Denali Therapeutics Inc. · NASDAQ:DNLI
Denali Therapeutics — Investor Day (December 2025)
136 slides from Denali Therapeutics's investor day presentation, Dec 4, 2025
Slide 1: Welcome to Denali Therapeutics 2025 Investor Day
1 Welcome to Denali Therapeutics 2025 Investor Day December 4, 2025 Exhibit 99.1
Slide 2: Forward-Looking Statements
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 “anticipa
Slide 3: Leading a New Era of BBB-Crossing Therapeutics: Key Messages
3 Leading a New Era of BBB-Crossing Therapeutics Key Messages Ryan Watts, Ph.D. Chief Executive Officer
Slide 4: Our Purpose
4 Deliver the power of biotherapeutics to the whole body, including the brain, transforming life for people living with serious diseases Our Purpose
Slide 5: Key Messages for Today
5 Key Messages for Today 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
Slide 6: A New Class of Biotherapeutics for the Whole Body, Including the Brain
6 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 systemica
Slide 7: Our Broad Therapeutic Portfolio
7 Our Broad Therapeutic Portfolio 1. FTD-GRN has a lysosomal phenotype and can be considered a rare lysosomal storage disease; 2. Regulatory applications filed to begin human clinical studies; 3. Protocol amended and response to FDA submitted regarding clinical hold; 4. Denali estimates of worldwide
Slide 8: Our D3 Strategy for Sustainable Value Creation
8 Our D3 Strategy for Sustainable Value Creation D3 – Deliver, Develop, Discover; ETV – Enzyme Transport VehicleTM; ATV – Antibody TransportVehicleTM; OTV – Oligonucleotide TransportVehicleTM; TV – TransportVehicleTM D3 Strategy: Discover, Develop and Deliver on the TransportVehicle platform opportu
Slide 9: On Track to Deliver Denali's D3X3 Goals: 3-Year Outlook
9 On Track to Deliver Denali’s D3X3 Goals: 3-Year Outlook Delivering 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 Proof of Concepts Alzheimer’s Disease • DNL628 (
Slide 10: Treating the Whole Body, Including the Brain
10 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 bio
Slide 11: TransportVehicle Distributes to Whole Body, Including Brain
11 TransportVehicle Distributes to Whole Body, Including Brain 1000 m Standard Antibody (IgG) TV-enabled Antibody (TfR) Whole Body Whole Body Brain Brain 5000 m5000 m Increased signal in brain, muscle, bone Surface vasculature accumulation Broad distribution throughout parenchyma and deep brain r
Slide 12: TransportVehicle Clinical Effects: MPS II Phase 1/2 Study
12 TransportVehicle Clinical Effects: MPS II Phase 1/2 Study Source – WORLD 2025; MPS II – Mucopolysaccharidosis Type II; CSF – Cerebrospinal fluid; CNS – Central nervous system; ETV – Enzyme Transport VehicleTM Our ETV franchise is clinically validated, derisking the broader TV platform Brain Body
Slide 13: Our TransportVehicle Platform Sets the Bar for BBB Delivery
13 Our TransportVehicle Platform Sets the Bar for BBB Delivery *includes regulatory applications to begin clinical studies for DNL628 and DNL952; BBB – Blood-brain barrier; TfR– Transferrin receptor; NfL – Neurofilament light chain BBB receptor binding site engineered into the Fc for optimal propert
Slide 14: TransportVehicle has Demonstrated Best-in-Class Properties
14 TransportVehicle has Demonstrated Best-in-Class Properties 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 Linker chemistry adv
Slide 15: TransportVehicle Has Broad Clinical Experience
15 TransportVehicleTM Has Broad Clinical Experience Includes companies with TfR-based platforms and is not a comprehensive list. Peer company estimates are based on publicly available sources, i.e., investor presentations, medical congress presentations, and actual number of participants enrolled in
Slide 16: ETV: Foundational Franchise for Lysosomal Storage Disorders
16 ETV: Foundational Franchise for Lysosomal Storage Disorders *Based on internal Denali estimates. TAM – Total Addressable Market; ETV – Enzyme Transport VehicleTM; ERT – Enzyme Replacement Therapy • ~30,000 people with LSDs worldwide • Single enzyme deficiencies • 2/3 LSDs with CNS manifestations
Slide 17: OTV & ATV: Opportunity to Set the Bar in Alzheimer's Disease
17 OTV & ATV: Opportunity to Set the Bar in Alzheimer’s Disease Walker L, Free Neuropath, 2020; Bengoa-Vergniory et al, Acta Neurop, 2021; ATV – Antibody TransportVehicleTM; OTV – Oligonucleotide TransportVehicleTM; AD – Alzheimer’s disease Unmet medical need provides opportunity for BBB-enabled AD
Slide 18: Today's Agenda
18 Today’s Agenda Session Topic Speaker Time Leading a New Era of BBB-Crossing Therapeutics Key Messages • Opportunity, Technology, Portfolio, 3-Year Goals Ryan Watts, Ph.D. Chief Executive Officer 8:30am ET Enzyme TransportVehicle (ETV) Franchise for Lysosomal Storage Disorders Overview • MPS II, M
Slide 19: Denali's Leadership Team
19 Denali’s Leadership Team Ryan Watts, Ph.D. Joe Lewcock, Ph.D. Alexander Schuth, M.D. Dana Andersen, Ph.D. Peter Chin, M.D. Cindy Dunkle Katie Peng Chris Walsh, J.D., Ph.D. Chief Executive Officer Chief Scientific Officer Chief Operating and Financial Officer Chief Technical and Manufacturing Offi
Slide 20: Analyst Day Guest Speakers
20 Analyst Day Guest Speakers Barbara Burton, M.D. Kim Stephens, Ph.D. Jason Madison • Professor of Pediatrics at Northwestern University and Attending Physician in Genetics, Genomics, and Metabolism at Lurie Children’s Hospital • Board certified in Pediatrics, Clinical Genetics, and Clinical Bioche
Slide 21: Enzyme TransportVehicle Franchise for Lysosomal Storage Disorders
21 Enzyme TransportVehicle Franchise for Lysosomal Storage Disorders Overview of MPS II, MPS IIIA and Pompe Disease Barbara Burton, M.D. Professor of Pediatrics at Northwestern University, Feinberg School of Medicine
Slide 22: What are LSDs?
