Slides
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1 Analyst Call February 5, 2026
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2 Forward-Looking Statements This presentation contains forward -looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 . These forward-looking statements do not relate strictly to historical or current facts and they may be accompanied by such words as “anticipate,” “believe,” “could,” “estimate,” “expected,” “forecast,” “intend,” “may,” “plan,” “potential,” “possible,” "future," “will” and other words and terms of similar meaning. All statements other than statements of historical facts contained in this presentation, including, witho ut limitation, statements regarding future results of operations and financial position of Denali Therapeutics Inc. (“Denali” or the “Company”); Denali’s business strategy and business plans, expected progress and expansion , and expected key milestones for Denali's therapeutic portfolio in 2026 and beyond; Denali’s ability to execute on its tailored manufacturing and commercial strategies and accelerate commercial launch readines s; the potential for Denali's product candidates to treat various neurodegenerative diseases including MPS I (Hurler Syndrome), MPS II (Hunter Syndrome), MPS IIIA (Sanfilippo Syndrome), PD, ALS, AD, FTD -GRN, UC, Gaucher's Disease, Pompe Disease, and related peripheral inflammatory diseases; planned preclinical studies and clinical trials and the expectations regarding the timing and availability of results and data from such studies and trials; plans, timelines, expectations related to Denali's TransportVehicleTM (TV) platform, its therapeutic and commercial opportunities, and the potential of TV -supported programs to be best-in-class; plans, timelines, and expectations related to the ETV franchise and ETV-enabled programs, including ETV:GAA, ETV:GCase, and ETV:IDUA, their therapeutic and commercial potential, and the timing and likelihood of planned regulatory filings; plan s, timelines, and expectations relating to DNL310 (ETV:IDS), including the Phase 2/3 COMPASS study and its ability to support global approvals, and the timi ng, likelihood, and scope of regulatory approvals and commercial launch; plans, timelines, and expectations related to DNL126 (ETV:SGSH), including the timing and availability of data from the Phase 1/2 study and likelihood and pathway of regulatory approval; plans, timelines, and expectations related to the OTV and OTV -enabled programs, including DNL628 (OTV:MAPT) and OTV:SNCA, their therapeutic and commer cial potential, the timing of study initiation and the availability of data, and the timing and likelihood of planned regulatory filings; plans, timelines, and expectations relating to DNL921 ( ATV:Abeta), including its therapeutic potential, the timing and likelihood of clinical proof of concept, and the timing of planned regulatory filings; plans, timelines, and expectations relating to DNL151; plans and expectations regar ding DNL593 (PTV:PGRN), the ongoing Ph1/2 study, and the timing and availability of data; plans, timelines, and expectations related to DNL952 (ETV:GAA), including the timing and availability of data; plans and e xpectations regarding Denali's global organization and clinical and manufacturing operations, its projected cash runway and likelihood of receipt of milestone payments, and its likelihood of achieving operat ional efficiencies; the expected timing and likelihood of success of Denali's commercial growth; and the potential market opportunities for each of Denali's programs, are forward -looking statements. Denali has based these forward-looking statements largely on its current expectations and projections about future events, and forward-looking statements regarding potential outcomes should not be interpreted as guarantees of futu re performance. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertaint ies and assumptions, including but not limited to: the risk of the occurrence of any circumstance that could give rise to the termination of Denali’s agreements with its collaborators; Denali’s and its collabor ators’ ability to complete the development and, if approved, commercialization of its product candidates; Denali’s and its collaborators’ ability to enroll patients in its ongoing and future clinical trials; Denali’s ab ility to manufacture and supply product candidates at clinical and commercial scale, including through its internal manufacturing capabilities and its reliance on third parties for the manufacture and supply of its product candidates; Denali’s dependence on successful development of its blood -brain barrier platform technology and TV-enabled product candidates; Denali’s and its collaborators’ ability to conduct or complete clinical t rials on expected timelines; the predictive value of Denali's biomarker selection; the occurrence of significant adverse events, toxicities or other undesirable side effects; the extent to which preclinical and e arly clinical results (including safety -related findings) predict later-stage outcomes; the uncertainty that product candidates will receive regulatory approval or be commercialized; Denali’s ability to continue to crea te a pipeline of product candidates or develop commercially successful products; Denali’s ability to obtain, maintain, or protect intellectual property rights related to its product candidates; Denali's achievement of planned milestones and realization of value; Denali’s ability to realize anticipated financial resources, including receipt of contingent royalty financing and milestone payments; implementation of Denali’s strategic plans for its business, product candidates, and blood -brain barrier platform technology; and other risks. In light of these risks, uncertainties and assumptions, the forward-looking statements in this presentation are inh erently uncertain and may not occur, and actual results could differ materially and adversely from those anticipated or implied in the forward -looking statements. Accordingly, you should not rely upon forward -looking statements as predictions of future events. Information regarding additional risks and uncertainties may be found in Denali’s most recent quarterly and annual reports filed with the Securities and Exchange Co mmission on Forms 10-Q and 10-K, respectively, as well as Denali’s future reports to be filed with the SEC. Denali does not undertake any obligation to update or revise any forward -looking statements, to conform thes e statements to actual results or to make changes in Denali’s expectations, except as required by law. The product candidates being developed by Denali are investigational and their safety and efficacy profiles remain unestablished. Denali's product candidates have not been approved by any health authority for any use. Accuracy of Data. This presentation contains statistical data based on independent industry publications or other publicly av ailable information, as well as other information based on Denali’s internal sources. Denali has not independently verified the accuracy or completeness of the data contained in these industry publications and other pu blicly available information. Accordingly, Denali makes no representations as to the accuracy or completeness of that data.
