Slides
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1 Transforming Life January 2026
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2 Forward-Looking Statements This presentation contains forward -looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 . These forward-looking statements do not relate strictly to historical or current facts and they may be accompanied by such words as “anticipate,” “believe,” “could,” “estimate,” “expected,” “forecast,” “intend,” “may,” “plan,” “potential,” “possible,” "future," “will” and other words and terms of similar meaning. All statements other than statements of historical facts contained in this presentation, including, witho ut limitation, statements regarding future results of operations and financial position of Denali Therapeutics Inc. (“Denali” or the “Company”); Denali’s business strategy and business plans, expected progress and expansion , and expected key milestones for Denali's therapeutic portfolio in 2026 and beyond; Denali’s ability to execute on its tailored manufacturing and commercial strategies and accelerate commercial launch readines s; the potential for Denali's product candidates to treat various neurodegenerative diseases including MPS I (Hurler Syndrome), MPS II (Hunter Syndrome), MPS IIIA (Sanfilippo Syndrome), PD, ALS, AD, FTD -GRN, UC, Gaucher's Disease, Pompe Disease, and related peripheral inflammatory diseases; planned preclinical studies and clinical trials and the expectations regarding the timing and availability of results and data from such studies and trials; plans, timelines, expectations related to Denali's TransportVehicleTM (TV) platform, its therapeutic and commercial opportunities, and the potential of TV -supported programs to be best-in-class; plans, timelines, and expectations related to the ETV franchise and ETV-enabled programs, including ETV:GAA, ETV:GCase, and ETV:IDUA, their therapeutic and commercial potential, and the timing and likelihood of planned regulatory filings; plan s, timelines, and expectations relating to DNL310 (ETV:IDS), including the Phase 2/3 COMPASS study and its ability to support global approvals, and the timi ng, likelihood, and scope of regulatory approvals and commercial launch; plans, timelines, and expectations related to DNL126 (ETV:SGSH), including the timing and availability of data from the Phase 1/2 study and likelihood and pathway of regulatory approval; plans, timelines, and expectations related to the OTV and OTV -enabled programs, including DNL628 (OTV:MAPT) and OTV:SNCA, their therapeutic and commer cial potential, the timing of study initiation and the availability of data, and the timing and likelihood of planned regulatory filings; plans, timelines, and expectations relating to DNL921 ( ATV:Abeta), including its therapeutic potential, the timing and likelihood of clinical proof of concept, and the timing of planned regulatory filings; plans, timelines, and expectations relating to DNL151; plans and expectations regar ding DNL593 (PTV:PGRN), the ongoing Ph1/2 study, and the timing and availability of data; plans, timelines, and expectations related to DNL952 (ETV:GAA), including the timing and availability of data; plans and e xpectations regarding Denali's global organization and clinical and manufacturing operations, its projected cash runway and likelihood of receipt of milestone payments, and its likelihood of achieving operat ional efficiencies; the expected timing and likelihood of success of Denali's commercial growth; and the potential market opportunities for each of Denali's programs, are forward -looking statements. Denali has based these forward-looking statements largely on its current expectations and projections about future events, and forward-looking statements regarding potential outcomes should not be interpreted as guarantees of futu re performance. