Overview and Strategy
−Removed: Our goal is to discover, develop, and deliver a new class of barrier-crossing therapeutics and to defeat degeneration.
−Removed: Historically, the blood-brain barrier ("BBB") has been a major challenge to the development of medicines for diseases of the central nervous system ("CNS").
−Removed: While the BBB protects the brain and is essential for our survival, it also prevents the delivery of medicines to the brain in sufficient quantities to have therapeutic effect.
−Removed: We have invented, developed, and validated a proprietary technology, called the TransportVehicle TM ("TV"), to address the BBB challenge.
−Removed: The TV has a modular design enabling 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.
−Removed: 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 CNS diseases.
−Removed: Now, with the invention and validation of our TV technology, we are leading the field in delivering on the potential of biotherapeutics to transform the lives of individuals with neurodegenerative, lysosomal, and other serious diseases.
+Added: Our purpose is to bring the power of biotherapeutics to the whole body, including the brain, by discovering, developing, and delivering medicines for people living with serious diseases.
+Added: Historically, the blood-brain barrier has been a major challenge to the development of medicines for diseases of the central nervous system.
+Added: While the blood-brain barrier protects the brain and is essential for our survival, it also prevents the delivery of medicines to the brain in sufficient quantities to have therapeutic effect.
+Added: We have invented, developed, and validated a proprietary technology, called the TransportVehicle TM ("TV"), to address the blood-brain barrier challenge and enable a new class of barrier-crossing therapeutics.
+Added: The TV has a modular design enabling delivery of large molecules, i.e., enzymes, oligonucleotides, and antibodies, to all tissues of the body, including the brain, by crossing the blood-brain barrier after systemic administration.
+Added: 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 diseases.
+Added: Now, with the invention and validation of our TV technology, we are leading the field in delivering on the potential of biotherapeutics to transform the lives of individuals with neurodegenerative diseases, lysosomal storage disorders, and other serious diseases.
We are building a broad portfolio of therapeutic candidates by investing in our 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.
Our most advanced TV-enabled program is tividenofusp alfa (DNL310, ETV:IDS) for the potential treatment of mucopolysaccharidosis II (" MPS II ", or Hunter syndrome ).
−Removed: We plan to submit a biologics license application ("BLA") for tividenofusp alfa under the FDA's accelerated approval pathway in early 2025 and we are preparing for a potential commercial launch in late 2025 or early 2026.
−Removed: Our 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”).
−Removed: Our small molecule clinical development portfolio includes BIIB122/DNL151 (small molecule LRRK2 inhibitor) for Parkinson’s disease;
−Removed: and DNL343 (small molecule eIF2B activator) for amyotrophic lateral sclerosis (“ALS”).
+Added: The biologics license application ("BLA") for tividenofusp alfa is under priority review for accelerated approval by the U.S.
+Added: Food and Drug Administration ("FDA"), and we have established commercial readiness in anticipation of the Prescription Drug User Fee Act (PDUFA) target action date of April 5, 2026.
+Added: Our TV-enabled clinical development portfolio also includes DNL126 (ETV:SGSH) for mucopolysaccharidosis IIIA (“MPS IIIA”, or Sanfilippo syndrome type A), DNL593 (PTV:PGRN) for frontotemporal dementia-granulin (“FTD- GRN ”), DNL628 (OTV:MAPT) for Alzheimer’s disease, and DNL952 (ETV:GAA) for Pompe disease.
We believe the combination of a clinically-validated delivery platform and a maturing therapeutic portfolio will position us for long-term success in our goal to deliver barrier-crossing, targeted, and effective medicines.
Key elements of our strategy include:
−Removed: 1) Discover and develop a new class of barrier-crossing therapeutics by leveraging our TV platforms and deep expertise in BBB biology to enhance the delivery of biotherapeutics to the brain and throughout the body.
+Added: Advance a new class of barrier-crossing therapeutics by leveraging our TV platforms and deep expertise in blood-brain barrier biology to enhance the delivery of biotherapeutics to the brain and throughout the body.
Accelerate and expand a broad portfolio of TV-based product candidates to fully unlock the potential of barrier-crossing therapeutics, applying patient-informed development and driving biomarker-guided regulatory approvals.
Launch initial products targeting rare lysosomal storage diseases as a strategic foundation for expansion into common neurodegenerative conditions and other serious diseases, while building integrated capabilities for long-term growth and profitability.
+Added: Our “D3X3” strategy reflects our next phase of execution and is anchored in our “Discover, Develop, Deliver” (D3) framework, with three-year objectives (X3) across our portfolio, as we transition from platform validation to delivery and scalable growth.
+Added: Our goals are to (i) deliver two growing commercial brands, tividenofusp alfa (ETV:IDS) for Hunter syndrome and DNL126 (ETV:SGSH) for Sanfilippo syndrome type A, establishing the foundation for a durable rare disease franchise;
+Added: (ii) achieve five clinical proof-of-concept readouts across our portfolio, including programs in Alzheimer’s disease (ATV:Abeta and OTV:MAPT), FTD- GRN (PTV:PGRN), Pompe disease (ETV:GAA), and Parkinson’s disease (LRRK2 inhibitor);
+Added: and (iii) advance four to six additional TV-enabled programs into the clinic ( Figure 1) .
+Added: We believe disciplined and efficient execution against these objectives will demonstrate the breadth and scalability of our TV platform, position us to deliver sustainable long-term growth, and advance our mission to unlock the full potential of biotherapeutics with the goal of transforming the lives of people living with serious diseases.
+Added: Denali’s D3X3 Three-Year Strategic Framework.
+Added: Illustration of Denali’s evolution over time in the context of our Discover, Develop, Deliver (D3) foundation and three-year (D3X3) objectives (2026 - 2028) to deliver two growing brands, achieve five clinical proof-of-concept readouts, and advance four to six new clinical programs as we transition from platform validation to commercial delivery and scalable growth.
We expect our first potential product launches will be with tividenofusp alfa for MPS II followed by DNL126 for MPS IIIA.
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Lysosomal storage diseases afflict more than 30,000 individuals worldwide.
−Removed: About two-thirds of these diseases affect the CNS;
−Removed: however, the current standard treatment, enzyme replacement therapy, does not address CNS manifestations, even for the lysosomal storage diseases where enzyme replacement therapy is available.
−Removed: Our ETV therapeutics are designed as next-generation enzyme replacement therapies to address both CNS and somatic manifestations of lysosomal storage diseases.
−Removed: Our planned BLA submission for tividenofusp alfa under the accelerated approval pathway is based on alignment with the FDA that cerebrospinal fluid ("CSF") heparan sulfate may be used as a surrogate biomarker for MPS II.
−Removed: Likewise, given that CSF heparan sulfate is also the primary substrate in MPS IIIA, we are seeking to align with the FDA on an accelerated approval path for DNL126.
−Removed: Together, we expect these two programs to be the foundation of a broad commercial franchise of ETV-enabled enzyme replacement therapies with a collective market potential of over $3 billion.
−Removed: We are 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 building a right-sized team in commercial and medical affairs to support tividenofusp alfa and additional ETV launches.
+Added: About two-thirds of these diseases affect the central nervous system;
+Added: however, the current standard treatment, enzyme replacement therapy, does not address central nervous system manifestations, even for the lysosomal storage diseases where enzyme replacement therapy is available.
+Added: Our ETV therapeutics are designed as next-generation enzyme replacement therapies to address both central nervous system and somatic manifestations of lysosomal storage diseases.
+Added: Our BLA submission for tividenofusp alfa under the accelerated approval pathway is based on alignment with the FDA that cerebrospinal fluid ("CSF") heparan sulfate may be used as a surrogate biomarker for MPS II.
+Added: Likewise, given that CSF heparan sulfate is also the primary substrate in MPS IIIA, we have aligned with the FDA on an accelerated approval path for DNL126.
+Added: Together, we expect these two programs to have a combined market opportunity of over $1 billion and to be the foundation of a broad commercial franchise of ETV-enabled enzyme replacement therapies with a collective market potential of over $5 billion.
+Added: We have established commercial readiness for tividenofusp alfa including continued dialogue with advocacy groups, prescribers and payers, and building a suite of patient support services and capabilities to enable access.
+Added: We have established a right-sized team in commercial and medical affairs to support tividenofusp alfa and additional ETV launches, including DNL126 (ETV:SGSH) for MPS IIIA.
We include PTV:PGRN as one of our ETV franchise programs as it has a similar mechanism of action in increasing levels of deficient or missing protein to improve lysosomal function.
We have an active collaboration with Takeda Pharmaceutical Company Limited ("Takeda") for the development and commercialization of TAK-594/DNL593 (PTV:PGRN) for FTD- GRN .
−Removed: We aim to leverage certain efficiencies of scale to support the commercialization of additional product candidates to create an enzyme replacement franchise enabled by our ETV platform.
−Removed: Our next ETV programs advancing to the clinic are DNL952 (ETV:GAA) for Pompe disease and DNL111 (ETV:Gcase) for Parkinson's disease.
−Removed: We intend to commercialize these product candidates, if approved, in key markets and/or leverage partnerships to ensure optimal access for patients.
−Removed: In parallel, we are advancing TV-enabled programs for common neurodegenerative diseases, such as Alzheimer’s disease and Parkinson's disease, which afflict over 40 million individuals worldwide.
−Removed: Our most advanced programs in the investigational new drug ("IND")-enabling stage of development are DNL628 (OTV:MAPT), DNL921 (ATV:Abeta), and DNL422 (OTV:SNCA).
−Removed: Along with amyloid plaques, tau tangles are a pathological hallmark of Alzheimer's disease.
+Added: We are initiating clinical development with DNL952 (ETV:GAA) for late-onset Pompe disease, expanding the reach of our TV platform into muscle disease.
+Added: We intend to commercialize these product candidates, if approved, in key markets and/or leverage partnerships or distributors to ensure optimal access for patients.
+Added: Launching in rare indications first gives us the opportunity to build and establish our own commercial organization so that we are poised for success in larger indications over time.
+Added: In parallel, we are advancing TV-enabled programs for common neurodegenerative diseases, such as Alzheimer’s disease and Parkinson's disease, which afflict over 40 million individuals worldwide and have a market potential of over $5 billion per indication.
+Added: We have advanced DNL628 (OTV:MAPT) targeting tau into a Phase 1b clinical study for Alzheimer’s disease, and we plan to submit a regulatory application in the first half of 2026 to begin clinical testing of DNL921 (ATV:Abeta) targeting amyloid plaques.
+Added: Amyloid plaques and tau tangles are pathological hallmarks of Alzheimer's disease.
We are targeting both of these pathologies with our ATV and OTV platforms, respectively, aiming to deliver the next generation of anti-amyloid therapeutics and a potential first-in-class anti-tau therapeutic.
1 unchanged sentence
Likewise, preclinical studies with OTV:MAPT have demonstrated robust and sustained reductions of tau protein.
−Removed: Toxic protein accumulation is also a hallmark in Parkinson's disease and we have demonstrated robust reductions of alpha-synuclein with OTV:SNCA in preclinical studies.
−Removed: For late-stage development and commercialization in common indications such as Alzheimer's disease and Parkinson's disease, we may plan to initially leverage strategic collaborations that contribute existing global infrastructure.
−Removed: Launching in rare indications first also gives us the opportunity to build and establish our own commercial organization so that we are poised for success in larger indications over time.
+Added: For late-stage development and commercialization in common indications, such as Alzheimer's disease, we may plan to initially leverage strategic collaborations that contribute existing global infrastructure.
In addition to our development programs for neurodegenerative and lysosomal storage diseases, we have a robust discovery effort to further expand our portfolio and capture the full potential of our TV platform to enhance delivery of biotherapeutics to all tissues in the body.
−Removed: We are pursuing opportunities of unmet need in multiple disease areas including oncology, inflammation, neuromuscular disease, and metabolic disease.
+Added: We are also pursuing opportunities of unmet need in other disease areas including oncology.
For example, we have engineered a bispecific ATV:HER2 antibody and have demonstrated preclinically improved peripheral anti-tumor activity as well as enhanced brain uptake of the bispecific ATV:HER2 as 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.
−Removed: Our 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 BBB.
+Added: Our therapeutic portfolio also includes BIIB122/DNL151 (LRRK2 inhibitor) for Parkinson's disease, a small molecule drug candidate that does not use the TV platform but is engineered with optimized chemical and physical properties to cross the blood-brain barrier.
Denali has an active collaboration with Biogen Inc.’s subsidiaries, Biogen MA Inc.
−Removed: (“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.
−Removed: Biogen is conducting the global Phase 2b LUMA study, which is evaluating the ability of BIIB122 to slow disease progression as compared to placebo in approximately 640 participants with early-stage Parkinson's disease;
−Removed: completion of enrollment is expected in 2025.
+Added: (“BIMA”) and Biogen International GmbH (“BIG”) (BIMA and BIG, collectively, “Biogen”) for the development and commercialization of BIIB122/DNL151.
+Added: Biogen is conducting the global Phase 2b LUMA study, which is evaluating the ability of BIIB122 to slow disease progression as compared to placebo in participants with early-stage Parkinson's disease.
+Added: A total of 650 participants were enrolled in LUMA and data are expected in mid-2026.
In addition, Denali is conducting the complementary Phase 2a BEACON study in LRRK2-associated Parkinson's disease with the aim to generate biomarker and safety data to inform how LRRK2 inhibition may impact this disease.
−Removed: Our 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.
−Removed: Healey & AMG Center for ALS at Massachusetts General Hospital ("MGH") in collaboration with the Northeast ALS Consortium ("NEALS").
−Removed: Following previously reported topline results 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.
+Added: In March 2025, we officially opened our clinical biomanufacturing facility in Salt Lake City, Utah, expanding our U.S.