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3 Leading a New Era of BBB-Crossing Therapeutics Key Messages Ryan Watts, Ph.D. Chief Executive Officer
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4 Our Purpose Deliver the power of biotherapeutics to the whole body, including the brain, transforming life for people living with serious diseases
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5 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 ATV TfR Tf Tf Endothelial Cell Membrane
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6 TransportVehicle : Enabling a New Class of Biotherapeutics Our TransportVehicle (TV) Platform enables TfR-mediated brain biodistribution and enhanced tissue delivery of biotherapeutics throughout the body with systemic administration Genetic medicines for the brain, delivered systemically Brain-penetrant immunotherapy for a wide range of diseases Enzyme TV (ETV) Oligonucleotide TV (OTV) Antibody TV (ATV) Enzyme replacement therapy for the body and brain TfR – Transferrin receptor
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7 Tividenofusp alfa (ETV:IDS; DNL310) ETV:SGSH (DNL126) PTV:PGRN (DNL593) ETV:GAA (DNL952) ETV:GCase (DNL111) ETV:IDUA (DNL622) MPS II (Hunter syndrome) MPS IIIA (Sanfilippo syndrome) FTD-GRN (Frontotemporal dementia-granulin) Pompe Disease Parkinson’s and Gaucher MPS I (Hurler syndrome) Patients WW1 ~2,000 ~1,500+ ~25,000+ ~5,000 – 10,000 ~300,000+ (GBA-PD) ~10,000 – 15,000 (GD) ~1,500+ Status Phase 2/3 BLA filing2 Phase 1/2 Phase 1/2 Phase 1 IND-enabling IND-enabling Building the Enzyme TransportVehicleTM (ETV) Franchise WW – Worldwide; BLA – Biologics License Application; IND – Investigational New Drug; GBA-PD – Parkinson’s Disease with GBA mutation; GD – Gaucher’s Disease; 1. Excluding China and India; 2. PDUFA target action date of 4/5/26 for accelerated approval We are developing the next generation of enzyme replacement therapies designed to treat brain and body manifestations of serious genetic diseases
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8 Denali Presentations at the 2026 WORLDSymposiumTM Date & Time Title Format Poster number Presenting Author Tuesday February 03, 2026 15:30-17:30 PST Persistent Clinical Burden and Unmet Needs in Hunter Syndrome (MPS II) in the United States: A Retrospective Cohort Study Poster 052 Barbara Burton Wednesday February 04, 2026 15:30-17:30 PST Enhanced correction of skeletal muscle and brain pathology in a Pompe mouse model using transferrin receptor-mediated delivery of GAA Poster 290 Rashi Priya Thursday February 05, 2026 11:00-12:00 PST Phase 1/2 Study of Intravenous Tividenofusp Alfa for Mucopolysaccharidosis Type II Oral presentation N/A Joseph Muenzer Thursday February 05, 2026 11:00-12:00 PST Preliminary Results from Phase 1/2, First-in-human, Open-label Study of DNL126 in Children with Mucopolysaccharidosis IIIA (MPS IIIA) Oral presentation N/A Elizabeth Jalazo Thursday February 05, 2026 15:30-17:30 PST Quality of Life, Unmet Needs, and Treatment Experience of People Living with MPS II and Their Caregivers: A Community Survey Poster 248 Kristin McKay Thursday February 05, 2026 15:30-17:30 PST Tividenofusp alfa treatment in a male sibling pair with non- neuronopathic mucopolysaccharidosis type II Poster 065 Irene Chang Thursday February 05, 2026 15:30-17:30 PST A Phase 1, Multicenter, Open-Label Study Design to Evaluate the Safety, T olerability, Pharmacokinetics, and Pharmacodynamics of DNL952 in Adult Participants with Late- Onset Pompe Disease Poster 204 Amy Berger Select presentations being discussed today on Denali’s Analyst Call PDFs of all presentations and posters are available on the Events page of the Investor section of Denali’s corporate website at https://investors.denalitherapeutics.com /events
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9 • Analysis from continued follow- up of Phase 1/2 study in Hunter syndrome (MPS II) reinforces the potential for tividenofusp alfa (DNL310) to address the full disease spectrum • We have established launch readiness in anticipation of April 5, 2026, Prescription Drug User Fee Act (PDUFA) date Key Messages for Today ERTs – enzyme replacement therapies; BLA – Biologics License Application Data and plans presented at this year’s WORLDSymposiumTM reflect the strong momentum of our Enzyme TransportVehicleTM franchise • Preliminary Phase 1/2 data in Sanfilippo syndrome type A (MPS IIIA) showed 80% mean CSF HS reduction and substantial reduction of disease biomarkers in the CNS and periphery • Safety profile generally consistent with established ERTs • Expect BLA filing and accelerated approval in 2027 Tividenofusp alfa (ETV:IDS; DNL310) ETV:SGSH (DNL126) ETV:GAA (DNL952) • Design of ongoing DNL952 (ETV:GAA) Phase 1 clinical study presented in addition to preclinical data that shows therapeutic potential to treat both muscle and nervous system manifestations of Pompe disease • Biomarker proof of concept data expected in 2027
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10 Enzyme TransportVehicle MPS II and MPS IIIA Peter Chin, M.D. Acting Chief Medical Officer and Head of Development
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11 Phase 1/2 Study of Intravenous Tividenofusp Alfa for Mucopolysaccharidosis Type II Professor Joseph Muenzer, MD, PhD University of North Carolina School of Medicine, Chapel Hill, NC, USA
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12BACKGROUND THE BBB CHALLENGE ETV • The BBB is a major obstacle for brain delivery of enzymes • ETV is designed to use the TfR to cross the BBB and enhance delivery of biotherapeutics into the brain • The TfR is the body’s mechanism for iron transport from blood into brain and is highly expressed at the BBB IV ADMINISTRATION AND BROAD BIODISTRIBUTION • Design of the ETV is optimized to enable DNL310 to cross the BBB and may also facilitate uptake into peripheral tissues Tividenofusp alfa has the potential to treat neuronopathic and somatic manifestations of MPS II 1. Muenzer et al. N Engl J Med 2026;394:39–50; 2. Bhalla A et al. Int J Mol Sci 2020;21:5188; 3. Ullman JC et al. Sci Transl Med 2020;12:eaay1163. BBB, blood–brain barrier; CNS, central nervous system; ETV, Enzyme TransportVehicle ; IDS, iduronate-2-sulfatase; IV, intravenous; MPS II, mucopolysaccharidosis type 2; Tf, transferrin; TfR, Tf receptor. DEVELOPING A THERAPY FOR MPS II (HUNTER SYNDROME) Tividenofusp alfa (DNL310) is an investigational IDS fusion protein engineered for CNS and peripheral delivery to address cog nitive, behavioral, and somatic disease control in MPS II with a weekly IV infusion 1–3 ETV IDS TfR
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13 TIVIDENOFUSP ALFA PHASE 1/2 STUDY IN PEDIATRIC PARTICIPANTS WITH MPS II • Study DNLI-E-0002 is an international, open-label, 24-week study with safety and open-label extension periods (NCT04251026) – Data are presented from the clinical cutoff date of March 28, 2025 (when the last participant completed the Week 49 visit) • 47 male participants with MPS II aged ≤ 18 years (ERT -naive and treatment-experienced) were enrolled into five cohorts (A –E) that differed in inclusion criteria for characteristics such as participant age and MPS II phenotype • Participants receiving SOC IV ERT at baseline switched to tividenofusp alfa without a washout period STUDY DESIGN Primary endpoints • Adverse events • IRRs • Other indicators of safety and tolerability Key secondary endpoints • CSF HS • Urine HS • Adaptive behavior (Vineland) • Liver volume Key exploratory endpoints • Serum NfL • CSF biomarkers • Hearing threshold • Cognition (BSID-III, KABC-II) Tividenofusp alfa (weekly IV) 24-week treatment period (Part 1) 24 weeks Safety ext (Part 2) 80 weeks Open-label ext (Part 3) 157 weeks 15 mg/kg 15 mg/kg7.5 mg/kg 24 weeks 15 mg/kg3 mg/kg 12 weeks 3, 7.5, or 15 mg/kg 12 weeks 15 mg/kg30 mg/kg15 mg/kg ≥ 4 weeks 7.5 mg/kg ≥ 2 weeks 3 mg/kg 2 weeks W104 W261W24 A B1 B2 B3 C D Cohort B 15 mg/kg cohorts (n = 27) Dose-finding cohorts (n = 20) E Figure adapted from New Engl J Med, Muenzer J et al., An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II, Vol. 394, pp. 39–50. Copyright © 2026 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. BSID-III, Bayley Scales of Infant Development, Third edition;CSF, cerebrospinal fluid; ERT, enzyme replacement therapy; ext, extension; HS, heparan sulfate; IRR, infusion-related reaction; KABC-II, Kaufman Assessment Battery for Children, Second Edition; NfL, neurofilament light chain; SOC, standard of care; W, week.
