1 Welcome to Denali Therapeutics 2025 Investor Day December 4, 2025 Exhibit 99.1

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, without 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 2025 and beyond; Denali’s ability to execute on its tailored commercial strategies and accelerate commercial launch readiness; 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, including the Enzyme TV (ETV), Antibody TV (ATV), Protein TV (PTV), and Oligonucleotide TV (OTV), and its ther apeutic and commercial opportunities; plans, timelines, and expectations related to the ETV platform 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; plans, timelines, and expectations relating to DNL310, including the ongoing Phase 1/2 study and Phase 2/3 COMPASS study, the timing of planned regulatory filings, and the timing, likelihood, and scope of regulatory approvals and commercial launch; plans, timelines, and expectations related to DNL126, 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 OTV:MAPT and OTV:SNCA, their therapeutic and commercial potential, and the timing and likelihood of planned regulatory filings; plans, timelines, and expectations relating to ATV:Abeta, including its therapeutic potential and the timing of planned regulatory filings; plans, timelines, and expectations relating to DNL151, including enro llment in the Ph2B LUMA study and Ph2A BEACON study; plans and expectations regarding DNL593, including enrollment of Cohort B in the Ph1/2 study; plans, timelines, and expectations related to DNL758 and enrollment in the Ph2 RESOLUTE study; plans and expectations regarding Denali's global organization and clinical and manufacturing operations, the expected timing and likeli hood of success of its commercial growth, and the potential value 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 future performance. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties 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 collaborators’ 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 reliance on third parties for the manufacture and supply of its product candidates for clinical trials; 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 trials on expected timelines; the predictive value of Denali's biomarker selection; the occurrence of significant adverse events, toxicities or other undesirable side effects; the potential for clinical trials of Denali’s product candidates to differ from preclinical, early clinical, preliminary or expected results; the uncertainty that product candidates will receive regulatory approval or be commercialized; Denali’s ability to continue to create 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; implemen tation 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 press release are inherently 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 Commission 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 these 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 available 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 publicati ons and other publicly available information. Accordingly, Denali makes no representations as to the accuracy or completeness of that data.

3 Leading a New Era of BBB-Crossing Therapeutics Key Messages Ryan Watts, Ph.D. Chief Executive Officer

4 Deliver the power of biotherapeutics to the whole body, including the brain, transforming life for people living with serious diseases Our Purpose

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 Near-Term Launches ► Launch of tividenofusp alfa (DNL310) in 2026 and DNL126 in 2027 lay the commercial foundation for 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 disease, provides several near-term high-value milestones Efficient Execution and Capital Allocation ► Well-capitalized and increasingly efficient capital allocation and execution timelines for long-term value creation ETV – Enzyme Transport VehicleTM; TfR – Transferrin receptor

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 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

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 aggregate prevalence, excluding China and India for the lysosomal storage disorders; MPS – Mucopolysaccharidosis; PD – Parkinson’s disease; AD – Alzheimer’s disease Lysosomal Storage Disorders Common Neurodegenerative Diseases >30,000 Patients WW4 $500M-$1B+ per Indication >40M Patients WW4 >$5B per AD/PD Indication 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 12,3 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 1b2 DNL921 ATV:Abeta AD IND-Enabling DNL111 ETV:GCase PD IND-Enabling DNL422 OTV:SNCA PD IND-Enabling

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 opportunity Deliver the blockbuster potential of ETV, ATV, OTV franchises Discover new TV targets and indications Develop first or best-in-class TV therapeutics Deliver Develop Discover D3

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 (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

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 biotherapeutics Blood Brain Blood-Brain Barrier TfR ATVTfR Tf Tf Endothelial Cell Membrane TfR – Transferrin receptor

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 regions Minimal or limited distribution in brain and bone

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 CSF Heparan Sulfate Biomarker of CNS disease Urine Heparan Sulfate Biomarker of peripheral disease

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 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 programs* • Demonstrated ability to correct neurodegeneration (e.g., NfL) • >10 Preclinical programs • >200 Subjects dosed • >11,000 Doses administered • >20 Publications in last 5 years • >350 Patents/Applications 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

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 adversely affects stability Full effector function increases anemia risk High affinity, bivalent binding leads to suboptimal brain biodistribution Low fidelity to natural protein increases risk of immunogenicity Conventional Fab Approaches TfR Binding TfR Binding TfR Binding TfR Binding

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 studies as posted on ClinicalTrials.gov as of December 3, 2025. Roche number of subjects does not include two Phase 3 studies in AD recently initiated and for which actual enrollment number is not available on ClinicalTrials.gov. Denali’s TV is the most clinically validated BBB technology with over 11,000 doses administered, and including patients who have been continuously dosed for more than 5 years Number of Clinical Programs Number of Study Subjects 0 1 2 3 4 5 Denali JCR Roche AbbVie Arrowhead Alector Bioarctic 0 50 100 150 200 250

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 • 23 ERTs currently marketed; ~$9B in sales • ~90% historical ERT approval rate • Traditional ERTs do not penetrate CNS • ETVs address full spectrum of the disease 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 >$1B* ETV Franchise TAM Delivering Next Generation Enzyme Replacement Therapy (ERT) >$5B* Total Market Opportunity # of patients ETV Disease Areas ETV

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 therapeutics with $5B+ market potential Targeting Abeta Plaques Targeting Tau Tangles Advancing the Next Generation of Therapeutics for AD OTVATV Reducing risk of amyloid-related imaging abnormalities (ARIA) Clearing amyloid plaque faster via better brain biodistribution Addressing tau pathology by suppressing MAPT expression