22 • A group of over 50 disorders, each associated with deficiency of a different lysosomal enzyme or transport protein • Inherited in an autosomal recessive or X-linked fashion • Very heterogenous What are LSDs? Figure 7-14, Biological Science, 2/e, ©2005 Pearson Prentice Hall, Inc.
Slide 23: MPS II (Hunter Syndrome)
JENALI . e / MPS Il (Hunter Syndrome). ° Ph ae *- 3 . os Zhe ’ ®
Slide 24: Hunter Syndrome (MPS II) overview
24 • Mucopolysaccharidosis (MPS) conditions are rare, progressive genetic disorders that can affect nearly every organ in the body1,2 • Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is one of 8 distinct MPS disorders – It is estimated that 1 in every 25,000 infants born will have an MP
Slide 25: What are Glycosaminoglycans (GAGs)?
25 • GAGs consist of a core protein plus simple carbohydrates to form a type of molecule called proteoglycans • Proteoglycans are expressed throughout the extracellular matrix and cell surface to support cell signaling and proliferation, tissue morphogenesis, and the interaction of growth factors Wh
Slide 26: Variability of MPS II
26 • MPS II occurs along a spectrum of severity but there are two major subtypes – the neuronopathic form (70% of cases) characterized by progressive neurodegeneration and cognitive decline and the non-neuronopathic or attenuated form (30%) characterized by normal or near-normal cognitive developmen
Slide 27: Real Patient Symptom Progression
27 Real Patient Symptom Progression 1. Wraith JE et al. Genet Med. 2008;10(7):508-516; 2. Burton K et al. Eur J Pediatr. 2012;17(2):631-639. 27 Aiden, Age 3 Aiden, Age 5 Abdominal Hernia1 Otitis Media1 Enlarged Tongue and Tonsils1 Developmental Delays2 Coarse Facial Features1 Stiff Joints and Claw-L
Slide 28: Later Signs/Symptoms of MPS II
28 • Progressive airway narrowing • Cardiac valve thickening and dysfunction, cardiomyopathy • Carpal tunnel syndrome • Retinal degeneration with progressive visual impairment • In neuronopathic patients, developmental slowing followed by progressive neurodegeneration • Death in teens for most neuro
Slide 29: Newborn Screening
29 Newborn Screening 29 • MPS II was added to RUSP in 2017; approximately 25% of US newborns are now screened but this is expected to increase rapidly
Slide 30: Current Treatment of MPS II
30 • Most affected individuals receive enzyme replacement therapy with Elaprase® from time of diagnosis • Surveillance for complications with symptomatic treatment as needed • Hematopoietic stem cell transplantation is used in some cases but relatively infrequently in North America. It provides soma
Slide 31: Limitations of Current ERT
31 • Does not cross the blood brain barrier in significant amounts so does not alter the course of neurodegeneration leading to death • Cardiac valve and airway issues continue to progress and are the major cause of death in attenuated patients • Does not prevent retinal disease • Does not prevent p
Slide 32: Unmet Need in MPS II
32 • A treatment is needed to address the progressive neurodegeneration and cognitive decline seen in the neuronopathic form of the disease • Better treatment for the hard to reach peripheral tissues in which disease progression continues to occur despite current ERT Unmet Need in MPS II 32
Slide 33: MPS IIIA (Sanfilippo A Syndrome)
33 MPS IIIA (Sanfilippo A Syndrome) 33
Slide 34: MPS IIIA – Sanfilippo Syndrome, Type A
34 • Autosomal recessive disorder resulting from deficiency of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH), also referred to as sulfamidase or heparan sulfate sulfatase. This leads to progressive accumulation of heparan sulfate. • Most common of the 4 types of MPS III, accounting for about 7
Slide 35: MPS IIIA – Clinical Findings
35 • Primarily ( but not exclusively) a neurologic disorder – Infants are normal at birth but exhibit developmental slowing at about 2 years of age with speech delay – Hyperactive/aggressive behavior at about age 3 – Developmental regression becomes apparent typically by 4-5 – Often initially misdia
Slide 36: MPS IIIA – Additional Findings
36 • Hepatosplenomegaly • Recurrent otitis media and other respiratory infections • Chronic or recurrent diarrhea • Coarse facial features- less prominent than in other MPS disorders • Prominent GI dysmotility late in the disease • Cardiac valve disease • Skeletal findings such as hip dysplasia MPS
Slide 37: MPS IIIA – Current Treatment
37 • Primarily symptomatic • No approved disease-modifying therapy; HSCT does not alter the course of the disease • Many patients currently receive anakinra (Kineret®) approved for a different disorder but with some data showing benefit in MPS III • Many therapeutic trials including trials of IV or
Slide 38: MPS IIIA – Unmet Need
38 • There is a pressing need for any disease-modifying therapy to health or slow down the relentless progression of the disease and prolong life • The focus is on the brain but if treatment of the brain is successful, the need for effective treatment of peripheral tissues is likely to become more p
Slide 39: Pompe Disease
JENALI / Pompe Disease
Slide 40: Pompe Disease
40 Pompe Disease Photos courtesy of Dr. Ficicioglu and Dr Herman F.M. Busch, Erasmus MC, Rotterdam, The Netherlands. 40