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14 PARTICIPANT ENROLLMENT AND DISPOSITION DISPOSITION 3 Failed screening a 50 Underwent screening 47 Were allocated to treatment screening 47 Entered the 24 -week treatment period (BL –W24) 46 Entered the safety ext period (W25–W104) 30 Entered the open -label ext period (W105+) 1 Discontinued 1 Experienced an adverse event 3 Discontinued 1 Was lost to follow-up 2 Withdrew consent 2 Discontinued 2 Withdrew consent 41 Ongoing Exposure summary n = 47 Median: 134 weeks Minimum: 19 weeks Maximum: 243 weeks aThree participants were excluded due to withdrawal of consent, missing/not available DQ at screening, and lack of preexisting liver enlargement. BL, baseline; DQ, developmental quotient.
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15 Substantial reductions and normalization of CSF and urine HS were achieved with tividenofusp alfa treatment, and these reductions were maintained long -term 15 CNS AND PERIPHERAL BIOMARKERS: CSF AND URINE HS RESULTS: BIOMARKERS CSF HS BL 24 49 104 153 201 Participants below ULN (n/N), % 93.2 97.7 96.4 95.2 92.90 44 43 28 21 1447n 0 −25 −50 −75Percent change (GMR to BL [95% CI]) Visit (week) Urine HS Participants below ULN (n/N), % 57.5 61.0 68.0 78.6 83.30 40 41 25 14 1247n BL 24 49 104 153 2017 17 2113 129 177 Visit (week) 0 −25 −50 −75Percent change (GMR to BL [95% CI]) Full methodologies for biomarker assays and statistical analyses are published in Muenzer et al. N Engl J Med 2026;394:39–50. ULN ranges were determined as the 97.5th percentile using CSF samples from 67 pediatric individuals without MPS II (median [min, max] age: 8.88 [0.06, 25.3] years) or urine samples from 149 pediatric individuals without MPS II (median [min, max] age: 4.93 [0.05, 17.2] years). CI, confidence interval; GMR, geometric mean ratio; ULN, upper limit of normal.15
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16 CNS BIOMARKERS: SERUM N fL 16Full methodologies for biomarker assays and statistical analyses are published in Muenzer et al. N Engl J Med 2026;394:39–50. ULN ranges from Schjørring et al. 2023 were used for serum NfL;1 if the participant was aged < 3 years at that visit, an upper limit of 16.6 ng/L was used, else an upper limit of 13.9 ng/L was used. 1. Schjørring ME et al. Scand J Clin Lab Invest 2023;83:403–7. Substantial reduction in serum NfL, a marker of neuronal damage, was achieved with tividenofusp alfa treatment, with normalization in most participants by Week 104 RESULTS: BIOMARKERS Serum NfL BL 24 49 104 153 201189177165117 1411299785736137137 Visit (week) 30 0 −30 −90 −60 Percent change (GMR to BL [95% CI]) Participants below ULN (n/N), % 24.4 26.2 75.0 85.7 61.519.1 45 42 28 21 1347n 16
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17 Hearing threshold as assessed by pure tone average (across 500, 1000, 2000, and 4000 Hz) decreased, reflecting improved hearing from baseline HEARING THRESHOLD Visit n CFB in dB, adjusted mean (95% CI) P value W24 27 −9.4 (−13.7, −5.0) < 0.0001 W49 28 −10.9 (−15.2, −6.6) < 0.0001 W104 15 −11.4 (−16.3, −6.5) < 0.0001 W153 11 −12.1 (−17.4, −6.8) < 0.0001 W201 7 −12.0 (−18.0, −5.9) 0.0002 Mean CFB in pure tone average by ABR (eHL) and audiometry (HL) Full methodologies for hearing assessments and statistical analyses are published in Muenzer et al. N Engl J Med 2026;394:39–50. Pure tone average is defined as the average across the four tested frequencies (500, 1000, 2000, and 4000 Hz) and was calculated only if numeric values for all individual frequencies were available. ABR, auditory brainstem response; CFB, change from baseline; dB, decibels; eHL, estimated hearing level; HL, hearing level; Hz, Hertz. 17 RESULTS: CLINICAL CFB (mean and 95% CI, dB) Pure tone average BL 24 49 104 153 201 Visit (week) 0 −5 −10 −20 −15 27 28 15 11 733n 17
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18 LIVER VOLUME: MRI (COHORTS C, D, AND E) 18 All participants had normal liver volume at Weeks 24, 49, and 153 RESULTS: CLINICAL Liver volume (mean multiples of normal and 95% CI) BL 24 49 153 1.4 1.3 1.0 0.9 Visit (week) 1.2 1.1 0.8 Liver volume (multiples of normal) Average normal liver volume 18 23 521na Population Percent [proportion (n/N)] c below the ULN b BL W24 W49 W153 All 76.2 (16/21) 100 (18/18) 100 (23/23) 100 (5/5) Liver volume (proportion below ULN) b aParticipants recruited early for whom ultrasound was used at baseline were switched to MRI at later visits; as a result, n at baseline does not match the n at later time points. bValues less than the upper bound of the 95% prediction interval for liver volume based on weight and height are defined as normal.1 cn is the number of participants with normal liver volume at that visit; N is the number of participants with available liver MRI volume value at that visit; proportion = n/N. 1. Herden U et al. Transpl Int 2013;26:1217–24. MRI, magnetic resonance imaging.18
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19 Improvement from baseline in adaptive behavior scores was observed in the younger age groups; stabilization was observed in the ≥ 4 years age group ADAPTIVE BEHAVIOR 19 Full methodologies for assessments of cognitive outcomes and adaptive behavior and statistical analyses are published in Muenzer et al. N Engl J Med 2026;394:39–50. ABRS-8 is derived sum of raw scores of eight subdomains (receptive, expressive, personal, interpersonal relationships, play and leisure, coping skills, fine motor, and gross motor). Hollow points indicate visits for which data for less than three participants are available. ABRS-8, eight-subdomain Adaptive Behavior Raw Score composite; Vineland-3, Vineland Adaptive Behavior Scales, Third Edition. RESULTS: CLINICAL ≥ 2 to < 4 years < 2 years ≥ 4 years < 2 years 5 5 5 15 5 4 12 1 ≥ 2 to < 4 years 9 9 8 7 6 27 6 48 8 88 7 4 36 3 ≥ 4 years 32 30 28 21 16 914 19 1425 25 2424 20 15 1317 10 Vineland-3 ABRS-8 200CFB (mean and 95% CI) 100 0 All BL 24 49 104 153 21313 129 17737 61 8573 117 165 189141 201 Visit (week) 44 41 29 22 1346n 1126 25 1838 37 3334 28 19 1623 19