+Added: manufacturing capabilities and strengthening supply chain control and operational efficiency.
+Added: We have begun manufacturing drug supply for clinical trials to support expansion of our TV-enabled therapeutic portfolio.
+Added: We employ standard antibody manufacturing processes, including Chinese hamster ovary cell culture and Protein A affinity purification, which are compatible with existing global manufacturing infrastructure and enable efficient scale-up.
+Added: We expect to continue a hybrid manufacturing strategy, utilizing both internal capabilities and external contract manufacturers for additional capacity, sterile fill-finish, and oligonucleotide synthesis, as appropriate, to support our pipeline and future commercial needs.
Collaborations and partnering are central components of our strategy to build, develop, and commercialize our portfolio of product candidates.
2 unchanged sentences
("Sanofi"), for the development and commercialization of SAR443122/DNL758 (peripherally restricted small molecule RIPK1 inhibitor) in ulcerative colitis.
−Removed: We hold significant development and commercialization rights to all of our CNS programs, including the programs which are subject to our collaboration agreements with Biogen and Takeda, where we share responsibility for clinical development and share commercialization rights in the United States and China.
−Removed: Our costs of developing programs associated with these collaborations are largely covered through upfront payments, expected incoming milestones and cost sharing.
−Removed: We are also eligible to receive royalty payments for SAR443122/DNL758 from Sanofi.
+Added: We hold significant development and commercialization rights to all of our central nervous system programs, including the programs which are subject to our collaboration agreements with Biogen and Takeda, where we share responsibility for clinical development and share commercialization rights in the United States and China.
+Added: Our costs of developing programs associated with these collaborations are largely covered through upfront payments, expected incoming milestone and royalty payments, and cost sharing.
We may seek additional strategic partnering opportunities as we strive to capture the full value of our portfolio and platforms.
−Removed: We are guided by the core Denali Values of trust, growth, grit and unity, and these values form the foundation of our Environmental, Social & Governance (“ESG”) practices.
−Removed: Our working culture seeks to develop quality leaders, foster diversity and inclusion, and emphasize continuous growth.
−Removed: We embrace differences and acknowledge the valuable perspectives that a diverse and inclusive workforce brings to problem-solving and invention.
+Added: We are guided by the core Denali Values of trust, growth, grit and unity.
+Added: Our working culture seeks to develop quality leaders, emphasize continuous growth, and promote problem-solving and invention.
We strive to manage our operations in a way that is sustainable and reduces our impact on the environment, including through a Green Alternative program, which provides researchers with information on suitable alternative chemicals that have a lower environmental impact for common solvents.
1 unchanged sentence
We also maintain an ongoing commitment to corporate governance principles, with oversight of ESG matters by Denali's Board of Directors, and strong performance orientation in our compensation program.
−Removed: Our Approach to Crossing Biological Barriers and Defeating Neurodegeneration
−Removed: Historically, the BBB has been a major challenge to the development of medicines for diseases of the CNS.
−Removed: As a tightly knit layer of endothelial cells lining the vasculature of the brain, the BBB protects the brain from threats such as harmful substances and infections by closely regulating transport of molecules from the blood into and out of the brain.
−Removed: While the BBB is essential for our survival, it also prevents the delivery of medicines to the brain in sufficient quantities to have therapeutic effect.
−Removed: We have pioneered and are developing a new class of biotherapeutics to directly address the BBB challenge.
+Added: Our TransportVehicle TM Platform
+Added: Historically, the blood-brain barrier has been a major challenge to the development of medicines for diseases of the central nervous system.
+Added: As a tightly knit layer of endothelial cells lining the vasculature of the brain, the blood-brain barrier protects the brain from threats such as harmful substances and infections by closely regulating transport of molecules from the blood into and out of the brain.
+Added: While the blood-brain barrier is essential for our survival, it also prevents the delivery of medicines to the brain in sufficient quantities to have therapeutic effect.
+Added: We have pioneered and are developing a new class of biotherapeutics to directly address the blood-brain barrier challenge.
We invented, developed, and continue to optimize a proprietary technology, called the TransportVehicle TM ("TV"), to deliver our large molecule biotherapeutic candidates to the brain after systemic administration.
−Removed: Clinical and preclinical studies with several of our TV-enabled product candidates demonstrated high concentrations and broad distribution in all explored regions of the CNS and in key CNS cell types and showed improved pharmacodynamic effects compared to standard biotherapeutics.
−Removed: We believe that the TV can significantly increase the probability of success of biotherapeutics for CNS indications and can enable many new effective medicines.
−Removed: Our TV technology is modular and enables several classes of biotherapeutics to more effectively cross the BBB, including enzymes, antibodies, oligonucleotides, and other proteins.
−Removed: 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 transport of proteins into the brain ( Figure 1 ) in a process called receptor mediated transcytosis.
+Added: Our research has shown that the TV platform enables efficient delivery of biotherapeutics throughout the body, including the brain and other tissues that are traditionally difficult to reach.
+Added: By engaging endogenous receptor-mediated transport pathways, such as the transferrin receptor ("TfR"), the TV enhances distribution beyond the vasculature, supporting uptake in the central nervous system as well as peripheral tissues such as muscle, bone, and other organs.
+Added: This whole-body delivery capability allows us to address diseases with both central and systemic manifestations using a single therapeutic approach.
+Added: Our TV technology is modular and enables brain delivery of several classes of biotherapeutics including enzymes, oligonucleotides, antibodies, and other proteins ( Figure 2 ).
Engineering brain delivery.
−Removed: Schematic of the TV platform and modalities, designed to cross the BBB through receptor mediated transcytosis, leveraging endogenous receptors expressed on endothelial cells of the central nervous system vasculature.
−Removed: Our 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.
−Removed: 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), we use an Fc domain (the "legs") ( Figure 2 ).
−Removed: We have engineered the BBB receptor binding site into one of the Fc's (monovalent binding) and we can optimize binding affinity (how tightly the Fc binds its BBB receptor target) to enhance brain delivery and limit receptor degradation.
+Added: Schematic of the TV platform and modalities, designed to cross the blood-brain barrier through receptor mediated transcytosis, leveraging endogenous receptors expressed on endothelial cells of the central nervous system vasculature.
+Added: Our TV technology is differentiated from other blood-brain barrier 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.
+Added: Compared to conventional approaches that use the Fab portion (the "arms") of a full-length antibody to bind to the targeted blood-brain barrier receptor (e.g.,TfR), we use an Fc domain (the "legs") ( Figure 3 ).
+Added: We have engineered the blood-brain barrier receptor binding site into one of the Fc's (monovalent binding) and we can optimize binding affinity (how tightly the Fc binds its blood-brain barrier receptor target) and epitope (where the Fc binds its blood-brain barrier receptor target) to enhance brain delivery and limit receptor degradation.
+Added: Clinical and preclinical studies with several of our TV-enabled product candidates demonstrated high concentrations and broad distribution in all explored regions of the central nervous system and in key central nervous system cell types and showed improved pharmacodynamic effects compared to standard biotherapeutics.
We can also modify the amino acid sequences in the Fc to enable "conditional effector function", which is important for optimal activity of certain molecules, such as ATV:Abeta, that require immune cell activity for therapeutic effect.
−Removed: 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.
−Removed: Further, as the BBB receptor binding site is a short amino acid sequence integrated into the Fc, the TV maintains high fidelity to the natural protein and does not require appended sequences, thereby limiting risk of immunogenicity and infusion-related reactions ("IRRs").
+Added: 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 TfR.
+Added: Further, as the blood-brain barrier receptor binding site is a short amino acid sequence integrated into the Fc, the TV maintains high fidelity to the natural protein and does not require appended sequences, thereby improving stability and limiting risk of immunogenicity and infusion-related reactions ("IRRs").
In addition, Fc engineering enables modularity for the broadest utility to transport biologics including enzymes, oligonucleotides, and antibodies.
−Removed: Denali’s TV technology is modular and highly differentiated.
−Removed: Our pipeline of TV-enabled programs currently includes three clinical-stage programs and more than ten programs in preclinical development.
+Added: Denali’s Fc-based TV technology is modular, designed to optimize brain delivery and safety, and is highly differentiated from conventional Fab-based approaches.
+Added: Across TV modalities, we have shown in preclinical and/or clinical studies that TV enables broader brain biodistribution, enhanced target engagement, and normalization of key disease biomarkers ( Figure 4 ).
+Added: More than 200 subjects have participated in clinical studies of our TV-enabled programs and more than 11,000 doses of TV-enabled therapeutics have been administered for up to over five years (as of November 3, 2025).
We achieved proof of concept with safety and 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.
−Removed: 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.
−Removed: 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.
−Removed: Our most advanced TV-enabled program is tividenofusp alfa (ETV:IDS) for which we plan to submit a 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.
−Removed: In addition, we will seek alignment with the FDA on an accelerated approval path for our second ETV clinical program, DNL126 (ETV:SGSH) for the treatment of MPS IIIA.
−Removed: Together, we expect these two programs to be the foundation of a broad franchise of TV-enabled enzyme replacement therapies for lysosomal storage diseases ( Figure 3 ), which affect more than 30,000 people worldwide.
−Removed: Current standard-of-care enzyme replacement therapy does not cross the BBB and therefore does not address debilitating and progressive CNS degeneration present in about two thirds of lysosomal storage diseases.
−Removed: In addition to enabling brain delivery of enzymes, ETV may enhance therapeutic enzyme delivery to peripheral organs and tissues through the same receptor mediated transcytosis pathway utilizing TfR.
−Removed: In fact, in the open-label Phase 1/2 study, we have observed that treatment with tividenofusp alfa is associated with further reductions in levels of urine heparan sulfate (a key biomarker used clinically to monitor treatment effect in the periphery) beyond those achieved with standard of care as well as normal liver volume irrespective of prior enzyme replacement therapy exposure in participants with MPS II.
−Removed: In addition to our MPS II and MPS IIIA programs, we are 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.
−Removed: Our 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.
−Removed: DNL622 (ETV:IDUA) is also in IND-enabling stage for Hurler syndrome (MPS I).
−Removed: We have built clinical manufacturing capabilities for our TV-enabled programs and continue to expand our commercial capabilities in lysosomal storage diseases.
−Removed: Launching in rare indications first gives us the opportunity to build and establish our commercial organization so that we are poised for success in larger indications over time.
−Removed: Our ETV franchise is intended to deliver the next generation of enzyme replacement therapies designed to treat CNS and somatic manifestations of lysosomal storage diseases and other serious genetic diseases.
−Removed: Our ETV franchise lays the foundation for value creation to fuel expansion of our TV portfolio utilizing our ATV and OTV platforms.
−Removed: In preclinical studies, broader brain biodistribution of ATV and OTV-enabled antibodies and oligonucleotides are achieved compared to non-TV-enabled standard antibodies and oligonucleotides ( Figure 4 ) .
−Removed: We have further engineered these platforms to optimize certain pharmacokinetic, pharmacodynamic, and safety properties.
−Removed: For example, our 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.
−Removed: This feature addresses a known safety liability of utilizing TfR associated with depletion of reticulocytes (immature red blood cells) in the bone marrow where transferrin receptor is highly expressed.
−Removed: With cisLALA, the ATV:Abeta construct remains "immune silent" when bound to TfR, thus minimizing the risk of anemia from reticulocyte loss.
−Removed: We are 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.
−Removed: Superior biodistribution across all brain regions in non-human primates with ATV (left) and OTV (right) compared to non-TV-enabled standard antibody and ASO.
−Removed: In addition to our current focus on neurodegenerative and lysosomal storage diseases, we are exploring programs in oncology, inflammation, neuromuscular disease, and metabolic disease ( Figure 5 ).
−Removed: We may develop these additional programs ourselves in the future or seek partnerships.
−Removed: Denali’s TV technology provides opportunities for platform expansion.
−Removed: We believe that we can further expand our portfolio by targeting other BBB receptors that may confer different properties from targeting TfR.
−Removed: For example, we are targeting CD98hc, an amino acid transporter highly expressed on the BBB ( Figure 6 ).
−Removed: Our preclinical studies have established TV CD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.
+Added: For example, we have demonstrated the ability to correct neurodegeneration observed as substantial reduction and normalization of levels of neurofilament light chain (“NfL”), a biomarker of neuronal damage, in the Phase 1/2 study of tividenofusp alfa for MPS II as well as in multiple animal models.
+Added: TV provides high and uniform deposition of ATV across the brain with systemic delivery;
+Added: Middle Panel:
+Added: TV enables sustained brain tau knockdown with OTV:MAPT systemic delivery;
+Added: TV enables ETV:IDS to reduce serum NfL by >80%, achieving normal levels.
+Added: We believe that we can further expand our portfolio by targeting other blood-brain barrier receptors that may confer different properties from targeting TfR.
+Added: For example, we are targeting CD98hc, an amino acid transporter highly expressed on the blood-brain barrier ( Figure 5 ).
+Added: Our preclinical studies have established TV CD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported blood-brain barrier platforms.
We believe that the distinct properties of our two TV platforms, TV TfR and TV CD98hc may enable selection of the optimal platform for a given drug target thereby expanding our portfolio opportunities.
−Removed: TV TfR targets the transferrin receptor and TV CD98hc targets the CD98hc an amino acid transporter.
−Removed: Both receptors are highly expressed on the BBB and can be utilized for brain delivery of biotherapeutics.
−Removed: Biomarker-Driven Development and Approval
−Removed: As part of our strategy, we identify and validate biomarkers which 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 progression of product candidates to the next phase of development.
−Removed: When practicable, we are developing patient selection biomarkers for our programs to enable 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.
−Removed: Ultimately, we expect 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.
