 2024, the company announced the execution of a Collaboration and Development Funding Agreement in January 2024 with a third party related to a global Phase 2a study of BIIB122/DNL151, which the company is operationalizing to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2.
In December 2024, the company announced that dosing had commenced in the Phase 2a study, called BEACON, which is expected to enroll approximately 50 participants into a double-blind treatment period of three months followed by an open-label extension.
Other LRRK2 Compounds
Genetic and functional studies have linked LRRK2 and other proteins that modulate lysosomal function to Crohn's disease. Excessive LRRK2 activity leads to a reduction in lysosomal function, which contributes to the inflammation and intestinal dyshomeostasis that are characteristic of this disorder. The company has discovered potent and selective small molecule inhibitors of LRRK2 and have selected a lead clinical candidate (DNL975) for the treatment of Crohn's disease.
DNL343 eIF2B Activator Program for ALS
In May 2023, the first participant with ALS was dosed with DNL343 (Regimen G) in the Phase 2/3 HEALEY ALS Platform Trial led by the Sean M. Healey & AMG Center for ALS (Healey Center) at Massachusetts General Hospital (MGH) in collaboration with the Northeast ALS Consortium (NEALS) clinical trial network. The HEALEY ALS Platform Trial is a large-scale collaborative effort made possible by contributions from patients and families, clinical trial sites, industry partners and research collaborators to evaluate multiple investigational therapies simultaneously with the goal of accelerating the development of potential new treatments for ALS. Therapeutic candidates that enter the platform trial are chosen by a group of expert ALS scientists and members of the Healey & AMG Center.
Eclitasertib (SAR443122/DNL758) RIPK1 Inhibitor Program for Peripheral Inflammatory Diseases: UC
As part of its parallel development strategy, the company has also developed a number of other structurally diverse CNS-penetrant and peripherally-restricted RIPK1 inhibitor molecules, which are included as part of the collaboration agreement with Sanofi, described in more detail in Business - Licenses and Collaborations below.
IND-Enabling Stage Programs
Beginning in 2025, the company expects to advance one to two additional programs to the clinic per year over the next three years across its TV-enabled franchises (ETV, OTV, and ATV).
Enzyme Transport Vehicle (ETV) Programs
DNL952 (ETV:GAA) for Pompe Disease
Acid alpha-glucosidase (GAA) is an enzyme that breaks down glycogen into glucose in the body's lysosomes. Pompe disease occurs due to lack of GAA enzyme activity, which leads to lysosomal glycogen accumulation and autophagic buildup resulting in cellular disruption. There are two types of Pompe disease: Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). IOPD affects the heart and causes ventilatory failure leading to early death, typically before one year age. LOPD can occur from early childhood through later decades in life and is characterized by slow progression, limb-girdle weakness leading to inability to walk, respiratory weakness leading to ventilator dependence, and CNS involvement. The estimated prevalence of Pompe disease is 5,000 to 10,000 people worldwide excluding India and China. Current standard of care is enzyme replacement therapy. Progressive motor weakness and respiratory failure remain unmet needs.
DNL111 (ETV:Gcase) for Parkinson's Disease and Gaucher Disease
DNL111 is composed of an engineered GCase variant for improved potency and fused to TV to replace GCase in all tissues, including the brain by crossing the BBB. In preclinical studies, ETV:Gcase shows improved substrate reduction in brain, liver and serum as compared to Gcase enzyme alone. Further it has engineered the recombinant Gcase enzyme for improved potency. Engineered ETV:GCase may enable highly stable and potent brain-penetrant enzyme replacement therapy for Parkinson’s disease and Gaucher disease.
DNL622 (ETV:IDUA) for MPS I (Hurler Syndrome)
DNL622 (ETV:IDUA) is composed of IDUA fused to TV, which is engineered to cross the BBB via RMT into the brain and to enable broad delivery of IDUA into cells and tissues throughout the body with the goal of treating MPS I. DNL622 is in the IND-enabling stage of preclinical development.
Oligonucleotide Transport Vehicle (OTV) Programs
Oligonucleotides, such as ASOs and siRNAs, are designed to modify gene expression and hold promise as therapeutics for neurological disorders. A major challenge in their development, however, is that oligonucleotides are unable to cross the blood-brain barrier (BBB) on their own. Oligonucleotides must be delivered directly to the CNS through invasive routes, such as intrathecal delivery and still may not distribute uniformly throughout the brain where treatment is needed. The company is using its OTV platform to enable brain delivery of oligonucleotides by crossing the BBB following systemic administration.