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20 Improvement from baseline in cognitive scores was observed in the younger age groups; stabilization was observed in the ≥ 4 years age group COGNITION 20Full methodologies for assessments of cognitive outcomes and adaptive behavior and statistical analyses are published in Muenzer et al. N Engl J Med 2026;394:39–50. Hollow points indicate visits for which data for less than three participants are available. RESULTS: CLINICAL ≥ 2 to < 4 years < 2 years ≥ 4 years < 2 years 5 5 4 15 5 4 2 ≥ 2 to < 4 years 9 8 8 6 6 16 6 42 8 ≥ 4 years 25 20 19 13 10 52 13 92 1 13 BSID-III cognitive raw score BL 24 49 104 153 20113 129 17737 61 73 CFB (mean and 95% CI) 40 20 0 30 10 −10 All 33 31 20 16 639n 13 9 5 23 19 13 Visit (week) 20
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21 SAFETY OVERVIEW RESULTS: SAFETY 1. Muenzer et al. N Engl J Med 2026;394:39–50. TEAE, treatment emergent adverse event. 21 Tividenofusp alfa 15 mg/kg had a manageable safety profile in pediatric participants with MPS II • Long-term exposure (median ~2.5 years) demonstrated a stable safety profile with no new safety signals since the primary analysis (October 9, 2024)1 • All participants experienced at least one TEAE; the maximum severity was moderate in 75% of participants • In total, 21 participants (45%) had at least one serious TEAE – Of these participants, three experienced serious TEAEs considered related to treatment (two had IRRs and one had anemia; previously reported; all continued to receive tividenofusp alfa in the study) • One participant (2.1%) discontinued treatment due to a TEAE Most frequently reported TEAEs Preferred term All cohorts (n = 47) n (%) of participants IRR 41 (87%) Upper respiratory tract infection 32 (68%) Pyrexia 28 (60%) Cough 23 (49%) Anemia 20 (43%) Diarrhea 20 (43%) Rash 20 (43%) Vomiting 20 (43%) COVID-19 18 (38%) Rhinorrhea 18 (38%) Nasal congestion 17 (36%) 21
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22 IRRs RESULTS: SAFETY • In total, 41 participants (87%) had at least one IRR; among the 47 total participants, the maximum severity was moderate in 55.3% of participants • IRRs were clinically manageable with standard premedications, slowing the infusion rate, and/or reducing the dose level aProportions were number of participants who had an IRR/number of participants exposed to tividenofusp alfa at any point during that time interval (maximum of one IRR (IRR with highest severity) per participant, per interval. 22 Proportion of participants with at least one IRR during each 4-week interval, categorized by severity a IRR severity Mild Moderate Severe75 50 Participants with at least one IRR (%) Weeks 25 0 IRRs, a known risk of ERTs, were the most common adverse event, decreasing in incidence and severity over time 22
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23 CONCLUSIONS • The majority of participants achieved normalization of CSF and urine HS, and serum NfL • Reduction and normalization in CNS and peripheral biomarkers was maintained through Week 201 23 CONCLUSIONS Treatment with tividenofusp alfa led to substantial reductions from baseline in CNS and peripheral biomarkers of disease While receiving tividenofusp alfa treatment, CNS and peripheral clinical outcomes showed: • Improvement from baseline in mean hearing threshold, as assessed by pure tone average • Normal liver volume at 24, 49, and 153 weeks • Improvement or stabilization relative to baseline on measures of adaptive behavior and cognition Tividenofusp alfa demonstrated a stable long-term safety profile with no new safety signals since the primary analysis • All study participants experienced TEAEs, with IRRs being the most common • For most participants, the maximum severity for TEAEs was moderate • Incidence and severity of IRRs decreased, and tolerability improved over time 23
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24 ACKNOWLEDGMENTS We would like to give a special thank you to the participants and families who generously contributed through their participation in this study sponsored by Denali Therapeutics Inc. We also thank the study principal investigators, collaborators, and the Denali Therapeutics team for the conduct of the study and data collection Coauthors: Thank you for your attention Barbara K Burton Paul Harmatz Deepa Rajan Simon A Jones Johanna M P van den Hout John J Mitchell Matthew D Troyer Natalie J Engmann Rupa Caprihan Akhil Bhalla Imanol Zubizarreta Mostafa Wali Peter Chin Carole Ho Tividenofusp alfa (DNL310) is an investigational drug and has not been approved by any Health Authority 24 COMPASS, a Phase 2/3, multicenter, double-blind, randomized efficacy and safety study of tividenofusp alfa vs idursulfase in MPS II, is ongoing (NCT05371613) 24
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25Poster #065 TIVIDENOFUSP ALFA TREATMENT IN A MALE SIBLING PAIR WITH NON-NEURONOPATHIC MUCOPOLYSACCHARIDOSIS TYPE II Irene Chang,1 Jacqeline Madden,1 Annie Sako,1 Jill Dwyer,1 Daniel Fertek,2 Adam Scheller,2 Sharon O’Byrne,2 Imanol Zubizarreta Arambarri,2 Peter Chin,2 Paul Harmatz1 1UCSF Benioff Children’s Hospital, Oakland, CA, USA; 2Denali Therapeutics Inc., South San Francisco, CA, USA WORLDSymposium 2026 Thursday February 5, 2026 from 15:30 to 17:30 PST Informed consents were obtained to present the information and videos on this poster. We give a special thank you to the participants and families who generously contributed through their participation. We also thank our collaborators and the Denali Therapeutics team for the conduct of the study and data collection.
