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Item 1. Business

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Overview and Strategy

Our goal is to discover, develop and deliver therapeutics to defeat degeneration.

We are a clinical stage biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (“BBB”) for neurodegenerative diseases and lysosomal storage diseases ("LSDs").

We have a diversified and differentiated portfolio of both small molecule and biotherapeutic medicines, comprising seven product candidates in clinical development across seven indications as well as more than a dozen preclinical therapeutic candidates.

Each of our programs has been engineered for efficient delivery across the BBB to increase drug exposure in the brain after systemic administration.

We have discovered and developed a proprietary platform technology called the Transport Vehicle (“TV”), which we have used in developing our portfolio of brain-penetrant therapies based on our Enzyme Transport Vehicle (“ETV”), A ntibody Transport Vehicle (“ATV”), Protein Transport Vehicle (“PTV”), and Oligonucleotide Transport Vehicle (“OTV”).

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 advance next-generation, targeted medicines for people living with neurodegenerative diseases.

We plan to further grow our discovery and clinical development capabilities, focusing on TV-enabled biotherapeutics programs for neurodegenerative diseases, and intend to build internal manufacturing capabilities and commercial infrastructure in a staged manner that is aligned with the progression of our portfolio.

We aim to serve patients as a fully integrated global organization.

We have three late-stage development programs:

tividenofusp alfa (DNL310, ETV:IDS) for mucopolysaccharidosis II (" MPS II ", or " Hunter syndrome ");

BIIB122/DNL151 (LRRK2 inhibitor) for Parkinson’s disease;

and DNL343 (eIF2B activator) for amyotrophic lateral sclerosis (“ALS”).

SAR443820/DNL788 (RIPK1 inhibitor) is being evaluated in a Phase 2 study for multiple sclerosis ("MS").

In addition, we are conducting a Phase 1/2 study of TAK-594/DNL593 (PTV:PGRN) for frontotemporal dementia-granulin (“FTD-GRN”) and a Phase 1/2 study of DNL126 (ETV:SGSH) for MPS IIIA (Sanfilippo syndrome).

Eclitasertib (SAR443122/DNL758, peripheral RIPK1 inhibitor) is in a Phase 2 study for ulcerative colitis ("UC").

As our portfolio matures and our company scales, we plan to maintain a deep focus on science to guide our efforts to discover, develop and deliver medicines to patients.

Our discovery and development strategy is guided by three overarching principles that we believe will significantly increase the probability of success and accelerate the timing to bring effective therapeutics to people living with neurodegenerative diseases and LSDs:

• Degenogenes:

Genetic Pathway Realization – each of our programs addresses a molecular target or biological pathway that is genetically validated to cause or increase the risk for neurodegenerative diseases.

• Brain Delivery:

Validation and Optionality – we engineer our product candidates to cross the BBB and act directly in the brain.

Our proprietary TV platform technology is designed to effectively deliver large therapeutic molecules, such as enzymes, proteins, antibodies, and oligonucleotides, across the BBB after intravenous administration.

• Biomarker-Driven Development and Approval – we discover, develop and use biomarkers to inform dose selection, assess clinical activity, and identify patients most likely to respond to our therapies.

We are actively engaged in discussions with health authorities regarding the potential use of biomarkers as primary clinical endpoints to support faster paths to approval.

Our target indications include diseases with large patient populations, such as Alzheimer’s disease and Parkinson’s disease, as well as rare indications, such as MPS II (Hunter syndrome), MPS IIIA (Sanfilippo syndrome Type A), FTD-GRN and ALS.

We expect our first potential product launches will be in rare disease categories.

Launching first in rare indications gives us the opportunity to build and establish our commercial organization so that we are poised for success in larger indications over time.

Our most advanced TV-enabled program, tividenofusp alfa (DNL310, ETV:IDS), is intended to replace the standard of care in Hunter syndrome, which belongs to a group of rare LSDs.

LSDs affect more than 30,000 individuals worldwide for whom central nervous system (“CNS”) manifestations and many somatic symptoms continue to remain unaddressed by the current standard of care, if available at all.

We aim to leverage certain efficiencies of scale to support the commercialization of additional product candidates to create an LSD franchise.

We are actively working toward building clinical manufacturing capabilities and continuing to expand our commercial capabilities in LSDs and intend to serve patients directly in several countries.

In parallel, we are advancing our programs for rare neurodegenerative diseases such as ALS and FTD, which impact around 500,000 individuals worldwide.

We may commercialize these product candidates, if approved, independently in key markets and/or leverage partnerships to ensure optimal access for patients.

For the common neurodegenerative diseases, such as Alzheimer’s disease and Parkinson's disease, which afflict 40 to 50 million individuals worldwide, we plan to initially leverage strategic collaborations that contribute existing global commercial infrastructure.

Our goal is to discover, develop, and deliver a new class of barrier-crossing therapeutics and to defeat degeneration.

Historically, the blood-brain barrier ("BBB") has been a major challenge to the development of medicines for diseases of the central nervous system ("CNS").

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.

We have invented, developed, and validated a proprietary technology, called the TransportVehicle TM ("TV"), to address the BBB challenge.

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.

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.

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.

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 ).

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.

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”).

Our small molecule clinical development portfolio includes BIIB122/DNL151 (small molecule LRRK2 inhibitor) for Parkinson’s disease;

and DNL343 (small molecule eIF2B activator) for amyotrophic lateral sclerosis (“ALS”).

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:

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.

2) 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.

3) 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.

We expect our first potential product launches will be with tividenofusp alfa for MPS II followed by DNL126 for MPS IIIA.

MPS II and MPS IIIA belong to a group of lysosomal storage diseases, which are caused by genetic mutations that lead to single-enzyme deficiencies.

Lysosomal storage diseases afflict more than 30,000 individuals worldwide.

About two-thirds of these diseases affect the CNS;

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.

Our ETV therapeutics are designed as next-generation enzyme replacement therapies to address both CNS and somatic manifestations of lysosomal storage diseases.

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.

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.

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.

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.

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.

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.

Our next ETV programs advancing to the clinic are DNL952 (ETV:GAA) for Pompe disease and DNL111 (ETV:Gcase) for Parkinson's disease.

We intend to commercialize these product candidates, if approved, in key markets and/or leverage partnerships to ensure optimal access for patients.

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.

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).

Along with amyloid plaques, tau tangles are a pathological hallmark 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.

Preclinical studies with ATV:Abeta have demonstrated potential for better efficacy and safety compared to a standard antibody, with superior plaque reduction and very low rates of amyloid related imaging abnormalities ("ARIA").

Likewise, preclinical studies with OTV:MAPT have demonstrated robust and sustained reductions of tau protein.

Toxic protein accumulation is also a hallmark in Parkinson's disease and we have demonstrated robust reductions of alpha-synuclein with OTV:SNCA in preclinical studies.

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.

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.

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.

We are pursuing opportunities of unmet need in multiple disease areas including oncology, inflammation, neuromuscular disease, and metabolic disease.

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.

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.

Denali has an active collaboration with Biogen Inc.’s subsidiaries, Biogen MA Inc.

(“BIMA”) and Biogen International GmbH (“BIG”) (BIMA and BIG, collectively, “Biogen”) for the development and commercialization of BIIB122/DNL151 (small molecule LRRK2 inhibitor) for Parkinson's disease.

Biogen is conducting the global Phase 2b LUMA study, which is evaluating the ability of BIIB122 to slow disease progression as compared to placebo in approximately 640 participants with early-stage Parkinson's disease;

completion of enrollment is expected in 2025.

In addition, Denali is conducting the complementary Phase 2a BEACON study in LRRK2-associated Parkinson's disease with the aim to generate biomarker and safety data to inform how LRRK2 inhibition may impact this disease.

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.

Healey & AMG Center for ALS at Massachusetts General Hospital ("MGH") in collaboration with the Northeast ALS Consortium ("NEALS").

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.

Collaborations and partnering are central components of our strategy to build, develop and commercialize our portfolio of product candidates.

We have numerous arrangements with biopharmaceutical companies, technology companies, academic institutions, foundations, and patient-focused data companies.

Notable active arrangements include those with Biogen Inc.’s subsidiaries, Biogen MA Inc.

(“BIMA”) and Biogen International GmbH (“BIG”) (BIMA and BIG, collectively, “Biogen”), Takeda Pharmaceutical Company Limited ("Takeda"), and Genzyme Corporation, a wholly owned subsidiary of Sanofi S.A.

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, Sanofi and Takeda, where we share responsibility for clinical development and share commercialization rights in the United States and China.

Notable active arrangements include those with Biogen and Takeda as described above and Genzyme Corporation, a wholly owned subsidiary of Sanofi S.A.

("Sanofi") for the development and commercialization of SAR443122/DNL758 (peripherally restricted small molecule RIPK1 inhibitor) in ulcerative colitis.

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.

Our costs of developing programs associated with these collaborations are largely covered through upfront payments, expected incoming milestones and cost sharing.

We are also eligible to receive royalty payments for SAR443122/DNL758 from Sanofi.

We may seek additional strategic partnering opportunities as we strive to capture the full value of our portfolio and platforms.

For example, the TV platform has potential applications beyond our core focus on neurodegeneration (e.g., oncology, infectious disease, neuropsychiatry, pain).

At Denali, 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.

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.

Our working culture seeks to develop quality leaders, foster diversity and inclusion, and emphasize continuous growth.

We embrace differences and acknowledge the valuable perspectives that a diverse and inclusive workforce brings to problem-solving and innovation.

We embrace differences and acknowledge the valuable perspectives that a diverse and inclusive workforce brings to 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.

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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.

Our Approach to Defeating Neurodegeneration

Our Scientific Principles

Degenogene Pathways

The number of genetic associations discovered in neurodegenerative diseases has grown rapidly in recent years.

Degenogenes are genes that when mutated cause, or are major risk factors for, neurodegenerative diseases.

Analysis of recently discovered degenogenes point to important disease pathways that, when dysregulated, increase the risk of developing neurodegenerative disease, and provide a strong scientific foundation for prioritizing drug development programs.

We currently focus on programs that seek to modulate three key disease pathways:

• Lysosomal Function – Dysfunction of the lysosomal system, the disposal and recycling compartment of the cell, is associated with several neurodegenerative diseases, including Parkinson's disease and neurodegeneration in the context of LSDs.

Degenogenes linked to lysosomal function include leucine-rich repeat kinase 2 ("LRRK2"), progranulin ("PGRN"), alpha-synuclein ("αSyn"), and lysosomal enzymes, including iduronate 2-sulfatase ("IDS"), sulfamidase ("SGSH"), and glucocerebrosidase ("GBA").

• Glial Biology – Glial cells, the resident immune cells of the brain, serve various functions including supporting neuronal health, pruning neuronal synapses, and providing immune surveillance and response in the brain.

Genetic and pathological data suggest that glial dysfunction significantly contributes to neurodegenerative diseases, such as Alzheimer’s disease.

Degenogenes that implicate immune dysfunction in the brain include triggering receptors expressed on myeloid cells 2 ("TREM2") and receptor interacting serine/threonine protein kinase 1 ("RIPK1"), a critical signaling protein in a canonical inflammatory and cell death pathway.

• Cellular Homeostasis – The brain is particularly susceptible to defects in lipid, protein or RNA homeostasis.

Mutations in several ALS and FTD degenogenes alter RNA homeostasis and increase cellular stress.