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertaint ies and assumptions, including but not limited to: the risk of the occurrence of any circumstance that could give rise to the termination of Denali’s agreements with its collaborators; Denali’s and its collabor ators’ ability to complete the development and, if approved, commercialization of its product candidates; Denali’s and its collaborators’ ability to enroll patients in its ongoing and future clinical trials; Denali’s ab ility to manufacture and supply product candidates at clinical and commercial scale, including through its internal manufacturing capabilities and its reliance on third parties for the manufacture and supply of its product candidates; Denali’s dependence on successful development of its blood -brain barrier platform technology and TV-enabled product candidates; Denali’s and its collaborators’ ability to conduct or complete clinical t rials on expected timelines; the predictive value of Denali's biomarker selection; the occurrence of significant adverse events, toxicities or other undesirable side effects; the extent to which preclinical and e arly clinical results (including safety -related findings) predict later-stage outcomes; the uncertainty that product candidates will receive regulatory approval or be commercialized; Denali’s ability to continue to crea te a pipeline of product candidates or develop commercially successful products; Denali’s ability to obtain, maintain, or protect intellectual property rights related to its product candidates; Denali's achievement of planned milestones and realization of value; Denali’s ability to realize anticipated financial resources, including receipt of contingent royalty financing and milestone payments; implementation of Denali’s strategic plans for its business, product candidates, and blood -brain barrier platform technology; and other risks. In light of these risks, uncertainties and assumptions, the forward-looking statements in this presentation are inh erently uncertain and may not occur, and actual results could differ materially and adversely from those anticipated or implied in the forward -looking statements. Accordingly, you should not rely upon forward -looking statements as predictions of future events. Information regarding additional risks and uncertainties may be found in Denali’s most recent quarterly and annual reports filed with the Securities and Exchange Co mmission on Forms 10-Q and 10-K, respectively, as well as Denali’s future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward -looking statements, to conform thes e statements to actual results or to make changes in Denali’s expectations, except as required by law. The product candidates being developed by Denali are investigational and their safety and efficacy profiles remain unestablished. Denali's product candidates have not been approved by any health authority for any use. Accuracy of Data. This presentation contains statistical data based on independent industry publications or other publicly av ailable information, as well as other information based on Denali’s internal sources. Denali has not independently verified the accuracy or completeness of the data contained in these industry publications and other pu blicly available information. Accordingly, Denali makes no representations as to the accuracy or completeness of that data.
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3 Our Purpose Deliver the power of biotherapeutics to the whole body, including the brain, transforming life for people living with serious diseases
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4 Key Messages Best-in-Class Blood-Brain Barrier (BBB) Platform ► TransportVehicle is the most validated, differentiated, and clinically -proven technology, enabling systemic delivery of biologics to the brain and other hard -to-target tissues Ready to Capture $1B+ Market Opportunity with Two Near-Term Launches ► Launch of tividenofusp alfa (DNL310) in 2026 and DNL126 in 2027 lay the commercial foundation for Enzyme TransportVehicle (ETV) franchise and leadership in next -generation enzyme replacement therapy Deep Pipeline Across High-Value Therapeutic Areas ► Broad clinical-stage pipeline, including two potential best -in-class TfR-enabled programs for Alzheimer’s, provides several near-term milestones Efficient Execution and Capital Allocation ► Leveraging learnings and organizational scale to accelerate timelines and reduce cost for long -term value creation 1H 2026 Expected Milestones ► Tividenofusp alfa approval decision, ETV:SGSH Phase 1/2 data at WORLD, and additional milestones (e.g., LRRK2 Phase 2b LUMA data and OTV:MAPT, ATV:Abeta, ETV:GAA Phase 1 study initiations) TfR – Transferrin receptor