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26 INTRODUCTION AND CASES Introduction • Tividenofusp alfa is an investigational drug designed to cross the blood –brain barrier and treat CNS and somatic manifestations of MPS II (Hunter syndrome) 1 • We present data for a male sibling pair enrolled in the ongoing open -label Phase 1/2 study of tividenofusp alfa (NCT04251026), including standard -of-care follow-up data beyond the study protocol • The Phase 1/2 study enrolled 47 male participants with MPS II into five cohorts (A–E), which differed in inclusion criteria • Both siblings were enrolled in cohort D for individuals with preexisting hepatomegaly and initiated tividenofusp alfa 15 mg/kg weekly intravenously in September 2022 • The younger sibling missed W24 assessments owing to illness not related to the study drug aDQ was calculated as developmental age divided by chronologic age multiplied by 100; a score of 100 indicates age-expected development. 1. Muenzer J et al. N Engl J Med 2026;394:39–50. ADA, antidrug antibody; CNS, central nervous system; DQ, developmental quotient; MPS II, mucopolysaccharidosis type II; Nab, neutralizing antibody. Table 1. Phase 1/2 study baseline demographics and clinical characteristics Older sibling Younger sibling Age at diagnosis 6Y0M 3Y10M Age at tividenofusp alfa initiation 6Y8M 4Y3M Race and ethnicity White, not Hispanic or Latino White, not Hispanic or Latino Genetic variant c.1583A>T; p.(Asp528Val) c.1583A>T; p.(Asp528Val) Iduronate-2-sulfatase activity < 1.5 nmol/h/mL < 1.5 nmol/h/mL Any prior therapy for MPS II No No Composite cognitive DQa 130.19 102.77 ADA and NAb status Negative Negative Height 120.4 cm 108.7 cm Weight 23.4 kg 19.8 kg Physical exam Orange peel rash on shoulders, mild coarse facial features, mild enlarged tongue, and very mild clawed hands (all clinically nonsignificant) Very mild clawed hands (clinically nonsignificant)
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27 BL, baseline; CSF, cerebrospinal fluid; DS, dermatan sulfate; HS, heparan sulfate; MPS II, mucopolysaccharidosis type II; ULN, upper limit of normal; W, week. Figure 2. Change from Phase 1/2 study baseline in CSF HS and DS, and urine HS and DS RESULTS Biomarker assessments from Phase 1/2 study • In both siblings, levels of CSF HS and DS, and urine HS and DS at study baseline were above the ULN • All levels normalized by W49 to within the range for children without MPS II and substantial reductions were maintained through W104 • For the older sibling (Figure 2): – CSF and urine HS were below the ULN at W24 and W21, respectively; CSF and urine DS were below the ULN at W49 – At W24, CSF HS and DS decreased from baseline by 80.5% and 65.2%, respectively; urine HS and DS decreased by 95.8% and 97.6%, respectively • At W49 (older sibling), CSF HS and DS decreased from baseline by 83.0% and 76.0%, respectively; urine HS and DS decreased by 93.8% and 98.5%, respectively • For the younger sibling (Figure 2): – W24 data are not available because the visit was missed. Urine HS and DS were below the ULN at W13; CSF HS and DS were below the ULN at W49 – At W49, CSF HS and DS decreased from baseline by 85.9% and 84.0%, respectively; urine HS and DS decreased by 93.7% and 97.8%, respectively
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28 Informed consents were obtained for the sibling pair with MPS II to present the information and videos on this poster. 1. Cacau L et al. Braz J Cardiovasc Surg 2016;31:381–8 6MWT, 6-minute walk test; W, week. RESULTS Somatic Manifestations • Per medical records, mild carpal tunnel syndrome was diagnosed on the older sibling’s right side (February 2023) and bilaterally in the younger sibling (August 2023). Follow -up testing in August 2024 showed their carpal tunnel syndrome to be resolved • In the Phase 1/2 study W24 interview, their parents noted improvements in both children’s wrists as they both wanted to play video games now and before they did not because their wrists hurt • The older sibling had impaired shoulder abduction at Phase 1/2 study baseline, which normalized at W104 • At their most recent 6MWT (August 2025), the older sibling and younger sibling reached 639 and 589 meters, respectively (distances within the typical ranges expected for boys of their age)1 • Both siblings followed typical height and weight trajectories expected for their ages, with the most recent height measurements for the older sibling and younger sibling around the 50th and 90th percentiles, respectively
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29 RESULTS CNS Manifestations • Select KABC-II subtest scores increased for both siblings from screening to W129 (Table 2) • By W129, both siblings demonstrated notable KABC -II gains • At W129, processing and cognitive abilities were in the above average to upper extreme ranges for age • Standard score gains indicate cognitive development exceeding age-matched KABC -II norms • Using age-constant norms, the younger sibling showed a faster rate of growth • KABC-II improvements were consistent with parent -reported academic and functional gains, supporting clinically meaningful cognitive change KABC-II, Kaufman Assessment Battery for Children, Second Edition; N/A, not administered; NVI, nonverbal index; W, week. aBased on age-appropriate norms; bBased on Age 5 norm set; cProrated per manual guidance.
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30 CONCLUSIONS AND DISCLOSURES This poster was sponsored by Denali Therapeutics Inc. Medical writing support was provided by Aimee Jones, PhD, and was funded by Denali Therapeutics Inc. IJC has conducted research funded by Denali Therapeutics, JCR Pharmaceuticals, Sanofi Genzyme, and Ultragenyx Pharmaceutical; and has received consulting fees from Chiesi Pharmaceutical. PH has conducted research funded by Adrenas Therapeutics, Amicus Therapeutics, Ascendis Pharma, ASPA Therapeutics, Azafaros, BioMarin Pharmaceutical, Calcilytix Therapetics, Denali Therapeutics, GC Pharma, Homology Medicines, Immusoft, JCR Pharmaceuticals, Orphazyme, Prevail Therapeutics, QED Therapeutics, REGENXBIO, Sangamo Therapeutics and Takeda; and has received consulting fees from Aeglea BioTherapeutics, Audentes Therapeutics, Capsida Biotherapeutics, Chiesi, Denali Therapeutics, EcoR1, EdiGene Biotechnology, Grace Science, Inventiva Pharma, JCR Pharmaceuticals, Neurogene, Novel Pharma, Orchard Therapeutics, Rallybio, Renoviron, SalioGen Therapeutics, and Ultragenyx. DF, ASc, SO, IZA, and PC are employees of Denali Therapeutics Inc., which has filed patent applications related to the subject matter. Tividenofusp alfa (DNL310) is an investigational drug and has not been approved by any health authority. Denali Therapeutics Inc. All rights reserved 2026. Conclusions • Tividenofusp alfa treatment substantially reduced and normalized MPS II disease biomarkers and improved somatic manifestations in siblings with non-neuronopathic MPS II • For cognition, KABC -II findings aligned with parent -reported academic and functional observations, supporting the interpretation of meaningful gains in cognitive abilities and processing • Given the open-label nature of the study, the results presented here should be interpreted with caution. COMPASS, a Phase 2/3, multicenter, double- blind randomized efficacy and safety study of Tividenofusp alfa vs idursulfase in MPS II is ongoing (NCT05371613) Scan the QR code to download a PDF of the poster and supplemental file