Slide 41: What is Pompe Disease
41 • It is a progressive, genetically determined disorder inherited in an autosomal recessive fashion • Biallelic mutations in the GAA gene lead to deficiency of the lysosomal enzyme alpha-glucosidase and progressive accumulation of glycogen in lysosomes of cells • Other names for Pompe disease used
Slide 42: Pompe Disease: Glycogen Storage Disorder Type II and Lysosomal Storage Disorder
42 Pompe Disease: Glycogen Storage Disorder Type II and Lysosomal Storage Disorder Rabin N, et al. Am J Med Genet C Semin Med Genet. 2012;160:13-21; Werneck LC, et al. Arq Neuropsiquiatr. 2013;71(5):284-289; National Institutes of Health. Genetics Home Reference. Pompe Disease. 2020. https://ghr.nlm
Slide 43: Infantile-Onset Pompe Disease (IOPD)
43 • Poor feeding/failure to thrive • Motor delay/muscle weakness • Hypertrophic cardiomyopathy • Onset within 1st few months of life • Death within 12-18 months of life without treatment • Emerging post-treatment phenotype includes persistent and progressive muscle weakness, hearing loss and white
Slide 44: Late-Onset Pompe Disease (LOPD)
44 • Onset across the lifespan: <12 months to 7th decade – Includes juvenile- and adult-onset forms • Progressive proximal and axial muscle weakness – Gower’s sign, winging scapula – Common misdiagnosis: LGMD • Respiratory dysfunction – Diaphragmatic weakness – Intercostal muscle weakness – Ventilat
Slide 45: Newborn Screening for Pompe Disease
45 Newborn Screening for Pompe Disease 45 • Added to the RUSP in 2015 • Now on the NBS panel in all 50 states
Slide 46: Current Treatment of Pompe Disease
46 • 3 approved forms of ERT available in US – Lumizyme – approved for both IOPD and LOPD – Nexviazyme – approved for LOPD in children and adults – Pombiliti – given with Opfolda (miglustat) approved for adults not improving on their current ERT • Patients with IOPD are treated urgently at time of d
Slide 47: How Well Does Current Treatment Work
47 • If immunologic issues are addressed with appropriate immune modulation, it is very effective for treatment of cardiomyopathy in IOPD and is live-saving • It is much less effective for skeletal muscle disease. Most patients exhibit modest improvement in muscle strength, mobility and respiratory
Slide 48: Why is Treatment Less Effective for Skeletal Muscle?
48 • Sparse M6P receptors compared with other tissues • Inadequate dosing • Late diagnosis in some patients with some muscle fibers destroyed and replaced with fat • Lysosomal rupture leads to accumulation of cytoplasmic glycogen which is not cleared by ERT targeted to the lysosome Why is Treatment
Slide 49: Unmet Need in Pompe Disease
49 • We likely need treatment of the brain in IOPD although the natural history of the brain disease has not yet been fully charted • Better treatment of the skeletal muscle disease is needed in both IOPD and LOPD Unmet Need in Pompe Disease 49
Slide 50: Tividenofusp Alfa: Clinical Development & Regulatory Path
50 Enzyme TransportVehicle Franchise for Lysosomal Storage Disorders Tividenofusp alfa: Clinical Development & Regulatory Path Peter Chin, M.D. Acting Chief Medical Officer and Head of Development
Slide 51: ETV Franchise Opportunity in Lysosomal Storage Disorders
51 ETV Franchise Opportunity in Lysosomal Storage Disorders ETV – Enzyme transport vehicle; LSDs – Lysosomal storage disorders; CNS – Central nervous system; ERTs – Enzyme replacement therapies ~90% historical approval rate Goal is to treat the full disease spectrum ETVs enable brain delivery of enz
Slide 52: Brain Delivery Is Critical Unmet Need of Hunter Syndrome Therapy
52 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 ERT designed to reduce the substrate of IDS (heparan sulfat
Slide 53: Tividenofusp Alfa Phase 1/2 Study Supporting US AA
53 Tividenofusp Alfa Phase 1/2 Study Supporting US AA Substantial long-term safety and efficacy experience informs positive benefit-risk profile in MPS II NCT04251026 Design • Duration: 24-week study + 80-week safety extension + open-label extension • Study Design: Open label Study Population • Neur
Slide 54: Tividenofusp Alfa Phase 1/2 in MPS II: Biomarker Effects
54 • Robust reductions from baseline in CSF heparan sulfate, serum neurofilament light, and urine heparan sulfate, with a majority in the normal range after treatment with tividenofusp alfa Tividenofusp Alfa Phase 1/2 in MPS II: Biomarker Effects MPS II – Mucopolysaccharidoses Type II; CSF – Cerebro
Slide 55: Tividenofusp Alfa Phase 1/2 in MPS II: Clinical Outcomes
55 Improvement in Adaptive Behavior Vineland-3 Improvement in Cognition BSID-III Improvement in Hearing Auditory Brainstem Response (PTA) • While on tividenofusp alfa, clinical outcomes showed skill gains relative to baseline in most participants on measures of adaptive behavior and cognition as wel
Slide 56: Tividenofusp Alfa Safety Summary
56 24-Week Treatment Period (BL to W24) n = 47 All Periods (BL to W261) n = 47 TEAE1, n (%) 47 (100) 47 (100) Mild 8 (17.0) 2 (4.3) Moderate 35 (74.5) 32 (68.1) Severe2 4 (8.5) 13 (27.7) Serious TEAE, n (%) 6 (12.8) 18 (38.3) Treatment-Related Serious TEAE 3 (6.4) 3 (6.4) Fatal TEAE, n (%) 0 0 TEAE