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5 A New Class of Biotherapeutics for the Whole Body, Including the Brain Our TransportVehicle (TV) Platform enables TfR-mediated brain biodistribution and enhanced tissue delivery of biotherapeutics throughout the body with systemic administration Genetic medicines for the brain, delivered systemically Brain-penetrant immunotherapy for a wide range of diseases Enzyme TV (ETV) Oligonucleotide TV (OTV) Antibody TV (ATV) Enzyme replacement therapy for the body and brain TfR – Transferrin receptor
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6 On Track to Deliver Denali’s D3X3 Goals: 3-Year Outlook Aiming to deliver near-term value from planned product launches, advancing a robust pipeline and capturing the full potential of the TransportVehicle 2 • Tividenofusp Alfa • DNL126 (ETV:SGSH) Clinical P roof of Concepts Alzheimer’s Disease • DNL628 (OTV:MAPT) • DNL921 (ATV:Abeta) Pompe Disease • DNL952 (ETV:GAA) FTD-GRN • DNL593 (PTV:PGRN) Parkinson’s Disease • DNL151 (LRRK2 inhibitor) 4-6 5 Growing Brands New Clinical Programs • Continued leadership and invention on BBB technologies Deliver Develop Discover D3 D3 – Deliver, Develop, Discover; BBB – Blood-brain barrier
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7 Our Broad Therapeutic Portfolio 1. FTD-GRN has a lysosomal phenotype and can be considered a rare lysosomal storage disease; 2. Denali estimates of worldwide aggregate prevalence, excluding China and India for the lysosomal storage disorders; 3. Lysosomal Storage Disorders Indication market based on Denali internal assessment as of Nov ’25 and other syndicated data (Evaluate Pharma, Historic Annu al WW Product Sales 2024, downloaded Dec 1 2025); 4. Alzheimer’s disease market opportunity based on Denali internal assessment as of Nov ‘25 and Evaluate Pharma Analyst Consensus Forecasts 2024 to 2034, Oct ‘25; 5. Parkinson’s disease market opportunity based on Denali internal assessment as of Nov ‘25 and other syndicated data (e.g., Herantis Pharma Plc Annual Report 2024; Herantis Pharma PLC (published March 31, 2025), Parkinson’s Diseases Treatment Market 2025 to 2030, Gran View Research, https:// www.grandviewresearch.com /industry-analysis/parkinsons-disease-treatment-market). MPS – Mucopolysaccharidosis; PD – Parkinson’s disease; AD – Alzheimer’s disease Lysosomal Storage Disorders Common Neurodegenerative Diseases >30,000 Patients WW2 $500M-$1B+ per Indication3 >40M Patients WW2 >$5B per AD/PD Indication4,5 Molecule Indication Stage tividenofusp alfa (ETV:IDS) MPS II Regulatory Filing DNL126 (ETV:SGSH) MPS IIIA Phase 1/2 DNL593 (PTV:PGRN) FTD-GRN1 Phase 1/2 DNL952 (ETV:GAA) Pompe Phase 1 DNL111 (ETV:GCase) Gaucher IND-Enabling DNL622 (ETV:IDUA) MPS I IND-Enabling Molecule Indication Stage BIIB122 LRRK2 Inhibitor PD Phase 2b DNL628 OTV:MAPT (tau) AD Phase 1b DNL921 ATV:Abeta AD IND-Enabling DNL111 ETV:GCase PD IND-Enabling DNL422 OTV:SNCA PD IND-Enabling
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TransportVehicle Platform
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9 Treating the Whole Body, Including the Brain TfR may also facilitate delivery into tissues such as bone, cartilage, and the heart Transferrin receptor (TfR) is highly expressed at the blood–brain barrier for natural iron transport Our TransportVehicle leverages TfR to enable brain delivery of biotherapeutics Blood Brain Blood-Brain Barrier
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10 TransportVehicle Distributes to Whole Body, Including Brain 1000 m Standard Antibody (IgG) TV-enabled Antibody (TfR) Whole Body Whole Body Brain Brain 5000 m 5000 m Increased signal in brain, muscle, bone Surface vasculature accumulation Broad distribution throughout parenchyma and deep brain regions Minimal or limited distribution in brain and bone