−Removed: We recognize the urgency for people living with neurodegenerative and lysosomal storage diseases to have effective treatment options.
−Removed: 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.
−Removed: We are actively engaged in efforts, which include collaboration with our 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.
−Removed: 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 our product candidates.
−Removed: In September 2024, we 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.
−Removed: 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.
−Removed: We intend to submit the BLA under the accelerated approval pathway in early 2025.
−Removed: CSF heparan sulfate is also the key disease biomarker for MPS IIIA (Sanfilippo syndrome), and we are seeking alignment with the FDA on an accelerated approval path for DNL126.
−Removed: We are developing a broad portfolio of targeted therapeutic candidates for neurodegenerative and lysosomal storage diseases with discovery efforts expanding into other serious disease areas ( Figure 7 ).
−Removed: Our programs are at various stages of clinical and preclinical development.
−Removed: In addition to our current clinical development portfolio, we expect to advance one to two new molecule entities (“NMEs”) into clinical development over the next three years beginning in 2025.
+Added: In addition, we have developed a dual TV platform that engages both TfR and CD98hc, combining complementary brain delivery properties and providing additional flexibility to optimize brain exposure across a range of therapeutic programs.
+Added: TV TfR targets TfR and TV CD98hc targets CD98hc, an amino acid transporter.
+Added: Both receptors are highly expressed on the blood-brain barrier and can be utilized for brain delivery of biotherapeutics.
+Added: Our Therapeutic Portfolio
+Added: Our therapeutic portfolio ( Figure 6 ) currently includes five clinical-stage TV-enabled programs and more than ten programs in preclinical development and spans a broad range of investigational therapies for neurodegenerative diseases, lysosomal storage disorders, and other serious diseases.
+Added: In addition to our current clinical development portfolio, we expect to advance four to six new molecule entities (“NMEs”) into clinical development over the next three years beginning in 2026.
We discuss our most advanced programs in further detail below.
−Removed: Our therapeutic portfolio is broad and diverse, spanning neurodegenerative diseases, lysosomal storage diseases, and other serious diseases that may be addressed by our TV platform for enabling and enhancing the delivery of biotherapeutics to target tissues.
−Removed: Clinical Programs
+Added: Our therapeutic portfolio is broad and diverse, spanning neurodegenerative diseases, lysosomal storage disorders, and other serious diseases that may be addressed by our TV platform for enabling and enhancing the delivery of biotherapeutics to target tissues.
+Added: Enzyme TransportVehicle TM Franchise
+Added: The Enzyme TransportVehicle TM ("ETV") franchise ( Figure 7 ) represents our first potential commercial application of the TV platform and is designed to address significant unmet needs in lysosomal storage disorders, many of which have both central nervous system and systemic manifestations.
+Added: By enabling efficient delivery of enzyme replacement therapies to the brain and throughout the body, the ETV franchise has the potential to improve upon existing standards of care that are limited by inadequate tissue distribution, and do not reach the brain in sufficient concentrations.
+Added: We believe the ETV franchise offers a substantial near- and long-term commercial opportunity, supported by validated disease biology, established regulatory pathways, and the historically high success rates of approximately 80 percent of enzyme replacement therapies in rare genetic diseases.
+Added: The ETV franchise is intended to serve as the commercial and financial foundation of our business, with the anticipated launch of tividenofusp alfa for Hunter syndrome and the advancement of additional ETV programs, including DNL126 for Sanfilippo syndrome type A, DNL593 for FTD- GRN , and DNL952 for Pompe disease.
+Added: Revenue generated from the ETV franchise is expected to support continued investment in our TV platform, enabling us to expand our pipeline across additional enzyme, antibody, and oligonucleotide-based therapeutics.
+Added: Through this strategy, we aim to build a sustainable, revenue-generating rare disease business while funding the long-term development of our broader platform across neurodegenerative and other serious diseases.
+Added: Our ETV franchise is intended to deliver the next generation of enzyme replacement therapies designed to treat central nervous system and somatic manifestations of lysosomal storage diseases and other serious genetic diseases.
+Added: ETV Clinical Programs
Tividenofusp alfa (DNL310, ETV:IDS) Enzyme Replacement Therapy Program for MPS II (Hunter Syndrome)
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The disease is characterized by a buildup of GAGs in lysosomes, the part of the cell that breaks down materials, including GAGs.
−Removed: The current standard of care enzyme replacement therapy partially treats the physical symptoms but does not cross the BBB, and as a result, cognitive and behavioral symptoms experienced by the majority of patients with MPS II are not addressed.
+Added: The current standard of care enzyme replacement therapy partially treats the physical symptoms but does not cross the blood-brain barrier, and as a result, cognitive and behavioral symptoms experienced by the majority of patients with MPS II are not addressed.
Therapies that address behavioral, cognitive, and somatic manifestations of the disease are one of the greatest unmet needs for this community.
−Removed: Tividenofusp alfa (DNL310, ETV:IDS), composed of the IDS enzyme fused to TV, is designed to deliver IDS into cells and tissues throughout the body, including the brain by crossing the BBB, with the goal of addressing behavioral, cognitive, and physical manifestations of Hunter syndrome (MPS II).
+Added: Tividenofusp alfa (DNL310, ETV:IDS), composed of the IDS enzyme fused to TV, is designed to deliver IDS into cells and tissues throughout the body, including the brain by crossing the blood-brain barrier, with the goal of addressing behavioral, cognitive, and physical manifestations of Hunter syndrome (MPS II).
In March 2021, the U.S.
2 unchanged sentences
In January, 2025, the FDA granted tividenofusp alfa Breakthrough Therapy Designation for MPS II.
−Removed: In September 2024, we 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.
+Added: In September 2024, we announced a successful Type C meeting with FDA’s Center for Drug Evaluation and Research (“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.
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.
−Removed: 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.
−Removed: We are engaged in prelaunch activities including continued dialogue with prescribers and payers, building a suite of patient support services and capabilities to enable broad access.
−Removed: We are building a right-sized team in commercial and medical affairs to support tividenofusp alfa and additional ETV product launches.
−Removed: The ongoing open-label extension of the Phase 1/2 study will generate long-term safety data.
+Added: In May 2025, we announced that the BLA was submitted under the accelerated approval pathway and included 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.
+Added: In July 2025, we announced that the FDA accepted the BLA submission and assigned a PDUFA target action date of January 5, 2026.
+Added: In October 2025, we announced that the FDA had extended its review timeline of the BLA and assigned a new PDUFA target date of April 5, 2026.
+Added: The extension followed our submission of updated clinical pharmacology data in response to an information request from the FDA as part of the standard review process and was not related to efficacy, safety or biomarkers.
+Added: The FDA classified the submission as a Major Amendment (MA) to the BLA, which, per FDA regulations, extended the review by three months.
+Added: No additional data were requested by the FDA in the MA letter.
+Added: We believe that the updated information submitted in the amendment does not affect the clinical pharmacology or benefit-risk conclusions of the BLA.
+Added: Tividenofusp alfa received Rare Pediatric Disease Designation (“RPDD”) status for the treatment of Hunter syndrome in January 2019.
+Added: In December 2025, we announced ongoing dialogue with the FDA related to the eligibility of tividenofusp alfa to receive a Rare Pediatric Disease Priority Review Voucher (“PRV”) upon approval.
+Added: Because we submitted a filing of our intent to request a PRV after the initial BLA submission, based on discussions with the FDA, we may not be eligible to receive the PRV.
+Added: Therefore, we are not including any potential future proceeds from the sale of a PRV in our financial planning.
+Added: We continue to work with the FDA and the FDA will determine whether to award a PRV upon approval of tividenofusp alfa.
+Added: The Late Cycle Meeting with the FDA has been completed and labeling discussions are ongoing.
+Added: We are building our launch plans in partnership with the MPS II community, and we are engaged in prelaunch activities, including continued dialogue with advocacy groups, prescribers and payers, and building a suite of patient support services and capabilities to enable access.
+Added: We have built a right-sized team in commercial and medical affairs to support tividenofusp alfa and additional ETV product launches.
We are also conducting the global Phase 2/3 COMPASS study, which will support global approval.
2 unchanged sentences
Cohort A includes children ages ≥2 to <6 years with neuronopathic disease;
−Removed: cohort B includes children ages ≥6 to <26 without neuronopathic disease.
−Removed: Enrollment of the planned 33 participants with neuronopathic MPS II in Cohort A was achieved in late 2024, and we decided to increase the sample size of Cohort A by 9 participants, bringing the total to 42 participants.
−Removed: Cohort B continues to enroll participants with non-neuronopathic MPS II.
−Removed: We have previously reported interim analyses from the Phase 1/2 study and most recently reported the primary analysis of efficacy and safety at the 2025 WORLD Symposium TM in February 2025.
−Removed: 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.
−Removed: The primary analysis included data from 47 participants who completed the 24-week treatment period and additional long-term follow-up.
−Removed: 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.
−Removed: In addition, long-term safety data with median follow-up of two years, and out to more than four years, demonstrated that tividenofusp alfa was generally well tolerated.
−Removed: Key results are summarized below.
−Removed: The primary efficacy and safety analysis reported at the 2025 WORLD Symposium TM demonstrated that treatment with tividenofusp alfa resulted in a substantial reduction from baseline in CSF and urine heparan sulfate levels by Week 24 with the majority of participants below the upper limit of the normal range;
−Removed: this effect was maintained through Week 153, or nearly three years, of treatment ( Figure 8 ).
−Removed: CNS and peripheral heparan sulfate.
−Removed: a Heparan sulfate was measured as a sum of the disaccharides D0A0, D0A6, D0S0, and D2S6 by mass spectrometry after enzymatic digestion.
−Removed: b Based on MMRM model with fixed effects for visit week, age group at tividenofusp alfa initiation, genotype, and baseline CSF or urine HS (urine HS was also adjusted for prior enzyme replacement therapy ("ERT") status group);
−Removed: only protocol planned visits consistent across all cohorts and with ≥ 5 observations were included in the model.
−Removed: c CFB for timepoints with collection for limited dose escalation cohorts:
−Removed: W5 (cohort A only), range:
−Removed: –24.9%, –93.1%;
−Removed: W7 (cohort B only), range:
−Removed: –67.3, –92.7%;
−Removed: W9 (cohort A only), range –36.1%, –92.5%.
−Removed: BL, baseline;
−Removed: CFB, change from baseline;
−Removed: CI, confidence interval;
−Removed: CNS, central nervous system;
−Removed: CSF, cerebrospinal fluid;
−Removed: MMRM, mixed model for repeated measures;
−Removed: ULN, upper limit of normal;
−Removed: Robust reduction from baseline in serum NfL, a marker of neuronal damage, was observed with long-term dosing with the majority of participants below the upper limit of the normal range at Week 104 ( Figure 9 ).
−Removed: Robust reduction of serum NfL, a marker of neuronal damage, was observed with long-term dosing.
−Removed: Mean hearing thresholds improved from baseline in all tested frequencies (500, 1000, 2000, 4000 Hz) and reductions were statistically significant from week 24 onward ( Figure 10 ).
−Removed: Hearing Thresholds.
−Removed: Mean change from baseline in pure tone average by ABR (eHL) and audiometry (HL).
−Removed: Pure tone average is defined as the average across the four tested frequencies (500, 1000, 2000, and 4000 Hz).
−Removed: Pure tone average is only calculated if the numeric values of all individual frequencies are available.
−Removed: ABR (dB eHL) and any available standard hearing or behavioral audiometry test (in dB HL) are pooled.
−Removed: ABR is prioritized if more than one test is available within the same participant and analysis visit.
−Removed: ABR, auditory brainstem response;
−Removed: BL, baseline;
−Removed: CFB, change from baseline;
−Removed: dB, decibels;
−Removed: eHL, estimated hearing level;
−Removed: HL, hearing level.
−Removed: Long-term data demonstrated continued improvements from baseline in cognition and adaptive behavior ( Figure 11 ).
−Removed: Cognition and Adaptive Behavior.
−Removed: a Based on MMRM model with fixed effects for visit week, age group at tividenofusp alfa initiation, genotype, and baseline BSID-IIII cognitive raw or Vineland-3 adaptive behavior raw composite score.
−Removed: Only visits with number of observation ≥ 5 were included in the statistical model.
−Removed: b Adaptive behavior raw composite is the derived sum of raw scores of eight subdomains (receptive, expressive, personal, interpersonal relationships, play and leisure, coping skills, fine motor, and gross motor).
−Removed: To evaluate change in adaptive behavior across both instruments, scores were converted from VABS-II to Vineland-3 using an errors-in-variables linear regression model adjusted by age.
−Removed: BL, baseline;
−Removed: BSID-III, Bayley Scales of Infant and Toddler Development, third edition;
−Removed: CFB, change from baseline;
−Removed: CI, confidence interval;
−Removed: MMRM, mixed model for repeated measures;
−Removed: VABS-II, Vineland Adaptive Behavior Scales, second edition;
−Removed: Vineland-3, Vineland Adaptive Behavior Scales, third edition;
−Removed: Administration of tividenofusp alfa was generally well tolerated in study participants.
−Removed: Most treatment-related adverse events ("TEAEs") were mild or moderate, including IRRs, anemia, vomiting, pyrexia, respiratory infections and rash.
−Removed: Serious TEAEs in three participants (6.4%) were manageable, with resolution or stabilization with continued treatment.
−Removed: One participant discontinued treatment for reasons related to a moderate IRR and other non-treatment-related adverse events.
+Added: cohort B includes children and adults ages ≥6 to <26 without neuronopathic disease.
+Added: Cohort A enrollment of a total of 44 participants was completed in December 2025, and Cohort B continues to enroll participants with non-neuronopathic MPS II.
