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ARO-MAPT Phase 1/2a Study Interim Clinical Data Update October 14, 2026
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Introduction and Agenda Vince Anzalone, CFA Senior Vice President ARO-MAPT Phase 1/2a Study Clinical Data Update
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3 Safe Harbor Statement This presentation contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of various factors and uncertainties, including, without limitation, our developmental stage and limited operating history, our ability to successfully and timely develop products, entering into new collaborations and achieving existing projected milestones, rapid technological changes in our markets, demand for our future products, legislative, regulatory and competitive developments and general economic conditions. Our Annual Report on Form 10-K, recent and forthcoming Quarterly Reports on Form 10-Q, recent Current Reports on Forms 8-K, and other SEC filings discuss some of the important risk factors that may affect our ability to achieve the anticipated results, as well as our business, results of operations and financial condition. Readers are cautioned not to place undue reliance on these forward- looking statements. Additionally, Arrowhead disclaims any intent to update these forward- looking statements to reflect subsequent developments.
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4 Agenda Topic Presenter Introduction Vince Anzalone, CFA Arrowhead SVP A New Era for RNAi Therapeutics Chris Anzalone, Ph.D. Arrowhead CEO Silencing MAPT in Alzheimer’s Disease and Other Tauopathies Adam Boxer, M.D., Ph.D. UCSF TRiMTM CNS-SC Platform & Overview of ARO-MAPT James Hamilton, M.D., MBA Arrowhead CMO/R&D Head Interim Results from Phase 1/2a Study James Hamilton, M.D., MBA Key Takeaways Chris Anzalone, Ph.D. Q&A Panel
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5 Adam Boxer, M.D., PhD Professor, Neurology Endowed Professor in Memory and Aging UCSF Weill Institute for Neurosciences Adam L. Boxer, MD, PhD, is a fellowship-trained, clinically active behavioral neurologist and Endowed Professor in Memory and Aging in the Department of Neurology at the University of California, San Francisco (UCSF), where he directs the Neurosciences Clinical Research Unit and the Alzheimer's Disease and Frontotemporal Dementia Clinical Trials Programs. Dr. Boxer is a co-principal investigator of ALLFTD, a 27-site North American research network focused on preparing for FTD clinical trials through biomarker and clinical endpoint development. He is the lead principal investigator for both the NIH Alzheimer's Disease Tau Platform (ATP) and the PSP Trial Platform (PTP), two new multidrug public-private clinical trial partnerships designed to accelerate the development of effective therapies. He has initiated and led multiple public-private partnerships focused on accelerating drug development for neurodegenerative disease, including the Neurofilament Surveillance Project, the FTD Treatment Study Group (now the FTD Research Roundtable), and the PSP Research Roundtable. Neurology Key Opinion Leader
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A New Era for RNAi Therapeutics Led by Arrowhead Chris Anzalone, Ph.D. President and CEO ARO-MAPT Phase 1/2a Study Clinical Data Update
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7 Expanding TRiM : Solving the Challenges of RNAi in the Brain Crossing the blood-brain barrier: Breaking through a major delivery challenge Preclinical studies demonstrate broad distribution and uniform target suppression across CNS, including deep brain Demonstrating functional/productive delivery: Deep and durable gene silencing Eliminating the need for IT administration: quarterly subcutaneous dosing simplifies treatment and opens opportunities to treat a variety of indications