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11 TransportVehicle Has Demonstrated Best-in-Class Properties 1. Includes regulatory applications to begin clinical studies for DNL628 and DNL952; 2. As of Oct 27, 2025; 3. As of Nov 3, 2025; 4. As of Dec 5, 2025. BBB – Blood-brain barrier; Fc – fragment crystallizable; TfR– Transferrin receptor; NfL – Neurofilament light chain BBB receptor binding site engineered into the Fc for optimal properties and modularity Brain Uptake Our Fc-based TransportVehicle (TV) Is Designed & Engineered to Optimize Brain Delivery Modularity Safety Architecture • 1st Potential FDA-approved TfR therapeutic to cross the BBB • 5 Clinical programs1,2 • Demonstrated ability to correct neurodegeneration (e.g., NfL) • >10 Preclinical programs2 • >200 Subjects dosed3 • >11,000 Doses administered3 • >20 Publications in last 5 years4 • >350 Patents/Applications4 Industry Leading Platform Enables broad ability to transport range of therapeutics, such as enzymes, oligos and antibodies Optimized affinity and epitope enhance brain delivery while limiting receptor degradation Conditional effector function avoids reticulocyte loss and minimizes anemia liability potential High fidelity to natural protein (e.g., no appended sequences) improves stability, limits immunogenicity and improves ease of manufacturing
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ETV Franchise Opportunity
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13 ETV Franchise Opportunity in Lysosomal Storage Disorders ETV – Enzyme transport vehicle; LSDs – Lysosomal storage disorders; CNS – Central nervous system; ERTs – Enzyme replacement therapies 1. Based on Denali internal assessment of ERTs that launched in any major market as a ratio of ERTs that have entered clinical development. ~80% historical ERT approval rate1 Goal is to treat the full disease spectrum ETVs enable brain delivery of enzymes to address cognitive and behavioral symptoms Potential to enhance peripheral delivery Targeting Brain & Body with ETVAddressing High Unmet Need • LSDs are single-enzyme deficiency diseases • 30,000 people with LSDs worldwide • 2/3 LSDs with CNS manifestations
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14 Tividenofusp alfa (ETV:IDS; DNL310) ETV:SGSH (DNL126) PTV:PGRN (DNL593) ETV:GAA (DNL952) ETV:GCase (DNL111) ETV:IDUA (DNL622) MPS II (Hunter syndrome) MPS IIIA (Sanfilippo syndrome) FTD-GRN (Frontotemporal dementia-granulin) Pompe Disease Parkinson’s and Gaucher MPS I (Hurler syndrome) Patients WW1 ~2,000 ~1,500+ ~25,000+ ~5,000 – 10,000 ~300,000+ (GBA-PD) ~10,000 – 15,000 (GD) ~1,500+ Status Phase 2/3 BLA filing2 Phase 1/2 Phase 1/2 Phase 1 IND-enabling IND-enabling Building the ETV Franchise Portfolio WW – Worldwide; BLA – Biologics License Application; IND – Investigational New Drug; GBA-PD – Parkinson’s Disease with GBA mutation; GD – Gaucher’s Disease; 1. Excluding China and India; 2. PDUFA target action date of 4/5/26 for accelerated approval We are developing the next generation of enzyme replacement therapies designed to treat brain and body manifestations of serious genetic diseases
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15 Tividenofusp alfa (ETV:IDS; DNL310) ETV:SGSH (DNL126) PTV:PGRN (DNL593) ETV:GAA (DNL952) ETV:GCase (DNL111) ETV:IDUA (DNL622) MPS II (Hunter syndrome) MPS IIIA (Sanfilippo syndrome) FTD-GRN (Frontotemporal dementia-granulin) Pompe Disease Parkinson’s and Gaucher MPS I (Hurler syndrome) Patients WW1 ~2,000 ~1,500+ ~25,000+ ~5,000 – 10,000 ~300,000+ (GBA-PD) ~10,000 – 15,000 (GD) ~1,500+ Status Phase 2/3 BLA filing2 Phase 1/2 Phase 1/2 Phase 1 IND-enabling IND-enabling Building the ETV Franchise Portfolio WW – Worldwide; BLA – Biologics License Application; IND – Investigational New Drug; GBA-PD – Parkinson’s Disease with GBA mutation; GD – Gaucher’s Disease; 1. Excluding China and India; 2. PDUFA target action date of 4/5/26 for accelerated approval We are developing the next generation of enzyme replacement therapies designed to treat brain and body manifestations of serious genetic diseases Focus for Today: Clinical-Stage Programs
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16 Brain Delivery Is Critical Unmet Need of Hunter Syndrome Therapy Traditional enzyme replacement therapy does not cross the blood brain barrier and only partially addresses peripheral manifestations Tividenofusp alfa is a brain- penetrant enzyme replacement therapy designed to reduce the substrate of IDS (heparan sulfate) throughout the body and treat neurocognitive and physical manifestations Monogenic lysosomal storage disorder caused by deficient iduronate-2-sulfatase (IDS) tividenofusp alfa (DNL310)