+Added: We have previously reported interim analyses from the Phase 1/2 study, and, most recently, the primary analysis upon which the BLA was based was published in The New England Journal of Medicine in January 2026 (Muenzer et al., NEJM , 2026).
+Added: The primary objective of the Phase 1/2 study was safety and tolerability, and secondary objectives evaluated central nervous system and peripheral effects of tividenofusp alfa by measuring the GAG heparan sulfate (HS) in cerebrospinal fluid (CSF) and urine, adaptive behavior and liver volume.
+Added: The study evaluated treatment in 47 ERT-naïve (n=15) and previously treated (n=32) study participants (aged 0.3–13 [median, 5] years), ranging from less severe to severe disease variants.
+Added: Safety and tolerability data were consistent with previously reported results from this Phase 1/2 trial ( Table 1 ).
+Added: The most common treatment-related adverse events were infusion-related reactions, which decreased in incidence with continued use ( Figure 8A ).
+Added: At baseline, 19% of the participants had anemia of grade 1 or higher.
+Added: Decreases in the hemoglobin level were observed early with tividenofusp alfa treatment but generally returned to baseline values ( Figure 8B ), were clinically manageable, and did not result in discontinuation of study participation.
+Added: Causes of anemia are probably multifactorial, including nutritional deficiencies, frequent phlebotomy early in the study, and possible immune effects such as the formation of antidrug antibodies.
+Added: Summary of Adverse Events in Phase 1/2 study of tividenofusp alfa (Muenzer et al ., NEJM, 2026)
+Added: Infusion-Related Reactions and Hemoglobin Levels over Time.
+Added: Infusion related reactions (A) decreased in frequency and severity over time and early decreases in hemoglobin levels (B) generally returned to baseline values, were clinically manageable, and did not result in discontinuation of study participation in the Phase 1/2 study of tividenofusp alfa (Muenzer et al ., NEJM, 2026).
+Added: Results from key secondary endpoints included:
+Added: • Mean CSF levels of HS, the primary substrate found in high levels in the brain of individuals with MPS II, were reduced from baseline by 91% (95% CI, 90% to 92%;
+Added: N=44) at Week 24 and maintained through Week 153 (92%;
+Added: 95% CI, 90% to 93%;
+Added: At Week 24, 93% of study participants reached levels within the range of children without MPS II ( Figure 9 ).
+Added: • Mean urine HS levels were reduced by 88% (95% CI, 85% to 90%;
+Added: N=40) from baseline at Week 24 and maintained through Week 153 (91%;
+Added: 95% CI, 87% to 94%;
+Added: At Week 24, 58% of participants reached levels in the range of children without MPS II ( Figure 9 ).
+Added: • Serum neurofilament light (NfL) chain levels, a well-established biomarker of neuronal injury and an exploratory endpoint of the study, were reduced by 21% (95% CI, 5% to 35%;
+Added: N=34) from baseline at Week 49.
+Added: At Week 153, NfL was reduced by 76% (95% CI, 68% to 82%;
+Added: N=13), and 85% of participants reached levels within the range of children without MPS II ( Figure 9 ).
+Added: • Clinical results included normalization in liver volume after 24 weeks, and as shown in Figure 10 , improvement in hearing thresholds across tested frequencies, and skill gains in most participants on measures of adaptive behavior and cognition.
2026 expected progress and milestones:
−Removed: • Submit BLA for tividenofusp alfa in MPS II under the accelerated approval pathway in early 2025
−Removed: commercial launch in late 2025 or early 2026
−Removed: DNL126 (ETV:SGSH) Program for MPS IIIA (Sanfilippo Syndrome A)
+Added: • Commercial launch pending approval with PDUFA target action date of April 5, 2026.
+Added: Treatment with tividenofusp alfa over a median duration of 2 years was associated with reductions in central nervous system and peripheral biomarkers of substrate accumulation and neuronal injury to levels within the range of unaffected children (Muenzer et al., NEJM 2026).
+Added: While on tividenofusp alfa, clinical outcomes showed skill gains relative to baseline on measures of adaptive behavior, cognition and hearing threshold improvement represented as pure tone average (PTA) (Muenzer et al ., NEJM, 2026).
+Added: DNL126 (ETV:SGSH) Program for MPS IIIA (Sanfilippo Syndrome Type A)
MPS III, also called Sanfilippo syndrome, is a rare, genetic lysosomal storage disease that causes neurodegeneration.
2 unchanged sentences
There are no approved treatments for MPS IIIA.
−Removed: DNL126 (ETV:SGSH) is composed of SGSH fused to TV, which is engineered to cross the BBB via receptor mediated transcytosis into the brain and to enable broad delivery of SGSH into cells and tissues throughout the body with the goal of treating MPS IIIA.
−Removed: In January 2024, we commenced dosing of 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.
−Removed: The core study period is 25 weeks (approximately 6 months) and is followed by a 72-week (approximately 18 month) open-label extension.
−Removed: In February 2024, we presented preclinical data at the 2024 WORLD Symposium TM demonstrating that DNL126 improved lysosomal and microglial morphology, neurodegeneration, and cognitive function in adult MPS IIIA mice.
+Added: DNL126 (ETV:SGSH) is composed of SGSH fused to TV, which is engineered to cross the blood-brain barrier via receptor mediated transcytosis into the brain and to enable broad delivery of SGSH into cells and tissues throughout the body with the goal of treating MPS IIIA.
+Added: Preclinical data demonstrate 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.
+Added: In January 2024, we commenced dosing of 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.
+Added: The core study period is 25 weeks followed by an open-label extension period through 193 weeks.
In June 2024, we 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, and collaborative engagement has commenced to support progress to a pre-BLA meeting.
−Removed: In November 2024, we announced that preliminary data from up to 25 weeks of dosing in the ongoing open-label Phase 1/2 study in MPS IIIA participants demonstrated a substantial reduction in CSF heparan sulfate levels from baseline, including normalization.
−Removed: The safety profile supports continued development.
−Removed: The most frequent treatment emergent adverse events were IRRs of mild and moderate severity in all participants.
−Removed: There was one serious adverse event considered by the investigator not related to drug.
−Removed: Based on the preliminary Phase 1/2 results and a positive regulatory environment, we expanded the Phase 1/2 study and we continue to assess development plans for DNL126 including an accelerated approval path.
+Added: In August 2025, we announced having reached alignment with the FDA’s CDER that cerebrospinal fluid heparan sulfate (CSF HS) may be considered a reasonably likely surrogate endpoint to predict clinical benefit and may therefore be used to support accelerated approval of DNL126 for MPS IIIA.
+Added: We also announced that additional 49-week data from the ongoing open-label Phase 1/2 study were consistent with previously announced 25-week data, demonstrating a significant reduction in CSF HS from baseline, including normalization, and a safety profile that supports continued development.
+Added: The Phase 1/2 study completed enrollment of a total of 20 participants with MPS IIIA in September 2025.
+Added: In February 2026, we reported preliminary results from the Phase 1/2 study at the WORLDSymposium.
+Added: Preliminary data from 14 participants enrolled at the time of the clinical data cut-off (June 4, 2025) were presented, including biomarker results from the dose-finding cohorts (n=8) and safety data from the dose-finding and efficacy cohorts (n=14).
+Added: Preliminary biomarker results from dose-finding cohorts showed treatment with DNL126 resulted in a mean reduction in cerebrospinal fluid heparan sulfate (CSF HS) of 80% (95% CI:
+Added: 43% to 93%) and 61% in CSF GM3 (95 % CI:
+Added: 36% to 76%), a bio marker of lysosomal function, from baseline at Week 49 ( Figure 11 ).
+Added: Normalization of CSF HS and CSF GM3 levels was observed in three and six of seven individuals, respectively, with CSF samples available at Week 49.
+Added: A mean reduction in urine HS of 83% (95% CI:
+Added: 77% to 87%) from baseline was observed at Week 49, and improvement in liver volume was observed as early as Week 25 ( Figure 12 ).
+Added: Preliminary safety data from dose finding and efficacy cohorts up to the data cutoff date, including 13 of 14 participants treated for at least 24 weeks and 8 of 14 participants treated for at least 48 weeks, demonstrated that the safety profile of DNL126 is generally consistent with established enzyme replacement therapies.
+Added: The most common treatment-related adverse events in the study were infusion-related reactions ( Table 2 ).
2026 expected progress and milestones:
−Removed: • Seek alignment with the FDA on an accelerated approval pathway for DNL126 for MPS IIIA
+Added: • Report preliminary data at WORLDSymposium ( presented February 2026 ).
+Added: • Initiate activities to begin the Phase 3 confirmatory study.
+Added: Robust reductions from baseline in CSF heparan sulfate and CSF GM3 with normalization of levels in 3 and 6 of 7 participants, respectively, who had CSF samples at Week 49 after treatment with DNL126.
+Added: Substantial reductions from baseline in urine HS and liver volume at the first post-baseline time point where these endpoints were measured.
+Added: Treatment-Emergent Adverse Events (TEAEs) reported in >30% of participants (n=14) from dose-finding and efficacy cohorts as of the clinical cutoff date (June 4, 2025).
TAK-594/DNL593 (PTV:PGRN) Program for FTD- GRN
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While the progression of symptoms varies by individual, FTD brings an inevitable decline in function together with changes in personality and social behaviors, and sometimes language and/or motor dysfunction.
−Removed: Mutations in the granulin (" GRN" ) gene, which encodes the PGRN protein, generally result in reduced levels of PGRN and are among the most common genetic causes of FTD.
+Added: Mutations in the granulin (" GRN" ) gene, which encodes the progranulin ("PGRN") protein, generally result in reduced levels of PGRN and are among the most common genetic causes of FTD.
It is estimated that FTD- GRN is 5-10% of the total FTD patient population, or more than 25,000 people worldwide.
There are currently no approved medicines to stop or slow the progression of FTD or FTD- GRN .
−Removed: TAK-594/DNL593 (PTV:PGRN) is an investigational, brain-penetrant PGRN replacement therapy enabled by Denali's TV platform and designed to restore PGRN levels in the brain without interfering with normal PGRN transport and processing.
+Added: TAK-594/DNL593 (PTV:PGRN) is an investigational, PGRN replacement therapy enabled by Denali's TV platform and designed to cross the blood-brain barrier and restore PGRN levels in the brain without interfering with normal PGRN transport and processing.
As described in more detail in “Business - Licenses and Collaborations” below, we are collaborating with Takeda to co-develop and co-commercialize TAK-594/DNL593 (PTV:PGRN).
7 unchanged sentences
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.
−Removed: 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.
−Removed: Both study participants’ IRRs resolved within the same day with infusion discontinuation and standard treatment measures.
+Added: The pause was based on infusion-related reactions reported in two study participants, one Grade 2 and one Grade 3 in severity and both deemed serious adverse events.
+Added: Both study participants’ infusion-related reactions 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.
−Removed: In August 2024, we 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.
−Removed: In January 2025, we announced that dosing is ongoing in the study.
−Removed: 2025 expected progress and milestones:
−Removed: • Continue dosing in Part B of the Phase 1/2 study in FTD-GRN
−Removed: BIIB122/DNL151 LRRK2 Inhibitor Program for Parkinson's disease
−Removed: Parkinson's disease is one of the most common brain diseases, affecting approximately 10 million people worldwide.
−Removed: It is considered to be a movement disorder because patients can experience tremors, slowness of movement, stiffness and difficulty with walking and balance.
−Removed: In addition, Parkinson's patients can have other non-motor type problems such as constipation, depression and memory loss.
−Removed: The Parkinson symptoms are a result of the loss of dopamine-producing cells in the brain, which is currently thought to be caused by a combination of genetic and environmental risk factors.
−Removed: Mutations in the LRRK2 gene are one of the most common genetic risk factors for Parkinson's disease.
−Removed: LRRK2 is involved in maintaining a healthy cellular environment by regulating lysosomal function through modification of Rab proteins.
−Removed: Increased levels of LRRK2 kinase activity lead to lysosomal dysfunction, which is believed to contribute to neurodegeneration.
−Removed: Inhibition of LRRK2 activity has the potential to slow the progression of Parkinson’s disease in patients, with and without known genetic risks based on restoration of lysosomal function.
−Removed: As described in more detail in “Business - Licenses and Collaborations” below, we are collaborating with Biogen to co-develop and co-commercialize our small molecule inhibitors of LRRK2 for Parkinson's disease.
−Removed: BIIB122/DNL151 is the most clinically advanced small molecule inhibitor of LRRK2 currently in clinical testing for Parkinson's disease.
−Removed: Biogen is conducting the global Phase 2b LUMA study, which commenced in May 2022 and is evaluating the efficacy and safety of BIIB122/DNL151 as compared to placebo in approximately 640 participants with early-stage Parkinson's disease.
−Removed: Enrollment of LUMA is expected to be completed in 2025.
−Removed: 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.
−Removed: Furthermore, 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 improvement of lysosomal function.
−Removed: BIIB122/DNL151 was generally well tolerated across a broad range of doses for up to 28 days, the longest treatment duration in both studies.
−Removed: In February 2024, we 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 we are operationalizing to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2.
−Removed: This agreement includes committed funding of $75.0 million, of which $25.0 million was received in 2024, and the remainder will be triggered based on time and operational milestones in the study.
−Removed: Biogen will continue to conduct the ongoing global Phase 2b LUMA study in early-stage Parkinson’s disease.
−Removed: Denali and Biogen will co-commercialize BIIB122/DNL151 assuming regulatory approval.
−Removed: The third party will be eligible to receive low single-digit royalties from Denali on annual worldwide net sales of LRRK2 inhibitors for the treatment of Parkinson’s disease, with royalty amounts varying based on the scope of the label .
−Removed: In December 2024, we 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.