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, MPS IIIA and Pompe Disease Barbara Burton, M.D. 8:45am ET MPS Diseases • Clinical Development & Regulatory Path • Market Opportunity & Commercial Launch Plans • MPS II Community Perspectives (Moderated Panel) Peter Chin, M.D., Acting Chief Medical Officer Katie Peng, Chief Commercial Officer Dr. Burton, Jason Madison and Kim Stephens, Ph.D. 9:05am ET Building a Broader ETV Portfolio Peter Chin, M.D. Acting Chief Medical Officer 10:05am ET 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 10:20am ET Next-Generation of TV-Enabled Therapeutics for AD Joe Lewcock, Ph.D. Chief Scientific Officer 10:30am ET Integrated Manufacturing Driving Speed, Flexibility and Value Dana Andersen, Ph.D. Chief Technical and Manufacturing Officer 10:50am ET Evolving Our Business Delivering the Value of the TransportVehicleTM Alexander Schuth, M.D. Chief Operating and Financial Officer 11:00am ET Q&A Portfolio and Strategy Denali’s Leadership Team 11:10am ET

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 Officer Acting Chief Medical Officer and Head of Development Chief People Officer Chief Commercial Officer General Counsel

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 Biochemical Genetics with research focused on inborn errors of metabolism and newborn screening • Leading researcher in metabolic and lysosomal disorders and author of 300+ peer-reviewed papers and co-editor of two textbooks • Executive Director of the Dr. Joseph Muenzer MPS Research and Treatment Center at UNC, Chapel Hill • Mother to Cole, who was diagnosed with MPS II when he was 2 ½ and has been in a clinical trial at UNC for the past ten years • Former co-chair of the Newborn Screening Committee for EveryLife Foundation • Board Member Emeritus for Project Alive, a research and advocacy organization for MPS II • Longtime member of the MPS II (Hunter syndrome) community and active leader based in Allentown, Pennsylvania • More than 25 years of service with the National MPS Society, including Board membership and founding the Adult Resource Committee; background in graphic design and music composition • Dedicated patient advocate contributing to multiple research studies and a unifying voice within the adult MPS community

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

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.

23 MPS II (Hunter Syndrome)

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 MPS disorder4 – Approximately 1 in every 100,000 infants will have Hunter syndrome. This is an X-linked disorder so almost all affected infants are male • MPS diseases are caused by a deficiency of lysosomal enzymes, which are needed to degrade glycosaminoglycans (GAGs) • The specific enzymatic deficient in MPS II is iduronate-2-sulfatase which is coded for by the IDS gene. Enzyme deficiency leads to progressive accumulation of the glycosaminoglycans heparan and dermatan sulfate. Hunter Syndrome (MPS II) is a Type of Mucopolysaccharidosis, a Subset of the Lysosomal Storage Disorders (LSDs)1,2 1. Giugliani R et al. Genet Mol Biol. 2014;37(2):315-329; 2. Wang RY et al; ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Genet Med. 2011;13(5):457-484; 3. Muenzer J. Rheumatology. 2011;50:v4-v12; 4. NINDS, Mucopolysaccharidoses Fact Sheet, November 2019. NIH Publication No. 19-NS-5115; 5. Meikle PJ et al. JAMA. 1999;281(3):249-254. 24

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 What are Glycosaminoglycans (GAGs)? Gal – Galactose; GalNAc – N-acetylgalactosamine; GlcA – Glucuronic acid; GlcNAc – N-acetylglucosamine; IdoA – Iduronic acid; Xyl – Xylose; Mizumoto S et al. Biomed Res Int. 2014;2014:495764. https://doi.org/10.1155/2014/495764. Accessed April 6, 2020. 25 Heparan Sulfate Dermatan Sulfate Core Protein

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 development without progressive decline • Within the neuronopathic subtype there is considerable variability in the pattern of decline • There are a small number of “intermediate” patients with stable mild to moderate cognitive impairment- 5-10% of total patients – may be classified in either neuronopathic group or attenuated group depending on definitions used Variability of MPS II

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-Like Hands1 Aiden’s age at symptom onset: 4-10 months Aiden’s age at symptom onset: 4-10 months Aiden’s age at symptom onset: 18 months Aiden’s age at symptom onset: 30 months Aiden’s age at symptom onset: 36 months Aiden’s age at symptom onset: 18 months

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 neuropathic patients; those with attenuated disease may live into their 40’s, 50’s or beyond Later Signs/Symptoms of MPS II 28

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

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 somatic benefit and may provide some CNS benefit if done within first year of life but data are limited. Current Treatment of MPS II 30

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 progressive hearing loss so most patients require hearing aids Limitations of Current ERT 31

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

33 MPS IIIA (Sanfilippo A Syndrome) 33

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 70% of cases • Overall incidence estimated at 1 in 125,000 births MPS IIIA – Sanfilippo Syndrome, Type A 34

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 misdiagnosed as ADHD, non-specific developmental delay or autism • Average age at clinical diagnosis 4-5 years; average age of death 10-15 years. Approximately 20 % of patients have a more attenuated course with later diagnosis and longer survival. MPS IIIA – Clinical Findings 35

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 IIIA – Additional Findings 36

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 intrathecal ERT and gene therapy have failed in past. The frustration in the patient community is very high. • No newborn screening underway at present but it is feasible MPS IIIA – Current Treatment 37