Eukaryotic initiation factor 2 B ("eIF2B") is an essential regulator of cellular stress, and modulators of eIF2B activity have been shown to be beneficial in numerous in vitro and in vivo models of neurodegenerative disease.

Other degenogenes linked to cellular homeostasis include amyloid precursor protein ("APP"), Tau and Apolipoprotein E (“ApoE”).

Engineering Brain Delivery

Our Approach to Crossing Biological Barriers and Defeating Neurodegeneration

Historically, the BBB has been a major challenge to the development of medicines for diseases of the CNS.

While the BBB protects the brain from threats such as harmful substances and infections by tightly regulating transport of molecules into and out of the brain, the BBB also prevents the delivery of small- and large-molecule medicines to the brain in sufficient quantities to have therapeutic effect.

We directly address the BBB challenge by engineering brain delivery for both small and large molecules.

Most small molecules are actively excluded from the brain by efflux pumps at the BBB;

it has been estimated that approximately 98% do not cross the BBB.

We have rigorously designed our small molecule therapeutic candidates to be orally bioavailable with chemical and physical properties that enable them to be readily absorbed from the gut and to penetrate the BBB while avoiding transporter-mediated efflux.

We invented, developed, and continue to optimize a proprietary technology, called the Transport Vehicle, to deliver our large molecule biotherapeutic candidates to the brain after systemic administration.

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.

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.

We have pioneered and are developing a new class of biotherapeutics to directly address the BBB 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.

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.

We believe that the TV can significantly increase the probability of success of biotherapeutics for CNS indications and can enable many new potential treatment options.

Our TV technology is modular and enables several classes of biotherapeutics to more effectively cross the BBB, including enzymes, antibodies, proteins and oligonucleotides.

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, or RMT.

We believe that the TV can significantly increase the probability of success of biotherapeutics for CNS indications and can enable many new effective medicines.

Our TV technology is modular and enables several classes of biotherapeutics to more effectively cross the BBB, including enzymes, antibodies, oligonucleotides, and other proteins.

The TV technology is engineered to engage specific BBB transport receptors, such as the transferrin receptor ("TfR") and CD98 heavy chain ("CD98hc"), which are highly expressed in brain capillaries and facilitate transport of proteins into the brain ( Figure 1 ) in a process called receptor mediated transcytosis.

Engineering brain delivery.

Schematic of the TV technologies, designed to cross the BBB through receptor-mediated transcytosis, leveraging endogenous receptors expressed on endothelial cells of the central nervous system vasculature.

Our pipeline of TV-enabled programs currently includes three clinical-stage programs and more than a dozen programs in preclinical development.

We demonstrated proof of concept with safety and pharmacokinetic and pharmacodynamic data from the ongoing Phase 1/2 study with DNL310 (ETV:IDS), and pharmacokinetic data from the ongoing Phase 1 study with TAK-594/DNL593 (PTV:PGRN), as well as data from several preclinical studies in mouse and nonhuman primate models.

Preclinical studies demonstrated robust and sustained pharmacodynamic effects in the brain after intravenous dosing of TV-enabled antibodies, enzymes, proteins, and antisense oligonucleotides ("ASOs"), while standard antibodies, enzymes, proteins and ASOs had no or minimal pharmacodynamic effects.

These data show that TV-enabled product candidates have the potential to achieve therapeutically relevant concentrations in the brain after systemic administration, making them potentially superior to traditional biologic therapeutics in targeting neurodegenerative diseases.

Our TV technology is differentiated from other BBB technologies through its engineering approach, which may provide superior therapeutic efficacy and safety through higher stability, exposure, and biodistribution of drug candidates in the brain ( Figure 2 ).

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.

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.

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 ).

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.

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.

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.

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").

In addition, Fc engineering enables modularity for the broadest utility to transport biologics including enzymes, oligonucleotides, and antibodies.

Denali’s TV technology is modular and highly differentiated.

Our most advanced TV-enabled program, DNL310 (ETV:IDS), is currently in an ongoing Phase 2/3 study for MPS II, and we are conducting Phase 1/2 studies of TAK-594/DNL593 (PTV:PGRN) and DNL126 (ETV:SGSH) for FTD-GRN and MPS IIIA, respectively.

In addition, OTV:MAPT, targeting tau for Alzheimer’s disease, and OTV:SNCA, targeting αSyn for Parkinson’s disease, are our two lead IND-enabling stage OTV programs.

Biogen licensed our ATV:Abeta program targeting amyloid beta for Alzheimer's disease, which is in the IND-enabling stage.

We believe that we can further expand our portfolio leveraging the modularity of the TV technology as well as additional BBB receptors.

In addition to our current focus on neurodegenerative diseases and LSDs, we are exploring programs in oncology (ATV:HER2) and infectious diseases as well as other neurological and neuromuscular indications ( Figure 3 ).

Our pipeline of TV-enabled programs currently includes three clinical-stage programs and more than ten programs in preclinical development.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

DNL622 (ETV:IDUA) is also in IND-enabling stage for Hurler syndrome (MPS I).

We have built clinical manufacturing capabilities for our TV-enabled programs and continue to expand our commercial capabilities in lysosomal storage diseases.

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.

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.

Our ETV franchise lays the foundation for value creation to fuel expansion of our TV portfolio utilizing our ATV and OTV platforms.

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 ) .

We have further engineered these platforms to optimize certain pharmacokinetic, pharmacodynamic, and safety properties.

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.

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.

With cisLALA, the ATV:Abeta construct remains "immune silent" when bound to TfR, thus minimizing the risk of anemia from reticulocyte loss.

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.

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.

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 ).

We may develop these additional programs ourselves in the future or seek partnerships.

Denali’s TV technology provides opportunities for platform expansion.

In addition to TfR, we are targeting CD98hc, an amino acid transporter highly expressed on the BBB ( Figure 4 ).

We believe that we can further expand our portfolio by targeting other BBB receptors that may confer different properties from targeting TfR.

For example, we are targeting CD98hc, an amino acid transporter highly expressed on the BBB ( Figure 6 ).

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.

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.

TV CD98hc targets the CD98hc an amino acid transporter, which is highly expressed on the BBB, for brain delivery of biotherapeutics.

TV TfR targets the transferrin receptor and TV CD98hc targets the CD98hc an amino acid transporter.

Both receptors are highly expressed on the BBB and can be utilized for brain delivery of biotherapeutics.

Biomarker-Driven Development and Approval

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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.

In certain indications, regulatory approval may limit the market of a product candidate to target patient populations when patient selection biomarkers are used.

In these indications, regulatory authorities may require us to run additional clinical trials prior to expanding the label for approval that includes a broader patient population.

We recognize the urgency for patients living with neurodegenerative and LSDs to have effective treatment options.

We recognize the urgency for people living with neurodegenerative and lysosomal storage diseases to have effective treatment options.

Biomarkers have successfully been used as primary clinical endpoints to secure a faster path to approval in indications such as ALS and Alzheimer’s disease.

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.

These efforts are in addition to ongoing discussions with health authorities regarding the potential use of biomarkers as primary clinical endpoints to support faster paths to approval for our product candidates.

The following table summarizes key information about our clinical programs and pipeline:

Denali’s current development pipeline.

We are developing a broad portfolio of targeted therapeutic candidates for neurodegenerative diseases and LSDs.

Our programs are at different stages of clinical and preclinical development.

In addition to our current clinical development portfolio, we expect to advance at least three new molecule entities (“NMEs”) into clinical development in the 2024 to 2025 timeframe.

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.

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.

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.

We intend to submit the BLA under the accelerated approval pathway in early 2025.

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.

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 ).

Our programs are at various stages of clinical and preclinical development.

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.

We discuss our most advanced programs in further detail below.

Late-Stage And Mid-Stage Clinical Programs

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.

Clinical Programs

Tividenofusp alfa (DNL310, ETV:IDS) Enzyme Replacement Therapy Program for MPS II (Hunter Syndrome)

MPS II, also called Hunter syndrome, is a rare genetic disease that affects over 2,000 individuals, primarily males, world-wide, and leads to behavioral, cognitive, and physical symptoms ultimately resulting in shortened lifespan.

MPS II is caused by mutations in the iduronate-2-sulfatase ( IDS ) gene, which leads to a deficiency of the IDS enzyme responsible for the breakdown of the glycosaminoglycans (GAGs) heparan and dermatan sulfate in lysosomes.

MPS II, also called Hunter syndrome, is a rare genetic disease that affects over 2,000 individuals, primarily males, in commercially accessible geographies world-wide and leads to behavioral, cognitive, and physical symptoms ultimately resulting in shortened lifespan.

MPS II is caused by mutations in the iduronate-2-sulfatase (" IDS" ) gene, which leads to a deficiency of the IDS enzyme responsible for the breakdown of the glycosaminoglycans ("GAGs") heparan sulfate and dermatan sulfate in lysosomes.

Symptoms often begin emerging around age two and include physical complications, including organ dysfunction, joint stiffness, hearing loss and impaired growth leading to short stature, and neurocognitive symptoms with impaired development.

The disease is characterized by a buildup of GAGs in lysosomes — the part of the cell that breaks down materials, including GAGs.

The current standard of care enzyme replacement therapy (" ERT ") 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.

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.

Therapies that address behavioral, cognitive, and somatic manifestations of the disease are one of the greatest unmet needs for this community.

DNL310 is a fusion protein composed of IDS fused to Denali’s proprietary ETV, which is engineered to cross the BBB via receptor-mediated transcytosis into the brain and to enable broad delivery of IDS into cells and tissues throughout the body with the goal of addressing the behavioral, cognitive, and physical manifestations of MPS II.

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).

In March 2021, the U.S.

Food and Drug Administration granted Fast Track designation to DNL310 for the treatment of patients with MPS II.

In May 2022, the European Medicines Agency ("EMA") granted DNL310 Priority Medicines designation.

DNL310 is an investigational product candidate and has not been approved by any Health Authority.

Based on supportive clinical and preclinical data to date, we are enrolling the Phase 2/3 COMPASS study in North America, South America, and Europe.

The Phase 2/3 COMPASS study is expected to enroll 54 participants with MPS II, with and without neuronopathic disease.

The participants are randomized 2:1 to receive either DNL310 or idursulfase, respectively.

Food and Drug Administration granted Fast Track designation to tividenofusp alfa for the treatment of patients with MPS II.

In May 2022, the European Medicines Agency ("EMA") granted tividenofusp alfa Priority Medicines designation.

In January, 2025, the FDA granted tividenofusp alfa Breakthrough Therapy Designation for MPS II.

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.

Agreement was reached that a reduction in CSF heparan sulfate is reasonably likely to predict clinical benefit and can be used as a surrogate endpoint to support accelerated approval for tividenofusp alfa in MPS II.

The BLA is intended to be submitted under the accelerated approval pathway in early 2025 and will include preclinical and clinical data on biomarkers (CSF and urine heparan sulfate and neurofilament light ("NfL")), safety data, and clinical data including liver volume, hearing thresholds, cognition, and adaptive behavior.

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.

We are building a right-sized team in commercial and medical affairs to support tividenofusp alfa and additional ETV product launches.

The ongoing open-label extension of the Phase 1/2 study will generate long-term safety data.

We are also conducting the global Phase 2/3 COMPASS study, which will support global approval.

The Phase 2/3 COMPASS study is being conducted in North America, South America, and Europe.

The participants are randomized 2:1 to receive either tividenofusp alfa or idursulfase, respectively.