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17 Tividenofusp Alfa Phase 1/2 in MPS II Published in NEJM Source: Muenzer et al. 2026 NEJM Infusion-related reactions, a known risk of ERTs, were the most common adverse event, decreasing in incidence and severity over time Summary of Adverse Events (Safety Analysis Population) Infusion- Related Reactions Over Time Hemoglobin Levels Over Time Weeks Percentage of Participants with ≥1 Reaction No. of Participants Weeks No. of Participants Base- line Mean Concentration (g/dl)
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18 Tividenofusp Alfa Phase 1/2 in MPS II Published in NEJM MPS II – Mucopolysaccharidoses Type II; CSF – Cerebrospinal fluid; HS – Heparan sulfate; NfL – Neurofilament light; Source: Muenzer et al. 2026 NEJM Treatment with tividenofusp alfa over a median duration of 2 years was associated with reductions in CNS and peripheral biomarkers of substrate accumulation and neuronal injury to levels within the range of unaffected children Normalization of Urine HS Biomarker of peripheral disease Normalization of NfL Biomarker of neuronal damage Normalization of CSF HS Biomarker of CNS disease
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19 Tividenofusp Alfa Phase 1/2 in MPS II Published in NEJM MPS II – Mucopolysaccharidoses Type II; CI – Confidence interval; BSID-III – Bayley Scales of Infant and Toddler Development-Third Edition; PTA – Pure tone average. Source: Muenzer et al. 2026 NEJM While on tividenofusp alfa, clinical outcomes showed skill gains relative to baseline on measures of adaptive behavior, cognition and hearing threshold improvement Improvement in Adaptive Behavior Vineland-3 Improvement in Cognition BSID-III Improvement in Hearing Auditory Brainstem Response (PTA) Adjusted Mean Change Adjusted Mean Change (dB) Adjusted Mean Change
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20 Tividenofusp Alfa Development and Regulatory Path PDUFA Target Action Date: April 5, 2026 Preparing for Commercial Launch • Filed BLA for accelerated approval; granted priority review • BLA includes data from open-label, global Phase 1/2 study (N=47) • Up to 18 years of age • Treatment duration up to five years • Measuring biomarkers, safety, and exploratory clinical outcomes • Randomized, double blind, controlled study (N~63) • Ages ≥2 to <6 y.o. (Cohort A, neuronopathic) • ≥6 to <26 y.o. (Cohort B, non-neuronopathic) • Co-primary endpoints: CSF HS and Vineland-III • Peripheral endpoints: liver/spleen volume, 6MWT , ABR and others Phase 2/3 Study Ongoing Supporting Global Approvals 47 Phase 1/2 participants 63 participants PDUFA – Prescription Drug User Fee Act; CSF – Cerebrospinal fluid; HS – Heparan sulfate; 6MWT – 6-minute walk test; ABR – Auditory brainstem response 1. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia; 2. Division of Human Genetics and Metabolism, Children’s Hospital of Philadelphia, Philadelphia. To summarize, tividenofusp alfa offers systemic therapy to address both the neurologic and somatic facets of MPS II, on the basis of compelling biomarker and clinical evidence. The results of this study mark a critical turning point and bring the field one s tep closer to the elusive goal of comprehensive disease modification. – Can Ficicioglu, M.D., Ph.D.,1,2 from “Breaking Barriers in Mucopolysaccharidosis Type II”, NEJM editorial 2026
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21 DNL126 (ETV:SGSH): Designed to Deliver SGSH to the Brain DNL126 aims to address the relentless neurodevelopmental disease progression in MPS IIIA TransportVehicle • Selected for FDA START program • Phase 1/2 study in MPS IIIA • Achieved biomarker proof-of-concept • Enrollment completed (n=20) • Data at WORLDSymposium (Feb 2026) • Aligned with FDA on accelerated approval path in MPS IIIA • Phase 3 protocol under development Program Status SGSH ETV:SGSH SGSH ETV – Enzyme TransportVehicleTM ; SGSH – N-sulfoglucosamine sulfohydrolase; FDA – U.S. Food and Drug Administration; START – Support for clinical Trials Advancing Rare disease Therapeutics