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31 Preliminary Results from Phase 1/2, First -in- Human, Open-Label Study of DNL126 in Children with Mucopolysaccharidosis IIIA (MPS IIIA) Elizabeth Jalazo, MD University of North Carolina, Chapel Hill,NC, USA 31
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32 MPS IIIA Pathogenesis, Biomarkers, and Clinical Manifestations BACKGROUND GM3, ganglioside monosialic 3; HS, heparan sulfate; MPS IIIA, mucopolysaccharidosis type IIIA; NfL, neurofilament light chain; SGSH, sulfoglucosamine sulfohydrolase. 1. Lavery C et al. Orphanet J Rare Dis 2017;12:168; 2. Harmatz P et al. Mol Genet Metab 2022;136:249–59; 3. Shapiro EG et al. Mol Genet Metab 2017;122S:1–7; 4. Wijburg FA et al. Acta Paediatr 2013;102:462–70; 5. Buhrman D et al. J Inherit Metab Dis 2014;37:431–7; 6. Heon-Roberts R et al. J Clin Med 2020;9:344; 7. Muschol N et al. Orphanet J Rare Dis 2022;17:391. Developmental delay and behavior problems, progressing to severe cognitive decline, and death in adolescence 1–4 TARGET PATHWAY CLINICAL Genetic deficiency in SGSH enzyme activity Lysosomal dysfunction Neurodegeneration Accumulation of heparan sulfate Accumulation of lysosomal lipids (e.g., GM3) Elevated biomarkers of neurodegeneration and neuroinflammation (e.g., NfL) Currently, there are no approved therapies for MPS IIIA, representing a high unmet medical need Impaired sleep5 Impaired hearing5 Somatic manifestations including diarrhea, hepatomegaly, and joint stiffness 3,6,7 32
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33 Our Approach to Enzyme Replacement Therapy BACKGROUND BBB, blood–brain barrier; ERT, enzyme replacement therapy; IV, intravenous; Tf, transferrin; TfR, transferrin receptor. Jefferies WA et al. 1984; Qian ZM et al. 2002; Bakardjiev AI, 2021; Arguello A et al. 2021; Arguello A, Mahon CS et al. 2022; Ullman JC et al. 2020; Wang S et al. 2020; Gammella E et al. 2017; Carlevaro MF, et al. 1997. THE BBB CHALLENGE DNL126 • The BBB is a major obstacle for brain delivery of enzymes • DNL126 is designed to use the TfR to cross the BBB and enhance delivery of biotherapeutics into the brain • The TfR is the body’s mechanism for iron transport from blood into brain and is highly expressed at the BBB IV ADMINISTRATION AND BROAD BIODISTRIBUTION • Design of DNL126 is optimized to enable it to cross the BBB and may also facilitate uptake into peripheral tissues DNL126 is an investigational ERT for MPS IIIA engineered to be brain penetrant and administered by IV infusion TfR binding site SGSH DNL126 (ETV:SGSH) TfR 33
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34 DNL126 Phase 1/2 Study in Pediatric Participants with MPS IIIA *Intraparticipant dose escalation occurred at varying times. CSF, cerebrospinal fluid; QW, once weekly; Q2W, once every 2 weeks; W, week. STUDY DESIGN Study enrollment (n = 20) completed in September 2025 High dose QW High dose Q2W Mid dose QW Low dose QW Low dose Q2W Week 193 Week 13 Week 25 Week 49 Week 97 A1 (n = 4) A2 (n = 4) A3 (n up to 10) B1 (n up to 4) B2 (n up to 4) Dose-finding Cohorts* Efficacy Cohorts* Primary Endpoint • Percent change from baseline in CSF HS at W49 (efficacy cohorts only) Secondary Endpoints • Percent change from baseline in urine HS at W49 • Change from baseline in liver volume at W49 • Percent change from baseline in serum NfL at W73 • Participants with CSF HS in normal range at W49 (efficacy cohorts only) • Study DNLI-I-0001 is a multicenter, open-label, 25-week study followed by an open-label extension period through 193 weeks (NCT06181136) in up to 26 pediatric participants with MPS IIIA in up to 5 cohorts • Preliminary data through cut-off date of June 4, 2025 – Safety Outcomes: Dose-finding and efficacy cohorts (n = 14) – Efficacy Outcomes: Dose-finding cohorts only; at Week 49, dose finding cohorts were receiving the high dose either QW or Q2W (n = 8) Cohort A1–A3: children with severe and attenuated phenotypes aged ≥ 2 to < 18 years Cohort B1: children < 28 months of age with a predicted severe phenotype Cohort B2: siblings of children in Cohort B1 34
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35 All Cohorts: Participant Demographics and Characteristics Dose-finding cohorts Efficacy cohorts* All cohorts (n = 14) Cohort A1 (n = 4) Cohort A2 (n = 4) Cohort A3 (n = 4) Cohort B1 (n = 2) DNL126 treatment duration Completed up to Week 25 4 (100.0%) 4 (100.0%) 4 (100.0%) 1 (50.0%) 13 (92.9%) Completed up to Week 49 4 (100.0%) 4 (100.0%) 0 (0.0%) 0 (0.0%) 8 (57.1%) Age at screening (months) Median 47.0 57.5 51.5 27.0 49.0 Min – Max 36.0 – 55.0 51.0 – 78.0 33.0 – 87.0 27.0 – 27.0 27.0 – 87.0 Sex Female 2 (50%) 4 (100%) 3 (75%) 0 9 (64.3%) Male 2 (50%) 0 1 (25%) 2 (100%) 5 (35.7%) Race White 4 (100%) 4 (100%) 4 (100%) 2 (100%) 14 (100%) Ethnicity Hispanic or Latino 0 1 (25%) 0 0 1 (7.1%) p.S298P heterozygous 1 (25%) 1 (25%) 1 (25%) 0 3 (21.4%) *No participants were enrolled in Cohort B2. DEMOGRAPHICS AND CHARACTERISTICS Study population includes a broad spectrum of pediatric ages and genotypes 35
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36 Preliminary Data Phase 1 Dose-finding Cohorts (A1 and A2) CNS Biomarkers: CSF Heparan Sulfate and GM3 RESULTS: BIOMARKERS *n = 7 at Week 49 as one participant had lumbar puncture performed early at Week 37. **Age -based biomarker reference ranges were established based on CSF samples from 67 individuals without MPS IIIA (median [min, max] age: 8.88 [0.06, 25.3] years). ***Age -based biomarker reference ranges were established based on GM3 samples from 70 individuals without MPS IIIA (median [min, max] age: 8.77 [0.06, 25.3] years). BL, baseline; CI, confidence interval; CNS, central nervous system; GMR, geometric mean ratio. In Cohorts A1 and A2 at Week 49: Mean reduction of 80% in CSF HS with 3 of 7* participants within normal range** Mean reduction of 61% in GM3 with 6 of 7* participants within normal range*** CSF GM3CSF HS Percent change (GMR to BL [95% CI]) BL 13 25 Visit (week) 49 8n 8 8 7 0 −25 −50 −75 −100 Percent change (GMR to BL [95% CI]) BL 13 25 Visit (week) 49 8n 8 8 7 0 −25 −50 −75 −100 36