Cohort A includes children ages ≥2 to <6 years with neuronopathic disease;

cohort B includes children ages ≥6 to <26 without neuronopathic disease.

Upon completion of the ongoing Phase 1/2 study, and together with data from the global COMPASS study, this combined data package is intended to support registration.

In parallel with the Phase 2/3 COMPASS study, we are also conducting a Phase 1/2 trial for DNL310 in patients with MPS II as a multicenter, multiregional, open-label, single-arm trial to assess the safety, pharmacokinetics, and pharmacodynamics of DNL310 administered once weekly by intravenous infusion.

We have previously reported interim analyses from the Phase 1/2 study and most recently at the 2024 WORLD Symposium TM in February 2024.

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.

Cohort B continues to enroll participants with non-neuronopathic MPS II.

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.

The Phase 1/2 study is a multicenter, multiregional, open-label, single-arm study to assess the safety, pharmacokinetics, and pharmacodynamics of tividenofusp alfa administered once weekly by intravenous infusion.

The primary analysis included data from 47 participants who completed the 24-week treatment period and additional long-term follow-up.

Long-term data demonstrated that robust reductions and normalization in key biomarkers from baseline were maintained over time with continued improvement in hearing, cognition and adaptive behavior.

In addition, long-term safety data with median follow-up of two years, and out to more than four years, demonstrated that tividenofusp alfa was generally well tolerated.

Key results are summarized below.

The additional data reported at the 2024 WORLD Symposium TM demonstrated that DNL310 enabled rapid and sustained normalization of heparan sulfate in cerebrospinal fluid ("CSF") with mean reductions from baseline of approximately 90% at weeks 24, 49, and 104.

Normalization of CSF heparan sulfate was observed even in participants with high levels of preexisting serum anti-iduronate-2-sulfatase antibodies ( Figure 6 ).

In urine, a high-magnitude and sustained reduction of heparan sulfate and dermatan sulfate after switching from standard-of-care ERT to DNL310 suggested added peripheral activity.

Normal levels of CSF HS were achieved and sustained over time, including in those with pre-existing high serum ADA.

Following treatment with DNL310, mean reductions of 64%, 60%, and 71%, representing near normalization or complete normalization, were observed in levels of gangliosides GM2 and GM3 and glucosylsphingosine lipids, respectively, at week 104 in participants receiving DNL310, which is consistent with improved lysosomal function.

Robust and sustained reduction in serum neurofilament light ("NfL"), a marker of neuronal damage, was observed, reaching statistical significance after 61 weeks and a reduction of 64% after two years of treatment with DNL310 ( Figure 7 ).

Changes in serum and CSF NfL from baseline to week 104 were correlated;

at week 104, there was a statistically significant 54% mean reduction from baseline in CSF NfL.

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;

this effect was maintained through Week 153, or nearly three years, of treatment ( Figure 8 ).

CNS and peripheral heparan sulfate.

a Heparan sulfate was measured as a sum of the disaccharides D0A0, D0A6, D0S0, and D2S6 by mass spectrometry after enzymatic digestion.

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);

only protocol planned visits consistent across all cohorts and with ≥ 5 observations were included in the model.

c CFB for timepoints with collection for limited dose escalation cohorts:

W5 (cohort A only), range:

–24.9%, –93.1%;

W7 (cohort B only), range:

–67.3, –92.7%;

W9 (cohort A only), range –36.1%, –92.5%.

BL, baseline;

CFB, change from baseline;

CI, confidence interval;

CNS, central nervous system;

CSF, cerebrospinal fluid;

MMRM, mixed model for repeated measures;

ULN, upper limit of normal;

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 ).

Robust reduction of serum NfL, a marker of neuronal damage, was observed with long-term dosing.

Exploratory clinical outcomes data from Vineland Adaptive Behavior Scales (VABS)-II and Bayley Scales of Infant and Toddler Development (BSID)-III assessments out to 104 weeks of treatment with DNL310 were reported for the first time at the 2024 WORLD Symposium TM .

Continued improvement and stabilization of adaptive behavior and cognitive scores suggest DNL310 has positive effects ( Figure 8 ).

Continued improvement and stabilization in sum of VABS-II scores and cognitive scores suggest DNL310 has positive effects.

Hearing, as assessed by auditory brainstem response ("ABR") testing, numerically improved over time after initiation of DNL310 across all frequencies ( Figure 9 ).

At week 104, ABR thresholds showed statistically significant improvements across three of the four frequencies, with a trend toward greater improvement at higher frequencies.

Changes of ABR thresholds with DNL310 treatment suggest improved hearing.

Generally positive somatic activity on multiple endpoints was observed in participants receiving DNL310.

Liver volume in standard-of-care ERT-naïve participants decreased by a mean of 25% from baseline at weeks 24 and 49.

In standard-of-care ERT-experienced participants liver volume decreased by a mean of 5% from baseline at week 49.

Spleen volume was normal in all participants at weeks 24 and 49 of DNL310 treatment.

At baseline, spleen volume was normal in all participants except 1 standard-of-care ERT-naïve participant, who had normal spleen volumes at weeks 24 and 49 of DNL310 treatment.

DNL310 continues to be generally well tolerated (median treatment duration 100 weeks and maximum treatment duration 161 weeks).

The most frequent treatment-emergent adverse events were infusion related reactions, which decreased in frequency and severity with continued dosing.

An independent data monitoring committee met in December 2023 and recommended that the study may continue without modifications.

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 ).

Hearing Thresholds.

Mean change from baseline in pure tone average by ABR (eHL) and audiometry (HL).

Pure tone average is defined as the average across the four tested frequencies (500, 1000, 2000, and 4000 Hz).

Pure tone average is only calculated if the numeric values of all individual frequencies are available.

ABR (dB eHL) and any available standard hearing or behavioral audiometry test (in dB HL) are pooled.

ABR is prioritized if more than one test is available within the same participant and analysis visit.

ABR, auditory brainstem response;

BL, baseline;

CFB, change from baseline;

dB, decibels;

eHL, estimated hearing level;

HL, hearing level.

Long-term data demonstrated continued improvements from baseline in cognition and adaptive behavior ( Figure 11 ).

Cognition and Adaptive Behavior.

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.

Only visits with number of observation ≥ 5 were included in the statistical model.

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).

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.

BL, baseline;

BSID-III, Bayley Scales of Infant and Toddler Development, third edition;

CFB, change from baseline;

CI, confidence interval;

MMRM, mixed model for repeated measures;

VABS-II, Vineland Adaptive Behavior Scales, second edition;

Vineland-3, Vineland Adaptive Behavior Scales, third edition;

Administration of tividenofusp alfa was generally well tolerated in study participants.

Most treatment-related adverse events ("TEAEs") were mild or moderate, including IRRs, anemia, vomiting, pyrexia, respiratory infections and rash.

Serious TEAEs in three participants (6.4%) were manageable, with resolution or stabilization with continued treatment.

One participant discontinued treatment for reasons related to a moderate IRR and other non-treatment-related adverse events.

2025 expected progress and milestones:

• Presentation of additional interim Phase 1/2 data at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium.

• Complete enrollment of global Phase 2/3 COMPASS study in MPS II.

DNL343 eIF2B Activator Program for ALS

We are developing DNL343 as a novel eIF2B activator with first-in-class potential for the treatment of ALS and other indications.

eIF2B is an intracellular protein complex that regulates protein synthesis and is required for neuronal health and function.

When neurons experience stress, activation of the integrated stress response ("ISR") pathway leads to suppression of eIF2B activity, resulting in impaired protein synthesis and formation of stress granules.

Stress granules are thought to be a precursor of TDP-43 aggregation, which is a hallmark pathology in ALS.

DNL343 is designed to activate eIF2B and thereby restore protein synthesis, disperse TDP-43 aggregates, and improve neuronal survival.

In May 2023, the first participant with ALS was dosed with DNL343 (Regimen G) in the Phase 2/3 HEALEY ALS Platform Trial led by the Sean M.

Healey & AMG Center for ALS ("Healey Center") at Massachusetts General Hospital ("MGH") in collaboration with the Northeast ALS Consortium ("NEALS") clinical trial network.

The HEALEY ALS Platform Trial is a large-scale collaborative effort made possible by contributions from patients and families, clinical trial sites, industry partners and research collaborators to evaluate multiple investigational therapies simultaneously with the goal of accelerating the development of potential new treatments for ALS.

Therapeutic candidates that enter the platform trial are chosen by a group of expert ALS scientists and members of the Healey & AMG Center.

Recruitment is ongoing in Regimen G (DNL343) of the Phase 2/3 HEALEY ALS Platform Trial.

Late-stage development of DNL343 is supported by results of Phase 1/1b studies in 95 healthy volunteers and 28 participants with ALS.

In April 2023, we presented final data from the 28-day treatment period of the Phase 1b study of DNL343 in participants with ALS at the 75th Annual Meeting of the American Academy of Neurology ("AAN").

The Phase 1b study is a multicenter, randomized, placebo-controlled, double-blind, 28-day trial followed by an 18-month open-label extension, designed to evaluate the safety, pharmacokinetics and pharmacodynamics of DNL343 participants with ALS.

Study results have demonstrated that once-daily oral dosing with DNL343 for 28 days was generally well tolerated and demonstrated extensive CSF penetration.

In addition, robust inhibition of biomarkers associated with the ISR pathway was observed in blood samples from study participants ( Figure 10 ).

Phase 1b results demonstrated 28-day dosing with DNL343 reduced ISR biomarkers (e.g., ATF4 protein and CHAC1 mRNA) in blood samples from ALS patients.

• Submit BLA for tividenofusp alfa in MPS II under the accelerated approval pathway in early 2025

commercial launch in late 2025 or early 2026

DNL126 (ETV:SGSH) Program for MPS IIIA (Sanfilippo Syndrome A)

MPS III, also called Sanfilippo syndrome, is a rare, genetic lysosomal storage disease that causes neurodegeneration.

There are four main types of MPS III, depending on the enzyme affected.

Type A is caused by genetic defects that result in reduction in the activity of N-sulfoglucosamine sulfohydrolase ("SGSH"), an enzyme responsible for degrading heparan sulfate in the lysosome.

There are no approved treatments for MPS IIIA.

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.

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.

The core study period is 25 weeks (approximately 6 months) and is followed by a 72-week (approximately 18 month) open-label extension.

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.

Peripheral treatment with ETV:SGSH lowered substrate accumulation (heparan sulfate) in the brain and in CSF, which was correlated with improved cognitive behavioral performance in adult MPS IIIA mice.

In June 2024, 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.

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.

The safety profile supports continued development.

The most frequent treatment emergent adverse events were IRRs of mild and moderate severity in all participants.

There was one serious adverse event considered by the investigator not related to drug.

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.

2025 expected progress and milestones:

• Complete enrollment of participants in Regimen G (DNL343) in Phase 2/3 HEALEY ALS Platform Trial.

SAR443820/DNL788 RIPK1 Inhibitor Program for CNS Disease:

As described in more detail in “Business - Licenses and Collaborations” below, we are collaborating with Sanofi on the development of small molecules that inhibit RIPK1, a critical signaling protein in the tumor necrosis factor (“TNF”) receptor pathway and a regulator of inflammation and cell death.

Increased RIPK1 activity in the brain drives neuroinflammation and cell necroptosis and contributes to neurodegeneration.

RIPK1 inhibition has been shown to have beneficial effects in preclinical models of ALS, MS, Alzheimer's disease, and other diseases.