Slide 57: Tividenofusp Alfa Global Phase 2/3 Study Design
57 Study Population • Cohort A: Neuronopathic MPS II, aged ≥2 to <6 years • Cohort B: Non-neuronopathic MPS II, aged ≥6 to <26 years • Receiving idursulfase for >4 months Key Endpoints • Cohort A: CSF HS, Vineland-3, BSID-II, serum NfL • Cohort B: 6MWT • Cohorts A & B: Urine HS and DS, Liver and Spl
Slide 58: Tividenofusp Alfa Development and Regulatory Path
58 Tividenofusp Alfa Development and Regulatory Path Robust data package supporting a target indication for the full MPS II phenotype spectrum PDUFA Target Action Date: April 5, 2026 Preparing for Commercial Launch • Filed BLA for accelerated approval; granted priority review • BLA includes data fro
Slide 59: MPS II siblings enrolled in the study: investigator perspective
1 JENALI « Pathogenic IDS variant (c.262C>T), absent I2S enzyme activity « Diagnosed at 3 years 8 months and 5 months of age, respectively, and treated with weekly idursulfase (0.5 mg/kg) ¢ Both enrolled in the Phase 1/2 study and received weekly tividenofusp alfa 15 mg/kg for > 4 years: - Older sta
Slide 60: Tividenofusp Alfa is the Cornerstone of the ETV Franchise
60 Tividenofusp Alfa is the Cornerstone of the ETV Franchise 1. Protocol amended and response to FDA submitted regarding clinical hold; US AA – United States Accelerated Approval; PDUFA – Prescription Drug User Fee Act; CSF – cerebrospinal fluid; IND – investigational new drug; TfR – transferrin rec
Slide 61: Overview of MPS IIIA (Sanfilippo Type A)
61 • Lysosomal storage disorder caused by deficiency in SGSH gene encoding sulfamidase • Disease hallmark is accumulation of glycosaminoglycan (GAG) heparan sulfate, particularly in CNS • ~1,500+ patients worldwide1. Life expectancy for MPS IIIA patients is 15 years2. • Almost all patients have CNS
Slide 62: DNL126 (ETV:SGSH) Delivers SGSH to the Brain
62 DNL126 (ETV:SGSH) Delivers SGSH to the Brain DNL126 aims to address the relentless neurodevelopmental disease progression in MPS IIIA TransportVehicle • Achieved biomarker proof-of-concept in Phase 1/2 • Aligned with FDA on accelerated approval path in MPS IIIA • Selected for FDA START program •
Slide 63: DNL126 Phase 1/2 Clinical Study: MPS IIIA
63 DNL126 Phase 1/2 Clinical Study: MPS IIIA (Sanfilippo type A) Phase 1/2 initial data to be presented in platform presentation at WORLD Symposium 2026 NCT06181136 Cohort A1• Cohorts A1 – A3: Severe and attenuated MPS IIIA aged ≥ 2 to < 18 years • Cohort B1: Severe MPS IIIA aged < 28 months • Cohor
Slide 64: Study Data for the DNL126 Accelerated Approval BLA
64 Study Data for the DNL126 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
Slide 65: Tividenofusp Alfa: Market Opportunity & Commercial Launch Plans
65 Enzyme TransportVehicle Franchise for Lysosomal Storage Disorders Tividenofusp Alfa: Market Opportunity & Commercial Launch Plans Katie Peng Chief Commercial Officer
Slide 66: Living it. Waiting for it. Watching it.
66 Living it. Denali Hunter Syndrome Patient Advocacy Survey Distributed 12/10/24-1/20/25; BBB – Blood-brain barrier; HCPs – Healthcare professionals Waiting for it. Watching it. – Message from current clinical study family to Denali We are simply amazed at his overall health and what he is capabl
Slide 67: Hunter Syndrome Patients Fall on a Disease Spectrum
67 Hunter Syndrome Patients Fall on a Disease Spectrum, with CNS and Peripheral Manifestations in All Tividenofusp alfa has the potential to address both CNS and peripheral manifestations of disease Peripheral Disease Manifestations Range from Mild to Significant Vary in severity; same symptoms may
Slide 68: Tivi Has the Potential to Reduce Disease Burden and Extend Survival
68 Tivi Has the Potential to Reduce the Disease Burden and Extend Survival, Leading to Growth in the MPS II Population 50% attenuated 50% severe 70% severe 30% attenuated Incidence Prevalence Current Standard Of Care Paradigm The prevalent MPS II population reflects a higher early death rate for ind
Slide 69: Tivi Setting a New Bar for the Treatment of MPS II
69 Tivi Setting a New Bar for the Treatment of MPS II All strategies and tactics are subject to Legal review prior to implementation; GAG – Glycosaminoglycans; FDA – U.S. Food and Drug Administration; MPS II – Mucopolysaccharidosis type II Tividenofusp alfa is an enzyme replacement therapy for all p
Slide 70: Our Stakeholders Are Ready and Waiting for Tivi
70 Our Stakeholders Are Ready and Waiting for Tivi 1. HCP Insights from HCP Survey (N=68) conducted in Q1 2025 and from KOL Adboard conducted March 2025; 2. Caregiver Insights from Caregiver Survey (N=47) Conducted Q4 2024; 3. Payer Insights from AdBoard conducted April 2025 and Payer Engagements; A
Slide 71: Strategy and Path to Establish Tivi as Standard of Care
71 Strategy and Path to Establish Tivi as Standard of Care All strategies and tactics are subject to Legal review prior to implementation; COE – Centers of excellence; P&T – Pharmacy & Therapeutics committee Activate and maintain switch to tividenofusp alfa Broad Patient Reach Through Community Cent
Slide 72: Strong Scientific Outreach and Community Engagement