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22 DNL126: Study Data for Accelerated Approval BLA – Biologics licensing application; AA – Accelerated approval; CSF – Cerebrospinal fluid; HS – Heparan sulfate Expected BLA submission and approval in 2027 Data for BLA Submission • At least 49 weeks of data for all participants (Cohorts A1-A3, B1; n=20) • CSF HS reduction from baseline in key efficacy cohorts (n=12) – surrogate endpoint reasonably likely to predict clinical benefit • Supportive data on central and peripheral biomarkers, clinical endpoints • Long-term safety up to ~2.5 years
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23 DNL593 Phase 1/2 Clinical Study for FTD-GRN FTD – Frontotemporal dementia; GRN – Granulin; MAD – Multiple ascending dose; PD – Pharmacodynamics; PK – Pharmacokinetics; SAD – Single ascending dose Phase 2 Part B interim data in patients with FTD-GRN expected to read out in 2026 • Part A: healthy volunteers aged ≥ 18 to ≤ 55 years • Part B: GRN mutation carriers; symptomatic participants diagnosed with FTD-GRN; aged ≥ 18 to ≤ 80 years • Part C: participants who complete Part B Study Population • Part A: safety, PK • Parts B & C: – Safety, PK, PD biomarkers – Clinical, neuropsychology, and imaging outcomes Goals & Objectives SAD Cohort MAD Cohort MAD Cohort C B A Optional OLE Ongoing Enrollment Completed NCT05262023 • Duration: 25-week core study + open label extension • Study Type: Randomized, placebo -controlled, double blind Study Plan DNL593 (PTV:PGRN)
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24 DNL952 Phase 1 Clinical Study for Pompe Disease Phase 1 biomarker data expected in 2027 ERT – enzyme replacement therapy; LOPD – Late Onset Pompe Disease; PK – Pharmacokinetics • Patients with Late Onset Pompe Disease (LOPD) • 2nd Gen ERT experienced (A Cohorts) and optional naïve (B Cohorts) Study Population • Safety • PK • Analysis of clinically established biomarkers • Immunogenicity Goals & Objectives Cohort Cohort Cohort B1 A2 A1 Optional: Treatment-Naïve 2nd Gen Treatment-Experienced • Duration: 24-week core study + 24 -week safety extension • Study Type: Open label Study Plan DNL952 (ETV:GAA) Optional: Additional Cohorts
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25 ETV: Foundational Franchise for Lysosomal Storage Disorders 1. Internal estimate for global market opportunity across MPS II and MPS IIIA 2. Global market opportunity based on Denali internal assessment as of Nov ’25 and other syndicated data (Evaluate Pharma, Historic Annual WW Product Sales 2024, downloaded Dec 1 2025, GC Pharma 2024 Investor Day Deck (https://www.gcbiopharma.com/eng/upload/CAO/C55/202510/9e38f129-d9f2-4307-bc4f-ca54f2340512.pdf); 3. Based on systemic ERTs with regulatory approvals in at least one major market (US, EU, Japan), excluding two ERTs that have been discontinued (Adagen and Ceredase); 4. Based on Denali internal assessment of ERTs that launched in any major market as a ratio of ERTs that have entered clinical development. 5. Based on Denali internal assessment as of Nov ’25 and other syndicated data (Evaluate Pharma, Historic Annual WW Product Sales 2024, downloaded Dec 1 2025, GC Pharma 2024 Investor Day Deck (https://www.gcbiopharma.com/eng/upload/CAO/C55/202510/9e38f129-d9f2-4307-bc4f-ca54f2340512.pdf). Protalix 2024 10-K, GMI Report 2024 (Oct'24, https://www.gminsights.com/industry-analysis/exocrine- pancreatic-insufficiency-treatment-market). USA vs QOL Medical Lawsuit (Filed July'24, https://www.mass.gov/doc/qol-medical-lawsuit/download). TAM – Total Addressable Market; ETV – Enzyme TransportVehicleTM • 23 ERT s currently marketed3; ~80% historical ERT approval rate4; ~$9B in sales5 • Traditional ERT s do not penetrate CNS whereas ETVs address full disease spectrum • $1B+ opportunity between MPS II & MPS IIIA – Plan to leverage existing Denali infrastructure across both launches – Ability to redeploy resources to translate into favorable margins • Established relationships with key stakeholders in the lysosomal storage disorders community • Ability to drive increasingly fast launches and product uptake throughout franchise ETV Franchise Worldwide Patient Prevalence 2,000 1,500 10,000 1,500 15,000 25,000 0 10000 20000 30000 40000 50000 MPS I GaucherMPS IIIA 55,000 Pompe FTD-GRNMPS II First Two Planned Near-Term Launches with Combined Market Opportunity of >$1B1 ETV Franchise TAM Delivering Next-Generation Enzyme Replacement Therapy (ERT)>$5B2 Total Market Opportunity # of patients ETV Disease Areas ETV