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8 Current Clinical Programs using New CNS Delivery
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Silencing MAPT in Alzheimer’s Disease and other Tauopathies Adam Boxer, M.D., Ph.D. Professor, Neurology Endowed Professor in Memory and Aging UCSF Weill Institute for Neurosciences ARO-MAPT Phase 1/2a Study Clinical Data Update
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10 Objectives • Review the current treatment landscape in Alzheimer’s disease • Understand the implications of recent therapeutic advances • Evaluate the rationale for tau-targeting approaches • Frame key considerations for next-generation therapies • Tau reduction for treatment of primary tauopathies
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11 Insoluble tau correlates with clinical features in tauopathies CTE AD PSP-RS Kretzschmar, Nat. Rev. Neurosci. 2009, 10: 70-77; Williams, Brain 2007, 130: 1566-1576; McKee, Brain 2013, 136: 43–64
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12 Targeting Tau in Tauopathies • Pathophysiology • Tau is the key pathogenic driver • Not secondary • Multiple mechanisms → “tau gain of function” Samudra and Boxer et al. Journal of Clinical Investigation. 2023. Neuronal Mechanisms of Tau Pathology Parra Bravo et al. Nature Reviews Molecular Cell Biology 2024. Role of Tau in Various Tauopathies
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13 Boxer and Sperling, Cell, 2023 Ca-tau-strophe Biomarkers of AD Pathogenesis
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14 Presentation Title Donanemab Effects in Prodromal- Mild AD (Ph3) Sims et al., JAMA Neurology 2023
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15 After Bateman & McDade, 2022; Boxer and Sperling, Cell, 2023 Hypothetical effects of current anti-amyloid immunotherapies
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16 16 Tau reduction as a therapeutic strategy (mice & humans) Roberson et al. Science 2007;316:750-754; Mummery, Nat Med, 2022; Edwards, JAMA Neurology, 2023 Alzheimer Mice Neurotoxin seizures CSF p-tau181 Ph2 results negative, but moving to Ph3
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17 Tau genetics: strong links to primary tauopathies (but not AD) Pick’s CBD PSP AD norm 3R 4R Brunden, Nat Rev Drug Dis 2009, 8: 783; Hoglinger, Nat Genet 2011; 43: 699; Khouri, Nat Comm 2015, 6:7247; Tabuzini, Hum Mol Gen 2012, 21: 4094 Jabbari, Ann Neurol, 2018: Jabbari, Lancet Neurol, 2021; Minikel, Nature 2024, 629: 624; Ma, Neurol Sci 2025, 46:6535–6541 Mouse models PSP, CBD GWAS H1/H1 Tau haplotype OR 5.46 (4.72–6.31) p = 1.5 x 10-116 Greater tau risk PSP & CBD H1c H2 (protective allele) not present in Asia TRIM11/17 & LRRK2 protective SNPs probability of success for drugs with genetic support is 2.6x greater
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18 Judith Steen lab: Kumar, et al, Cell, 2026 Insoluble tau >50 fold higher in AD than PSP (signal/ noise)
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19 Is tau the central pathogenic species in tauopathies? TauERC Aβ TauLC Tauhipp, cortexAD clinical disease TauERC Aβ, etc TauLC Tauhipp, cortex clinical disease or FTLD-MAPT MAPT mutation Taubrain clinical diseaseTaumutant / alt ratio PSP ???? Taubrain clinical diseaseTaualt ratio
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20 Reducing tau leads to cognitive benefits in AD with Aβ still present Diranersen Ph2 (Celia) results presented at AAIC 2026 • Reduced cognitive decline • No effect on functional decline • Lowest dose most effective • Dose-related side effects: confusion & falls (~1 week post injection) • Side effects limiting efficacy? • inflammation, osmotic, etc • Tau reduction not benign (on target)? • Too late in disease? • Need to remove Aβ & tau (& α-syn)? (tau isn’t the only cause of decline) • Would 1° tauopathies respond better? Improved: Cognitive function (ADAS-cog): 42% slowing No effect: Activities of daily living (ADCS-ADL-MCI) Tau PET (SUVR)