In August 2024, the company's preclinical research related to OTV was published in Science Translational Medicine. Denali scientists described using OTV, which is an engineered TV conjugated to an ASO, for the delivery of therapeutic molecules to the mouse and nonhuman primate brain. The research demonstrated that OTV can successfully cross the blood-brain barrier (BBB) following intravenous administration and provide cumulative and sustained knockdown of the ASO target gene expression across multiple CNS regions and all major cell types, including endothelial cells, neurons, astrocytes, microglia, and oligodendrocytes. Additionally, OTV enabled knockdown of the ASO target gene expression in historically difficult-to-target peripheral muscle tissues, including skeletal and cardiac muscle.
The company's two most advanced OTV programs are designed to knock down the expression of genes in the brain that encode for proteins, which can form toxic aggregates in diseases, such as Alzheimer's disease and Parkinson's disease. DNL628 (OTV:MAPT) is a therapeutic candidate targeting tau for Alzheimer's disease. In a mouse model, the company has demonstrated that brain MAPT RNA and tau protein knockdown persists for greater than 15 weeks following intravenous delivery of OTV:MAPT.
Antibody Transport Vehicle (ATV) Programs
DNL921 Antibody Transport Vehicle Amyloid Beta (ATV:Abeta) Program
The company's ATV:Abeta program utilizes the ATV platform to enable increased brain exposure and target engagement of Abeta plaques while avoiding ARIA. In preclinical studies in mice, ATV:Abeta was shown to be superior in reducing amyloid plaque load and oligomeric Abeta load compared to a conventional Abeta antibody, while essentially eliminating ARIA. These preclinical studies provide the first mechanistic understanding of how ARIA can be prevented by virtue of ATV-enabled brain delivery of Abeta antibodies through microvessels, largely bypassing arteries, which contain the majority of the vascular amyloid responsible for inducing ARIA. Furthermore, the company's unique Fc engineering allows for conditional effector function through a cisLALA mutation, which preserves the ability for ATV:Abeta to engage microglia for plaque phagocytosis while mitigating TfR-related hematology liabilities such as depletion of reticulocytes.
Discovery Programs
In addition to its development portfolio for neurodegenerative and lysosomal storage diseases, the company has a robust discovery effort to further expand and capture the full potential of its TV platform to enhance the delivery of biotherapeutics to all tissues in the body. It is pursuing opportunities of unmet need in multiple disease areas, including oncology, inflammation, neuromuscular disease, and metabolic disease. For example, using ATV, the company has engineered mono- and bispecific formats of HER2 antibodies. Human epidermal growth factor receptor 2 (HER2) is a growth factor receptor that is over-expressed in multiple cancers, including breast, colorectal, and gastric cancer. Up to half of patients diagnosed with metastatic HER2-positive breast cancer develop brain metastases for which limited treatment options exist. In preclinical mouse studies, the company has demonstrated improved anti-tumor activity of ATV-enabled HER2 antibodies in a HER2-positive peripheral tumor model. Its bispecific ATV:HER2 antibody demonstrated improved peripheral anti-tumor activity compared to non-ATV HER2 antibodies, as well as enhanced brain uptake compared to a non-ATV HER2 antibody. The data support the potential for ATV:HER2 to treat HER2-positive peripheral tumors and brain metastases and further validate the potential for TV applications in oncology.
Licenses and Collaborations
Biogen License and Collaboration Agreement and Right of First Negotiation, Option and License Agreement
In October 2020, the company entered into a Definitive LRRK2 Collaboration and License Agreement (‘LRRK2 Agreement’) pursuant to which the company granted Biogen a license to co-develop and co-commercialize its small molecule LRRK2 inhibitor program (the ‘LRRK2 Program’), and a Right of First Negotiation, Option and License Agreement (the ‘ROFN and Option Agreement’), pursuant to which the company granted an option and right of first negotiation to certain of its programs utilizing its TV technology platform, including its amyloid beta program (collectively the ‘Biogen Collaboration Agreement’), with Biogen Inc.’s subsidiaries, Biogen MA Inc. (‘BIMA’) and Biogen International GmbH (‘BIG’) (BIMA and BIG, collectively, ‘Biogen’). In August 2023, the company executed an Amendment to the Definitive LRRK2 Collaboration and License Agreement and Waiver of and Amendment to Right of First Negotiation, Option, and License Agreement (the ‘Biogen Amendment’).