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Alzheimer’s Disease Opportunity
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27 Aiming to Transform Treatment of Alzheimer’s Disease 1. Alzheimer’s disease market opportunity based on Denali internal assessment as of Nov ‘25 and Evaluate Pharma Analyst Consensus Forecasts 2024 to 2034, Oct ’25 ATV – Antibody TransportVehicleTM; OTV – Oligonucleotide TransportVehicleTM; AD – Alzheimer’s disease Targeting Abeta Plaques Targeting Tau Tangles TransportVehicleTM Therapeutics Are Designed to Improve Safety and Efficacy OTVATV Reduce risk of amyloid-related imaging abnormalities (ARIA) Clear amyloid plaque faster via better brain biodistribution Address tau pathology by suppressing MAPT expression Walker L, Free Neuropath, 2020 Bengoa-Vergniory et al, Acta Neurop, 2021 Unmet medical need provides opportunity for BBB-enabled AD therapeutics with $5B+ market potential1
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28 ATV:Abeta Displays Reduced ARIA Due to TfR-Mediated Brain Uptake Pizzo et al., Science, 2025. ATV – Antibody TransportVehicleTM ; ARIA – amyloid related imaging abnormalities; TfR – transferrin receptor; MRI – magnetic resonance imaging; QW IP – once weekly intraperitoneal; CSF – cerebrospinal fluid; PVS – perivascular space; Aβ – amyloid beta Bypassing vascular plaque via TfR-mediated entry into the brain through capillaries and venules improves ARIA safety Colocalized Vascular Abeta & huIgG 100 m Conventional Anti-Abeta ATV-Enabled Anti-Abeta Route of Entry into Brain Artery / Arteriole Zone Microvessel (capillary) Zone Incidence of MRI Lesions 5xFAD; TfRmu/hu KI; QW IP
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29 DNL921 Optimized for Robust Brain Delivery, Safety & Stability 1. Single dose, IV 10 mg/kg (molar-matched); 2. hlgG Capture vs. TfR Capture ELISA; 3. Competitor Molecules generated at Denali based on publicly available information on TfR-binding anti-Abeta antibodies currently under development DNL921 (ATV:Abeta) TV TfR Binding 1 TfR Binding 2 3 Molecule Architecture Epitope Effector Function Control Control IgG N/A Full DNL921 TV- TfR in Fc Apical Conditional Competitor #1 C-term TfR Protease Full Competitor #2 C-term TfR Apical Full Competitor #3 C-term TfR Apical None Competitor Molecules3 TfR Binding cisLALA Abeta Binding TfR Binding
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30 DNL921 Phase 1/1b Clinical Study for Alzheimer’s Disease SAD – Single Ascending Dose; MAD – Multiple Ascending Dose; PET – positron emission tomography IND/CTA submission planned for 1H 2026 Potential for safety and clinical proof of concept in 2027 / SAD: Healthy Volunteers MAD: Patients with biomarker confirmed Alzheimer’s disease Study Population • Safety • Impact on amyloid plaque load • Dose selection • Additional biomarkers/imaging Goals & Objectives MAD Cohort MAD Cohort MAD Cohort C B A • Duration: 28 weeks • Study Type: Randomized, placebo -controlled, double blind Study Plan DNL921 (ATV:Abeta) SAD Phase 3Phase 1/1b
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31 DNL628 Displays Robust and Sustained Knockdown in Mice Expressing Human Tau Robust and sustained reduction in tau protein with DNL628 Brain MAPT RNA and Tau Protein Knockdown (KD) Persists for >12 Weeks After Dosing 0 4 8 12 16 0.0 0.5 1.0 1.5 Weeks post study start (Dosing period = 3wks, so subtract 3 for Weeks post final dose) MAPT RNA expression (Normalized to Gapdh and Saline) DNL628 Knockdown Timecourse in hTau x hTfR mice DNLI-24-23 and DNLI-23-202 MAPT RNA Tau Protein Relative expression vs. controls (RNA norm to Gapdh; Protein norm to BCA) Saline-treated controls 0 4 8 12 16 0.0 0.5 1.0 1.5 Weeks post study start (Dosing period = 3wks, so subtract 3 for Weeks post final dose) MAPT RNA expression (Normalized to Gapdh and Saline) DNL628 Knockdown Timecourse in hTau x hTfR mice