Slide 1: ARO-MAPT Phase 1/2a Study Interim Clinical Data Update
ARO-MAPT Phase 1/2a Study Interim Clinical Data Update October 14, 2026
Slide 2: Introduction and Agenda
ARO-MAPT Phase 1/2a Study Clinical Data Update Introduction and Agenda Vince Anzalone, CFA Senior Vice President
Slide 3: Safe Harbor Statement
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 ma
Slide 4: Agenda
Agenda Topic Presenter Vince Anzalone, CFA Introduction Arrowhead SVP Chris Anzalone, Ph.D. A New Era for RNAi Therapeutics Arrowhead CEO Adam Boxer, M.D., Ph.D. Silencing MAPT in Alzheimer’s Disease and Other Tauopathies UCSF James Hamilton, M.D., MBA TRiMTM CNS-SC Platform & Overview of ARO-MAPT A
Slide 5: Neurology Key Opinion Leader
Neurology Key Opinion Leader 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 o
Slide 6: A New Era for RNAi Therapeutics Led by Arrowhead
ARO-MAPT Phase 1/2a Study Clinical Data Update A New Era for RNAi Therapeutics Led by Arrowhead Chris Anzalone, Ph.D. President and CEO
Slide 7: Expanding TRiM: Solving the Challenges of RNAi in the Brain
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:
Slide 8: Current Clinical Programs using New CNS Delivery
Current Clinical Programs using New CNS Delivery 8
Slide 9: Silencing MAPT in Alzheimer's Disease and other Tauopathies
ARO-MAPT Phase 1/2a Study Clinical Data Update 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
Slide 10: Objectives
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
Slide 11: Insoluble tau correlates with clinical features in tauopathies
Insoluble tau correlates with clinical features in tauopathies AD PSP-RS CTE Kretzschmar, Nat. Rev. Neurosci. 2009, 10: 70-77; Williams, Brain 2007, 130: 1566-1576; McKee, Brain 2013, 136: 43–64 11
Slide 12: Targeting Tau in Tauopathies
Targeting Tau in Tauopathies • Pathophysiology Role of Tau in Various Tauopathies • Tau is the key pathogenic driver • Not secondary • Multiple mechanisms → “tau gain of function” Neuronal Mechanisms of Tau Pathology Parra Bravo et al. Nature Reviews Molecular Cell Biology 2024. Samudra and Boxer et
Slide 13: Biomarkers of AD Pathogenesis
Biomarkers of AD Pathogenesis Ca-tau-strophe Boxer and Sperling, Cell, 2023 13
Slide 14: Donanemab Effects in Prodromal-Mild AD (Ph3)
Donanemab Effects in Prodromal- Mild AD (Ph3) Presentation Title Sims et al., JAMA Neurology 2023 14
Slide 15: Hypothetical effects of current anti-amyloid immunotherapies
Hypothetical effects of current anti-amyloid immunotherapies After Bateman & McDade, 2022; Boxer and Sperling, Cell, 2023 15
Slide 16: Tau reduction as a therapeutic strategy (mice & humans)
Tau reduction as a therapeutic strategy (mice & humans) Alzheimer Mice CSF p-tau181 Neurotoxin seizures Ph2 results negative, but moving to Ph3 16 Roberson et al. Science 2007;316:750-754; Mummery, Nat Med, 2022; Edwards, JAMA Neurology, 2023 16
Slide 17: Tau genetics: strong links to primary tauopathies (but not AD)
Tau genetics: strong links to primary tauopathies (but not AD) probability of success for drugs with genetic support is 2.6x greater Mouse models PSP, CBD GWAS H1/H1 Tau haplotype OR 5.46 (4.72–6.31) p = 1.5 x 10-116 H2 (protective allele) not present in Asia Greater tau risk PSP & CBD H1c TRIM11/17
Slide 18: Insoluble tau >50 fold higher in AD than PSP
Insoluble tau >50 fold higher in AD than PSP (signal/ noise) Judith Steen lab: Kumar, et al, Cell, 2026 18
Slide 19: Is tau the central pathogenic species in tauopathies?