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 pressing MPS IIIA – Unmet Need 38

40 Pompe Disease Photos courtesy of Dr. Ficicioglu and Dr Herman F.M. Busch, Erasmus MC, Rotterdam, The Netherlands. 40

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 in past: acid maltase deficiency, glycogen storage disease type II What is Pompe Disease Leslie N, Bailey L. In: Adam MP, et al. GeneReviews. University of Washington, Seattle; 2007 [updated 2017], pp 1993-2019 41

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.nih.gov/condition/pompe-disease#statistics Incidence: 1 in 20,000; Males and Females Affected in Equal Numbers

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 matter changes in the brain with progressive neurologic decline reported in a few Infantile-Onset Pompe Disease (IOPD) Hirschhorn R, Reuser AJ. In Scriver CR, et al; eds. The Metabolic and Molecular Bases of Inherited Disease. NY: McGraw -Hill, 2001, pp 3389-3420; van den Hout HM, et al. Pediatrics. 2003;112(2):332- 340; EBIX A.D.A.M; Images. http://www.adamimages.com/Illustration/SearchResult/1/hypotonia 43

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 – Ventilatory support may be needed at night • No apparent cardiac involvement Late-Onset Pompe Disease (LOPD) Leslie N, Bailey L. In: Adam MP, et al. GeneReviews. University of Washington, Seattle; 2007 [updated 2017], pp 1993-2019; Heaver C, et al. Orthoped Trauma. 2019;33(4)239-248; Oncohema Key. https://oncohemakey.com/13-pompe-disease/. 44

45 Newborn Screening for Pompe Disease 45 • Added to the RUSP in 2015 • Now on the NBS panel in all 50 states

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 diagnosis. Patients with LOPD diagnosed clinically are offered treatment at diagnosis; those diagnosed by NBS are monitored and treated once symptoms appear Current Treatment of Pompe Disease 46

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 function after onset of treatment followed by variable period of stability but ultimate disease progression. • Long term data not available for the two newer ERT’s but the improvement seen is incremental when patients are switched. Considerable unmet need still exists How Well Does Current Treatment Work 47

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 Less Effective for Skeletal Muscle? 48

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

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

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 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

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 sulfate) throughout the body and treat neurocognitive and physical manifestations Monogenic lysosomal storage disorder caused by deficient iduronate-2-sulfatase (IDS) tividenofusp alfa (DNL310) ERT – Enzyme replacement therapy

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 • Neuronopathic and non- neuronopathic MPS II, aged ≤18 years • ERT-naïve and treatment- experienced Key Endpoints • Primary: Adverse events, Infusion-related reactions, other indicators of safety and tolerability • Secondary: CSF HS, Urine HS, Adaptive behavior (Vineland), Liver volume • Exploratory: Serum NfL, CSF biomarkers, hearing thresholds, cognition (BSID, KABC) B3 was part of the dose-finding cohorts; BSID – Bayley Scales of Infant Development; CSF – Cerebrospinal fluid; ERT – Enzyme replacement therapy; ext – Extension; HS – Heparan sulfate; IV – Intravenous; KABC – Kaufman Assessment Battery for Children; MPS II – Mucopolysaccharidosis type II; NfL – Neurofilament light chain; SOC – Standard of care; Source: WORLD 2025.

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 – Cerebrospinal fluid; HS – Heparan sulfate; NfL – Neurofilament light; Source: WORLD 2025. First and only therapy in development for MPS II to achieve normalization of key biomarkers Normalization of Urine HS Biomarker of peripheral disease Normalization of NfL Biomarker of neuronal damage Normalization of CSF HS Biomarker of CNS disease

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 well as hearing threshold improvement from baseline in all tested frequencies Tividenofusp Alfa Phase 1/2 in MPS II: Clinical Outcomes MPS II – Mucopolysaccharidoses Type II; CI – Confidence interval; BSID-III – Bayley Scales of Infant and Toddler Development-Third Edition; PTA – Pure tone average; Source: WORLD 2025. Data supports impact on clinical outcomes important to individuals and families with MPS II

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 Leading to Discontinuation, n (%) 1 (2.1) 1 (2.1) • Across all periods, most participants (72%) had TEAEs that were mild or moderate in severity – One participant (2.1%) discontinued due to a TEAE; discontinuation was in part due to a TEAE of IRR (and other adverse events considered not related to drug) – Three participants (6.4%) had serious TEAEs that were considered related to treatment • Two participants with IRRs (one mild, one severe)3; both recovered and received subsequent doses • One participant with anemia (moderate CTCAE grade); participant remains stable with continued dosing • In the 24-week treatment period (BL to W24), the most frequent TEAEs (>20%) were IRRs3, anemia, vomiting, pyrexia, upper respiratory infection, and rash; the majority of these were mild to moderate in severity – Most IRRs were clinically manageable with standard pre-medications and/or adjustment of infusion time – Anemia-related adverse events generally improved over time Tividenofusp Alfa Phase 1/2 in MPS II: Safety 1. TEAE by maximum severity; 2. Missing intensity was summarized as severe; 3. IRRs including allergic reactions and anaphylaxis; BL – Baseline; CTCAE – Common terminology criteria for adverse events; IRR – Infusion-related reaction; MPS II – Mucopolysaccharidosis type 2; TEAE – Treatment emergent adverse event; W – Week. Phase 1/2 safety and clinical data supports broad indication for treatment of full spectrum of MPS II