72 Strong Scientific Outreach and Community Engagement All strategies and tactics are subject to Legal review prior to implementation; HCPs – Healthcare professionals Continued engagement with the Hunter syndrome community and HCPs Scientific Outreach Advocacy Partnerships & Community Council Policy
Slide 73: Denali Pricing Principles
73 Denali Pricing Principles Expect to price tivi at a premium to standard of care, balancing access with the value to patients Access Enable broad, equitable, and sustainable access for patients, the healthcare system, and society Value of Our Medicines Reflect the clinical, economic, and societal
Slide 74: Broad Reimbursement Supported by Clear Clinical Value Proposition
74 Broad Reimbursement Supported by Clear Clinical Value Proposition for Tividenofusp Alfa All strategies and tactics are subject to Legal review prior to implementation; ERT – Enzyme replacement therapy; SoC – Standard of care; MPS II – Mucopolysaccharidosis type II; GAG – Glycosaminoglycans • Prog
Slide 75: Concentrated Stakeholders Enable Us to Reach All Patients
75 Concentrated Stakeholders Enable Us to Reach All Patients Treated Across the 80 to 100 Centers of Excellence in the U.S. All strategies and tactics are subject to Legal review prior to implementation; MPS II – Mucopolysaccharidosis type II 400 to 500 patients in the US on SoC ERT Most MPS II pati
Slide 76: Concentrated Stakeholders Enable Us to Reach All Treaters
76 Concentrated Stakeholders Enable Us to Reach All Treaters Across the 80 to 100 Centers of Excellence in the U.S. All strategies and tactics are subject to Legal review prior to implementation; MPS II – Mucopolysaccharidosis type II 400 to 500 patients in the US on SoC ERT Denali has already estab
Slide 77: Built a Winning Team Ready for Launch
77 Built a Winning Team Ready for Launch All strategies and tactics are subject to Legal review prior to implementation; LSD – Lysosomal storage disorders Leadership Team US Field Team Significant Experience Across Functions ✓ Product Strategy ✓ US and Global Marketing ✓ US and Ex-US Market Access ✓
Slide 78: Tividenofusp Alfa Launch Expected to Follow Established Rare Disease Launch Dynamics
78 Tividenofusp Alfa Launch Expected to Follow Established Rare Disease Launch Dynamics All strategies and tactics are subject to Legal review prior to implementation; HCPs – Healthcare professionals; SoC – Standard of care • Physicians start prescribing tivi • Many patients wait until their schedul
Slide 79: Majority of Global Market Available Based on U.S. Accelerated Approval
79 Majority of Global Market Available Based on U.S. Accelerated Approval and/or Phase 1/2 Data Note: Based on estimated WW split of Elaprase annual revenues of $650M to $700M, assuming we launch in ~90-95% of Elaprase geographies; 1. COMPASS Phase 2/3 data not needed for regulatory filings; All str
Slide 80: Building a Rare Disease Franchise: First Two Near-Term Launches
80 Building a Rare Disease Franchise: First Two Near-Term Launches Combined Opportunity of >$1B All strategies and tactics are subject to Legal review prior to implementation. Tivi US Revenue Tivi Int’l Revenue DNL126 US Revenue DNL126 Int’l Revenue Successfully Launching Tividenofusp Alfa Will Be t
Slide 81: Moderated Panel: MPS II Community Perspectives
81 Enzyme TransportVehicle Franchise for Lysosomal Storage Disorders Moderated Panel: MPS II Community Perspectives Barbara Burton, M.D., Kim Stephens, Ph.D., and Jason Madison
Slide 82: Building a Broader ETV Portfolio
82 Enzyme TransportVehicle Franchise for Lysosomal Storage Disorders Building a Broader ETV Portfolio Peter Chin, M.D. Acting Chief Medical Officer and Head of Development
Slide 83: DNL593 (PTV:PGRN) Delivers PGRN to Key Cell Types in the Brain
83 DNL593 (PTV:PGRN) Delivers PGRN to Key Cell Types in the Brain *In collaboration with Takeda DNL593/TAK-594* approach is highly differentiated from competitor PGRN approaches TransportVehicle Full Length PGRN • Molecule delivers full length PGRN that retains binding to Sortilin receptor • TfR tun
Slide 84: PGRN Depletion Results in Lysosomal Abnormalities Rescued by DNL593
84 PGRN Depletion Results in Lysosomal Abnormalities Rescued by DNL593 Logan et al. Cell 2021 In preclinical models, DNL593 improves both glial activation and neurodegeneration biomarkers relevant in FTD-GRN LAMP2 Lysosome Marker BMP Lipid critical for lysosome activity PGRN Localized to lysosome Sa
Slide 85: DNL593 Mechanism Is Distinct from Other Therapeutic Approaches
85 DNL593 Mechanism Is Distinct from Other Therapeutic Approaches Modified from Simon et al. TICB 2022 DNL593 is a protein replacement therapy designed to restore extracellular and lysosomal PGRN while Anti-Sortilin MOA boosts extracellular PGRN but leaves lysosomal deficiency unresolved Normal Func
Slide 86: DNL593 Phase 1/2 Clinical Study
86 DNL593 Phase 1/2 Clinical Study 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 will read out in 2026 • Part A: healthy volunteers aged ≥ 18
Slide 87: Efficacy and Safety to Date by Franchise Program