LRRK2 Agreement
The LRRK2 Agreement includes the company's small molecule LRRK2 inhibitors (LRRK2 Products) that penetrate the blood-brain barrier (BBB), including DNL201 and BIIB122/DNL151, as well as those that do not penetrate the BBB. Based on the totality of preclinical and clinical data to date, both DNL201 and BIIB122/DNL151 (two chemically distinct LRRK2 inhibitors) have met the company's requirements to proceed into further late-stage clinical testing; however, BIIB122/DNL151 has been selected to proceed due to its pharmacokinetic properties that provide additional dosing regimen flexibility.
Sanofi Collaboration and License Agreement
In October 2018, the company entered into a collaboration agreement with Genzyme Corporation, a wholly owned subsidiary of Sanofi S.A. (Sanofi), pursuant to which certain small molecule compounds that bind to and inhibit RIPK1 (RIPK1 Inhibitors) contributed by both Sanofi and the company will be developed and commercialized.
Takeda Option and Collaboration Agreement
In January 2018, the company entered into a collaboration agreement (Takeda Collaboration Agreement) with Takeda Pharmaceutical Company Limited (Takeda), pursuant to which it granted Takeda an option with respect to its ATV:BACE1/Tau, ATV:TREM2, and PTV:PGRN programs. The Takeda Collaboration Agreement became effective in February 2018, following the satisfaction of certain requirements of the Hart-Scott-Rodino Antitrust Improvements Act of 1976. In February 2019, the company amended the agreement to replace the ATV:BACE1/Tau program with the ATV:Tau program, and in March 2022, the parties mutually agreed to terminate activity on the ATV:Tau program over which Takeda had its option to develop and commercialize jointly with the company. Takeda exercised the options for the PTV:PGRN program in November 2021.
F-star License and Collaboration Agreement
In August 2016, the company entered into a license and collaboration agreement (F-star Collaboration Agreement) with F-star Gamma Limited (F-star Gamma), F-star Biotechnologische Forschungs-und Entwicklungsges m.b.H (F-star GmbH), and F-star Biotechnology Limited (F-star Ltd) (collectively referred to as F-star).
Genentech Exclusive License Agreement
In June 2016, the company entered into an exclusive license agreement with Genentech, Inc. (Genentech). The agreement provides the company access to Genentech’s LRRK2 inhibitor small molecule program for Parkinson’s disease. Under the agreement, Genentech granted the company (i) an exclusive, worldwide, sublicensable license under Genentech’s rights to certain patents and patent applications directed to small molecule compounds that bind to and inhibit LRRK2, and (ii) a non-exclusive, worldwide, sublicensable license to certain related know-how, in each case, to develop and commercialize certain compounds and licensed products incorporating any such compound. The company is obligated to use commercially reasonable efforts during the first three years of the agreement to research, develop, and commercialize at least one licensed product.
Manufacturing
The company relies on third-party contract development and manufacturing organizations (CDMOs) to manufacture and supply its preclinical and clinical materials used during the development of its product candidates. It has established relationships with several CDMOs, including Lonza Sales AG (Lonza). Effective September 2017, the company entered into a development and manufacturing services agreement with Lonza, which has been subsequently amended to add scope of work. This agreement, as amended, is referred to as the DMSA or the Lonza agreement. Pursuant to the Lonza agreement, Lonza agreed to provide clinical development and manufacturing services with respect to certain of the company's biologic products on a fee-for-service basis.
Intellectual Property
As of December 31, 2024, the company's owned and licensed patent portfolio includes over 1,700 patents and patent applications, including over 30 licensed U.S. issued patents and 40 owned U.S. issued patents, covering certain aspects of its proprietary technology, product candidates, and related inventions and improvements. The patent portfolio also includes over 500 licensed patents issued in jurisdictions outside of the United States, and over 850 owned patent applications pending in jurisdictions outside of the United States that, in many cases, are counterparts to the foregoing U.S. patents and patent applications. For its product candidates and TV platform, the company generally pursues or in-licenses patent protection covering compositions of matter, methods of use, and manufacture.