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 Spleen MRI volume, Patient / Caregiver Impression of Change, Safety Tividenofusp Alfa Global Phase 2/3 Study Design Rigorous design to confirm efficacy and safety and support global approvals NCT05371613 Design • Duration: Cohort A: 96-week study + extension | Cohort B: 48-week study + extension • Study Design: Randomized double-blinded active control BSID – Bayley Scales of Infant Development; CSF – Cerebrospinal fluid; ERT – Enzyme replacement therapy; HS – Heparan sulfate; IV – Intravenous; MPS II – Mucopolysaccharidosis type II; NfL – Neurofilament light chain; SOC – Standard of care

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 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

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 receptor; GAA – acid alpha-glucosidase enzyme; LSD – lysosomal storage disorders The ETV franchise can deliver transformative treatments for the LSD community Immediate 2026 Near / Mid Term 2027 – 2028 Mid / Long Term 2028+ Clinical Value Potential Tividenofusp alfa (MPS II) First commercial launch US AA PDUFA April 5, 2026 Initial International Launches Full Global Potential • Only therapy shown to normalize disease biomarkers in CSF and periphery DNL126 (MPS IIIA) Path to US AA US AA Global Launch • Ability to normalize CSF heparan sulfate DNL952 (Pompe Disease) IND application filed1 Global Launch • TfR-enhanced delivery of GAA to muscle

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 symptoms, including developmental delay, behavioral disturbances, seizures, and cognition and motor decline following onset (typically between ages of 2 and 6) • No current standard of care, but gene and cell therapies in clinical development Overview of MPS IIIA (Sanfilippo Type A) 1. Excluding China and India; 2. Lavery et al. 2017 Orphanet J Rare Dis; CNS – Central nervous system Currently no disease-modifying therapies are available

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 • Phase 1/2 enrollment completed • Phase 3 protocol under development Program Status SGSH ETV:SGSH SGSH FDA – U.S. Food and Drug Administration; START – Support for clinical Trials Advancing Rare disease Therapeutics

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 • Cohort B21: Siblings of participants in B1 Study Population • Safety • CSF HS • Serum NfL • Urine HS • Liver Volume • PK • Immunogenicity Key Endpoints Dose Finding Cohorts Key Efficacy Cohorts Cohort A2 Cohort B1 Cohort A3 Treatment Period • Duration: 25-week core study + open label extension • Study Design: Open label 1. No participants enrolled in optional Cohort B2. CSF – Cerebrospinal fluid; HS – Heparan sulfate; MPS IIIA – Mucopolysaccharidosis type IIIA; NfL – Neurofilament light chain; PK – Pharmacokinetics

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; 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

65 Enzyme TransportVehicle Franchise for Lysosomal Storage Disorders Tividenofusp Alfa: Market Opportunity & Commercial Launch Plans Katie Peng Chief Commercial Officer

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 capable of that we never dreamed possible when we received his diagnosis. ​ He has a rich vocabulary and imagination, loves listening to books, and he literally never stops talking. We are able to engage in so many family activities we enjoy together that we weren't sure we would ever be able to do as a whole family. With that said, life is not simple or easy by any means. It is really incredible to reflect on how far he has come, while also making us wish that we could have begun treatment so much earlier … It makes us wonder (and hope) for what could be for those children who will … someday be able to initiate brain-targeted therapy at the earliest possible moment. We are literally changing the future, truly creating a future that hasn't existed, for every family that comes ahead. Recent community survey in partnership with Project Alive. Change is not easy. As new treatments emerge, we know families are watching closely — seeking reassurance through others’ experiences and outcomes. Our goal is to make these early experiences with tivi both positive and inspiring, building confidence for families considering a future switch. From lived experiences to hopeful anticipation — the Hunter community’s voices guide our next chapter. “60% of respondents emphasized the need for therapies that cross the BBB — underscoring the urgency for options that address cognition.” ✓ Engagement with HCPs ✓ Payer and access strategy ✓ Working with advocacy to shape our plans ✓ Dedicated Patient Services Team

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 occur as in severe patients, although over longer time CNS Symptoms Appear and Progress Over Time e.g., behavioral issues, inattentiveness, retinal degeneration Significant Peripheral Disease e.g., facial dysmorphism, enlarged spleen/liver, joint stiffness, and eventually pulmonary and cardiac complications Severe Phenotype Attenuated Phenotype Birth Age 10 Age 20 Age 30+ Significant CNS Disease e.g., reduced cognitive function, communication skills, motor skills (some require wheelchair) Significantly Shorter Lifespan (10-20 years) Lifespan into Early Adulthood CNS – Central nervous system

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 individuals born with severe disease Future Tivi Treatment Paradigm Prevalence Larger MPS II population overall as individuals treated with tivi live longer, healthier lives ~30 pts diagnosed per year in U.S. ~400-500 pts in U.S. ~2000 pts WW MPS II – Mucopolysaccharidosis type II; WW – worldwide

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 people with Hunter syndrome. It is the first therapy to treat both the brain and body, and the only therapy to normalize GAG levels. Broad Indication Statement Differentiated Positioning Reason to Believe No need to determine disease severity (pending FDA label) Only option to address all disease manifestations GAG normalization fundamental to tivi's potential of delivering superior clinical outcomes