SAR443820/DNL788 is our lead CNS-penetrant RIPK1 inhibitor in clinical development.

Sanofi completed a Phase 1 trial of SAR443820/DNL788 in healthy volunteers, which demonstrated high brain penetrance and robust target engagement at doses that were generally well tolerated.

In February 2024, Sanofi informed us that the Phase 2 HIMALAYA study evaluating SAR443820/DNL788 in participants with amyotrophic lateral sclerosis (ALS) did not meet the primary endpoint of change in ALS Functional Rating Scale-Revised (ALSFRS-R).

Sanofi intends to present the detailed efficacy and safety results of the ALS Phase 2 HIMALAYA study at a future scientific forum.

Sanofi is evaluating SAR443820/DNL788 in another Phase 2 clinical trial in participants with multiple sclerosis (MS), and the outcome of HIMALAYA study has no impact on the ongoing MS study.

• Seek alignment with the FDA on an accelerated approval pathway for DNL126 for MPS IIIA

TAK-594/DNL593 (PTV:PGRN) Program for FTD-GRN

FTD is the most common form of dementia in people under 60 years of age.

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.

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.

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.

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.

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).

Preclinical proof of concept demonstrates that PTV enhances uptake of recombinant PGRN by multiple cell types in the brain, including neurons and microglia, as compared to non-PTV PGRN.

In addition, TAK-594/DNL593 rescued both neurodegeneration and microglial dysfunction in PGRN-deficient mice.

Our improved mechanistic understanding of the role of PGRN in lysosomal function indicates that intravenous delivery of TAK-594/DNL593 followed by PTV-enhanced transport to the brain may be an effective therapeutic approach to increase PGRN levels in lysosomes.

Together with Takeda, we initiated a Phase 1/2 clinical trial of TAK-594/DNL593 for FTD-GRN in 2022.

Results from Part A of this study evaluating TAK-594/DNL593 in healthy subjects were presented at the Alzheimer's Association International Conference in July 2023.

Single doses of TAK-594/DNL593 were generally well-tolerated and resulted in substantial increases in CSF PGRN levels, suggesting that brain delivery of TAK-594/DNL593 was achieved and that TAK-594/DNL593 has the potential to address PGRN deficiency ( Figure 12) .

Dose-dependent increase in CSF PGRN in healthy volunteers with intravenous TAK-594/ DNL593.

In January 2024, Denali announced that enrollment and dosing were voluntarily paused in Part B of the Phase 1/2 study to implement protocol modifications.

The pause was based on IRRs reported in two study participants, one Grade 2 and one Grade 3 in severity and both deemed serious adverse events.

Both study participants’ IRRs resolved within the same day with infusion discontinuation and standard treatment measures.

TAK-594/DNL593 was otherwise well-tolerated in the study, with all other adverse events reported as mild in severity.

In August 2024, 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.

In January 2025, we announced that dosing is ongoing in the study.

2025 expected progress and milestones:

• Continue Phase 2 K2 study in MS

• Continue dosing in Part B of the Phase 1/2 study in FTD-GRN

BIIB122/DNL151 LRRK2 Inhibitor Program for Parkinson's disease

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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.

Enrollment of LUMA is expected to be completed in 2025.

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.

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BIIB122/DNL151 was generally well tolerated across a broad range of doses for up to 28 days, the longest treatment duration in both studies.

In June 2023, Denali in conjunction with Biogen, and based on review of portfolio timelines and resource prioritization, announced plans to revise the clinical development program for BIIB122/DNL151.

Prior to the planned revisions, the BIIB122 clinical development program encompassed two global late-stage clinical trials:

the Phase 2b LUMA study in participants with early-stage Parkinson’s disease noted above;

and the Phase 3 LIGHTHOUSE study in participants with Parkinson’s disease related to pathogenic variants of LRRK2, which commenced in September 2022.

In consideration of the LIGHTHOUSE study’s complexity, including the long timeline with anticipated study completion in 2031, we and Biogen agreed to refocus efforts to enable a timely readout on efficacy in idiopathic early-stage Parkinson’s disease while gaining further clinical data in Parkinson’s disease with and without pathogenic variants in LRRK2.

The planned revisions to the BIIB122 clinical development program were not based on any safety or efficacy data from studies of BIIB122.

We have since modified the LUMA study’s enrollment criteria to allow for inclusion of eligible participants with Parkinson’s disease and a confirmed pathogenic variant of LRRK2, in addition to continuing to enroll eligible participants with idiopathic early-stage Parkinson’s disease.

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 plans to solely operationalize to evaluate safety and biomarkers associated with BIIB122 in participants with Parkinson’s disease and confirmed pathogenic variants of LRRK2.

This agreement includes committed funding of $75.0 million, of which $12.5 million was received in January 2024, and the remainder will be triggered based on time and operational milestones in the study.

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.

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.

Biogen will continue to conduct the ongoing global Phase 2b LUMA study in early-stage Parkinson’s disease.

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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 .

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.

2025 expected progress and milestones:

• Continue Phase 2b LUMA study in early-stage PD.

• Initiate Phase 2a study in PD related to pathogenic variants of LRRK2.

• Complete enrollment of the Phase 2b LUMA study in early-stage PD

• Continue enrollment in the Phase 2a study in PD related to pathogenic variants of LRRK2

Other LRRK2 Compounds

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As described in more detail in “Business - Licenses and Collaborations” below, we are collaborating with Biogen on the Peripheral LRRK2 program.

DNL343 eIF2B Activator Program for ALS

DNL343 is a novel small molecule investigational therapeutic that targets eIF2B, a central regulator of the integrated stress response ("ISR").

The ISR appears to be overactive in ALS, leading to the formation of stress granules containing TDP-43.

The buildup of TDP-43 is harmful and leads to neuronal degeneration.

In preclinical data, inhibition of the ISR by DNL343 dissolves TDP-43 containing stress granules and decreases biomarkers of the ISR.

Early clinical studies demonstrated that once-daily oral dosing with DNL343 was generally well tolerated and exhibited extensive penetration of CSF.

In addition, robust inhibition of biomarkers associated with the ISR pathway was observed in blood samples from study participants.

In May 2023, the first participant with ALS was dosed with DNL343 (Regimen G) in the Phase 2/3 HEALEY ALS Platform Trial led by the Sean M.

Healey & AMG Center for ALS ("Healey Center") at Massachusetts General Hospital ("MGH") in collaboration with the Northeast ALS Consortium ("NEALS") clinical trial network.

Therapeutic candidates that enter the platform trial are chosen by a group of expert ALS scientists and members of the Healey & AMG Center.

In May 2024, we announced completion of enrollment in Regimen G.

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.

2025 expected progress and milestones:

• Further analyses from Regimen G (DNL343) in Phase 2/3 HEALEY ALS Platform Trial.

Eclitasertib (SAR443122/DNL758) RIPK1 Inhibitor Program for Peripheral Inflammatory Diseases:

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Sanofi is solely responsible for the development and commercialization of peripherally restricted RIPK1 inhibitors.

In October 2023, Sanofi announced that the development of eclitasertib in cutaneous lupus erythematosus (CLE) was being discontinued because the Phase 2 proof-of-concept study did not meet its primary endpoint (percent change from baseline in Cutaneous Lupus Erythematosus Disease Area

and Severity Index-A (CLASI-A) at week 12).

Eclitasertib was found to be generally well-tolerated.

Sanofi is conducting a Phase 2 study of eclitasertib in patients with ulcerative colitis.

Recruitment for the trial is ongoing.

Recruitment for the trial is ongoing and data are expected in 2026.

2025 expected progress and milestones:

• Continue Phase 2 UC study

EARLY-STAGE CLINICAL AND PRECLINICAL PROGRAMS

TAK-594/DNL593 (PTV:PGRN) Program for FTD-GRN

FTD is the most common form of dementia in people under 60 years of age.

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.

It is estimated that FTD-GRN is 5-10% of the total FTD patient population.

There are currently no approved medicines to stop or slow the progression of FTD or FTD-GRN.

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), an investigational, brain-penetrant PGRN replacement therapy enabled by Denali's PTV platform and designed to restore PGRN levels in the brain without interfering with normal PGRN transport and processing.

Preclinical proof of concept demonstrates that PTV enhances uptake of recombinant PGRN by multiple cell types in the brain, including neurons and microglia, as compared to non-PTV PGRN.

In addition, TAK-594/DNL593 rescued both neurodegeneration and microglial dysfunction in PGRN-deficient mice.

Together with Takeda, we initiated a Phase 1/2 clinical trial of TAK-594/DNL593 for FTD-GRN in 2022.

Results from Part A of this study evaluating TAK-594/DNL593 in healthy subjects were presented at the Alzheimer's Association International Conference in July 2023.

Dose-dependent increase in CSF PGRN in healthy volunteers with intravenous TAK-594/ DNL593.

In January 2024, Denali announced that enrollment and dosing were voluntarily paused in Part B (n=9 dosed to date) of the TAK-594/DNL593 Phase 1/2 study in participants with FTD-GRN to implement protocol modifications.

The pause was based on infusion-related reactions (IRRs) reported in two study participants, one Grade 2 and one Grade 3 in severity and both deemed serious adverse events.

Both study participants’ IRRs resolved 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.

The protocol modification will allow for premedication and other measures aimed at reducing the risk of IRRs.

2024 expected progress and milestones:

• Resume Part B of the Phase 1/2 study in FTD-GRN.

DNL126 (ETV:SGSH) Program for MPS IIIA (Sanfilippo Syndrome A)

DNL126 (ETV:SGSH) is our second most advanced ETV program following DNL310 (ETV:IDS).

DNL126 is an investigational therapy in development for the potential treatment of MPS IIIA (Sanfilippo syndrome A), a rare LSD that causes fatal brain damage.

MPS IIIA is caused by genetic defects that result in a reduction in the activity of SGSH, an enzyme responsible for degrading heparan sulfates in the lysosome.

There are no approved treatments for MPS IIIA.

In January 2024, we commenced dosing in a Phase 1/2 study of DNL126 in MPS IIIA.

This is a small, multicenter, open-label, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory clinical efficacy of DNL126 in participants with Sanfilippo syndrome Type A (MPS IIIA).

The core study period is 25 weeks (approximately 6 months) and is followed by a 72-week (approximately 18 month) open-label extension.

In February 2024, we presented supportive 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.

As shown in ( Figure 12), 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.

(A) In MPS IIIA mice, treatment with ETV:SGSH (low and high doses) lowered accumulation of heparan sulfate (HS) in the brain and in CSF compared to vehicle-treated mice.

Bar graphs display mean ± SEM and p values:

one-way ANOVA with Dunnett’s multiple comparison test;

**p < 0.01, ****p < 0.0001.

(B) Lower HS levels were correlated with improved cognitive performance of adult MPS IIIA mice on a spatial learning and memory assay, the active place avoidance (APA) task.

Correlations were calculated using nonparametric Spearman’s correlation coefficient with two-tailed 95% confidence intervals.

Correlation graphs depict linear regression line.

2024 expected progress and milestones:

• Biomarker proof of concept and safety data from the Phase 1/2 study in late 2024.

IND-Enabling Stage Programs

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).