−Removed: 2025 expected progress and milestones:
−Removed: • Complete enrollment of the Phase 2b LUMA study in early-stage PD
−Removed: • Continue enrollment in the Phase 2a study in PD related to pathogenic variants of LRRK2
−Removed: Other LRRK2 Compounds
−Removed: Genetic and functional studies have linked LRRK2 and other proteins that modulate lysosomal function to Crohn's disease.
−Removed: Excessive LRRK2 activity leads to a reduction in lysosomal function, which contributes to the inflammation and intestinal dyshomeostasis that are characteristic of this disorder.
−Removed: We have discovered potent and selective small molecule inhibitors of LRRK2 and have selected a lead clinical candidate (DNL975) for treatment of Crohn's disease.
−Removed: As described in more detail in “Business - Licenses and Collaborations” below, we are collaborating with Biogen on the Peripheral LRRK2 program.
−Removed: DNL343 eIF2B Activator Program for ALS
−Removed: DNL343 is a novel small molecule investigational therapeutic that targets eIF2B, a central regulator of the integrated stress response ("ISR").
−Removed: The ISR appears to be overactive in ALS, leading to the formation of stress granules containing TDP-43.
−Removed: The buildup of TDP-43 is harmful and leads to neuronal degeneration.
−Removed: In preclinical data, inhibition of the ISR by DNL343 dissolves TDP-43 containing stress granules and decreases biomarkers of the ISR.
−Removed: Early clinical studies demonstrated that once-daily oral dosing with DNL343 was generally well tolerated and exhibited extensive penetration of CSF.
−Removed: In addition, robust inhibition of biomarkers associated with the ISR pathway was observed in blood samples from study participants.
−Removed: 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.
−Removed: Healey & AMG Center for ALS ("Healey Center") at Massachusetts General Hospital ("MGH") in collaboration with the Northeast ALS Consortium ("NEALS") clinical trial network.
−Removed: 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.
−Removed: Therapeutic candidates that enter the platform trial are chosen by a group of expert ALS scientists and members of the Healey & AMG Center.
−Removed: In May 2024, we announced completion of enrollment in Regimen G.
−Removed: In January 2025, we announced that the primary and key secondary endpoints were not met in the HEALEY ALS platform trial and that further analyses are anticipated later in 2025, including NfL and other fluid biomarkers, data from pre-specified subgroups, as well as extended findings from the active treatment extension period.
−Removed: 2025 expected progress and milestones:
−Removed: • Further analyses from Regimen G (DNL343) in Phase 2/3 HEALEY ALS Platform Trial.
−Removed: Eclitasertib (SAR443122/DNL758) RIPK1 Inhibitor Program for Peripheral Inflammatory Diseases:
−Removed: As part of our parallel development strategy, we have 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.
−Removed: Sanofi is solely responsible for the development and commercialization of peripherally restricted RIPK1 inhibitors.
−Removed: Sanofi is conducting a Phase 2 study of eclitasertib in patients with ulcerative colitis.
−Removed: Recruitment for the trial is ongoing and data are expected in 2026.
+Added: In August 20 24, we 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 infusion-related reactions , and prescreening of participants for Cohort B2 had begun.
+Added: In January 2025, we announced that dosing was ongoing in the study.
+Added: In February 2026, we announced that enrollment in the study is complete with a total of 40 participants with FTD- GRN enrolled.
2026 expected progress and milestones:
−Removed: • Continue Phase 2 UC study
−Removed: IND-Enabling Stage Programs
−Removed: Beginning in 2025, we expect to advance one to two additional programs to the clinic per year over the next three years across our TV-enabled franchises (ETV, OTV, and ATV).
−Removed: IND-enabling stage programs include:
−Removed: • DNL952 (ETV:GAA) for Pompe disease
−Removed: • DNL111 (ETV:Gcase) for Parkinson’s disease and Gaucher disease
−Removed: • DNL622 (ETV:IDUA) for Hurler syndrome (MPS I)
−Removed: • DNL628 (OTV:MAPT) targeting tau for Alzheimer’s disease
−Removed: • DNL422 (OTV:SNCA) targeting alpha synuclein for Parkinson’s disease
−Removed: • DNL921 (ATV:Abeta) targeting Abeta for Alzheimer’s disease
−Removed: These programs are described below.
−Removed: Enzyme Transport Vehicle (“ETV”) Programs
+Added: • Interim data from Phase 1/2 Part B study in participants with FTD- GRN.
DNL952 (ETV:GAA) for Pompe disease
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Infantile Onset Pompe Disease ("IOPD") and Late Onset Pompe Disease ("LOPD").
−Removed: IOPD affects the heart and causes ventilatory failure leading to early death, typically before one year age.
−Removed: 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.
+Added: IOPD affects the heart and causes ventilatory failure leading to early death, typically before one year age if left untreated.
+Added: 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 central nervous system involvement.
The estimated prevalence of Pompe disease is 5,000 to 10,000 people worldwide excluding India and China.
−Removed: Current standard of care is enzyme replacement therapy.
+Added: The current standard of care is enzyme replacement therapy.
Progressive motor weakness and respiratory failure remain unmet needs.
1 unchanged sentence
In preclinical studies, compared to standard of care enzyme replacement therapies, ETV:GAA has demonstrated superior correction of glycogen load in the brain and in muscle tissue with normalization of lysosomal volume and correction of autophagy ( Figure 14 ).
+Added: In November 2025, we announced submission of an Investigational New Drug ("IND") application to the FDA to begin clinical studies of DNL952.
+Added: In December 2025, we announced that the IND application for the Phase 1 study of DNL952 has been placed on clinical hold.
+Added: The FDA requested a protocol amendment to include a lower starting dose, revised inclusion criteria, certain safety monitoring commitments, and stopping rules.
+Added: These requests were related to preclinical hypersensitivity reactions observed in GAA mouse models, which are commonly observed across all GAA enzyme replacement therapies in mice.
+Added: The FDA did not request additional nonclinical studies.
+Added: We submitted a response to the FDA in December 2025 and announced in January 2026 that the FDA lifted the clinical hold.
+Added: We are proceeding with the planned Phase 1 study.
+Added: As part of our global development strategy for DNL952, we submitted a Clinical Trial Application (“CTA”) in the UK and Europe in the first quarter of 2026.
+Added: The clinical development plan for DNL952 includes an initial Phase 1 study in participants with LOPD, with planned cohorts evaluating different dose regimens of DNL952 in participants previously treated with second-generation enzyme replacement therapies, as well as optional additional cohorts, including treatment-naïve participants.
+Added: The study is intended to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of DNL952.
+Added: 2026 expected progress and milestones:
+Added: • Initiate dosing in Phase 1 clinical study of DNL952 in participants with LOPD.
In a rodent model of Pompe, ETV:GAA is superior to standard of care, alglucosidase alfa (Alg.) and avalglucosidase alfa-ngpt (Aval.), in correction of glycogen load in brain and in muscle (left) and superior reduction of lysosomal volume and autophagy in muscle (right).
6 unchanged sentences
anemia resulting in fatigue.
−Removed: Some people with Gaucher disease have CNS involvement:
+Added: Some people with Gaucher disease have central nervous system involvement:
abnormal eye movements, muscle rigidity, swallowing difficulties, and seizures.
3 unchanged sentences
Peripheral enzyme replacement therapy is the current standard of care for Gaucher disease, and no GBA-PD specific treatments currently approved.
−Removed: 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.
−Removed: In preclinical studies, ETV:Gcase shows improved substrate reduction in brain, liver and serum as compared to Gcase enzyme alone.
−Removed: Further we have engineered the recombinant Gcase enzyme for improved potency.
−Removed: Engineered ETV:GCase may enable highly stable and potent brain-penetrant enzyme replacement therapy for Parkinson’s disease and Gaucher disease.
+Added: DNL111 is composed of an engineered GCase variant with improved potency, fused to TV to enable replacement of GCase in peripheral tissues and the brain via blood–brain barrier transport.
+Added: In preclinical studies, ETV:GCase demonstrated enhanced substrate reduction in brain, liver, and serum compared to GCase enzyme alone.
+Added: This engineered ETV:GCase approach may enable a stable, potent, brain-penetrant enzyme replacement therapy for Parkinson’s disease and Gaucher disease.
+Added: DNL111 is currently in the IND-enabling stage of preclinical development .
DNL622 (ETV:IDUA) for MPS I (Hurler syndrome)
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MPS I is characterized by alterations in the skeleton, heart, respiratory system, and brain and affects approximately 1,500 individuals worldwide.
−Removed: 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.
+Added: DNL622 (ETV:IDUA) is composed of IDUA fused to TV, which is engineered to cross the blood-brain barrier via receptor-mediated transcytosis 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 currently in the IND-enabling stage of preclinical development.
−Removed: Oligonucleotide Transport Vehicle (“OTV”) Programs
−Removed: Oligonucleotides, such as ASOs and siRNAs, are designed to modify gene expression and hold promise as therapeutics for neurological disorders.
−Removed: A major challenge in their development, however, is that oligonucleotides are unable to cross the BBB on their own.
−Removed: Currently, 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.
−Removed: We are using our OTV platform to enable brain delivery of oligonucleotides by crossing the BBB following systemic administration.
+Added: Alzheimer’s Disease Portfolio
+Added: Alzheimer’s disease represents a large and growing unmet medical need, and recent advances in biomarkers and disease-modifying therapies have increased confidence in the ability to intervene earlier and more effectively in the disease course.
+Added: Despite these advances, existing antibody and nucleic acid therapeutic approaches are limited by suboptimal delivery to the brain, dose-related safety concerns, and, specific to antibodies or nucleic acid therapies respectively, difficultly engaging intracellular targets or the need for frequent or invasive administration.
+Added: We believe that improved delivery of biotherapeutics across the blood-brain barrier is critical to achieving greater efficacy, improved safety, and more convenient dosing in Alzheimer’s disease, particularly as treatment paradigms shift toward earlier-stage and presymptomatic patient populations
+Added: Our approach to Alzheimer’s disease leverages the TV platform to enhance brain delivery of antibodies and oligonucleotide-based therapeutics targeting key disease-driving pathologies, including amyloid beta and tau.
+Added: Our Alzheimer’s disease portfolio includes TV-enabled antibody programs designed to improve plaque clearance while potentially reducing vascular-related safety risks, as well as oligonucleotide programs intended to achieve broad and uniform distribution throughout the brain.
+Added: We expect to use validated fluid and imaging biomarkers to inform patient selection, assess target engagement, and enable efficient clinical development.
+Added: Through this strategy, we aim to apply the TV platform to address limitations of existing therapies and advance next-generation treatments with the potential to modify disease progression across multiple stages of Alzheimer’s disease.
+Added: DNL628 Oligonucleotide TransportVehicle TM Microtubule-Associated Protein Tau (OTV:MAPT) for Alzheimer’s disease
+Added: Oligonucleotide-based therapeutics, such as ASOs and siRNAs, are designed to modify gene expression and hold promise as therapeutics for neurological disorders.
+Added: A major challenge in their development, however, is that oligonucleotides are unable to cross the blood-brain barrier on their own.
+Added: Currently, oligonucleotides must be delivered directly to the central nervous system through invasive routes such as intrathecal delivery and still may not distribute uniformly throughout the brain where treatment is needed.
+Added: We are using our OTV platform to enable brain delivery of oligonucleotides by crossing the blood-brain barrier following systemic administration.
In August 2024, our preclinical research related to OTV was published in Science Translational Medicine .
Denali scientists describe using OTV, which is an engineered TV conjugated to an ASO, for delivery of therapeutic molecules to the mouse and nonhuman primate brain.
−Removed: Our research demonstrated that OTV can successfully cross the 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.
−Removed: Additionally, OTV enabled knockdown of the ASO target gene expression in historically difficult to target peripheral muscle tissues, including skeletal and cardiac muscle.
−Removed: In comparison to other clinically relevant ASO delivery platforms, including direct delivery of a non-TV-enabled ASO into CSF, systemic OTV enabled a much more uniform ASO biodistribution profile ( Figure 14 ) and knockdown of the target.
−Removed: Our two most advanced OTV programs are designed to knock down 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.
−Removed: DNL628 (OTV:MAPT) is a therapeutic candidate targeting tau for Alzheimer's disease.
−Removed: In a mouse model, we have demonstrated that brain MAPT RNA and tau protein knockdown persists for greater than 15 weeks following intravenous delivery of OTV:MAPT ( Figure 14 ).
−Removed: Extended knockdown duration of action may enable less frequent maintenance dosing.
−Removed: Similarly, we are advancing DNL422 (OTV:SCNA) targeting alpha-synuclein for Parkinson's disease.
−Removed: OTV provides uniform ASO deposition in the brain with intravenous (IV) delivery (left).
−Removed: Brain MAPT RNA and tau protein knockdown persists for >15 weeks following four IV doses of OTV:MAPT.
−Removed: A ntibody Transport Vehicle (“ATV”) Programs
−Removed: DNL921 Antibody Transport Vehicle Amyloid beta (ATV:Abeta) program
+Added: Our research demonstrated that OTV can successfully cross the blood-brain barrier following intravenous administration and provide cumulative and sustained knockdown of the ASO target gene expression across multiple central nervous system regions and all major cell types, including endothelial cells, neurons, astrocytes, microglia, and oligodendrocytes.
+Added: In comparison to other clinically relevant ASO delivery platforms, including intrathecal delivery of a non-TV-enabled ASO, systemic OTV enabled a much more uniform ASO biodistribution profile ( Figure 15 ) and knockdown of the target.
+Added: OTV demonstrated uniform ASO deposition in the nonhuman primate brain with intravenous (IV) delivery in contrast to intrathecally administered oligonucleotides, which showed limited penetration into deeper brain regions and high localized exposure in the spinal cord (left panel).