87 Franchise Current Study Efficacy to Date Safety to Date tividenofusp alfa DNL310 MPS II (Hunter syndrome) Phase 1/2 DNLI-E-0002 Primary analysis1 • >90% reduction in CSF HS • Normalization of CSF and urine HS • Reduction and normalization of serum NfL • IRR’s clinically manageable and decrease ov
Slide 88: DNL952 (ETV:GAA) Enhances Delivery of GAA to Muscle
88 DNL952 (ETV:GAA) Enhances Delivery of GAA to Muscle DNL952 aims to improve GAA delivery to muscle over existing therapy and deliver GAA to the brain TransportVehicle • Molecule delivers GAA to whole body, including difficult to access tissues • TfR tuned to maximize delivery of GAA to both muscle
Slide 89: DNL952 (ETV:GAA) Superior to Competitor Enzyme in Both Muscle and Brain
89 DNL952 (ETV:GAA) Superior to Competitor Enzyme in Both Muscle and Brain Standard of care: Aval. – avalglucosidase alfa-ngpt DNL952 improves muscle and CNS biomarkers relative to 2nd generation ERT in a preclinical model Plasma Neurofilament Multiple Dose, IV (10X EOW) Muscle Lysosome Volume Multi
Slide 90: DNL952 Phase 1/2 Clinical Study Plan
90 DNL952 Phase 1 Clinical Study Plan Phase 1 biomarker data expected in 20271 Cohort Cohort Cohort B1 A2 A1 • 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 biomar
Slide 91: Building the ETV Franchise Portfolio
91 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 W
Slide 92: Why Now Is the Time for Breakthroughs in AD
92 TransportVehicle Platform: Transforming Treatment for Alzheimer’s Disease (AD) Why Now Is the Time for Breakthroughs in AD Ryan Watts, Ph.D. Chief Executive Officer
Slide 93: Opportunity is Breaking Open in Alzheimer's Disease
93 Opportunity is Breaking Open in Alzheimer’s Disease (AD) TfR – Transferrin receptor; ARIA – Amyloid-related imaging abnormalities • Discovery programs for multiple AD targets • Best in class opportunities to improve efficacy and safety Opportunity for New Therapies to Improve Efficacy and Safety
Slide 94: Three Pillars of Alzheimer's Disease Pathology
94 Three Pillars of Alzheimer’s Disease Pathology Walker L, Free Neuropath, 2020; Bengoa-Vergniory et al, Acta Neurop, 2021; Fernandez-Arjona et al, Frontiers, 2017 94 Amyloid-Beta (Abeta) Plaques 1 Neurofibrillary (Tau) Tangles 2 Neuroinflammation & Hypometabolism 3 Disease Pathology Often thought
Slide 95: Alzheimer's Disease Progresses Over Decades
95 No Disease CDR = 0 CDR = 0.5 1 2 3 Onset of Cognitive Impairment Preclinical AD (~15-20 years) Symptomatic AD (~7-10 years) Alzheimer’s Disease Progresses Over Decades Left image from Carney Institute for Brain Science / Brown University (HEAD Study); Right image adapted from Long and Holtzman (2
Slide 96: Advancements in Biomarkers Enable AD Trial Optimization
96 Advancements in Biomarkers Enable AD Trial Optimization AD trial precision, speed and efficiency improved by recent biomarker breakthroughs Blood PET CSF Advancements Patient ID Abeta pTau Abeta Tau Abeta • Tests less expensive and less invasive • Accurately IDs patients for study inclusion Patie
Slide 97: AD Treatment Landscape is Rapidly Evolving
97 AD Treatment Landscape is Rapidly Evolving TransportVehicle is positioned to deliver best in class Next-Gen TfR-enabled therapies for AD Safety Efficacy Route of Administration 1st Gen Abeta (Abeta mAbs) – + IV Risk of ARIA; modest benefit Next-Gen Abeta TfR-Enabled Antibody + +++ IV, SC Better b
Slide 98: The Future of Alzheimer's Disease Prevention
98 C o g n it iv e F u n ct io n Years Preclinical MCI Dementia Aging The Future of Alzheimer’s Disease Prevention: Treating Before Cognitive Decline Begins We See a Promising Future for AD with the TransportVehicle Preclinical Alzheimer’s Disease PET Amyloid / Tau Cognitive Decline Future State: Ea
Slide 99: Next-Generation of TV-Enabled Therapeutics for AD
99 TransportVehicle Platform: Transforming Treatment for Alzheimer’s Disease (AD) Next-Generation of TV-Enabled Therapeutics for AD Joe Lewcock, Ph.D. Chief Scientific Officer
Slide 100: DNL921 (ATV:Abeta) Designed to Maximize Efficacy and Improve Safety
100 DNL921(ATV:Abeta) Designed to Maximize Efficacy and Improve Safety DNL921 is highly differentiated and has potential for best-in-class BBB-enabled Abeta mAb TransportVehicle cisLALA Abeta Binding • TfR engagement tuned to maximize CNS biodistribution and target engagement while minimizing ARIA •
Slide 101: DNL921 Exhibits Superior Target Engagement and Deeper Brain Penetration
101 DNL921 Exhibits Superior Target Engagement and Deeper Brain Penetration Compared to First Gen Anti-Abeta 10 mg/kg, 24 hrs post-dose, iDISCO-cleared hemibrain; signal represents amyloid plaque engagement DNL921 1st Generation Anti-Abeta
Slide 102: ATV:Abeta Displays Reduced ARIA Due to TfR-Mediated Brain Uptake
102 ATV:Abeta Displays Reduced ARIA Due to TfR-Mediated Brain Uptake Pizzo et al., Science, 2025 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-Abe
Slide 103: DNL921 Displays Greater Amyloid Plaque Engagement than Competitor TfR Architectures
103 DNL921 Displays Greater Amyloid Plaque Engagement than Competitor TfR Architectures ATV:Abeta is highly differentiated and has potential for best-in-class BBB-enabled Abeta mAb C-term TfR Abeta (10mg/kg) DNL921 (10mg/kg) Day 1 Post-Dose Plaque Associated Antibody Plaque Associated Microglia Fema