IND-enabling stage programs include:

• DNL952 (ETV:GAA) for Pompe disease

• DNL111 (ETV:Gcase) for Parkinson’s disease and Gaucher disease

• DNL622 (ETV:IDUA) for Hurler syndrome (MPS I)

• DNL628 (OTV:MAPT) targeting tau for Alzheimer’s disease

• DNL422 (OTV:SNCA) targeting alpha synuclein for Parkinson’s disease

• DNL921 (ATV:Abeta) targeting Abeta for Alzheimer’s disease

These programs are described below.

Enzyme Transport Vehicle (“ETV”) Programs

DNL952 (ETV:GAA) for Pompe disease

Acid alpha-glucosidase ("GAA") is an enzyme that breaks down glycogen into glucose in the body's lysosomes.

Pompe disease occurs due to lack of GAA enzyme activity, which leads to lysosomal glycogen accumulation and autophagic buildup resulting in cellular disruption.

There are two types of Pompe disease:

Infantile Onset Pompe Disease ("IOPD") and Late Onset Pompe Disease ("LOPD").

IOPD affects the heart and causes ventilatory failure leading to early death, typically before one year age.

LOPD can occur from early childhood through later decades in life and is characterized by slow progression, limb-girdle weakness leading to inability to walk, respiratory weakness leading to ventilator dependence, and CNS involvement.

The estimated prevalence of Pompe disease is 5,000 to 10,000 people worldwide excluding India and China.

Current standard of care is enzyme replacement therapy.

Progressive motor weakness and respiratory failure remain unmet needs.

DNL952 (ETV:GAA) is composed of GAA fused to TV and is engineered to replace GAA in all tissues, including TfR-enabled biodistribution to muscle and brain, for the treatment of Pompe disease.

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 13 ).

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).

DNL111 (ETV:Gcase) for Parkinson's disease and Gaucher disease

Glucocerebrosidase ("GCase") is an enzyme that breaks down lipids in the lysosome.

Aberrant GCase substrate storage drives lysosomal dysfunction and is associated with Gaucher disease and Parkinson's disease.

Homozygous loss-of-function mutations in the GBA1 gene, which encodes the GCase enzyme, leads to Gcase enzyme deficiency resulting in Gaucher disease.

Gaucher disease can be associated with debilitating symptoms including a swollen belly from spleen and liver enlargement;

bone pain and easily fractured and weak bones;

anemia resulting in fatigue.

Some people with Gaucher disease have CNS involvement:

abnormal eye movements, muscle rigidity, swallowing difficulties, and seizures.

There are an estimated 10,000 to 15,000 people with Gaucher disease worldwide (excluding China and India).

Approximately 10% of all Parkinson's disease patients are heterozygous carriers of a loss-of-function GBA1 mutation, leading to lysosomal dysfunction which is strongly associated with neuroinflammation/degeneration.

There are an estimated 300,000 GBA-PD patients worldwide (excluding China and India).

Peripheral enzyme replacement therapy is the current standard of care for Gaucher disease, and no GBA-PD specific treatments currently approved.

DNL111 is composed of an engineered GCase variant for improved potency and fused to TV to replace GCase in all tissues, including the brain by crossing the BBB.

In preclinical studies, ETV:Gcase shows improved substrate reduction in brain, liver and serum as compared to Gcase enzyme alone.

Further we have engineered the recombinant Gcase enzyme for improved potency.

Engineered ETV:GCase may enable highly stable and potent brain-penetrant enzyme replacement therapy for Parkinson’s disease and Gaucher disease.

DNL622 (ETV:IDUA) for MPS I (Hurler syndrome)

Alpha-L-iduronidase (“IDUA”) is an enzyme responsible for degrading heparan and dermatan sulfate in the lysosome.

Genetic defects in IDUA result in a reduction or absence of lysosomal IDUA activity and cause Hurler syndrome (or MPS I), which is characterized by alterations in the skeleton, heart, respiratory system, and brain.

DNL622 (ETV:IDUA) is a recombinant IDUA enzyme engineered to cross the BBB, to replace IDUA, and to treat the cognitive, behavioral and physical manifestations of the disease.

Alpha-L-iduronidase (“IDUA”) is as enzyme responsible for degrading heparan and dermatan sulfate in the lysosome.

Genetic defects in the gene encoding IDUA result in deficient enzyme activity, leading to MPS I (Hurler syndrome).

MPS I is characterized by alterations in the skeleton, heart, respiratory system, and brain and affects approximately 1,500 individuals worldwide.

DNL622 (ETV:IDUA) is composed of IDUA fused to TV, which is engineered to cross the BBB via RMT into the brain and to enable broad delivery of IDUA into cells and tissues throughout the body with the goal of treating MPS I.

DNL622 is currently in the IND-enabling stage of preclinical development.

Antibody Transport Vehicle Amyloid beta (ATV:Abeta) program

Targeting Abeta plaques in the brain has been investigated by the field as a therapeutic approach to treat AD, and two Abeta-targeted antibodies have received accelerated approval from the U.S.

These accelerated approvals were based on clinical data demonstrating that treatment was associated with a reduction in the accumulation of Abeta plaque in the brain, a defining feature of AD.

Subsequently, the U.S.

FDA converted one of the antibodies to traditional approval following a determination that a confirmatory trial verified clinical benefit.

Our ATV:Abeta program utilizes the TfR TV platform to enable increased brain exposure and target engagement of anti-Abeta.

In preclinical studies in mice, superior amyloid plaque binding ( Figure 13A ) and reduction ( Figure 13B ) with ATV:Abeta was demonstrated compared to a conventional Abeta antibody, which may enable a wider therapeutic window in treating AD as compared to conventional anti-Abeta therapy.

In addition, Biogen has shown in a mouse model of AD the potential for ATV:Abeta to reduce the risk of amyloid-related imaging abnormalities (ARIA) associated with the treatment of Alzheimer’s disease ( Figure 13C ).

Preclinical data showing superior amyloid plaque binding (A), superior plaque reduction (B), and fewer to no ARIA events (C).

In April 2023, Biogen exercised its exclusive option to license ATV:Abeta using TV TfR and is responsible for its development and commercialization.

2024 expected progress and milestones:

• IND-enabling studies.

Oligonucleotide Transport Vehicle ("OTV") Platform

Oligonucleotides, such as ASOs, are a novel class of biotherapeutics with the potential to address the root cause of many diseases through modulation of gene expression.

This class, however, has been limited in its potential for treatment of neurodegenerative diseases, primarily due to the challenge of delivering effective amounts of drug to relevant brain regions.

Direct injection into the CSF (e.g., intrathecal injection) or certain brain regions has not achieved the robust biodistribution into deep brain tissue, which may be necessary for effective therapeutic activity.

Nonhuman primate data demonstrated that intravenous delivery of an ASO enabled by our OTV technology resulted in broad brain biodistribution of the ASO ( Figure 14 ), which was superior to intrathecal administration of the ASO.

These data support the potential of our OTV platform to enable peripheral administration of oligonucleotide therapeutics and to address a wide range of neurodegenerative and other neurological diseases.

Broad brain biodistribution of an intravenously administered ASO enabled by our OTV technology (right) as compared to limited brain biodistribution of ASO delivered intrathecally (left).

In January, we announced that OTV:MAPT targeting tau for Alzheimer’s disease and OTV:SNCA targeting αSyn for Parkinson’s disease are the first programs in the IND-enabling stage of development.

( Figure 15 ).

As shown in ( Figure 16 ), we have optimized lead ASOs to achieve robust knock-down of human MAPT expression in the hTau x TfRmu/hu mouse brain.

OTV is designed to open a large potential indication space in neurodegeneration and beyond by enabling superior biodistribution of ASOs across brain regions, providing superior knockdown of target gene expression across cell types, and enabling intravenous dosing of oligonucleotide therapeutics for CNS delivery.

OTV:MAPT and OTV:SNCA are lead OTV programs in the IND-enabling stage of development .

OTV:MAPT in an unmodified format achieves approximately 20% knockdown.

After optimizing the OTV molecule through protein, linker, and/or oligonucleotide engineering, the five new OTV:MAPT Leads (L1-L5) provided >50% human MAPT knockdown in hTau x TfRmu/hu KI mice, with L4 providing 75% human MAPT knockdown.

2024 expected progress and milestones:

• IND-enabling studies with OTV:MAPT and OTV:SNCA.

Other TV-Enabled Discovery Programs

Denali continues to use deep scientific expertise in neurodegeneration biology and the BBB to discover and develop medicines and platforms with the focus on programs enabled by the TV and targeting common neurodegenerative disease, including Alzheimer’s and Parkinson’s, and LSDs.

Our portfolio includes additional preclinical programs, including programs targeting TREM2 (“ATV:TREM2”) and HER2 (“ATV:HER2”).

In August 2023 we announced that, in agreement with Takeda, the companies would discontinue clinical development of TAK-920/DNL919 (ATV:TREM2) in Alzheimer’s disease.

This was a strategic decision based on the totality of clinical data emerging from the single ascending dose Phase 1 study of TAK-920/DNL919 in healthy volunteers and in consideration of the rapidly evolving treatment landscape for Alzheimer's disease whereby an understanding of drug combinations with newly approved therapies will be important.

A preliminary analysis of Phase 1 data indicated robust target engagement and effects on microglial biomarkers (e.g., CSF1R, SPP1, IL1RA, IP10, MIP1b, MCP-1), which were consistent with preclinical studies that demonstrated that ATV:TREM2 induced robust changes to a responsive microglial cell state (van Lengerich B, et al.

Nat Neurosci.

In the Phase 1 study, TAK-920/DNL919 was clinically well tolerated at doses with demonstrated changes in CSF biomarkers and there were no serious adverse events or severe treatment emergent adverse events;

however, safety signals of moderate, reversible hematologic effects were observed at the highest dose tested, suggesting a narrow therapeutic window for the Alzheimer’s disease patient population.

The Phase 1 safety findings are believed to be specific to properties of TAK-920/DNL919 and TREM2 biology.

Denali and Takeda will continue to focus research efforts on molecules in preclinical development, including exploration of potential combination therapy given recent new drug approvals in Alzheimer's disease.

Oligonucleotide Transport Vehicle (“OTV”) Programs

Oligonucleotides, such as ASOs and siRNAs, are designed to modify gene expression and hold promise as therapeutics for neurological disorders.

A major challenge in their development, however, is that oligonucleotides are unable to cross the BBB on their own.

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.

We are using our OTV platform to enable brain delivery of oligonucleotides by crossing the BBB 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.

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.

Additionally, OTV enabled knockdown of the ASO target gene expression in historically difficult to target peripheral muscle tissues, including skeletal and cardiac muscle.

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.

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.

DNL628 (OTV:MAPT) is a therapeutic candidate targeting tau for Alzheimer's disease.

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 ).

Extended knockdown duration of action may enable less frequent maintenance dosing.

Similarly, we are advancing DNL422 (OTV:SCNA) targeting alpha-synuclein for Parkinson's disease.

OTV provides uniform ASO deposition in the brain with intravenous (IV) delivery (left).

Brain MAPT RNA and tau protein knockdown persists for >15 weeks following four IV doses of OTV:MAPT.

A ntibody Transport Vehicle (“ATV”) Programs

DNL921 Antibody Transport Vehicle Amyloid beta (ATV:Abeta) program

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;

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.

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.

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 ).

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.

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).

Preclinical data showing superior amyloid plaque reduction ( A ), superior oligomeric plaque reduction ( B ), fewer to no ARIA events ( C ), and preservation of reticulocytes ( D ).

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.

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.