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37 Preliminary Data Phase 1 Dose-finding Cohorts (A1 and A2) Peripheral Measures: Urine HS and Liver Volume RESULTS: BIOMARKERS Open circles represent timepoints with less than three samples. MRI, magnetic resonance imaging; SD, standard deviation. * ULN ranges were determined as the 97.5th percentile using urine samples from 149 pediatric individuals without MPS IIIA (me dian [min, max] age: 4.93 [0.05, 17.2] years). ** One participant had MRI performed outside of Week 49 analysis window, and one did not have data available at time of data cut. Values less than the upper bound of the 95% prediction interval for liver volume based on weight and height are defined as no rmal (Herden U et al. Transpl Int 2013;26:1217–24). In Cohorts A1 and A2 at Week 49: Mean reduction of 83% in urine HS, 0 of 8 participants within normal range* Mild hepatomegaly improved by Week 25; 6 of 6 participants within normal range** Urine HS • Substantial reduction observed by Week 3 – Variability in response beyond Week 3 due to intra participant differences in dose frequency and dose escalation Liver volume • Mean liver volumes 1.72 times normal at baseline • At Week 49, mean reduction of 0.6 (SD: 0.14) in liver volume multiples of normal Percent change (GMR to BL [95% CI]) BL 19 4937253 7 13 Visit (week) 61 8 7 6 6 54n 7 8 2 0 −25 −50 −75 −100 Liver volume (mean multiples of normal and 95% CI) BL 25 Visit (week) 49 8n 7 6 2.0 1.8 1.6 1.4 1.2 1.0 37
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38 All Cohorts: Safety Overview • All participants (n = 14) experienced a TEAE assessed by the investigator as related to the study intervention • The majority of participants experienced TEAEs with a maximum severity of Grade 1 or Grade 2 – There were no Grade 4 or Grade 5 TEAEs • Serious TEAEs were reported in 4 (28.6%) participants; none were considered treatment- related • IRRs were common and reported in all participants • There were no deaths or TEAEs that led to early discontinuation from the study intervention or the study AESI, adverse event of special interest; IRR, infusion -related reaction; TEAE, treatment -emergent adverse event. RESULTS: SAFETY Preliminary data demonstrate that the safety profile of DNL126 in children with MPS IIIA was generally consistent with established enzyme replacement therapies TEAEs reported in >30% of participants Preferred term All cohorts (n = 14) [n (%)] Infusion-related reaction 14 (100) Upper respiratory infection 9 (64.3) Vomiting 9 (64.3) Nasal congestion 7 (50.0) Cough 6 (42.9) Diarrhea 5 (35.7) Ear infection 5 (35.7) Fall 5 (35.7) Gastroenteritis 5 (35.7) Irritability 5 (35.7) 38
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39 All Cohorts: Infusion-related Reactions RESULTS: SAFETY Infusion-related reactions by cohort and study week • IRR frequency and/or severity decreased after Week 25 in all cohorts (limited data available for Cohorts A3 and B1) • Reduced IRR severity and/or frequency through Week 25 were observed in cohorts utilizing gradual dose escalation (Cohorts A2, A3 and B1) • IRRs were manageable with premedications, infusion-rate adjustments, and/or infusion interruptions – Slow graduated rates adapted from Castells (2008) were utilized to prevent further IRRs in one participant NA, not available. The denominator for the interval is based on the total number of infusions administered during the interval, and the numerato r represents the total number of infusions with an IRR during the interval, in which only the most severe one per dosing visit, per participant is counted. As of the data cut date, no Cohort A3 participants had reached Week 50 and no Cohort B1 participants had reached Week 26. Castells MC et.al. J Allergy Clin Immunol 2008;122:574-80. Infusion related reactions by cohort and study week 100 75 50 25 0 Percentage of infusions (%) Cohort A1, N=4 Cohort A2, N=4 Cohort A3, N=4 Cohort B1, N=2 NA NA NA Study week Mild Moderate Severe 39
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40 Conclusions CONCLUSIONS Preliminary results support continued evaluation of DNL126 in the ongoing efficacy cohorts • All participants experienced TEAEs; the majority of TEAEs were mild or moderate in severity • No treatment-related serious TEAEs, treatment discontinuations or study discontinuations were reported • Frequently reported TEAEs included IRRs, upper respiratory infection, vomiting, nasal congestion, and cough • IRRs were manageable and decreased in frequency and severity over time – Reduced IRR severity and/or frequency was observed in cohorts utilizing gradual dose escalation Preliminary safety data in pediatric participants with MPS IIIA treated with DNL126 were generally consistent with established ERTs Preliminary results from dose-finding cohorts demonstrate that 49 weeks of DNL126 treatment resulted in substantial reductions in CSF and peripheral biomarkers, with some participants achieving normalization • CSF HS: 80% mean reduction at Week 49, with normalization in 3 of 7 participants • CSF GM3: 61% mean reduction at Week 49, with normalization in 6 of 7 participants • Urine HS: 83% mean reduction at Week 49, no participants within normal range • Improvement in mild hepatomegaly observed as early as Week 25, with normalization in 6 of 6 participants at Week 49 40
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41 Acknowledgements We give a special thank you to the participants and families who generously contributed through their participation We also thank our collaborators and the Denali Therapeutics team for the conduct of the study and data collection Co-authors: Thank you for your attention DNL126 is an investigational drug and has not been approved by any health authority John A Bernat, University of Iowa Health Care, Iowa City, IA Jimmy Holder, Baylor College of Medicine, Houston, TX Ana-Claire L Meyer, Denali Therapeutics, San Francisco, CA Audrey Gill, Denali Therapeutics, San Francisco, CA Nikhil J Pandya, Denali Therapeutics, San Francisco, CA Jana Matuskova, Denali Therapeutics, San Francisco, CA Carole Ho, Denali Therapeutics, San Francisco, CA Matthew D Troyer, Denali Therapeutics, San Francisco, CA Young S Oh, Denali Therapeutics, San Francisco, CA Paul Harmatz, UCSF Benioff Children’s Hospital, Oakland, CA 4141
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42 Enzyme TransportVehicle Pompe Disease Joe Lewcock, Ph.D. Chief Scientific Officer
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43Poster #290 ENHANCED CORRECTION OF SKELETAL MUSCLE AND BRAIN PATHOLOGY IN A POMPE MOUSE MODEL USING TRANSFERRIN RECEPTOR-MEDIATED DELIVERY OF GAA Rashi Priya, Cinthia V Pastuskovas, Hoang Nguyen, Isabel Becerra, Manuel Montalban, Rajarshi Ghosh, Chau Tran, Jamal Alkabsh, Sonnet Davis, Audrey Reeves, Romeo Maciuca, Tianao Yuan, Jung H Suh, Meng Fang, Neal Gould, Anastasia Henry, Sarah Huntwork-Rodriguez, Stephanie Coffin, Annie Arguello, Cathal Mahon Denali Therapeutics Inc., South San Francisco, CA, USA WORLDSymposium 2026 Wednesday February 4, 2026 from 15:30 to 17:30 PST We thank the Denali Therapeutics team for their contributions to the study design.