Slide 104: Engineering a Better Amyloid Beta Targeting Therapeutic
104 Engineering a Better Amyloid Beta Targeting Therapeutic 1. Denali internal results and published data demonstrates effector function is required for maximal plaque clearance. 2. Assessment based on Denali’s preclinical data DNL921 (ATV:Abeta) has the potential to be the best-in-class anti-amyloi
Slide 105: DNL921 Clinical Study Design Enables Rapid Proof of Concept
105 DNL921 Clinical Study Design Enables Rapid Proof of Concept SAD – Single Ascending Dose; MAD – Multiple Ascending Dose 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 dise
Slide 106: DNL628 (OTV:MAPT) Enables Tau Knockdown Throughout CNS
106 DNL628 (OTV:MAPT) Enables Tau Knockdown Throughout CNS Following Peripheral Administration DNL628 has best in class potential based on improved brain biodistribution via peripheral administration • TfR engagement optimized to maximize CNS uptake & biodistribution of oligo • Biologic and oligo po
Slide 107: OTV Eliminates Sharp ASO Gradient that Results from IT Dosing
107 OTV Eliminates Sharp ASO Gradient that Results from IT Dosing Barker et al., STM, 2024 OTV IV ASO IT Cervical Lumbar Cervical Lumbar Spinal Cord Enhanced ASO Deposition in Brain Regions that are Challenging to Target OTV IV ASO IT S tr ia tu m C e re b e ll u m
Slide 108: DNL628 Displays Robust and Sustained Knockdown in Mice
108 DNL628 Displays Robust and Sustained Knockdown in Mice Expressing Human Tau Triangles indicate individual doses over two week time period 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.
Slide 109: DNL628 Clinical Plan Designed to Quickly Determine Tau Knockdown in Brain
109 DNL628 Clinical Plan Designed to Quickly Determine Tau Knockdown in Brain CTA submitted October 2025 Clinical biomarker data expected by 1H 2027 Patients with biomarker confirmed early Alzheimer’s disease (CDR 0.5 to 1, MMSE 20-30) Study Population • Safety • Impact on Tau levels • Dose Selectio
Slide 110: Our TransportVehicle Platform Sets the Bar for BBB Delivery
110 Our TransportVehicle Platform Sets the Bar for BBB Delivery Our Fc-based TransportVehicle (TV) Is Designed & Engineered to Optimize Brain Delivery BBB receptor binding site engineered into the Fc for optimal properties and modularity Architecture Modularity Safety Brain Uptake1 3 2 4 High fideli
Slide 111: Modularity: TransportVehicle Can Deliver Diverse Therapeutic Modalities
111 Study Week % C h a n g e f ro m B a s e li n e S e ru m N fL 60 40 20 0 -20 -40 -60 -80 -100 BL 7 13 24 37 49 61 73 85 97104 117 129 Modularity: TransportVehicle Can Deliver Diverse Therapeutic Modalities Khoury et al. Nature Communications (in press); NfL – Neurofilament light, a marker of neur
Slide 112: Modularity: TransportVehicle Is Compatible with Multiple Oligonucleotide-based Therapeutics
112 Modularity: TransportVehicle Is Compatible with Multiple Oligonucleotide-based Therapeutics 1. OTV:siRNA and OTV:PMO generated using publicly available oligo sequences as tools for platform proof of concept OTV:siRNA1 Achieves Target Knockdown via RISC OTV:PMO1 Achieves Isoform Modulation via Sp
Slide 113: Modularity: TransportVehicle Is Capable of Leveraging Additional BBB Transporters
113 May 2020 Modularity: TransportVehicle Is Capable of Leveraging Additional BBB Transporters We continue to invent and lead the BBB field TfR remains most validated transporter with demonstrated high capacity in humans CD98hc TV Platform • Highly expressed on brain endothelial cells • Capacity and
Slide 114: Brain Uptake: Optimized Affinity Drives Brain Biodistribution and Efficacy
114 Brain Uptake: Optimized Affinity of TransportVehicle Drives Brain Biodistribution and Efficacy Arguello et al., JEM, 2022 ETV:IDS shows broader biodistribution and greater GAG reduction than high affinity TfR in MPS II mouse model; results are consistent with clinical data from both architecture
Slide 115: Safety: Robust Brain Delivery Without Impacting Reticulocytes
115 Safety: TransportVehicle Engineering Enables Robust Brain Delivery Without Impacting Reticulocytes Competitor Molecules generated at Denali based on publicly available information on TfR-binding anti-Abeta antibodies currently under development Molecule Architecture Epitope Effector Function Con
Slide 116: Architecture: Engineering of TfR Binding into Fc Domain Improves Stability
116 TfR Binding Abeta Binding Intact Molecule hlgG Capture vs. TfR Capture ELISA, Single Dose IV 10 mg/kg Architecture: Engineering of TfR Binding into Fc Domain in TransportVehicle Improves Stability Competitor Molecules generated at Denali based on publicly available information on TfR-binding ant
Slide 117: TV Is Differentiated Relative to Other BBB Approaches
117 TV Is Differentiated Relative to Other BBB Approaches Heatmap based on publicly disclosures and head to head (H2H) data generated at Denali in preclinical models for any direct comparisons DENALI JCR Pharma Roche Aliada/Abbvie Arrowhead BioArctic Alector TfR Binding Format Engineered into Fc Hig
Slide 118: Expanding the TV Franchise