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; All strategies and tactics are subject to Legal review prior to implementation. Patients & Caregivers Payers • Recognize significant unmet needs across brain and body • 90% view tivi’s data as highly motivating to prescribe • No overall concerns with safety profile • Perceive significant unmet needs, across brain and body • 80%+ are aware of new treatments coming and excited to try tivi • Advocacy orgs and peer to peer communications most influential • Robust payer engagement underway • Perceive therapeutic benefit due to ability to cross the BBB • View tivi’s benefit/risk profile favorably Physicians

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 Centered, High-Touch Engagement Model Seamless Access for All Patients Payer education Engaging P&T at COEs Strong partnership Disease state awareness campaign Medical congresses COE engagement Comprehensive patient support programs Experienced distribution network Account profiling & in-servicing Experienced field team ready to go Payer & P&T Preparation Community & Advocacy Scientific & Clinical Engagement Patient Access & Support Provider & Institutional Preparation Drive fast broad coverage

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 Support

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 value delivered by our medicines Affordability Address affordability by providing comprehensive support to patients and families Fuel R&D Ensure our ability to fuel R&D in the pursuit of meaningful and impactful treatments All strategies and tactics are subject to Legal review prior to implementation.

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 • Progressive disease with widespread organ involvement • Significant decline across brain and body Significant Disease Burden Current SoC ERT: • Does not treat CNS symptoms • Cannot adequately penetrate hard-to-reach peripheral tissues Current SoC Leaves Many Unmet Needs • U.S. prevalence of ~400 – 500 patients • ~1-2 MPS II patients per 1-million-member plan Low Budget Impact • ~50/50 across Commercial & Medicaid • Longer time to coverage on Medicaid compared with commercial Commercial & Medicaid Value Proposition: Tividenofusp alfa could become the first FDA-approved ERT to cross the BBB to target the CNS and eliminate GAG buildup in both brain and body for all MPS II patients Payer coverage will be achieved by communicating compelling tividenofusp alfa value proposition

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 patients treated by clinical geneticists at ~80-100 genetic centers MPS II Patient Distribution MPS II Treating Physician Distribution

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 established relationships with all major MPS II treatment centers MPS II Patient Distribution Denali’s Established Relationships

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 ✓ Market Planning and Analytics ✓ Medical Affairs & Med Info ✓ Field Sales ✓ Field Medical ✓ Patient Advocacy 25+ Successful Product/Indication Launches Worldwide Including Rare Diseases Deep Industry and Disease Expertise ✓ 25 Years Average Biopharma Industry Experience ✓ 96% LSD / Rare Disease Experience ✓ Average Rare Disease Experience: 12 Years Multiple Successful Product Launches All Rare Diseases

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 scheduled visit to discuss tivi • Commercial insurance approvals by policy; Medicaid more limited Initial uptake constrained by operational aspects of launch • Hospitals need to stock tivi • HCPs discuss with families • Insurance approval only by medical exception • Need to schedule initial infusion • HCPs see tivi as the SoC • All patients offered tivi as an option, including those newly diagnosed • Streamlined access for most patients (Commercial and Medicaid) • Patient persistence and growth leads to sustained revenue growth ~First Quarter of Launch ~First Year of Launch Years 2-4 of Launch Initial Phase Early-Stage Adoption Streamlined Adoption Preparing for Patient Uptake Patient Uptake In Full Swing Continued Patient Uptake and Persistence Leads to Fast Revenue Growth Patients on Drug Revenue

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 strategies and tactics are subject to Legal review prior to implementation. • We will pursue ex-U.S. approvals via the U.S. Certificate of Pharmaceutical Product (CPP) for marketing authorization or conditional pathways, as available • We are targeting all ~2,000 patients worldwide in commercially accessible geographies ~33% of Market ~33% of Market ~33% of Market Short Term1 (2026-2027) Mid-Term1 (2027-2028) Longer Term (2028+)

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 the Bedrock of a Successful Commercial Franchise Significant Near-Term Opportunity Infrastructure Synergies Established LSD Leadership • Revenue starting 2026 • $1B+ Opportunity between MPS II and MPS IIIA • Plan to leverage existing Denali infrastructure across both launches • Ability to redeploy resources to translate into favorable margins • Established relationships with key LSD stakeholders • Ability to drive increasingly fast launches and product uptake throughout franchise R e v e n u e Time

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

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

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 tuned to maximize delivery of PGRN to the CNS and uptake into lysosomes of neurons and glial cells • Fc domain portion of TransportVehicle improves manufacturability and drug-like properties Key Characteristics Program status: Phase 1/2 Study Ongoing PTV:PGRN

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 Saline Treatment Grn –/–; TfR KI DNL593 Treatment Grn –/–; TfR KI 20 µm 20 µm GFAP CSF Neurofilament Light (NfL) G F A P I I B A 1 I C D 6 8

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 Function Normal FunctionPartial FunctionAbnormal Function FTD-GRN Healthy Patients Untreated Patients Anti-Sortilin Antibody DNL593 DNL593/TAK-594Endogenous PGRN Sortillin Tf Receptor (TfR) Anti-Sortillin Antibody

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 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 Enrolling (Screening Closed) Completed NCT 05262023 Treatment Period • Duration: 25-week core study + open label extension • Study Design: Randomized double blinded placebo controlled