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21 Disease specific tau aggregate structures: impact on treatments? Fitzpatrick, Nature, 2017; Falcon, Nature, 2018, Shi, Nature, 2022; Horie, Brain, 2021; Samudra, J. Clin Invest, 2023; Lane-Donovan & Boxer, Neurotherapeutics, 2024 earlier immunotherapies gosuranemab, tilavonemab, semorinemab, zagotenemab, posdinemab newer immunotherapies AADvac1, E2814, bepranemab, BMS986; MK-2214; VY7523; ADELY01 genetic therapies ASO’s siRNA’s post-translational modifiers O-glcNACase inhibitors (ceperognastat) Alzheimer’s Disease Progressive Supranuclear Palsy 4R 4R 3R/4R 3R/4R 3R
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22 MTBR targeted mAb shows potential benefits in early AD Transcellular spread of toxic tau? Relevant for human disease? Insoluble tau in brain (PET) Cognitive status (ADAS-cog) Parra Bravo et al. Nature Reviews Molecular Cell Biology 2024 Bepranemab data presented at CTAD 2024
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23 Phase 3 trial: NCT07498426 Hoglinger et al, presented at AD/PD2026 Tau reduction stabilizes neurodegeneration in PSP (tau ASO Ph1)
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24 • Targeting tau reflects close clinico-pathologic correlation • Reduced production and targeting all forms of tau – pragmatic solution • Exciting early results with gene silencing • Global unmet need for AD and Primary Tauopathies • Rationale for expansion beyond Alzheimer’s disease Summary
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TRiMTM CNS-SC Platform & Overview of ARO-MAPT James Hamilton MD, MBA Chief Medical Officer and Head of R&D ARO-MAPT Phase 1/2a Study Clinical Data Update
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26 TRiM Platform: Targeted RNAi Molecule TRiM is a Modular, Structurally Simple Platform to: Optimize siRNA sequence selection Address multiple cell types Provide reproducibility of GLP tox and manufacturing Move rapidly from idea to the clinic 1 2 3 4
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27 Delivering siRNA Across the Blood Brain Barrier: CNS-Targeting TRiM Platform via Subcutaneous Administration • Ligand-driven delivery • Effective and durable reduction in expression levels • Convenient subcutaneous (SC) administration (quarterly dosing) • Favorable safety profile (rodent and NHP >10x margin over efficacious dose) TfR1-Targeting Ligand Linker siRNA Systemic Delivery Platform Targeting the CNS
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28 ARO-MAPT Achieves Deep Knockdown of MAPT mRNA Throughout the CNS with Subcutaneous Administration in Cyno 1x 1x Control ARO-MAPT SC MAPT mRNA shown in purple 20x 20x Frontal Cortex Motor Cortex Temporal Cortex Caudate Putamen Thalamus Hippocampus Pons Medulla Cervical Spinal Cord Thoracic Spinal Cord Lumbar Spinal Cord 0.0 0.5 1.0 1.5 2.0 Relative Expression 3 x 3 mpk, SC, qw, D29 0.25 Control ARO-MAPT MAPT mRNA Depletion in HippocampusMAPT mRNA Reduction in NHP CNS Regions mRNA Knockdown Corroborated by RNAscope
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29 Tau Protein Reduction in Cerebrospinal Fluid in Monkeys Study Day: 1 8 15 43 71 99 127 156 239 0 50 100 150 200 250 0.0 0.2 0.4 0.6 0.8 1.0 t-tau normalized to individual pre-dose Mean + SEM Days Tau Protein Reduction Maintained at 50–60% Up to 4 Months After Last Dose. 7x3 mg MAPT siRNA/kg SC: 3 Weekly Loading Doses + 4 Monthly Maintenance Doses Last Dose CSF T-Tau Levels
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30 BBB Platform Achieves Uniform Reduction Across the Brain MAPT mRNA Reduction in NHP Brain Regions by SCMAPT mRNA Reduction in NHP Brain Regions by IT Subcutaneous Administration: • Even mRNA reduction across brain regions, including deep brain. Intrathecal Administration: • Minimal mRNA reduction in deep brain regions.