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44 Denali’s TransportVehicle (TV) platform harnesses the transferrin receptor (TfR) to enhance distribution via receptor-mediated cellular uptake and transcytosis DNL952 DNL952 IS A NOVEL, INVESTIGATIONAL ERT FOR POMPE DISEASE DESIGNED TO IMPROVE GAA DELIVERY TO MUSCLE AND THE NERVOUS SYSTEM MUSCLE BLOOD NERVOUS SYSTEM Engineered Fc TfR-binding site TV GAA 44
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45 PD RESPONSE OF DNL952 AFTER MULTIPLE DOSES ADMINISTERED EOW SHOWS NEAR NORMALIZATION OF GLYCOGEN LEVELS IN MUSCLE AND BRAIN Gaa KO;TfRmu/hu KI animals (n = 8 per group) received five IV dosings of DNL952 (low, med, or high dose) or aval (20 mg/kg) administered EOW. Vehicle-treated Gaa WT;TfRmu/hu KI (n = 5) and Gaa KO; TfRmu/hu KI (n = 5) mice served as the nondisease and disease comparator groups, respectively. Levels were assessed using an LC-MS/MS–based method. Data are presented as mean ± SEM. ***P < 0.001; ****P < 0.0001 Glycogen levels in (A) quadriceps muscle and (B) brain tissue measured at 14 days after the fifth dose Repeated dosing with DNL952 achieved near -complete glycogen normalization in muscle and brain and demonstrated greater improvement than with avalglucosidase alfa
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46 Immunofluorescence staining with LAMP2 and P62 in quadriceps muscle after multiple doses (A) Representative images of immunofluorescence of LAMP2 (cyan) and P62 (magenta) of Gaa WT;TfRmu/hu KI (n = 5) and Gaa KO;TfRmu/hu KI mice treated with vehicle, DNL952 (low, med, or high dose), or aval (20 mg/kg) at 14 days after the final dose are shown; n = 3–5 per group. Scale bar = 2 mm. (B,C) Data are mean ± SEM of quantified (B) LAMP2 and (C) P62 signal. **P < 0.01; ****P < 0.0001. MULTIPLE DOSES OF DNL952 REDUCES MARKERS OF LYSOSOMAL AND AUTOPHAGIC DYSFUNCTION Potential to address nervous system involvement that contributes to deficits in IOPD & possibly weakness in LOPD A Next-Generation ERT for Pompe Disease Differentiated mechanism of action: Engaging the TfR + M6PR to improve cellular uptake & lysosomal delivery Improved pharmacodynamic response: Enhanced correction of glycogen & downstream pathology, including autophagy
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47 CONCLUSIONS AND DISCLOSURES This poster was sponsored by Denali Therapeutics Inc. RP, CVP, HN, IB, MM, RG, CT, JA, SD, AR, RM, TY, JHS, MF, NG, AH, SH-R, SC, AA, and CM are employees of Denali Therapeutics Inc., which has filed patent applications related to the subject matter. The trademarks ETV, TV, and TransportVehicle, whether registered or unregistered, are all trademarks of Denali Therapeutics Inc. DNL952 is an investigational drug and has not been approved by any health authority. Denali Therapeutics Inc. All rights rese rved 2026. Conclusions • Together, the in vitro and in vivo data highlight the differentiated mechanism of action of DNL952 and the speed, depth, and breadth of PD response of DNL952 in muscle and the nervous system, supporting the potential of DNL952 as an innovative new ERT for Pompe di sease Scan the QR code to download a PDF of the poster and supplemental file
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48Poster #204 A PHASE 1, MULTICENTER, OPEN-LABEL STUDY DESIGN TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF DNL952 IN ADULT PARTICIPANTS WITH LATE-ONSET POMPE DISEASE Amy C Berger, Isaac V Cohen, Marisa Goo, Sarah Huntwork-Rodriguez, Shyeilla Dhuria, Matthew D Troyer, Carole Ho, Danna Jennings Denali Therapeutics Inc., South San Francisco, CA, USA WORLDSymposium 2026 Thursday February 5, 2026 from 15:30 to 17:30 PST We thank the Denali Therapeutics team for their contributions to the study design.
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49 STUDY DNLI-J-0001: A PHASE 1 OPEN-LABEL STUDY OF DNL952 STUDY OVERVIEW Key eligibility All cohorts • Age ≥ 18 and ≤ 75 years • Confirmed diagnosis of LOPD • Upright FVC ≥ 30% of predicted normal value • Able to ambulate ≥ 40 meters (use of assistive devices is acceptable) A cohorts: ERT- experienced • Have received avalglucosidase alfa or cipaglucosidase alfa at a dose of 20 mg/kg every 2 weeks for at least 12 months Optional B cohorts: ERT-naïve • Have not received any ERT for at least 12 months and have received no more than four total doses at any time Sample size • Up to 32 participants Key endpoints Primary • Safety and tolerability Secondary • PK and immunogenicity Exploratory • PD: Urine Glc4, serum CK, and exploratory biomarkers • Efficacy: Motor and respiratory strength and function and patient-reported outcomes
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50 CONCLUSIONS AND DISCLOSURES This poster was sponsored by Denali Therapeutics Inc. ACB, IVC, MG, SH-R, SD, and DJ are employees of Denali Therapeutics Inc., which has filed patent applications related to the subject matter. CH and MDT were employees of Denali Therapeutics Inc. at the time the study was designed. The trademarks ETV, TV, and TransportVehicle, whether registered or unregistered, are all trademarks of Denali Therapeutics Inc. DNL952 is an investigational drug and has not been approved by any health authority. Denali Therapeutics Inc. All rights rese rved 2026. • DNL952 is an investigational, next-generation ERT for Pompe disease that leverages the TfR to improve enzyme delivery to muscles and to the nervous system • Study DNLI-J-0001 is the first-in-human study of DNL952 • Safety, PK, and PD data obtained in this study will support identification of a well tolerated and potentially effective dose for future studies in Pompe disease • For more information, please visit ClinicalTrials.gov (NCT07354724) Scan the QR code to download a PDF of this poster
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51 Leading a New Era of BBB-Crossing Therapeutics Conclusions Ryan Watts, Ph.D. Chief Executive Officer
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52 • Analysis from continued follow- up of Phase 1/2 study in Hunter syndrome (MPS II) reinforces the potential for tividenofusp alfa (DNL310) to address the full disease spectrum • We have established launch readiness in anticipation of April 5, 2026, Prescription Drug User Fee Act (PDUFA) date Key Messages for Today ERTs – enzyme replacement therapies; BLA – Biologics License Application Data and plans presented at this year’s WORLDSymposiumTM reflect the strong momentum of our Enzyme TransportVehicleTM franchise • Preliminary Phase 1/2 data in Sanfilippo syndrome type A (MPS IIIA) showed 80% mean CSF HS reduction and substantial reduction of disease biomarkers in the CNS and periphery • Safety profile generally consistent with established ERTs • Expect BLA filing and accelerated approval in 2027 Tividenofusp alfa (ETV:IDS; DNL310) ETV:SGSH (DNL126) ETV:GAA (DNL952) • Design of ongoing DNL952 (ETV:GAA) Phase 1 clinical study presented in addition to preclinical data that shows therapeutic potential to treat both muscle and nervous system manifestations of Pompe disease • Biomarker proof of concept data expected in 2027
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53 image mask Q&A