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 over time • Anemia: early declines in hemoglobin generally returning to baseline, clinically manageable, no discontinuations due to anemia • Anemia frequently observed at baseline in MPS II ETV:SGSH DNL126 MPS IIIA (Sanfilippo syndrome) Phase 1/2 DNLI-I-0001 Initial data2 • Biomarker POC achieved • IRR’s clinically manageable and decrease over time • Anemia: mild anemia (Grade 1) in 1 participant with iron deficiency at baseline PTV:PGRN DNL593 FTD-GRN (Frontotemporal dementia-granulin) Phase 1/2 DNLI-H-0001 Blinded study ongoing3 • Dose-dependent increase in CSF progranulin in healthy volunteers • IRR’s appear clinically manageable with standard measures including pre-medications • No anemia-related TEAEs to date Accumulating ETV Clinical Experience Supports Broad Platform Potential 1. October 9, 2024 CCOD (N=47); 2. June 4, 2025 CCOD (N=14); 3. As of November 20, 2025; CCOD – clinical cut off date Robust CNS activity and manageable safety observed across multiple ETV programs

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 and CNS • Fc domain portion of TransportVehicle improves manufacturability and drug-like properties Key Characteristics GAA Enzyme Program status: Protocol amended and response to FDA submitted regarding clinical hold ETV:GAA

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 Multiple Dose, IV (5X EOW) Gaa WT-Vehicle Gaa KO-Vehicle Gaa KO-DNL952; Med Gaa KO-Aval; Med Gaa KO-DNL952; Low Gaa KO-DNL952; High LAMP2

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 biomarkers • Immunogenicity Goals & Objectives 2nd Gen Treatment-Experienced Optional: Treatment-Naïve Optional: Additional Cohorts Treatment Period • Duration: 24-week core study + 24-week safety extension • Study Design: Open label 1. Protocol amended and response to FDA submitted regarding clinical hold; ERT – Enzyme replacement therapy; LOPD – Late onset Pompe disease; PK – Pharmacokinetics

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 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 IND application submitted3 IND-enabling IND-enabling Building the ETV Franchise Portfolio WW – Worldwide; BLA – Biologics license application; IND – Investigational new drug application; 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; 3. Protocol amended and response to FDA submitted regarding clinical hold We are developing the next generation of enzyme replacement therapies designed to treat brain and body manifestations of serious genetic diseases

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

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 Unmet Needs Include: • Faster plaque reduction • Lower doses • More convenient delivery • Reduced risk of ARIA Recent Advances Bring New Hope to People Living with AD • New anti-amyloid therapies are the first disease modifying treatments • New biomarkers and imaging tools • New targets show promise in clinical testing, e.g., tau • TfR-based targeting technology shows promise in clinical testing Denali is Positioned to Deliver the Next Generation of AD Therapies ATV:Abeta OTV:MAPT 55 Million People Live with AD and Other Forms of Dementia We Aim to Deliver Effective Medicines with Broad Societal Impact

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 to be the “trigger” that kicks-off the disease Most closely associated with cognitive decline in AD Characterized by microglial activation Therapeutic Strategy Anti-Abeta clinically validated Knockdown of Tau emerging as optimal strategy Currently higher biology risk; ideal mechanism unclear TV Opportunity Clear path to differentiate with TfR TfR delivery enables improved BioD and peripheral dosing TfR delivery possible pending target validation

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 (2019) Cell Volume 179, Issue 2p312-339 Major AD Pathophysiological Hallmarks in Relation to Clinical Course Hallmarks of AD Pathology Major AD Pathophysiological Hallmarks Synaptic/ Neuronal Function and Density Aβ Deposition (neuritic plaques) Microglia and Astrocyte Activation Tau Pathology (NFT)

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 Patient Stratification – Tau – • Stratification by tau severity predicts clinical progression rate and response magnitude Target Engagement (TE) pTau Abeta Tau Tau pTau • Enables assessment of magnitude and duration of tau therapy • Enables TE assessment for Abeta therapy Current Biomarkers in AD Clinical Studies

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 brain uptake, faster plaque clearance and safer route of entry into brain 1st Gen Tau (ASO/siRNA) + + IT Limited brain biodistribution Next-Gen Tau TfR-Enabled ASO/siRNA + ++ IV Better brain uptake and more convenient / less invasive

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: Early Diagnosis & Safe Treatments Goal: Treat Early to Prevent Decline • Earliest stages of AD • Brain changes begin • No signs of cognitive decline • Positive brain biomarkers (lesions) • Accessible screening, simple blood tests • Safe treatments, i.e., minimize ARIA risk • Prevent cognitive decline

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

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 • cisLALA architecture that is unique to TV allows molecule to safely retain effector function • Designed to preferentially bind oligomeric Abeta and minimize monomer binding Key Characteristics Program status: IND/CTA filing in 1H 2026 ATV:Abeta

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

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-Abeta Route of Entry into Brain Artery / Arteriole Zone Microvessel (capillary) Zone Anti-Abeta (5-10 mg/kg) ATV: Abeta (1.75-3 mg/kg) ATV: Abeta (5-10 mg/kg) # o f M ic e w it h A R IA E v e n t Time (weeks) Incidence of MRI Lesions 5xFAD; TfRmu/hu KI; QW IP

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 Females Males Control IgG C-term TfR, Effector-Positive 10 mg/kg DNL921 10 mg/kg DNL921 3 mg/kg DNL921 1 mg/kg Day 1 Post-Dose cisLALA ATV:Abeta Abeta Binding TfR Binding C-term TfR Abeta TfR Binding Abeta Binding