+Added: OTV delivered IV showed enhanced ASO deposition in brain regions that are challenging to target including the striatum and cerebellum (right panel).
+Added: DNL628 is our TV-enabled ASO program targeting microtubule-associated protein tau ( MAPT ) for the treatment of Alzheimer’s disease and other tauopathies.
+Added: Using the TV platform, DNL628 is engineered to facilitate efficient delivery across the blood-brain barrier, with the goal of achieving sustained reduction of tau expression in relevant neuronal populations.
+Added: DNL628 is designed to address key limitations of existing tau-targeted approaches by enabling systemic administration with broad and uniform distribution throughout the brain and reducing intracellular tau that is inaccessible to antibody-based approaches.
+Added: Preclinical studies in disease-relevant animal models expressing human tau demonstrated DNL628 achieved potent and durable reductions in MAPT RNA and tau protein levels following systemic dosing, with sustained knockdown observed well beyond the dosing period ( Figure 16 ).
+Added: These data support the potential for less frequent dosing and more uniform target engagement compared to existing approaches, which we believe may be important for achieving meaningful and durable therapeutic effects in tau-driven neurodegenerative diseases.
+Added: Brain MAPT RNA and tau protein knockdown (KD) persisted for >12 weeks after dosing with DNL628 in mice.
+Added: Based on these preclinical findings, we believe DNL628 has the potential to be a best-in-class tau-targeted therapy by combining potent tau reduction with improved brain distribution and a differentiated safety and convenience profile.
+Added: By reducing total tau expression rather than targeting specific post-translational tau species, DNL628 is designed to broadly address tau pathology across disease stages and brain regions.
+Added: The clinical development plan for DNL628 includes a Phase 1b multiple ascending dose study, which will evaluate safety, pharmacokinetics, and pharmacodynamic biomarkers of tau reduction.
+Added: We expect to leverage cerebrospinal fluid and imaging biomarkers to assess target engagement and inform dose selection, with the goal of generating initial clinical biomarker data in the first half of 2027 to guide subsequent development decisions.
+Added: 2026 expected progress and milestones:
+Added: • Initiate dosing in Phase 1b clinical study of DNL628 in participants with Alzheimer’s disease
+Added: DNL921 Antibody TransportVehicle TM Amyloid beta (ATV:Abeta) program for Alzheimer’s disease
The accumulation of Abeta plaque in the brain is a defining feature of Alzheimer's disease.
Recently approved Abeta-directed antibody therapeutics were shown in clinical studies to reduce Abeta plaque and have modest efficacy in slowing disease progression;
−Removed: however, these therapies have safety concerns including the potential for amyloid-related imaging abnormalities ("ARIA") in the brain, which is a major barrier to their broad adoption in treating Alzheimer's disease.
+Added: however, these therapies are limited by suboptimal brain distribution, dose- and exposure-related safety concerns, including amyloid-related imaging abnormalities (“ARIA”), and administration and safety monitoring requirements that may constrain broader or earlier use.
+Added: As treatment paradigms increasingly shift toward earlier and potentially preclinical stages of Alzheimer’s disease, there remains a significant unmet need for therapies that can achieve more efficient and uniform brain target engagement with improved safety and dosing flexibility.
Thus, there is a significant opportunity for improving the efficacy and safety of Abeta-directed antibodies, and we are using our ATV platform to develop the next generation of these therapies.
Our ATV:Abeta program utilizes the ATV platform to enable increased brain exposure and target engagement of Abeta plaques while avoiding ARIA.
−Removed: In preclinical studies in mice, ATV:Abeta was shown to be superior in reducing amyloid plaque load ( Figure 15A ) and oligomeric Abeta load ( Figure 15B ) compared to a conventional Abeta antibody, while essentially eliminating ARIA ( Figure 15C ).
+Added: In preclinical studies in mice, ATV:Abeta was shown to be superior in reducing amyloid plaque load and oligomeric Abeta load ( Figure 17 ) compared to a conventional Abeta antibody.
+Added: ATV-enabled antibodies also essentially eliminate ARIA ( Figure 18 ).
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 and largely bypassing arteries, which contain the majority of the vascular amyloid that is responsible for inducing ARIA.
−Removed: Furthermore, our 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 ( Figure 15D).
−Removed: Preclinical data showing superior amyloid plaque reduction ( A ), superior oligomeric plaque reduction ( B ), fewer to no ARIA events ( C ), and preservation of reticulocytes ( D ).
+Added: Furthermore, as published in Pizzo et al ., Science, 2025, our 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 ( Figure 18).
+Added: Preclinical mouse data showing superior amyloid plaque reduction (left), superior oligomeric plaque reduction (right) with DNL921 compared to a non-TV enabled anti-Abeta
+Added: Preclinical studies in a mouse model demonstrated that an ATV-enabled Abeta displays fewer to no ARIA events (left) and preservation of reticulocytes (right).
+Added: DNL921 (ATV:Abeta) is our TV-enabled antibody targeting amyloid beta and is designed to enhance brain delivery while maintaining antibody effector function in a differentiated molecular architecture.
+Added: By incorporating the TV directly into the antibody structure, DNL921 is engineered to engage the transferrin receptor to facilitate receptor-mediated transport across the blood-brain barrier, enabling deeper and more uniform penetration into brain parenchyma compared to conventional antibodies.
+Added: This integrated design is intended to improve plaque engagement throughout the brain while reducing perivascular localization, which we believe may contribute to vascular-related safety liabilities observed with existing therapies.
+Added: In preclinical studies, DNL921 demonstrated substantially greater amyloid plaque engagement and deeper brain penetration compared to first-generation anti-amyloid antibodies, with labeling observed across cortical and subcortical regions rather than being restricted to superficial or perivascular areas ( Figure 19 ).
+Added: In head-to-head comparisons with other transferrin receptor-enabled competitor molecules, DNL921 showed increased plaque binding efficiency at lower doses and reduced vascular engagement with higher engagement of plaque-associated microglia, which are involved in amyloid clearance ( Figure 20 ).
+Added: In preclinical studies comparing DNL921 with other TfR-based brain shuttle approaches in a humanized mouse model that allows for cross-platform comparisons ( Figure 21 ), DNL921 demonstrated approximately two-fold higher brain concentrations.
+Added: This increased brain uptake was associated with greater in vivo molecular stability, with a higher proportion of intact DNL921 maintained over time relative to Fab-based shuttle formats.
+Added: In addition, DNL921 preserved effector function without inducing measurable reductions in reticulocytes, in contrast to certain TfR-binding molecules associated with hematologic effects.
+Added: Whole mount imaging of brains from a mouse model of Alzheimer’s disease reveals substantially improved engagement of antibody with plaque following dosing with DNL921 compared to a non-TV enabled anti-Abeta antibody.
+Added: Images show increased antibody associated with amyloid plaque and less vascular staining with DNL921 compared to a non-TV enabled Abeta antibody.
+Added: The increased antibody engagement leads to increased engagement with plaque-associated microglia.
+Added: Studies comparing TV-enabled DN921 to molecules representing competitor TfR-based blood-brain barrier programs in a mouse model that expressed the full TfR extracellular domain reveals higher brain uptake and more intact molecule with DNL921 compared to competitor platforms.
+Added: Based on these data, we believe DNL921 has the potential to be a best-in-class amyloid beta therapy by combining efficient brain delivery, robust plaque engagement, and a differentiated safety profile that may enable lower doses, longer dosing intervals, or alternative routes of administration.
+Added: The clinical development plan for DNL921 includes an initial Phase 1/1b study designed to evaluate safety, tolerability, pharmacokinetics, and biomarker-based measures of target engagement, including amyloid imaging and fluid biomarkers.
+Added: The study is structured to enable rapid assessment of proof of mechanism and dose selection, with the potential to advance efficiently into later-stage clinical development.
+Added: We expect to leverage validated biomarkers to inform patient selection and clinical decision making, with the goal of generating early clinical data to guide subsequent development in Alzheimer’s disease.
+Added: 2026 expected progress and milestones:
+Added: • Initiate dosing in Phase 1/1b clinical study of DNL921 in healthy volunteers and participants with Alzheimer’s disease.
+Added: Our Small Molecule Programs
+Added: BIIB122/DNL151 LRRK2 Inhibitor Program for Parkinson's disease
+Added: Parkinson's disease is one of the most common brain diseases, affecting approximately 10 million people worldwide.
+Added: It is considered to be a movement disorder because patients can experience tremors, slowness of movement, stiffness and difficulty with walking and balance.
+Added: In addition, Parkinson's patients can have other non-motor type problems such as constipation, depression and memory loss.
+Added: The Parkinson symptoms are a result of the loss of dopamine-producing cells in the brain, which is currently thought to be caused by a combination of genetic and environmental risk factors.
+Added: Mutations in the LRRK2 gene are one of the most common genetic risk factors for Parkinson's disease.
+Added: LRRK2 is involved in maintaining a healthy cellular environment by regulating lysosomal function through modification of Rab proteins.
+Added: Increased levels of LRRK2 kinase activity lead to lysosomal dysfunction, which is believed to contribute to neurodegeneration.
+Added: Inhibition of LRRK2 activity has the potential to slow the progression of Parkinson’s disease in patients, with and without known genetic risks based on restoration of lysosomal function.
+Added: As described in more detail in “Business - Licenses and Collaborations” below, we are collaborating with Biogen to co-develop and co-commercialize our small molecule inhibitors of LRRK2 for Parkinson's disease.
+Added: BIIB122/DNL151 is the most clinically advanced small molecule inhibitor of LRRK2 currently in clinical testing for Parkinson's disease.
+Added: Biogen is conducting the global Phase 2b LUMA study, which commenced in May 2022 and is evaluating the efficacy and safety of BIIB122/DNL151 as compared to placebo.
+Added: Enrollment of 650 participants with early-stage Parkinson's disease was completed in March 2025.
+Added: 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.
+Added: Furthermore, 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 improvement of lysosomal function.
+Added: BIIB122/DNL151 was generally well tolerated across a broad range of doses for up to 28 days, the longest treatment duration in both studies.
+Added: In February 2024, we 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 Denali is operationalizing to evaluate safety and biomarkers associated with dosing BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2.
+Added: This agreement includes committed funding of $75.0 million, of which $50.0 million has been received through 2025, and the remainder will be triggered based on operational milestones in the study.
+Added: Biogen will continue to conduct the ongoing global Phase 2b LUMA study in early-stage Parkinson’s disease.
+Added: Denali and Biogen will co-commercialize BIIB122/DNL151 assuming regulatory approval.
+Added: The third party will be eligible to receive low single-digit royalties from Denali on annual worldwide net sales of LRRK2 inhibitors for the treatment of Parkinson’s disease, with royalty amounts varying based on the scope of the label .
+Added: In December 2024, we 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.
+Added: 2026 expected progress and milestones:
+Added: • Data from the Phase 2b LUMA study in early-stage PD in mid-2026.
+Added: Other LRRK2 Compounds
+Added: Genetic and functional studies have linked LRRK2 and other proteins that modulate lysosomal function to Crohn's disease.
+Added: Excessive LRRK2 activity leads to a reduction in lysosomal function, which contributes to the inflammation and intestinal dyshomeostasis that are characteristic of this disorder.
+Added: We have discovered potent and selective small molecule inhibitors of LRRK2 and have selected a lead clinical candidate (DNL975) for treatment of Crohn's disease.
+Added: As described in more detail in “Business - Licenses and Collaborations” below, we are collaborating with Biogen on the Peripheral LRRK2 program.
+Added: Eclitasertib (SAR443122/DNL758) RIPK1 Inhibitor Program for Peripheral Inflammatory Diseases:
+Added: As part of our parallel development strategy, we have also developed 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.
+Added: Sanofi is solely responsible for the development and commercialization of peripherally restricted RIPK1 inhibitors.
+Added: Sanofi is conducting a Phase 2 study of eclitasertib in patients with ulcerative colitis;
+Added: data readout expected in the first half of 2026, as planned.
+Added: 2026 expected progress and milestones:
+Added: • Data from the Phase 2 UC study in the first half of 2026.
Discovery Programs
In addition to our development portfolio for neurodegenerative and lysosomal storage diseases, we have a robust discovery effort to further expand and capture the full potential of our TV platform to enhance delivery of biotherapeutics to all tissues in the body.
−Removed: We are pursuing opportunities of unmet need in multiple disease areas including oncology, inflammation, neuromuscular disease, and metabolic disease.
For example, using ATV, we have engineered mono- and bispecific formats of HER2 antibodies.
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LRRK2 Agreement
−Removed: The LRRK2 Agreement includes our small molecule LRRK2 inhibitors (“LRRK2 Products”) that penetrate the BBB, including DNL201 and BIIB122/DNL151, as well as those that do not penetrate the BBB.
−Removed: Based on the totality of preclinical and clinical data to date, both DNL201 and BIIB122/DNL151 (two chemically distinct LRRK2 inhibitors) have met our requirements to proceed into further late-stage clinical testing, however, BIIB122/DNL151 has been selected to proceed due to pharmacokinetic properties that provide additional dosing regimen flexibility.
+Added: The LRRK2 Agreement includes our small molecule LRRK2 inhibitors (“LRRK2 Products”) that penetrate the BBB, including DNL201 and BIIB122/DNL151, as well as those that do not penetrate the BBB, with BIIB122/DNL151 currently proceeding in clinical development.
Under the terms of the LRRK2 Agreement, Biogen paid us a $400.0 million upfront payment in October 2020.
77 unchanged sentences
In February 2019, we 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.
−Removed: Takeda exercised the options for the PTV:PGRN program in November 2021.
+Added: Takeda exercised its option for the PTV:PGRN program in November 2021.