Human epidermal growth factor receptor 2 ("HER2") is a growth factor receptor that is over-expressed in multiple cancers, including breast, colorectal, and gastric cancer.

Up to half of patients diagnosed with metastatic HER2-positive breast cancer have brain metastases for which limited treatment options exist.

Using ATV, we have engineered mono- and bispecific formats of HER2 antibodies.

Up to half of patients diagnosed with metastatic HER2-positive breast cancer develop brain metastases for which limited treatment options exist.

In preclinical mouse studies, we have demonstrated improved anti-tumor activity of ATV-enabled HER2 antibodies in a HER2-positive peripheral tumor model.

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In August 2023, upon execution of the Biogen Amendment, Biogen also agreed to waive its right of first negotiation on two additional TV-enabled therapeutics, which we initially granted to Biogen under the ROFN and Option Agreement.

Under the ROFN and Option Agreement, Biogen paid us a $160.0 million upfront payment in October 2020 and a $5.0 million option exercise payment in April 2023 for the ATV:Abeta program.

With respect to the ATV:Abeta license granted by us to Biogen, Biogen is obligated to pay to us an aggregate of up to $142.5 million in development milestone payments, an aggregate of up to $180.0 million upon first commercial sale, and up to $190.0 million of net sales-based milestone payments.

Furthermore, Biogen is obligated to pay us royalties in the mid-single digit percentages, upon the achievement of certain sales thresholds.

Exclusivity of ROFN and Option Agreement

Until termination or expiration of the ROFN and Option Agreement, neither party may conduct preclinical, clinical or commercial activities involving certain therapeutic products directed to ATV TfR :Abeta, unless the therapeutic is included under the collaboration and only to the extent such activity is permitted under the ROFN and Option Agreement or the therapeutic is a product that includes AAVs, oligonucleotides or small molecules.

Each party may terminate the Biogen Collaboration Agreement in its entirety, if the other party remains in material breach of the Biogen Collaboration Agreement following a cure period to remedy the material breach.

After giving a specified amount of prior notice to us, Biogen may terminate the Biogen Collaboration Agreement for convenience in its entirety or, in the case of the LRRK2 Agreement, with respect to one or more specified regions of the world, and in the case of the Biogen Collaboration Agreement, with respect to any Option Program for one or more specified regions or in its entirety.

We may terminate the LRRK2 Agreement if Biogen fails to conduct meaningful activities to advance the development or commercialization of any LRRK2 Products for a specified period of time, unless Biogen cures such failure within a certain period of time.

We may terminate the Biogen Collaboration Agreement if Biogen challenges any patents licensed to it under the Biogen Collaboration Agreement.

We and Biogen may each terminate the Biogen Collaboration Agreement in its entirety if the other party is declared insolvent or in similar financial distress.

On July 26, 2024, a Side Letter to the ROFN and Option Agreement was executed, pursuant to which, effective as of the date of the Side Letter, Biogen terminated its license to the ATV:Abeta program enabled by our TfR-targeting technology against amyloid beta for the potential treatment of Alzheimer's disease, and granted us rights to data generated during the collaboration.

The side letter also effected the immediate termination of the ROFN and Option Agreement;

as such, we expect to receive no future milestone or royalty payments from Biogen related to the ATV:Abeta program.

Common Stock Purchase Agreement

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In connection with the sale of shares, we entered into a standstill and stock restriction agreement (the "Biogen Standstill Agreement") with Biogen, pursuant to which Biogen agreed to certain transfer and standstill restrictions, which have now expired, with the exception of certain volume limitations.

Biogen remains entitled to certain demand registration rights for the shares received in the transaction under the terms of the Biogen Standstill Agreement.

Sanofi Collaboration and License Agreement

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("Sanofi") pursuant to which certain small molecule compounds that bind to and inhibit RIPK1 (“RIPK1 Inhibitors”) contributed by Sanofi and by us will be developed and commercialized.

The Sanofi Collaboration Agreement became effective in November 2018 when the requirements of the Hart-Scott-Rodino Antitrust Improvements Act of 1976 were satisfied.

We and Sanofi are jointly developing products containing RIPK1 Inhibitors for neurological indications, such as Alzheimer’s disease and MS, and Sanofi is developing products containing RIPK1 Inhibitors for systemic inflammatory indications, such as UC.

The Sanofi Collaboration Agreement includes our and Sanofi’s RIPK1 Inhibitors that measurably penetrate the BBB ("CNS Products"), and our and Sanofi’s RIPK1 Inhibitors that do not measurably penetrate the BBB ("Peripheral Products").

The two most advanced RIPK1 Inhibitors in the collaboration are SAR443820/DNL788, and eclitasertib (SAR443122/DNL758).

SAR443820/DNL788 is a CNS Product that was discovered by us and licensed to Sanofi who has completed Phase 1 trials in healthy volunteers, and is leading a Phase 2 clinical trial in patients with MS.

Eclitasertib is a Peripheral Product discovered by us, and licensed to Sanofi who is leading a Phase 2 clinical trial in patients with UC.

The Sanofi Collaboration Agreement became effective in November 2018 when the requirements of the Hart-Scott-Rodino Antitrust Improvements Act of 1976 were satisfied, and included our and Sanofi’s RIPK1 Inhibitors that measurably penetrate the BBB ("CNS Products"), and our and Sanofi’s RIPK1 Inhibitors that do not measurably penetrate the BBB ("Peripheral Products").

We and Sanofi were jointly developing products containing RIPK1 Inhibitors for neurological indications, such as Alzheimer’s disease and MS, until the 2024 discontinuations of the HIMALAYA and K2 phase 2 studies evaluating SAR443820/DNL788 in participants with ALS and multiple sclerosis, respectively.

On February 24, 2025, Denali and Sanofi executed a side letter terminating Sanofi's license to the CNS Products program including SAR443820/DNL788.

Sanofi continues to develop eclitasertib (SAR443122/DNL758), a Peripheral Product discovered by us, and licensed to Sanofi who is leading a Phase 2 clinical trial in patients with UC.

License Grant

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When the Sanofi Collaboration Agreement became effective in November 2018, Sanofi paid us $125.0 million upfront.

Under the Sanofi Collaboration Agreement, Sanofi is required to make milestone payments up to approximately $1.1 billion upon achievement of certain clinical, regulatory and sales milestone events.

Such milestone payments include $215.0 million in clinical milestone payments and $385.0 million in regulatory milestone payments for CNS Products, as defined, that are developed and approved in the United States, Europe and in Japan for three indications, including Alzheimer's disease.

Sanofi has made payments of $65.0 million for CNS clinical milestones through December 31, 2023.

The cumulative earned and potential milestones include $120.0 million in clinical milestone payments, $175.0 million in regulatory milestone payments and $200.0 million in commercial milestone payments for Peripheral Products, as defined, that are developed and approved in the United States, Europe and in Japan for three indications.

Sanofi has made payments of $35.0 million for peripheral clinical milestones through December 31, 2023 .

We will share profits and losses equally with Sanofi for CNS Products sold in the United States and China, and receive variable royalties on net sales for CNS Products sold outside of the United States and China and for Peripheral Products sold worldwide, each as further described below.

Sanofi is required to make milestone payments totaling up to approximately $495.0 million upon achievement of certain clinical, regulatory and sales milestone events for the Peripheral Products.

Such milestone payments include $120.0 million in clinical milestone payments, $175.0 million in regulatory milestone payments and $200.0 million in commercial milestone payments for Peripheral Products, as defined, that are developed and approved in the United States, Europe and in Japan for three indications.

Sanofi has made payments of $35.0 million for Peripheral Product clinical milestones through December 31, 2024, and a further $65.0 million for CNS Product clinical milestones through the same date .

Subsequent to the side letter executed on February 24, 2025, we expect to receive no future milestone or royalty payments from Sanofi related to the CNS Products program.

We will receive variable royalties on net sales for Peripheral Products sold worldwide, each as further described below.

RIPK1 Inhibitors contributed by Sanofi and developed and commercialized under the Sanofi Collaboration Agreement will be subject to lower milestone and royalty payments to us compared to RIPK1 Inhibitors contributed by us.

We will also retain responsibility for certain payment obligations under our agreement with an academic institution which licensed certain intellectual property to us that we are sublicensing to Sanofi under the Sanofi Collaboration Agreement.

Program for Development and Commercialization of CNS Products

We and Sanofi jointly develop CNS Products pursuant to a global development plan ("CNS Development Plan").

We will be responsible, at our cost, for conducting Phase 1 and Phase 2 trials for CNS Products for Alzheimer’s disease and any activities required to support such clinical trials and specific for Alzheimer’s disease.

Sanofi is responsible, at its cost, for all other Phase 1 and Phase 2 trials for CNS Products, including for MS.

Sanofi will lead the conduct of all Phase 3 and later stage development trials for CNS Products, with Sanofi and us funding 70% and 30% of such costs, respectively.

The Sanofi Collaboration Agreement contains certain protections for us with respect to Phase 3 development costs not included in the initial budget for the CNS Development Plan agreed to by the parties, including a deferral mechanism for costs incurred above the budgeted amounts for such trials and for costs incurred in respect of Phase 3 and other clinical trials not contemplated in the initial CNS Development Plan.

In addition, we have the ability to opt out of the cost-profit sharing provisions of the Sanofi Collaboration Agreement, as further described below.

Sanofi will lead commercialization activities globally for CNS Products.

We may elect to conduct certain co-commercialization activities outside of MS with respect to each CNS Product in the United States and/or China, provided that the cost-profit sharing provisions of the Sanofi Collaboration Agreement for the relevant CNS Product are still in effect, as further described below.

We may opt out of the cost-profit sharing provisions of the Sanofi Collaboration Agreement for CNS Products in the United States and China on a CNS product-by-CNS Product and country-by-country basis.

Sanofi may also terminate our cost-profit sharing provisions of the Sanofi Collaboration Agreement in its entirety if, following notice from Sanofi and a cure period, we fail to satisfy our cost-sharing obligations.

After such an opt out by us or termination by Sanofi, we will no longer be obligated to share in the development and commercialization costs for the applicable CNS Products and we will not share in the applicable profits from such CNS Products.

Instead, we will be entitled to receive tiered royalties on net sales of the applicable CNS Products in the relevant country (or countries).

The royalty rates will be a percentage in the low double digits to mid-teens, but may increase to the mid-teens to low-twenties percentages for all countries in which Sanofi is paying royalties on the applicable CNS Products, if we have met certain co-funding thresholds at the time of our election or Sanofi’s termination of our cost-profit sharing rights and obligations.

Program for Development and Commercialization of Peripheral Products

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Manufacturing

Sanofi will be responsible for delivering all supplies for current and future clinical trials and commercial production for CNS Products and Peripheral Products.

Sanofi will be responsible for delivering all supplies for current and future clinical trials and commercial production for Peripheral Products.

However, we retain manufacturing rights for certain independent clinical activities.

For any CNS Product with respect to any country for which Sanofi is required to pay royalties on net sales and for each Peripheral Product, Sanofi will pay royalties to us on a country-by-country basis until the latest of (i) the expiration of certain patents covering the relevant product, (ii) the expiration of all regulatory exclusivity for that product in the applicable country, and (iii) an agreed period of time after the first commercial sale of that product in the applicable country.

If, in a particular country, a CNS Product for which Sanofi is required to pay royalties or a Peripheral Product is not covered by specified patent rights in that country or net sales in that country decrease below specified thresholds as a result of generic competition, Sanofi’s royalty obligations in the applicable country would be reduced or would terminate as specified in the Sanofi Collaboration Agreement.