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-amyloid immunotherapy Approved Amyloid Beta Immunotherapies Modest clinical benefit with significant risk of ARIA and slow plaque reduction Opportunity for next-generation therapies to improve safety and efficacy Desired Feature ABBV-1758 Trontinemab DNL9212 Properties Optimized TfR Binding + + ++ Effector Function None Full Conditional Efficacy Better Brain Uptake ++ ++ +++ Improved Plaque Clearance –1 ++ +++ Safety Avoid ARIA ++ + +++ Avoid Anemia +++ + +++ Avoid Immunogenicity – – ++ All TfR-Based Anti-Amyloid Beta Therapeutics are Not Engineered Equal

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 disease Study Population • Safety • Impact on Amyloid Plaque Load • Dose Selection • Additional biomarkers/imaging Ph1b Objectives Duration: 28 weeks Endpoints: Safety, Amyloid PET, Additional Biomarkers MAD Cohort MAD Cohort MAD Cohort C B A SAD Study Design Ph 3Ph 1/1b

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 portion of molecule are engineered to improve exposure and safety • Design principles can be readily applied to additional OTV programs Key Characteristics Program status: CTA Filed October 2025 OTV:MAPT TransportVehicle MAPT ASO

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

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 0.5 1.0 1.5 Weeks post study start (Dosing period = 3wks, so subtract 3 for Weeks post final dose) M A P T R N A e x p re s s io n (N o rm a liz e d t o G a p d h a n d S a lin e ) DNL628 Knockdown Timecourse in hTau x hTfR mice DNLI-24-23 and DNLI-23-202 MAPT RNA Tau Protein R e la ti v e e x p re s s io n v s . c o n tr o ls (R N A n o rm t o G a p d h ; P ro te in n o rm t o B C A ) 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) M A P T R N A e x p re s s io n (N o rm a liz e d t o G a p d h a n d S a lin e ) DNL628 Knockdown Timecourse in hTau x hTfR mice DNLI-24-23 and DNLI-23-202 MAPT RNA Tau Protein IV doseTarget 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) M A P T R N A e x p re s s io n (N o rm a liz e d t o G a p d h a n d S a lin e ) DNL628 Knockdown Timecourse in hTau x hTfR mice DNLI-24-23 and DNLI-23-202 MAPT RNA Tau Protein R e la ti v e e x p re s s io n v s . c o n tr o ls (R N A n o rm t o G a p d h ; P ro te in n o rm t o B C A ) 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) M A P T R N A e x p re s s io n (N o rm a liz e d t o G a p d h a n d S a lin e ) DNL628 Knockdown Timecourse in hTau x hTfR mice DNLI-24-23 and DNLI-23-202 MAPT RNA Tau Protein IV dose Protein PT RNA D se

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 Selection • Additional biomarkers/imaging Ph1b Objectives Duration: 24 weeks Endpoints: Safety, CSF Tau, Additional Biomarkers MAD Cohort MAD Cohort MAD Cohort C B A Study Design Ph 3Ph 2Ph 1b

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 fidelity to natural protein (e.g., no appended sequences) improves stability, limits immunogenicity and improves ease of manufacturing Enables broad ability to transport range of therapeutics, such as enzymes, oligos and antibodies Conditional effector function avoids reticulocyte loss and minimizes anemia liability potential Optimized affinity and epitope enhance brain delivery while limiting receptor degradation

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 neurodegeneration; Source: tau – Denali data on file, NfL – Adapted from SSIEM 2024 TransportVehicle enables broader brain biodistribution, enhanced target engagement, and normalization of key disease biomarkers ATV ETV TV enables ETV:IDS to reduce serum NfL by >80%, achieving normal levels TV provides high and uniform deposition of ATV across the brain with systemic delivery OTV TV enables sustained brain tau knockdown with OTV:MAPT systemic delivery Tau Knockdown NfL Correction 1.5 1.0 0.5 0.0 0 4 8 12 16 R e la ti v e E x p re s s io n v s . C o n tr o ls (R N A n o rm t o G a p d h ; P ro te in n o rm t o B C A ) Weeks Post Study Start Tau Protein MAPT RNA 1

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 Splicing Interference Brain MAPT RNA and Tau Protein Brain MAPT RNA Brain 4R MAPT RNA 1

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 kinetics distinct from TfR; opportunity for distinct target classes Dual TV Platform Binds Both TfR and CD98hc TfR TV Platform • Highly expressed on brain endothelium • Undergoes constitutive endocytosis and recycling = high transport capacity • Leveraging capacity of two transporters enables maximal brain uptake TfR CD98hc CD98hc TfR 1

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 architectures ETV:IDS High Affinity IgG:IDS Brain GAG Levels TfR Paratope TfR Epitope IDS 24 Hours 24 Hours 2

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 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 Brain Concentration Single Dose, IV 10 mg/kg (molar-matched) Immature Reticulocytes Single Dose, IV 10 mg/kg (molar-matched) 3

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 anti-Abeta antibodies currently under development Appended TfR binding regions on competitor molecules are clipped in vivo; may limit brain uptake Molecule Architecture Epitope Effector Function 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 DNL921 only molecule that remains intact C-term TfR Abeta Potential clipping of TfR binding region ATV:AbetacisLALA Abeta Binding TfR Binding 4