Takeda exercised its option for the ATV:TREM2 program in December 2021.
In February 2025, after mutual agreement to discontinue preclinical activities on ATV:TREM2, Takeda delivered notice of its election to terminate the ATV:TREM2 program on February 26, 2025, as per the terms of the Takeda Collaboration Agreement.
−Removed: The ATV:TREM2 program termination will become effective 60 days following the notice date.
+Added: The ATV:TREM2 program termination became effective 60 days following the notice date.
Research Phase and Takeda’s Option
41 unchanged sentences
In addition, we are required to make contingent payments, to F-star Ltd and the former shareholders of F-star Gamma, up to a maximum amount following completion of the research phase of the F-star collaboration of $243.0 million in the aggregate upon the achievement of certain defined preclinical, clinical, regulatory and commercial milestones.
−Removed: These include up to $3.0 million in preclinical contingent payments, $30.0 million in clinical contingent payments, $60.0 million in regulatory contingent payments and $150.0 million in commercial contingent payments.
+Added: These include up to $3.0 million in preclinical contingent payments, $30.0 million in clinical contingent payments, $60.0 million in regulatory contingent payments, including $36.0 million due upon regulatory approval of tividenofusp alfa in the United States, and $150.0 million in commercial contingent payments.
We have made payments of $49.8 million through December 31, 2025 in the aggregate consisting of up-front, preclinical and clinical contingent consideration.
−Removed: This contingent consideration payment fully satisfies the Company's clinical contingent consideration obligations under the Purchase Agreement.
Under the terms of the original F-star Collaboration Agreement, we could nominate up to three Fcab targets (“Accepted Fcab Targets”) within the first three years of the date of the F-star Collaboration Agreement.
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We do not have the right to terminate the agreement without cause, but may terminate the agreement for Genentech’s material breach, subject to specified notice and cure provisions.
+Added: Royalty Pharma Funding Agreement
+Added: In December 2025, we entered into a synthetic royalty funding agreement (the “Royalty Agreement”) with Royalty Pharma plc (“Royalty Pharma”).
+Added: Pursuant to the Royalty Agreement, Royalty Pharma has agreed to provide us with up to $275.0 million in funding in exchange for a 9.25% royalty on future net sales of tividenofusp alfa.
+Added: The transaction is subject to various closing conditions, including our achieving U.S.
+Added: Food and Drug and Administration (FDA) accelerated approval of tividenofusp alfa on or before June 30, 2026.
+Added: At the closing, Royalty Pharma will make an initial payment of $200.0 million.
+Added: We will receive an additional payment of $75.0 million upon approval of tividenofusp alfa by the European Medicines Agency (EMA) on or before December 31, 2029.
+Added: The royalty payments to Royalty Pharma will cease upon reaching a multiple of 3.0x, or 2.5x if achieved by the first quarter of 2039.
+Added: We will retain all worldwide development and commercialization rights to tividenofusp alfa.
Manufacturing
−Removed: We believe it is important to our business success to have a reliable, high-quality preclinical and clinical drug supply chain.
−Removed: As we mature as a company and approach commercial stage operations, securing reliable high-quality commercial drug supply will be critical, and we intend to evaluate both third-party manufacturers as well as building out internal commercial manufacturing capabilities and capacity.
−Removed: If tividenofusp alfa is approved for the treatment of Hunter syndrome, we expect to use third-party contract manufacturers to supply commercial product .
−Removed: We currently rely on third-party contract development and manufacturing organizations ("CDMOs"), to manufacture and supply our preclinical and clinical materials used during the development of our product candidates.
−Removed: We have established relationships with several CDMOs, including Lonza Sales AG ("Lonza").
−Removed: Effective September 2017, we entered into a development and manufacturing services agreement with Lonza, which we have subsequently amended to add scope of work.
−Removed: We refer to this agreement, as amended, as the DMSA or the Lonza agreement.
−Removed: Pursuant to the Lonza agreement, Lonza agreed to provide clinical development and manufacturing services with respect to certain of our biologic products on a fee-for-service basis.
−Removed: In April 2023 we entered into, and subsequently amended, a lease for a clinical manufacturing site in Salt Lake City, Utah.
−Removed: We are in the final stages of building out the facility, and beginning in 2025, we plan to use the facility to expand our clinical manufacturing capabilities for biologic therapeutics including the manufacture of materials for toxicology studies and drug substance for early human clinical studies, with the goal of increasing flexibility and speed in advancing new investigational therapies into clinical trials.
+Added: We believe it is important to our business success to have a reliable, high-quality drug supply chain to support our preclinical and clinical development activities and, if approved, the commercialization of our product candidates.
+Added: We currently rely on third-party contract development and manufacturing organizations (“CDMOs”) to manufacture and supply preclinical and clinical materials used in the development of our product candidates, and we have established relationships with several CDMOs, including Lonza Sales AG (“Lonza”), which provides development and manufacturing services with respect to certain of our biologic products on a fee-for-service basis.
+Added: As we mature as a company and advance product candidates toward commercialization, securing and maintaining reliable, high-quality drug supply chains for each product candidate will be critical.
+Added: We have established a third-party supply chain for tividenofusp alfa and, if approved for the treatment of Hunter syndrome, we plan to continue to rely on third-party contract manufacturers for its commercial supply.
+Added: Over time, we intend to complement our use of third-party manufacturers by selectively developing internal manufacturing capabilities, including for commercial supply, to support the advancement and commercialization of our product candidates.
+Added: In early 2025, we commenced operations at our clinical manufacturing site in Salt Lake City, Utah, expanding our clinical manufacturing capabilities for biologic therapeutics, including the manufacture of materials for toxicology studies and drug substance for human clinical studies.
+Added: This facility represents an initial step in building internal manufacturing capabilities, with the goal of increasing flexibility and speed in advancing new investigational therapies into clinical trials.
Commercialization Plan
We do not currently have any approved drugs.
−Removed: We are expecting a potential US launch in the second half of 2025 or early 2026.
−Removed: With this possibility, we are building marketing, product distribution and sales capabilities.
−Removed: Our vision, however, is to become a fully integrated, independent global leader in neurodegeneration with capabilities spanning discovery, development, manufacturing, and commercial in order to optimize speed, quality, and level of patient access to our medicines.
−Removed: We look to grow strategically both in terms of therapeutic areas of high unmet need, starting with lysosomal storage diseases with CNS pathology and expanding into large neurodegenerative disorders, as well as from a geographic perspective, with an initial focus on establishing a commercial presence in the United States and the European Union ("EU"), with subsequent global expansion (including China).
+Added: The PDUFA date for our lead asset, tividenofusp alfa, is currently April 5, 2026.
+Added: With this timeline in mind, over the course of 2025 we invested in building right-sized marketing, product distribution, and sales capabilities for the U.S.
+Added: As of the date of this filing, we have established our U.S.
+Added: commercial infrastructure to support a potential commercial launch following the PDUFA date.
+Added: We expect to continue to refine these capabilities through and following launch, including distribution planning and logistics, to support the U.S.
+Added: launch of tividenofusp alfa.
+Added: In parallel, we are engaging in discussions with potential regional commercial partners regarding possible paths for selective expansion into certain markets outside the United States, subject to applicable regulatory requirements.
+Added: Our vision is to become a fully integrated, independent global leader in delivering the power of biotherapeutics to the whole body, including the brain, transforming the lives of people living with serious diseases.
+Added: We apply our capabilities in discovery, development, manufacturing, and commercial in order to optimize speed, quality, and patient access to our medicines.
+Added: We look to grow strategically both in terms of therapeutic areas of high unmet need, starting with lysosomal storage diseases and expanding into large neurodegenerative disorders and other serious diseases, as well as from a geographic perspective, with an initial focus on building a commercial presence in the United States and the European Union ("EU"), and establishing a network of specialized regional partners to access other major markets.
For programs covered by collaboration agreements (including those with Takeda, Sanofi, and Biogen), we expect to commercialize only in certain geographies, as defined by the terms of the agreements with the counterpart, and rely on our partners to provide commercialization infrastructure for the rest of the world.
The biotechnology and pharmaceutical industries, including in the neurodegenerative disease field, are characterized by rapidly advancing technologies, strong competition and an emphasis on intellectual property.
−Removed: We face substantial competition from many different sources, including large and specialty pharmaceutical and biotechnology companies, academic research institutions, governmental agencies and public and private research institutions.
We believe that the key competitive factors affecting the success of any of our product candidates will include efficacy, safety profile, method of administration, cost, level of promotional activity and intellectual property protection.
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• Alzheimer’s Disease:
−Removed: Treatments currently approved in some geographies for Alzheimer’s Disease include the amyloid beta-directed antibody therapies Aduhelm (Biogen), LEQEMBI (Eisai/Biogen), and Kisunla (Eli Lilly).
−Removed: Additionally, potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), Roche (including Genentech, its wholly owned subsidiary), AbbVie, Bristol Myers Squibb, Prothena, Regeneron, Alnylam, Eisai, and BioArctic in various stages of development.
+Added: Treatments currently approved in some geographies for Alzheimer’s Disease include the amyloid beta-directed antibody therapies ADUHELM (Biogen), LEQEMBI (Eisai/Biogen), and KISLUNA (Eli Lilly).
+Added: Additionally, potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Biogen/lonis, Arrowhead, Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), Roche (including Genentech, its wholly owned subsidiary), AbbVie, Bristol Myers Squibb, Prothena, Regeneron, Alnylam, Eisai, and BioArctic in various stages of development.
• Parkinson’s Disease:
−Removed: Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Roche/Prothena (including Genentech, its wholly owned subsidiary), Ionis, Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), AstraZeneca, Takeda, Oncodesign/Servier, and Neuron23 in various stages of development.
−Removed: Treatments currently approved in some geographies for ALS include Radicava (Mitsubishi Tanabe Pharma) and Qalsody (Biogen).
−Removed: Additionally, potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Clene Nanomedicine, AB Science, Novartis, Bristol Myers Squibb, Calico/AbbVie, and Zydus in various stages of development.
+Added: Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Roche/Prothena (including Genentech, its wholly owned subsidiary), Ionis, Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), AstraZeneca, Takeda, Oncodesign/Servier, Neuron23 and AbbVie in various stages of development.
Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including GSK/Alector, Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), Passage Bio, AviadoBio, Vesperbio, Arkuda Therapeutics, and Orchard Therapeutics in various stages of development.
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The currently approved treatments for lysosomal storage diseases are conventional enzyme-based therapies.
−Removed: Various BBB-penetrant and direct to CNS delivered ERTs and gene therapies are being developed by several large and specialty pharmaceutical and biotechnology companies, including JCR Pharmaceuticals, RegenxBio, Kyowa Kirin/Orchard Therapeutics, and Ultragenyx in various stages of development.
−Removed: In addition, there are companies that are developing technologies that would compete directly with our technologies, including:
−Removed: • Blood-Brain Barrier Technology:
−Removed: There are several large and specialty pharmaceutical and biotechnology companies developing BBB delivery technologies that utilize RMT, including JCR Pharmaceuticals, Roche (including Genentech, its wholly owned subsidiary), Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), Abbvie, Regeneron, BioArctic, Alector and Bicycle Therapeutics, among others.
+Added: Various BBB-penetrant and direct to CNS delivered ERTs and gene therapies are being developed by several large and specialty pharmaceutical and biotechnology companies, including JCR Pharmaceuticals, RegenxBio, Kyowa Kirin/Orchard Therapeutics, and Ultragenyx, and are in various stages of development.
+Added: In addition, companies are developing technologies that would compete directly with our TV technology.
+Added: These include several large and specialty pharmaceutical and biotechnology companies developing BBB delivery technologies that utilize RMT, including JCR Pharmaceuticals, Roche (including Genentech, its wholly owned subsidiary), Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), Abbvie, Regeneron, BioArctic, Alector, Bicycle Therapeutics, Ossianix, Vect-Horus, Sanofi, and ABL Bio, among others.
Intellectual Property
4 unchanged sentences
issued patents, covering certain aspects of our proprietary technology, our product candidates, and related inventions and improvements.
−Removed: 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.
+Added: The patent portfolio also includes over 500 licensed patents issued in jurisdictions outside of the United States, and over 950 owned patents and 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.
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In addition, we license 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.
−Removed: ETV Platform, ETV:IDS, and ETV:SGSH Programs
+Added: ETV Platform and Programs
We own 12 patent families directed to our ETV platform and related products, including ETV:IDS, ETV:SGSH, ETV:GAA, ETV:Gcase, and ETV:IDUA.
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Of the 12 patent families, 3 families relate to the composition of matter of our ETV:SGSH structures, including DNL126.
+Added: This includes 1 issued U.S.
+Added: patent, which is expected to expire in 2041, not including any patent term adjustments and any patent term extensions.
Any patents issuing from these families are expected to expire between 2039 and 2046, respectively, not including any patent term adjustments and any patent term extensions.
+Added: Of the 12 patent families, 2 families relate to the composition of matter of our ETV:GAA structures, including DNL952.
+Added: This includes 1 issued U.S.
+Added: patent, which is expected to expire in 2044, not including any patent term adjustments and any patent term extensions.
PTV:PGRN Program
We own 4 patent families directed to our PTV:PGRN program.
−Removed: This includes an issued U.S.
+Added: This includes 1 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 our PTV:PGRN molecules, including TAK-594/DNL593.
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Our PTV:PGRN program is subject to our Takeda collaboration.
−Removed: Oligonucleotide Transport Vehicle Platform
−Removed: We own 7 patent families related to our OTV platform, including OTV:MAPT and OTV:SNCA.
+Added: Oligonucleotide Transport Vehicle Platform and Programs
+Added: We own 7 patent families directed to our OTV platform, including OTV:MAPT and OTV:SNCA.