TV Platform
The company owns 10 patent families related to its TV platform. These include a family directed to the composition and sequences of its TfR-binding TVs, the earliest of which are expected to expire in 2038, not including any patent term adjustments and any patent term extensions. The company also holds 7 issued U.S. patents, which are also expected to expire in 2038, not including any patent term adjustments and any patent term extensions, as well as pending patent applications related to other TV platforms. Other families related to the TV platform, if issued, are expected to expire in 2038 or later, all not including any patent term adjustments and any patent term extensions. In addition, the company licenses multiple patent families from F-star, the earliest issued patents of which are expected to expire in 2026, not including any patent term adjustments and any patent term extensions.
ETV Platform, ETV:IDS, and ETV:SGSH Programs
The company owns 11 patent families directed to its ETV platform and related products, including ETV:IDS, ETV:SGSH, ETV:GAA, ETV:Gcase, and ETV:IDUA. This portfolio includes 1 issued U.S. patent, which is expected to expire in 2038, not including any patent term adjustments and any patent term extensions, directed to the composition of matter of its ETV:IDS molecules, including DNL310. The company also owns 4 additional patent families directed to various aspects of its DNL310 program, which, if issued, are expected to expire in 2039 or later, all not including any patent term adjustments and any patent term extensions. Of the 11 patent families, 3 families relate to the composition of matter of its ETV:SGSH structures, including DNL126. Any patents issuing from these families are expected to expire between 2039 and 2045, respectively, not including any patent term adjustments and any patent term extensions.
PTV:PGRN Program
The company owns 4 patent families directed to its PTV:PGRN program. This includes an issued U.S. patent, which is expected to expire in 2040, not including any patent term adjustments and any patent term extensions, directed to the composition of matter of its PTV:PGRN molecules, including TAK-594/DNL593. The company also owns an additional patent family directed to the composition of matter of its PTV:PGRN structures, including TAK-594/DNL593, the earliest of which are expected to expire in 2039, not including any patent term adjustments and any patent term extensions. Additionally, the company owns patent families directed to various aspects of its TAK-594/DNL593 program, which, if issued, are expected to expire in 2039 or later, all not including any patent term adjustments and any patent term extensions. The PTV:PGRN program is subject to the company's collaboration with Takeda.
Oligonucleotide Transport Vehicle Platform
The company owns 7 patent families related to its OTV platform, including OTV:MAPT and OTV:SNCA. These families are directed to the compositions and methods of use of its OTVs, including DNL628 (OTV:MAPT) and DNL422 (OTV:SNCA), and if issued, are expected to expire between 2042 and 2045, not including any patent term adjustments and any patent term extensions.
LRRK2 Inhibitor Program
The company's LRRK2 program is subject to its collaboration agreement with Biogen. For this program, it licenses multiple patent families from Genentech directed to, among other things, DNL201, BIIB122/DNL151, and other related compounds, which are expected to expire in 2031, not including any patent term adjustments and any patent term extensions. Furthermore, the company owns additional patent families that have projected expiration dates in 2038 or later, not accounting for any patent term adjustments and any patent term extensions, related to the LRRK2 program. Additionally, the company owns a patent family that includes 3 issued U.S. patents, which are expected to expire in 2037, not including any patent term adjustments and any patent term extensions, directed to the composition of matter of BIIB122/DNL151 and methods of treatment using BIIB122/DNL151, respectively, as well as pending patent applications and granted patents in jurisdictions outside the U.S.
RIPK1 Inhibitor Program
The company's RIPK1 program is subject to its collaboration agreement with Sanofi. It owns 7 patent families directed to its RIPK1 inhibitor program. These include 3 issued U.S. patents, including one directed to the composition of matter of eclitasertib (SAR443122/DNL758), which is expected to expire in 2037, not including any patent term adjustments and any patent term extensions.
eIF2B Activator Program
The company owns 9 patent families directed to its eIF2B activator program, including 4 patent families directed to DNL343 that are expected to expire in 2038 or later, with the remaining families directed to other eIF2B compounds expiring between 2038 and 2040, not including any patent term adjustments and any patent term extensions.
Trademarks
The company uses Denali, the Denali Therapeutics logo, ATV, ETV, OTV, PTV, TV, TransportVehicle, and other marks as trademarks in the United States and other countries.
Research and Development
The company’s research and development expenses were $396.4 million for the year ended December 31, 2024.
History
The company was incorporated in 2013. It was formerly known as SPR Pharma Inc. and changed its name to Denali Therapeutics Inc. in 2015.