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31 TfR1 BBB siRNA Delivery Platform Improves Homogeneity of Brain Distribution versus IT Administered ASO (without a lumbar puncture) Collins et al. CTAD 2025. TfR1-ligand Conjugated siRNA – NHPs Administration: IV/SC Distribution: Capillary Network • Homogenous delivery (location, location, location) • Broad pharmacodynamic effect • Greater exposure Non-shuttled ASO – Humans Administration: LP Distribution: CSF Flow • Heterogenous delivery • Lesser exposure
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Clinical Study Update from AROMAPT-SC-1001 James Hamilton MD, MBA Chief Medical Officer and Head of R&D ARO-MAPT Phase 1/2a Study Clinical Data Update
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33 AROMAPT-SC-1001: Phase 1 Study in Healthy Volunteers and Patients with Alzheimer’s Disease (AD) Cohort A3b (Low dose ARO-MAPT) (n=8) Cohort B3 (Low dose ARO-MAPT) (n=16) Cohort A4b (Mid dose ARO-MAPT) (n=8) Cohort B4 (Mid dose ARO-MAPT) (n=16) Cohort A5b (High dose ARO-MAPT) (n=8) Cohort B5 (High dose ARO-MAPT) (n=16) Cohort A1 (2.1 mg/kg ARO-MAPT) (n=8) Single dose at Day 1; No LP Cohort A2 (2.1 mg/kg ARO-MAPT, D1/8/15) (n=8) Loading dose (Day 1, 8, 15) Cohort A3a (6.4 mg/kg ARO-MAPT, D1/8/15) (n=8) Loading dose (Day 1, 8, 15) Cohort A4a (12.8 mg/kg ARO-MAPT) (n=8) Loading dose (Day 1, 8, 15) Cohort A5a (12.8 mg/kg ARO-MAPT) (n=8) Loading dose (Day 1, 15) *dose represents total conjugate dose Part 1A NHV (6 Active : 2 Placebo) Part 1B NHV (6 Active : 2 Placebo) Part 2 AD Patients (12 Active : 4 Placebo) All Healthy Volunteer Cohorts Fully Enrolled
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34 AD Cohort Patient Population Key Inclusion Criteria: • Age 50-80 • Early Alzheimer’s Disease as defined by CDR and MMSE cutoffs • Presence of at least one biomarker (CSF, Plasma or PET) consistent with Alzheimer’s • Not using or planning to use AD disease modifying therapies (including anti-amyloid monoclonal antibodies)
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35 NHV Enrollment Completed in NZ (August 2026) Early Alzheimer’s Disease (Part 2)NHV (Part 1a and Part 1b) Canada UK Australia New Zealand AROMAPT-SC-1001: Sites Open in UK, Canada, AU, and NZ
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36 Key Endpoints CSF = cerebrospinal fluid; BD = brain-derived Safety Pharmacokinetics Exploratory 1° 2° NHVs • CSF total tau (t-tau) • Plasma brain-derived (BD) tau AD Subjects: • Plasma and CSF Biomarkers • Tau-PET SUVR change • MRI Brain volumetry • Cognitive and functional scores • CDR-SB, ADAS-Cog13, ADCS-ADL
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37 Baseline NHV Characteristics SD = standard deviation; CSF = cerebrospinal fluid; BD = brain-derived. 1. High SD due to single healthy volunteer with elevated CSF tau at baseline; when excluded, mean (SD) = 51.4 (34.2) pg/mL. 2. Data cutoff: 25aug26, prior to full enrollment of Part 1b AROMAPT-SC-1001 Characteristic Part 1a (N=41) Part 1b (N=16)2 Age, mean (SD), years 42.2 (12.6) 41.7 (11.4) Sex Female, n (%) 21 (51.2) 9 (56.2) Male, n (%) 20 (48.8) 7 (43.8) Race American Indian or Alaska Native, n (%) 3 (7.3) 0 (0.0) Asian, n (%) 3 (7.3) 3 (18.8) Black or African American, n (%) 0 (0.0) 0 (0.0) Native Hawaiian or Pacific Islander, n (%) 2 (4.9) 1 (6.2) White, n (%) 26 (63.4) 10 (62.5) Other, n (%) 2 (4.9) 0 (0.0) Multiple, n (%) 5 (12.2) 2 (12.5) Baseline CSF Tau, mean (SD), pg/mL 63.7 (71.3) 1 [n=32] 48.8 (18.0) [n=8] Baseline plasma BD-tau, mean (SD), pg/mL 8.5 (3.1) [n=32] 8.3 (2.4) [n=8]
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38 Loading Dose of ARO-MAPT Achieved Individual CSF tau reduction of Up to 85% with Mean Reduction of Up to 73% at Day 105, Duration Supports Dosing Every 3 Months CSF t-tau: Part 1A, Loading Dose Only *Cohort A5a is not dosed on Day 8.