118 Expanding the TV Franchise We aim to recognize the full value of the TransportVehicleTM platform Each TV Franchise has a market potential of $5B+ M a rk e t O p p o rt u n it y ( $ B ) Investing now to unlock full potential ETV Enzymes >$5 $1-$5 <$1 2026+ Lysosomal Storage Disorders & Neurodegen
Slide 119: Integrated Manufacturing Driving Speed, Flexibility and Value
119 Integrated Manufacturing Driving Speed, Flexibility and Value Dana Andersen, Ph.D. Chief Technical and Manufacturing Officer
Slide 120: Denali Platform Enables Efficient Manufacturing
120 Denali Platform Enables Efficient Manufacturing TransportVehicleTM (TV) architecture uses antibody-like manufacturing processes Vial Thaw Expansion Harvest Protein A Affinity Chromatography 2X Chromatography Virus Filtration Formulation & Filling • Architecture enables 3-column antibody-like pur
Slide 121: Denali Has Built Internal Manufacturing Capability
121 Denali Has Built Internal Manufacturing Capability State-of-the-art Salt Lake City facility built for efficiency, flexibility, and speed to clinic GMP Manufacturing Facility Completed and Operational (Q1 2025) • Purpose-built to support clinical production across the TransportVehicleTM platform
Slide 122: Manufacturing Highlights
122 Manufacturing Highlights All future early clinical products and commercial launch of DNL126 planned from this facility Denali’s Manufacturing Facility Flexible, Efficient Operations 2025 • ~70,000 sq. ft. GMP facility constructed for < $80M in Salt Lake City, UT • 2 × 2000-L fermenters with puri
Slide 123: Integrated Manufacturing Drives Speed, Flexibility & Value
123 GMP Mfg & IND Prep GMP Mfg & IND Prep Integrated Manufacturing Drives Speed, Flexibility & Value End-to-end capabilities accelerate development, reduce risk, and strengthen long-term economics Select Final Sequence IND Initiate multiple cell lines earlier GLP Tox Mfg GLP Tox Mfg Molecule selecti
Slide 124: Evolving Our Business: Delivering the Value of the TransportVehicle
124 Evolving Our Business Delivering the Value of the TransportVehicle Alexander Schuth, M.D. Chief Operating and Financial Officer
Slide 125: Growing and Executing the Leading Portfolio of BBB-Enabled Programs
125 Growing and Executing the Leading Portfolio of BBB-Enabled Programs Leading a new class of biologic therapeutics that can reach the whole body, including the brain OO Neuro- Degenerative Diseases Lysosomal Storage Disorders Other Indications Neuro- Muscular Diseases Global Network of Partners In
Slide 126: Broad Portfolio to Create Near-Term and Long-Term Value
126 Broad Portfolio to Create Near-Term and Long-Term Value Molecule Indication IND- Enabling Phase 1 Phase 2 Phase 3 Reg. Filing Partner Tividenofusp Alfa (DNL310) ETV:IDS MPS II (Hunter) DNL126 ETV:SGSH MPS IIIA (Sanfilippo type A) DNL593 PTV:PGRN FTD-GRN Takeda DNL9521 ETV:GAA Pompe DNL111 ETV:GC
Slide 127: Integrated Capabilities to Execute for Long Term Value
127 Integrated Capabilities to Execute for Long Term Value • 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
Slide 128: Capital to Execute: Strong Financial Foundation
128 Capital to Execute Strong Financial Foundation $873M + $275M 2 Commercial Launches Cash and investments as of Q3 2025 plus new royalty financing1 Potential revenues from tivi and DNL126 Key Capital Allocation Priorities Invest Strategically • Successful launches of tividenofusp alfa and DNL126 •
Slide 129: Royalty Financing Agreement with Royalty Pharma
129 Royalty Financing Agreement with Royalty Pharma (12/4/25) 1. $200M funded upon U.S. approval by June 30, 3026, and $75M upon EMA approval by Dec 31, 2029 Investment to support successful commercial launch and portfolio execution 9.25% royalty payable on worldwide net sales of tividenofusp alfa $
Slide 130: Efficient Capital Allocation and Acceleration in Execution
130 Efficient Capital Allocation and Acceleration in Execution 1) PDUFA date April 5, 2026 for DNL310; 2) Potential AA in Q4 2027 Develop next programs with significantly increased speed and cost efficiency Applying Learnings, Leveraging Networks and Capturing Operational Synergies Potential 1st Lau
Slide 131: Collaborations Are Central to Our Execution Strategy
131 Collaborations Are Central to Our Execution Strategy Note: Includes current and former partners Network in academia and industry strengthens depth in science and global reach in execution
Slide 132: Entering a New Phase on the Path to the Summit
132 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 Proof of Concepts5 4-6 New Clinical ProgramsDiscover Develop Deliver 2015 2025 2020 D3X3 Value 3-Year Goals (D3X3)
Slide 133: 2026-2027 Expected Milestones
133 2026-2027 Expected Milestones 2026 2027 Drug Candidate Therapeutic Area 1H 2H 1H 2H Tividenofusp alfa MPS II (Hunter syndrome) DNL126 (ETV:SGSH) MPS IIIA (Sanfilippo syndrome) DNL593 (PTV:PGRN) FTD-GRN DNL628 (OTV:MAPT) Alzheimer’s disease DNL952 (ETV:GAA)1 Pompe disease DNL151 / BIIB122 Parkins
Slide 134: Our Purpose
134 Deliver the power of biotherapeutics to the whole body, including the brain, transforming life for people living with serious diseases Our Purpose
Slide 135: Q&A: Denali's Leadership Team
135 image mask Q&A Denali’s Leadership Team
Slide 136: Thank You
Thank You