DNLI-24-23 and DNLI-23-202 MAPT RNA Tau Protein IV dose Target protein KD Saline-Treated Controls 0 4 8 12 16 0.0 0.5 1.0 1.5 Weeks post study start (Dosing period = 3wks, so subtract 3 for Weeks post final dose) MAPT RNA expression (Normalized to Gapdh and Saline) DNL628 Knockdown Timecourse in hTau x hTfR mice DNLI-24-23 and DNLI-23-202 MAPT RNA Tau Protein Relative expression vs. controls (RNA norm to Gapdh; Protein norm to BCA) Saline-treated controls 0 4 8 12 16 0.0 0.5 1.0 1.5 Weeks post study start (Dosing period = 3wks, so subtract 3 for Weeks post final dose) MAPT RNA expression (Normalized to Gapdh and Saline) DNL628 Knockdown Timecourse in hTau x hTfR mice DNLI-24-23 and DNLI-23-202 MAPT RNA Tau Protein IV dose Tau Protein MAPT RNA IV Dose
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32 Study Population Phase 1b Objectives MAD Cohort MAD Cohort MAD Cohort C B A Study Plan Phase 1b initiation 1H 2026 Clinical biomarker data expected by 1H 2027 / DNL628 Phase 1b Clinical Study for Alzheimer’s Disease CDR – Clinical Dementia Rating; MMSE – Mini-Mental State Examination; MAD – Multiple Ascending Dose; CSF – cerebrospinal fluid Patients with biomarker confirmed early Alzheimer’s disease (CDR 0.5 to 1, MMSE 20-30) • Safety • Impact on tau levels • Dose selection • Additional biomarkers/imaging • Duration: 24 weeks • Study Type: Randomized, placebo -controlled, double blind DNL628 (OTV:MAPT) Phase 3Phase 2Phase 1b NCT07328451
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Evolving Our Business
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34 Integrated Capabilities to Execute for Long-Term Value BBB – blood-brain barrier; TV – TransportVehicleTM; NeuroD – neurodegeneration; LSD – lysosomal storage disorders; Clin Ops – Clinical Operations; HR – Human Resources; CMC – Chemistry, Manufacturing & Controls; G&A – General & Administrative • Scale to successfully discover, develop, manufacture and commercialize • Integrated infrastructure with ~520 full time employees in South San Francisco, Salt Lake City and Zürich Scale and Infrastructure Established Capabilities Discovery Development CMC G&A Commercial Zurich, Switzerland South San Francisco, California Salt Lake City, Utah Translational Sciences Technical Operations Manufacturing Early Clinical & Clin Ops Development Sciences Regulatory & Biometrics Late Clinical & Safety BBB and TV Biology NeuroD and LSD Pathway Biology Legal & HR Finance & Business Operations Commercial Medical Affairs & Patient Advocacy Biotherapeutics Discovery Industry Leading BBB Science : 30+ PhDs, >20 publications; in-vivo facility, imaging Full commercial team with deep rare disease experience In-house manufacturing for clinical and commercial supply: speed, quality, cost advantage
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35 Capital to Execute 1. Royalty financing will contribute $200M upon approval of DNL310 by June 30, 2026 and an additional $75M upon EMA approval by December 31, 2029; 2. Approximately $213M in gross proceeds related to underwritten public offering in December 2025 of shares of Denali’s common stock and, in lieu of common stock to certain investors, pre-funded warrants Strong Financial Foundation ~$873M + $488M 2 Near-term Commercial Launches Cash and investments as of Q3 2025 plus royalty financing 1 and equity capital raise2 (Dec ’25) Potential revenues from Tivi and DNL126 Key Capital Allocation Priorities Invest Strategically • Successful launches of tividenofusp alfa and DNL126 • Focused R&D investments to accelerate and expand pipeline Maintain Capital Optionality • Partnerships remain core to strategy • Diversifying sources of capital Drive Capital Efficiency • Apply learnings from tividenofusp alfa to develop next programs faster and at lower cost 3 Partnerships Cost share and potential milestone income
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36 Entering a New Phase on the Path to the Summit Pioneering a new class of biotherapeutics and capturing the full potential of the TransportVehicle 2 Growing Brands Clinical P roof of Concepts5 4-6 New Clinical ProgramsDiscover Develop Deliver 2015 2025 2020 D3X3 3-Year Goals (D3X3)
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Thank You