During the term of the Sanofi Collaboration Agreement, neither we nor Sanofi may conduct IND-enabling, clinical or commercial activities involving any RIPK1 Inhibitor, anywhere in the world, unless the RIPK1 Inhibitor is included by us or Sanofi, as the case may be, under the collaboration and only to the extent such activity is permitted under the Sanofi Collaboration Agreement.

Each party may terminate the Sanofi Collaboration Agreement in its entirety, or with respect to a particular program (i.e., the CNS Products program or Peripheral Products program), as applicable, if the other party remains in material breach of the Sanofi Collaboration Agreement following a cure period to remedy the material breach.

For each Peripheral Product, Sanofi will pay royalties to us on a country-by-country basis until the latest of (i) the expiration of certain patents covering the relevant product, (ii) the expiration of all regulatory exclusivity for that product in the applicable country, and (iii) an agreed period of time after the first commercial sale of that product in the applicable country.

If, in a particular country, a Peripheral Product is not covered by specified patent rights in that country or net sales in that country decrease below specified thresholds as a result of generic competition, Sanofi’s royalty obligations in the applicable country would be reduced or would terminate as specified in the Sanofi Collaboration Agreement.

During the term of the Sanofi Collaboration Agreement, neither we nor Sanofi may conduct IND-enabling, clinical or commercial activities involving any Peripheral Product, anywhere in the world, unless the Peripheral Product is included by us or Sanofi, as the case may be, under the collaboration and only to the extent such activity is permitted under the Sanofi Collaboration Agreement.

Each party may terminate the Sanofi Collaboration Agreement in its entirety, or with respect to a particular program, as applicable, if the other party remains in material breach of the Sanofi Collaboration Agreement following a cure period to remedy the material breach.

After giving a specified amount of prior notice to us, Sanofi may terminate the Sanofi Collaboration Agreement for convenience in its entirety, with respect to any particular program, or with respect to one or more specified regions of the world.

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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.

Takeda exercised the options for the PTV:PGRN and ATV:TREM2 programs in November 2021 and December 2021, respectively.

Takeda exercised the options 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.

The ATV:TREM2 program termination will become effective 60 days following the notice date.

Research Phase and Takeda’s Option

Under the Takeda Collaboration Agreement we were responsible, at our cost, for conducting activities relating to pre-IND development of biologic products directed to the identified targets and enabled by our BBB delivery technology targeting TfR during the applicable option period.

Under the Takeda Collaboration Agreement we were responsible, at our cost, for conducting activities relating to pre-IND development of biologic products directed to the identified targets and enabled by our TV technology targeting TfR during the applicable option period.

The option period continued for each target until the first biologic product candidate directed to the relevant target was IND-ready or about five years after selection of the target, whichever was earlier.

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Collaboration Activities Following Takeda’s Option Exercise

Subsequent to Takeda exercising its option with respect to a particular target and collaboration program (i.e., the biologic products directed to the target for which Takeda has exercised its option), Takeda has the right to develop and commercialize, jointly with us, a specified number of biologic products enabled by our BBB technology that were developed during the option period and which are directed to the relevant target, and we are obligated to grant to Takeda a co-exclusive license under the intellectual property we control related to those biologic products.

Subsequent to Takeda exercising its option with respect to a particular target and collaboration program (i.e., the biologic products directed to the target for which Takeda has exercised its option), Takeda has the right to develop and commercialize, jointly with us, a specified number of biologic products enabled by our TV technology that were developed during the option period and which are directed to the relevant target, and we are obligated to grant to Takeda a co-exclusive license under the intellectual property we control related to those biologic products.

Takeda was obligated to pay us a $5.0 million option fee for each target for which Takeda exercised its option, and we received fees totaling $10.0 million from Takeda in 2021 for option exercise payments for the PTV:PGRN and ATV:TREM2 programs.

Since Takeda exercised its option for both collaboration programs, Takeda may be obligated to pay us up to an aggregate of $280.0 million upon achievement of certain clinical milestone events and up to an aggregate of $200.0 million in regulatory milestone events relating to receipt of regulatory approval in the United States, certain European countries and Japan.

Further, Takeda may also be obligated to pay us up to $75.0 million per biologic product upon achievement of a certain sales-based milestone, or an aggregate of $150.0 million if one biologic product from each program achieves the milestone.

Further, we and Takeda share equally the development and commercialization costs, and, if applicable, the profits, for each collaboration program.

However, for each collaboration program, we may elect not to continue sharing development and commercialization costs, or Takeda may elect to terminate our cost-profit sharing rights and obligations if, following notice from Takeda and a cure period, we fail to satisfy our cost sharing obligations with respect to the relevant collaboration program.

After such an election by us or termination by Takeda becomes effective, we will no longer be obligated to share in the development and commercialization costs for the relevant collaboration program, and we will not share in any profits from that collaboration program.

Subsequent to the ATV:TREM2 termination, Takeda may be obligated to pay us milestones related to the PTV:PGRN program, including up to $140.0 million upon achievement of certain clinical milestone events and up to $100.0 million in regulatory milestone events relating to receipt of regulatory approval in the United States, certain European countries and Japan.

Further, Takeda may also be obligated to pay us up to $75.0 million upon achievement of a certain sales-based milestone.

Further, we and Takeda share equally the development and commercialization costs, and, if applicable, the profits, for the PTV:PGRN program.

However, we may elect not to continue sharing development and commercialization costs, or Takeda may elect to terminate our cost-profit sharing rights and obligations if, following notice from Takeda and a cure period, we fail to satisfy our cost sharing obligations.

After such an election by us or termination by Takeda becomes effective, we will no longer be obligated to share in the development and commercialization costs for the PTV:PGRN program, and we will not share in any profits from that program.

Instead, we will be entitled to receive tiered royalties.

The royalty rates will be in the low- to mid-teen percentages on net sales, or low- to high-teen percentages on net sales if we have met a certain co-funding threshold at the time of our election to opt out of co-development or Takeda’s termination of our cost-profit sharing rights and obligations, and, in each case, these royalty rates will be subject to certain reductions specified in the Takeda Collaboration Agreement.

Takeda will pay these royalties to us for each biologic product included in the relevant collaboration program, on a country-by-country basis, until the latest of (i) the expiration of certain patents covering the relevant biologic product, (ii) the expiration of all regulatory exclusivity for that biologic product, and (iii) an agreed period of time after the first commercial sale of that biologic product in the applicable country, unless biosimilar competition in excess of a significant level specified in the Takeda Collaboration Agreement occurs earlier, in which case Takeda’s royalty obligations in the applicable country would terminate.

For each collaboration program for which we are sharing costs and profits with Takeda, we will lead the conduct of clinical activities for each indication up to the first trial with a clinical outcomes-based efficacy endpoint, and Takeda will lead the conduct of all subsequent clinical activities for that indication.

For each collaboration program for which we are sharing costs and profits with Takeda, we and Takeda will jointly commercialize biologic products included in the relevant collaboration program in the United States and China.

Unless we have opted out of cost-sharing for both collaboration programs, we have the right to lead commercialization activities in the United States for one collaboration program and Takeda will lead commercialization activities in the United States for all collaboration programs for which we do not lead commercialization activities.

Further, Takeda will lead commercialization activities in China and will solely conduct commercialization activities in all other countries.

We have the right to lead all manufacturing activities for all collaboration programs for which the parties are sharing costs and profits.

Takeda will pay these royalties to us, on a country-by-country basis, until the latest of (i) the expiration of certain patents covering the biologic product, (ii) the expiration of all regulatory exclusivity for that biologic product, and (iii) an agreed period of time after the first commercial sale of that biologic product in the applicable country, unless biosimilar competition in excess of a significant level specified in the Takeda Collaboration Agreement occurs earlier, in which case Takeda’s royalty obligations in the applicable country would terminate.

For the PTV:PGRN program for which we are sharing costs and profits with Takeda, we will lead the conduct of clinical activities for each indication up to the first trial with a clinical outcomes-based efficacy endpoint, and Takeda will lead the conduct of all subsequent clinical activities for that indication.

We and Takeda will jointly commercialize biologic product(s) included in the PTV:PGRN program in the United States and China.

Takeda will lead commercialization activities in the United States and China and will solely conduct commercialization activities in all other countries.

We have the right to lead all manufacturing activities for the PTV:PGRN program.

Information on cost sharing reimbursements between us and Takeda is included in this Annual Report on Form 10-K in our financial statements and the related notes and the section titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations.”

Unless the Takeda Collaboration Agreement is terminated earlier, until expiration of an agreed period of time after the first regulatory approval in the United States or Europe of a biologic product within the applicable collaboration program, neither party may conduct clinical or commercial activities involving antibodies or protein-based therapeutic products directed to the same target (or in the case of a bi-specific program, the same combination of targets) that have an intended therapeutic effect in diseases and conditions of the CNS (including LSDs), except to the extent permitted under the Takeda Collaboration Agreement.

Unless the Takeda Collaboration Agreement is terminated earlier, until expiration of an agreed period of time after the first regulatory approval in the United States or Europe of a biologic product within the PTV:PGRN program, neither party may conduct clinical or commercial activities involving antibodies or protein-based therapeutic products directed to the same target (or in the case of a bi-specific program, the same combination of targets) that have an intended therapeutic effect in diseases and conditions of the CNS (including lysosomal storage diseases), except to the extent permitted under the Takeda Collaboration Agreement.

Each party may terminate the Takeda Collaboration Agreement in its entirety, or with respect to a particular collaboration program, as applicable, if the other party remains in material breach of the Takeda Collaboration Agreement following a cure period to remedy the material breach.

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The collaboration was designed to leverage F-star’s modular antibody technology and our expertise in the development of therapies for neurodegenerative diseases.

In connection with the entry into the F-star collaboration agreement, we also purchased an option for an upfront option fee of $0.5 million , which we refer to as the buy-out-option, to acquire all of the outstanding shares of F-star Gamma pursuant to a pre-negotiated buy-out option agreement (the “Option Agreement”).

In May 2018, we exercised such buy-out option and entered into a Share Purchase Agreement (the “Purchase Agreement”) with the shareholders of F-star Gamma and Shareholder Representative Services LLC, pursuant to which we acquired all of the outstanding shares of F-star Gamma (the “Acquisition”).

The agreement included the purchase of an option for $0.5 million to acquire all outstanding shares pursuant to a pre-negotiated buy-out option agreement.

We exercised this buy-out option in May 2018 and entered into a Share Purchase Agreement with the shareholders of F-star Gamma and Shareholder Representative Services LLC (the "Acquisition").

As a result of the Acquisition, F-star Gamma became a wholly-owned subsidiary of the Company and we changed the entity’s name to Denali BBB Holding Limited.

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We believe it is important to our business success to have a reliable, high-quality preclinical and clinical drug supply chain.

As we mature as a company and approach commercial stage operations, securing reliable high-quality commercial drug supply will be critical.

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.

If tividenofusp alfa is approved for the treatment of Hunter syndrome, we expect to use third-party contract manufacturers to supply commercial product .

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.

We have established relationships with several CDMOs, including Lonza Sales AG ("Lonza") and WuXi Biologics Limited ("Wuxi").

We have established relationships with several CDMOs, including Lonza Sales AG ("Lonza").

Effective September 2017, we entered into a development and manufacturing services agreement with Lonza, which we have subsequently amended to add scope of work.