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39 Consistent individual response to ARO-MAPT, maximal individual response of 85%
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40 ARO-MAPT Demonstrates a Favorable Safety Profile N of Subjects with Treatment-Emergent AEs Characteristic Placebo (N=15) ARO-MAPT Part 1A (N=30) ARO-MAPT Part 1B (N=12) Overall Any TEAEs, n (%) 8 (53.3) 27 (90.0) 10 (83.3) Serious TEAEs, n (%) 0 (0.0) 0 (0.0) 0 (0.0) Deaths, n (%) 0 (0.0) 0 (0.0) 0 (0.0) Discontinuations due to TEAE, n (%) 0 (0.0) 0 (0.0) 0 (0.0) Reported in >10% of the Study Participants Injection site reaction, n (%) 1 (6.7) 6 (20.0) 3 (25.0) Vessel puncture site bruise, n (%) 0 (0.0) 4 (13.3) 3 (25.0) Upper respiratory tract infection, n (%) 0 (0.0) 5 (16.7) 2 (16.7) Back pain, n (%) 1 (6.7) 5 (16.7) 0 (0.0) Headache, n (%) 2 (13.3) 6 (20.0) 4 (33.3) ARO-MAPT was well tolerated in normal healthy volunteers. • Most TEAEs were Grade 1 (mild) • No serious TEAEs • No TEAEs led to study or study drug discontinuation No persistent anemia or neurobehavioral AEs. Data cutoff Aug 25, 2026
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41 Next Steps Finish dosing in MAD NHV cohorts (data update in 2027) Enrollment in early AD Cohorts (data update in 2027) Engage with FDA in anticipation of Phase 2 studies in MAPT-FTD and PSP
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42 Conclusions Arrowhead’s subcutaneous CNS siRNA delivery platform has been well tolerated to date in NHVs and AD patients Subcutaneous administration of ARO-MAPT in NHVs demonstrated deep, dose-dependent, and durable knockdown of CSF t-tau with potential for more homogenous brain distribution These data represent initial clinical validation of ARO-MAPT and importantly of the TRiMTM CNS platform which is an important milestone for Arrowhead and for our partners using this platform In addition to ARO-MAPT, Arrowhead has multiple wholly owned CNS targeted brain shuttle delivered preclinical development programs including two planned CTAs for YE 2026 or early 2027
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Key Takeaways Chris Anzalone, Ph.D. President and CEO ARO-MAPT Phase 1/2a Study Clinical Data Update
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44 Key Takeaways A major scientific breakthrough: Clinically validated delivery across the blood- brain barrier that overcomes central obstacles of CNS siRNA medicines A platform with expansive potential: The technology could support an entire pipeline targeting neurodegenerative diseases, psychiatric conditions, sleep disorders, migraine, obesity, and other neurological conditions Simple treatment: Subcutaneous administration eliminates the need for spinal injections, making treatment more practical for large patient populations ARO-MAPT is a candidate with substantial potential: Tau reduction could be an important treatment for Alzheimer’s disease and, nearer-term, a powerful treatment for multiple primary tauopathies
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45 Liver Lung Skeletal Muscle CNS Adipose Ocular Cardio- myocyte Strong clinical validation Deep lung clinical validation Mid clinical stage Early clinical stage Early clinical stage Preclinical stage Preclinical stage TRiM Platforms Drive Robust Pipeline for Multiple Tissue Types Arrowhead now has clinical proof of concept for delivery to and knockdown in a 5th organ system
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46 Multiple “firsts” in 2026 In less than 12 months, Arrowhead further solidified its position as the leading RNAi innovator with the following “firsts” Clinical PoC for brain delivery of siRNA after subcutaneous injection Clinical PoC for silencing two genes with a single RNAi molecule Clinical PoC for deep and durable knockdown of an adipocyte expressed gene 1 2 3
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47 Questions? Answers.