These families are directed to compositions and methods of use of our 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.
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These include 13 issued U.S.
−Removed: patent, 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.
−Removed: eIF2B Activator Program
−Removed: We own 9 patent families directed to our 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.
+Added: 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.
+Added: ATV:Abeta Program
+Added: We own 4 patent families directed to our ATV:Abeta program.
+Added: This includes a family directed to our composition of matter of DNL921, which is expected to expire in 2046, not accounting for any patent term adjustments and any patent term extensions.
We cannot guarantee that our owned and licensed pending patent applications, or any patent applications that we may in the future file or license from third parties, will result in the issuance of patents.
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The patent positions of biotechnology companies like ours are generally uncertain and involve complex legal, scientific and factual questions.
+Added: Geopolitical actions in the United States and in foreign countries could increase the uncertainties and costs surrounding the prosecution or maintenance of our patent applications or those of any current or future licensors and the maintenance, enforcement or defense of our issued patents or those of any current or future licensors.
Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties.
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The preclinical developmental stage generally involves laboratory evaluations of drug chemistry, formulation and stability, as well as studies to evaluate pharmacology, pharmacokinetics and toxicity in animals, which support subsequent clinical testing.
−Removed: The sponsor must submit the results of the preclinical studies, together with manufacturing information, analytical data, any available clinical data or literature, and a proposed clinical protocol, to the FDA as part of the IND.
+Added: The sponsor must submit the results of the preclinical studies, together with chemistry, manufacturing, and control information, analytical data, including pharmacology and toxicology information, any available clinical data or literature, investigator's brochure, and a proposed clinical protocol, among other information, to the FDA as part of the IND.
An IND is a request for authorization from the FDA to administer an investigational product to humans, and must become effective before human clinical trials may begin.
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The application may include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings.
−Removed: Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use and/or from a number of alternative sources, including studies initiated by investigators or cooperative clinical groups.
+Added: Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use and/or from a number of alternative sources, including but not limited to studies initiated by investigators or cooperative clinical groups.
To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of FDA.
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The FDA does not always meet its PDUFA goal dates for standard and priority NDAs or BLAs, and the review process may be extended by FDA requests for additional information or clarification.
−Removed: Before approving an NDA or BLA, the FDA will conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements.
+Added: Before approving an NDA or BLA, the FDA may conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements.
The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
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Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.
+Added: Further, FDA’s “real time” release of newly issued Complete Response Letters associated with withdrawn or abandoned applications, if applicable to any of our product candidates, can materially impact our business and competitive advantage.
If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed.
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2021), in January 2023, the FDA published a notice in the Federal Register to clarify that while the agency complies with the court’s order in Catalyst, the FDA intends to continue to apply its longstanding interpretation of the regulations to matters outside of the scope of the Catalyst order – that is, the agency will continue tying the scope of orphan-drug exclusivity to the uses or indications for which a drug is approved, which permits other sponsors to obtain approval of a drug for new uses or indications within the same orphan designated disease or condition that have not yet been approved.
−Removed: It is unclear how future litigation, legislation, agency decisions, and administrative actions will impact the scope of the orphan drug exclusivity.
−Removed: In June 2024, the U.S.
−Removed: Supreme Court overruled the Chevron doctrine, which gives deference to regulatory agencies’ statutory interpretations in litigation against federal government agencies, such as the FDA, where the law is ambiguous.
−Removed: This landmark Supreme Court decision may invite various stakeholders to bring lawsuits against the FDA to challenge longstanding decisions and policies, including FDA’s statutory interpretations of market exclusivities and the “substantial evidence” requirements for drug approvals, which could lead to uncertainties in the industry.
−Removed: Further, changes in the leadership of the FDA and other federal agencies under the new presidential administration may lead to new policies and changes in the regulations that may impact our clinical development and timelines.
+Added: The Consolidated Appropriations Act of 2026, signed into law in February 2026, codified this longstanding FDA interpretation of the Orphan Drug Act.
Expedited Development and Review Programs
101 unchanged sentences
If any such changes were to be imposed, they could adversely affect the operation of our business.
+Added: For example, in June 2024, the U.S.
+Added: Supreme Court overruled the Chevron doctrine, which gives deference to regulatory agencies’ statutory interpretations in litigation against federal government agencies, such as the FDA, where the law is ambiguous.
+Added: This landmark Supreme Court decision may invite various stakeholders to bring lawsuits against the FDA to challenge longstanding decisions and policies, which could lead to uncertainties in the industry.
+Added: Further, changes in the leadership of the FDA and other federal agencies under the current administration, as well as new legislative, executive, and other administration actions implemented by the government may impact our clinical development and timelines.
Patent-Term Restoration and Marketing Exclusivity
79 unchanged sentences
These include allowing the federal government to negotiate a maximum price paid by Medicare for certain single source drugs responsible for significant Medicare spending, imposing penalties and excise tax for manufacturers that fail to comply with the drug price negotiation requirements, requiring inflation rebates for all Medicare Part B and Part D drugs, with limited exceptions, if their drug prices increase faster than inflation, and redesigning Medicare Part D to reduce out-of-pocket prescription drug costs for beneficiaries, among other changes.
−Removed: Various industry stakeholders, including certain pharmaceutical companies and the Pharmaceutical Research and Manufacturers of America, have initiated lawsuits against the federal government asserting that the price negotiation provisions of the IRA are unconstitutional.
−Removed: The impact of these judicial challenges, legislative, executive, and administrative actions, and any future healthcare measures and agency rules implemented by the new administration on us and the pharmaceutical industry as a whole is unclear.
+Added: Various industry stakeholders have initiated lawsuits against the federal government asserting that the price negotiation provisions of the IRA are unconstitutional.
+Added: Further, the current administration has issued executive orders focused on decreasing prescription drug prices, including directing the Secretary of HHS to establish a mechanism through which American patients can buy drugs directly from manufacturers who sell at a most-favored-nation price and directing the U.S.
+Added: Trade Representative and Secretary of Commerce to take action to ensure foreign countries are not engaged in practices that purposefully and unfairly undercut market prices and drive price hikes in the United States.
+Added: In November 2025, CMS announced a voluntary initiative called the GENEROUS Model (GENErating cost Reductions for U.S.
+Added: Medicaid Model) to introduce the option of most-favored-nation pricing to the Medicaid program, whereby a drug manufacturer may voluntarily offer supplemental rebates to participating state Medicaid programs for a manufacturer’s covered outpatient drugs.
+Added: Government agreements with pharmaceutical companies and other government measures that use most-favored-nation pricing targets for prescription drugs, including the use of international pricing reference to set drug prices in the United States, or that increase generic and biosimilar drug entry sooner than expected can have a material adverse effect on our industry, ability to set adequate pricing for new drugs to recover research and development costs, ability to attract potential investors and potential buyers in the future.
+Added: The impact of these legislative, executive, and administrative actions, and any future healthcare measures and agency rules implemented by the new administration on us and the pharmaceutical industry as a whole is unclear.
The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our product candidates if approved.
13 unchanged sentences
Historically, products launched in the EU do not follow price structures of the United States and generally prices tend to be significantly lower.
+Added: Physician Payment Transparency (“Sunshine Act”) and Open Payments
+Added: The Physician Payments Sunshine Act, enacted as part of the Affordable Care Act, and its implementing regulations require certain pharmaceutical and biological product manufacturers to collect and report annually to the Centers for Medicare & Medicaid Services (“CMS”) information regarding payments and other transfers of value provided to U.S.
+Added: physicians, certain other healthcare providers, and teaching hospitals, as well as ownership and investment interests held by such individuals.
+Added: CMS makes this information publicly available through the Open Payments program.
+Added: Although we are not currently subject to the Sunshine Act’s reporting requirements with respect to commercial activities, we expect that, upon obtaining FDA approval of our lead asset, tividenofusp alfa, and commencing commercialization in the United States, we will become subject to these requirements.
+Added: As we prepare for potential commercialization, we are continuing to develop and implement policies, procedures, systems, and internal controls designed to identify, track, review, and report applicable payments and other transfers of value accurately and in a timely manner.
+Added: Compliance with the Sunshine Act and Open Payments program will require ongoing investment in compliance infrastructure and may result in increased operational complexity and administrative burden.
+Added: Information disclosed through Open Payments is publicly available and may be subject to review, dispute, and scrutiny by healthcare providers, regulators, payors, the media, and the public.
+Added: Such disclosure may result in reputational risk, misinterpretation of reported data, or increased scrutiny of our interactions with healthcare providers.
+Added: The regulatory requirements governing Open Payments are complex and continue to evolve, including through changes in interpretation, expansion of covered recipients, and modifications to reporting thresholds and categories.
+Added: Failure to comply with applicable Sunshine Act reporting and recordkeeping requirements, whether due to errors in data collection, interpretation, or reporting, or the actions of third parties acting on our behalf, could subject us to civil monetary penalties, enforcement actions, and reputational harm, which could adversely affect our business, financial condition and results of operations.
Financial Information about Segments
3 unchanged sentences
As of December 31, 2025 , we had approximately 503 full-time employees.
−Removed: A large majority of our employees work out of our headquarters location in South San Francisco, CA, with the remainder working out of our locations in Salt Lake City, Utah and Zurich, Switzerland.
−Removed: Our human capital strategy aims to attract new talent and retain and incentivize existing employees by investing in their professional development, as well as providing them with challenging and rewarding opportunities for personal growth.
−Removed: Our working environment is guided by the core Denali values of trust, growth, grit and unity, and reinforced by developing quality leadership, fostering diversity and inclusion, emphasizing continuous growth, creating opportunities for engagement, and embracing our goal to defeat degeneration.
−Removed: Our values-driven culture is complemented by our incentive plans, which serve to (1) attract and retain employees through the granting of stock-based and cash-based compensation awards;
−Removed: and (2) motivate employees to perform to the best of their abilities and achieve our objectives, thereby increasing the value and success of our company.
+Added: A large majority of our employees work out of our headquarters location in South San Francisco, CA, with the remainder working remotely or out of our locations in Salt Lake City, Utah and Zurich, Switzerland.
+Added: Our human capital strategy is to inspire talented individuals to contribute to our mission through a combination of financial incentives, opportunities for professional growth, and a supportive, values-driven culture.
+Added: We offer competitive compensation packages comprised of cash-based salaries and bonus opportunities as well as long-term equity incentive grants.
+Added: We support our employees and their dependents with a comprehensive benefits package, which includes a 401(k) match and the opportunity to participate in an Employee Stock Purchase Plan.
+Added: We foster professional growth through formal and informal learning opportunities, and encourage frequent feedback through our continuous engagement management approach.
+Added: Our culture is rooted in our core Denali values of trust, growth, grit, and unity, and we collaboratively strive towards our company goal of delivering effective medicines to transform the lives of people living with neurodegenerative, lysosomal, and other serious diseases.
Key areas of focus for Denali include:
6 unchanged sentences
since we commenced operations in 2015, we have had zero reportable regulatory safety incidents.
−Removed: Diversity and Inclusion.
−Removed: Denali embraces differences and acknowledges the valuable perspectives that a diverse workforce brings to problem-solving.
−Removed: Our Unity in Diversity team spearheads action-oriented diversity programs, such as social responsibility through community leadership and volunteerism, investment in STEM-focused outreach, and creating a safe place for expression and ideas.
−Removed: As part of our plan to create a more inclusive workplace, we have adopted a zero tolerance policy towards harassment and discrimination and created safe avenues for employees to submit complaints, including an anonymous hotline and a formal complaint system that allows for direct access to our human resources department.
−Removed: We have implemented several measures to ensure that we are accountable for making progress on our diversity and inclusion initiatives.
−Removed: Diversity and inclusion objectives are embedded in our annual performance goals.
−Removed: We also ensure pipeline diversity by partnering with each division in their workforce planning forecasts to develop initiatives and goals to recruit diverse talent across all leadership and skill areas.
−Removed: As of December 31, 2024 , approximately 54% of our workforce and 50% of managers were female.
−Removed: As of December 31, 2024 , ethnic or racial minorities represented approximately 55% of our workforce and 45% of our managers.
+Added: Unity and Collaboration.
+Added: Denali embraces differences and acknowledges the value that multiple perspectives brings to problem-solving.
+Added: Employee-led teams spearhead action-oriented programs, such as social responsibility through volunteerism and investment in STEM-focused outreach.
+Added: To foster an inclusive workplace, we enable multiple avenues for employees to raise concerns, including an anonymous hotline and direct access to our human resources department.
Training and Development.
2 unchanged sentences
We provide technical, leadership and compliance training to all employees in several formats, including through live seminars, online trainings and professional organizations.
−Removed: Managers are given annual training to hone their supervisory skills and better support their employees’ development;
−Removed: they are, in turn, accountable for guiding the development of a personal and professional growth plan for each employee.
−Removed: In addition, Denali has designed employee development programs to help employees develop essential skills that are aligned to promote growth and Denali’s values.
+Added: Managers are given training to hone their supervisory skills and better support their employees’ development;
+Added: they are, in turn, accountable for continuously engaging with employees and providing ongoing feedback and support.
Flexible Work Options.
−Removed: The global pandemic has accelerated our capabilities and culture with respect to flexible work.
−Removed: Denali values workplace flexibility and hybrid ways of working, and has introduced a policy which we believe balances more workplace flexibility with time together to collaborate and connect in person.
−Removed: We use enhanced tools and technology designed to help us optimize productivity and collaboration while facilitating a hybrid work environment for our diverse workforce.
+Added: Denali values workplace flexibility and hybrid ways of working, and has a policy which we believe balances more workplace flexibility with time together to collaborate and connect in person.
+Added: We use tools and technology designed to help us optimize productivity and collaboration.
Corporate Information
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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.