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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.

We do not currently operate facilities for product manufacturing, storage, distribution or testing.

In April 2023 we entered into, and subsequently amended, a lease for a clinical manufacturing site in Salt Lake City, Utah after terminating our previous SLC lease in March 2023.

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.

The build-out of the Utah site is in process, and we currently expect to begin operations and manufacturing at the facility in 2024.

We currently do not need commercial manufacturing capacity.

When and if this becomes relevant, we intend to evaluate both third-party manufacturers as well as building out internal capabilities and capacity.

In April 2023 we entered into, and subsequently amended, a lease for a clinical manufacturing site in Salt Lake City, Utah.

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.

Commercialization Plan

We do not currently have any approved drugs and we do not expect to have any approved drugs in 2024.

Therefore, we have no sales, marketing or commercial product distribution capabilities at the current time.

We do not currently have any approved drugs.

We are expecting a potential US launch in the second half of 2025 or early 2026.

With this possibility, we are building marketing, product distribution and sales capabilities.

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.

We look to grow strategically both in terms of therapeutic areas of high unmet need, starting with LSDs 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).

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).

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.

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• Alzheimer’s Disease:

Treatments currently approved in some geographies for Alzheimer’s Disease include amyloid beta-directed antibody therapies from Biogen and Eisai.

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), Alector, and AbbVie in various stages of development.

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).

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.

• Parkinson’s Disease:

Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Prothena/Roche (including Genentech, its wholly owned subsidiary), Novartis/UCB, Biogen, Ionis, Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), AstraZeneca, Takeda, Oncodesign/Servier, and Neuron 23 in various stages of development.

Treatments currently approved in some geographies for ALS include Relyvrio/Albrioza (Amylyx Pharmaceuticals), Radicava (Mitsubishi Tanabe Pharma) and Qalsody (Biogen).

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, and Calico/AbbVie in various stages of development.

Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies, including Alector/GSK, Eli Lilly (including Prevail Therapeutics, its wholly owned subsidiary), Passage Bio, AviadoBio, Vesperbio, Arkuda Therapeutics, Biomarin, and Orchard Therapeutics in various stages of development.

The currently approved treatments for LSDs are enzyme-based therapies.

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.

Treatments currently approved in some geographies for ALS include Radicava (Mitsubishi Tanabe Pharma) and Qalsody (Biogen).

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.

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.

• Lysosomal storage diseases:

The currently approved treatments for lysosomal storage diseases are conventional enzyme-based therapies.

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.

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• Blood-Brain Barrier Technology:

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), Alector, Bioarctic, Bicycle Therapeutics among others.

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.

Intellectual Property

Our intellectual property is critical to our business and we strive to protect it, including by obtaining and maintaining patent protection in the United States and internationally for our product candidates, novel biological discoveries and BBB platform technology, including new targets and applications, and other inventions that are important to our business.

We also rely on trademarks, trade secrets, know-how, continuing technological innovation and licensing opportunities to develop and maintain our proprietary position.

Our intellectual property is critical to our business and we strive to protect it, including by obtaining and maintaining patent protection in the United States and internationally for our product candidates, novel biological discoveries and TV platform, including new targets and applications, and other inventions that are important to our business.

We also rely on trademarks, trade secrets, know-how, continuing technological invention and licensing opportunities to develop and maintain our proprietary position.

As of December 31, 2024 , our owned and licensed patent portfolio includes over 1,700 patents and patent applications, including over 30 licensed U.S.

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patents and patent applications.

For our product candidates and our BBB platform technology, we generally pursue or in-license patent protection covering compositions of matter, methods of use, and manufacture.

We own 11 patent families related to our BBB platform technology.

For our product candidates and our TV platform, we generally pursue or in-license patent protection covering compositions of matter, methods of use, and manufacture.

We own 10 patent families related to our TV platform.

These include a family directed to the composition and sequences of our TfR-binding TVs, the earliest of which are expected to expire in 2038, not including any patent term adjustments and any patent term extensions.

We also have 7 issued U.S.

patents, which are also expected to expire in 2038, not including any patent term adjustments and any patent term extensions, as well as pending patent applications, to other BBB platform technology.

Other families related to BBB platform technology, if issued, are expected to expire in 2038 or later, all not including any patent term adjustments and any patent term extensions.

patents, which are also expected to expire in 2038, not including any patent term adjustments and any patent term extensions, as well as pending patent applications, to other TV platform.

Other families related to TV platform, if issued, are expected to expire in 2038 or later, all not including any patent term adjustments and any patent term extensions.

In addition, 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.

ETV Platform, ETV:IDS, and ETV:SGSH Programs

We own 10 patent families directed to our ETV platform and related products, including ETV:IDS, ETV:

SGSH, and ETV:IDUA.

We own 11 patent families directed to our ETV platform and related products, including ETV:IDS, ETV:SGSH, ETV:GAA, ETV:Gcase, and ETV:IDUA.

This includes 1 issued U.S.

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Of the 11 patent families, 3 families relate to the composition of matter of our ETV:SGSH structures, including DNL126.

Any patents issuing from these families are expected to expire in 2039 and 2041, respectively, not including any patent term adjustments and any patent term extensions.

Any patents issuing from these families are expected to expire between 2039 and 2045, respectively, not including any patent term adjustments and any patent term extensions.

PTV:PGRN Program

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Our PTV:PGRN program is subject to our Takeda collaboration.

ATV:TREM2 Program

We own 6 patent families related to our ATV:TREM2 program.

These families include a granted U.S.

patent, which is expected to expire in 2041, not including any patent term adjustments and any patent term extensions, directed to the composition of matter of our ATV:TREM2 molecules .

The other 5 patent families, if issued, are expected to expire between 2038 and 2043, all not including any patent term adjustments and any patent term extensions.

Our ATV:TREM2 program is subject to our Takeda collaboration.

Oligonucleotide Transport Vehicle Platform

We own 3 patent families related to our OTV platform.

These families are directed to compositions and methods of use of our OTVs, and if issued, are expected to expire between 2042 and 2043, not including any patent term adjustments and any patent term extensions.

We own 7 patent families related 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.

LRRK2 Inhibitor Program

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We own 7 patent families directed to our RIPK1 inhibitor program.

These include a family with one issued U.S.

patent, directed to the composition of matter of our current RIPK1 lead, SAR443820/DNL788, which is expected to expire in 2038, not including any patent term adjustments and any patent term extensions.

We also own a patent family that includes 2 issued U.S.

patents, which are expected to expire in 2037, not including any patent term adjustments and any patent term extensions, and pending patent applications, which include those directed to the composition of matter of eclitasertib (SAR443122/DNL758), as well as other RIPK1 inhibitor compounds.

These include 3 issued U.S.

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.

eIF2B Activator Program

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For more information regarding the risks related to our intellectual property, see "Risk Factors - Risks Related to Our Intellectual Property."

In addition to patent protection, we also rely on trademark registration, trade secrets, know how, other proprietary information and continuing technological innovation to develop and maintain our competitive position.

In addition to patent protection, we also rely on trademark registration, trade secrets, know how, other proprietary information and continuing technological invention to develop and maintain our competitive position.

We seek to protect and maintain the confidentiality of proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

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The process generally involves the following:

• Completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice ("GLP"), requirements;

• Completion of extensive nonclinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice ("GLP"), requirements;

• Submission of an IND to the FDA, which must become effective before human interventional clinical trials may begin;

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Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that our product candidates do not undergo unacceptable deterioration over their shelf life.

We may be required to develop and implement additional clinical trial policies and procedures designed to help protect subjects from public health concerns, such as the COVID-19 pandemic.

For example, the FDA has issued various guidance documents on conducting clinical trials during the pandemic, including certain reporting requirements and additional guidance on good manufacturing practice considerations for responding to COVID-19 infection.

We may be required to develop and implement additional clinical trial policies and procedures designed to help protect subjects from public health concerns, such as a global pandemic.

For example, the FDA has issued various guidance documents on conducting clinical trials during the COVID-19 pandemic, including certain reporting requirements and additional guidance on good manufacturing practice considerations for responding to global pandemic infection.

NDA/BLA Review Process

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The results of preclinical studies and clinical trials are then submitted to the FDA as part of an NDA or BLA, along with the proposed labeling, and information relating to the product's chemistry, manufacturing, and controls, among other information, to ensure consistent product quality, safety, and efficacy.

In short, the NDA or BLA is a request for approval to market the drug or biologic for the specified indication(s) and must contain proof of safety and efficacy for a drug or safety, purity and potency for a biologic.

In short, the NDA or BLA is a request for approval to market the drug or biologic for the specified indication(s) and must contain sufficient evidence of efficacy, acceptable safety profile, and appropriate quality attributes.

The application may include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings.

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It is unclear how future litigation, legislation, agency decisions, and administrative actions will impact the scope of the orphan drug exclusivity.

In June 2024, the U.S.

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.

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.

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.

Expedited Development and Review Programs

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Similar to the United States, the various phases of preclinical and clinical research in the EU are subject to significant regulatory controls.

In the EU, a clinical trial application, or CTA, must be submitted to each country’s national health authority and an independent ethics committee, respectively.

Once the CTA is approved in accordance with a country’s requirements, clinical study development may proceed.

In the EU, a clinical trial application, or CTA, must be submitted to the Clinical Trials Information System under the Clinical Trial Regulation EU No 536/2014 and an independent ethics committee, respectively.

Once the CTA is approved in accordance with a EMA requirements, clinical study development may proceed.

The clinical studies must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

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The Clinical Trials Regulation harmonizes the processes for assessment and supervision of clinical trials throughout the EU.

Under the Regulation, sponsors can submit one online application via a single online platform known as the Clinical Trials Information System (CTIS) for approval to run a clinical trial in several European countries, making it more efficient to carry out such multinational trials.

Under the Regulation, sponsors submit one online application via a single online platform known as the Clinical Trials Information System ("CTIS") for approval to run a clinical trial in several European countries, making it more efficient to carry out such multinational trials.

A transition period applies to clinical trial submissions under the Regulation.

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Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

In August 2022, Congress passed the Inflation Reduction Act of 2022, which includes prescription drug provisions that have significant implications for the pharmaceutical industry and Medicare beneficiaries.

In August 2022, Congress passed the Inflation Reduction Act of 2022 ("IRA"), which includes prescription drug provisions that have significant implications for the pharmaceutical industry and Medicare beneficiaries.

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.

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.

The impact of these judicial challenges, legislative, executive, and administrative actions, and any future healthcare measures and agency rules implemented by the Biden administration on us and the pharmaceutical industry as a whole is unclear.

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.

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.

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We manage our operations as a single reportable segment for the purposes of assessing performance and making operating decisions.

See "Note 1 - Significant Accounting Policies" in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K.

See "Note 14 - Segment information" in the notes to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K.

Employees and Human Capital Resources

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The information in or accessible through the SEC and our website or social media sites does not constitute part of this Annual Report on Form 10-K or any other report or document we file with the SEC, and any references to our website and social media sites are intended to be inactive textual references only.

We use Denali®, the Denali Therapeutics logo, and other marks as trademarks in the United States and other countries.

We use Denali®, the Denali Therapeutics logo, ATV, ETV, OTV, PTV, TV, TransportVehicle TM , and other marks as trademarks in the United States and other countries.

This Annual Report on Form 10-K contains references to our trademarks and service marks and to those belonging to other entities.

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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.

What changed 10-K

Item 1. Business