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 High affinity antibody fusion Fab fusion Single-chain variable fragment fusion High affinity single-chain Fab Single-chain variable fragment fusion Single-chain variable fragment fusion TfR Binding Domain Apical Apical Apical Protease-like Apical Protease-like Apical Modularity Enzymes, Abs, oligos, proteins Enzymes, gene therapy Abs Abs Oligos Abs Claimed but limited data Brain Uptake Optimized for each program High affinity limits uptake Inferior compared H2H with TV Inferior compared H2H with TV No H2H data vs TV platform Inferior compared H2H with TV No H2H data vs TV platform Safety Conditional effector function Safety caps at low doses Some anemia Safety strategy may limit efficacy No data reported Preclinical data only Retic loss in monkey reported Architecture No appended sequences Dose limited Immunogenicity/ stability concern Immunogenicity/ stability concern Rapid clearance predicted Immunogenicity/ stability concern Immunogenicity/ stability concern TransportVehicle 1 3 2 4 TfR Binding TfR Binding TfR Binding TfR Binding TfR Binding TfR Binding Clinical stage; No data reported PreclinicalClinical data reported TfR Binding

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 & Neurodegeneration Additional Indications Lysosomal Storage Disorders ATV Antibodies OTV Oligonucleotides ETV Enzymes >10 Additional Preclinical Programs Continued Invention Across TV Platform 3 IND Enabling Programs 2020

119 Integrated Manufacturing Driving Speed, Flexibility and Value Dana Andersen, Ph.D. Chief Technical and Manufacturing Officer

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 purification process • Fits seamlessly within global antibody manufacturing capacity • Royalty-free cell line and vector Platform Efficiency • Efficient processes enable projected COGS <20% of revenue • Reduces cost and time to IND • High productivity TV processes will support large markets Cost Impact • Leverage CDMOs for large-scale manufacturing to manage capacity and efficiency • Drug product and oligonucleotide manufacturing outsourced until internalization is beneficial Strategic Use of Partners Viral Inactivation Ultrafiltration/ Diafiltration Scale-up & Fed-batch Production ATV Antibodies OTV Oligos ETV Enzymes

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 Strategic Benefits Speed & Flexibility • Enables rapid scale-up and response to evolving program needs • Can nimbly reprioritize schedule when data supports moving quickly Cost Efficiency • Integrated development & manufacturing has reduced cost to IND • Eliminates reservation fees at CDMOs Risk Reduction • Increases control over supply chain and product quality • Mitigates tariff exposure Integrated Platform Advantage • Supports broad application of TransportVehicleTM technology • Learnings leveraged across portfolio to increase efficiency ETV OTV ATV

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 purification train • Designed for single-use technology and modular expansion • Up to 40 batches per year with staff expansion • Single-use design enables rapid changeover between programs • Supports both early clinical and commercial manufacturing 8 GMP & GLP batches Successful GMP audit enabling EU clinical supply

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 selection Molecule selection Timelines Reduced by 3-6 Months IND Acceleration Through Integration • Enables parallel risk-taking and quickly responding to data • Avoids restrictions from CDMO capacity constraints • Accelerating IND timelines by ~1 quarter for first 2 programs Strategic Control & Risk Reduction • Reshored DNL126 manufacturing for BLA filing and commercial launch • Reduces at-risk manufacturing by enabling rapid response to demand signals Economic & Strategic Advantages • Optimized DNL126 production scale reduced COGS by ~50% • Increased process understanding and proprietary manufacturing IP Traditional Path Using CDMO Internally Enabled Path Manufacture when ready

124 Evolving Our Business Delivering the Value of the TransportVehicle Alexander Schuth, M.D. Chief Operating and Financial Officer

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 Integrated Internal Capabilities Efficient Resource Allocation Speed in Development Broad Opportunity Efficient Execution

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:GCase Gaucher/ Parkinson’s disease DNL622 ETV:IDUA MPS I (Hurler) DNL628 OTV:MAPT (tau) Alzheimer’s disease DNL921 ATV:Abeta Alzheimer’s disease DNL422 OTV:SNCA Parkinson’s disease BIIB122 LRRK2 Inhibitor Parkinson’s disease Biogen Eclitasertib (SAR443122) RIPK1 inhibitor Ulcerative colitis Sanofi ATV Small MoleculeETVOTV $500 - $1B $5B+ per indication per indication 1. Protocol amended and response to FDA submitted regarding clinical hold

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 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

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 • 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 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

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 $275M potential total funding1: $200M at US approval and $75M at EMA approval Royalty payments capped at 2.5x by Q1 2039 and 3x thereafter

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 Launch DNL3101 Potential 2nd Launch DNL1262 Acceleration / Cost Saving Number of Patients to Enable Accelerated Approval 47 20 55% Total Manufacturing Costs $280M $100M 65% Time from FIH to Potential US Approval 5 yrs 8 months 4 yrs 30% Total Expected Development Costs to Approval $700M $340M 50% • Streamlined clinical studies and validated biomarkers • Established relationships with stakeholders (health authorities, KOLs, patient groups, policy makers) • Preferred partnerships with clinical sites and CROs • In-house manufacturing for all future TV programs • Commercial infrastructure to support future launches Case Study: DNL126 vs. DNL310

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

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)

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 Parkinson’s disease DNL921 (ATV:Abeta) Alzheimer’s disease US Accelerated Approval COMPASS Phase 1/2 Phase 3 BLA for AA Submission Phase 1/2 Phase 1b Phase 1b Phase 1 Phase 2b (LUMA) Phase 2a (BEACON) Phase 1b Phase 1 Phase 1/1b US Accelerated Approval Safety Trial Initiation Data Submission/Approval 1. Protocol amended and response to FDA submitted regarding clinical hold

134 Deliver the power of biotherapeutics to the whole body, including the brain, transforming life for people living with serious diseases Our Purpose

135 image mask Q&A Denali’s Leadership Team