Is tau the central pathogenic species in tauopathies? Aβ AD TauLC TauERC Tauhipp, cortex clinical disease or Aβ, etc clinical disease TauLC TauERC Tauhipp, cortex PSP ???? Taualt ratio Taubrain clinical disease FTLD-MAPT MAPT mutation Taumutant / alt ratio Taubrain clinical disease 19
Slide 20: Reducing tau leads to cognitive benefits in AD with Aβ still present
Reducing tau leads to cognitive benefits in AD with Aβ still present Improved: Cognitive function (ADAS-cog): 42% slowing • Reduced cognitive decline • No effect on functional decline • Lowest dose most effective • Dose-related side effects: confusion & falls (~1 week post injection) Tau PET (SUVR)
Slide 21: Disease specific tau aggregate structures: impact on treatments?
Disease specific tau aggregate structures: impact on treatments? 3R/4R Alzheimer’s Disease 3R/4R 3R 4R post-translational modifiers O-glcNACase inhibitors (ceperognastat) genetic therapies Progressive ASO’s 4R Supranuclear siRNA’s Palsy earlier immunotherapies newer immunotherapies gosuranemab, tila
Slide 22: MTBR targeted mAb shows potential benefits in early AD
MTBR targeted mAb shows potential benefits in early AD Insoluble tau in brain (PET) Transcellular spread of toxic tau? Relevant for human disease? Cognitive status (ADAS-cog) Parra Bravo et al. Nature Reviews Molecular Cell Biology 2024 Bepranemab data presented at CTAD 2024 22
Slide 23: Tau reduction stabilizes neurodegeneration in PSP (tau ASO Ph1)
Tau reduction stabilizes neurodegeneration in PSP (tau ASO Ph1) Hoglinger et al, presented at AD/PD2026 Phase 3 trial: NCT07498426 23
Slide 24: Summary
Summary • 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 24
Slide 25: TRiM CNS-SC Platform & Overview of ARO-MAPT
ARO-MAPT Phase 1/2a Study Clinical Data Update TRiMTM CNS-SC Platform & Overview of ARO-MAPT James Hamilton MD, MBA Chief Medical Officer and Head of R&D
Slide 26: TRiM Platform: Targeted RNAi Molecule
TRiM Platform: Targeted RNAi Molecule TRiM is a Modular, Structurally Simple Platform to: 1 Optimize siRNA sequence selection 2 Address multiple cell types 3 Provide reproducibility of GLP tox and manufacturing 4 Move rapidly from idea to the clinic 26
Slide 27: Delivering siRNA Across the Blood Brain Barrier via Subcutaneous Administration
Delivering siRNA Across the Blood Brain Barrier: CNS-Targeting TRiM Platform via Subcutaneous Administration Systemic Delivery Platform Targeting the CNS Linker • Ligand-driven delivery • Effective and durable reduction in expression levels • Convenient subcutaneous (SC) administration (quarterly do
Slide 28: ARO-MAPT Achieves Deep Knockdown of MAPT mRNA Throughout the CNS
ARO-MAPT Achieves Deep Knockdown of MAPT mRNA Throughout the CNS with Subcutaneous Administration in Cyno MAPT mRNA Reduction in NHP CNS Regions MAPT mRNA Depletion in Hippocampus 3 x 3 mpk, SC, qw, D29 2.0 Control ARO-MAPT 1x Control 1x ARO-MAPT SC 1.5 Relative Expression 1.0 20x 20x 0.5 0.25 0.0 r
Slide 29: Tau Protein Reduction in Cerebrospinal Fluid in Monkeys
Tau Protein Reduction in Cerebrospinal Fluid in Monkeys 7x3 mg MAPT siRNA/kg SC: 3 Weekly Loading Doses + 4 Monthly Maintenance Doses Study Day: 1 8 15 43 71 99 127 156 239 1.0 Last Dose CSF T-Tau Tau Protein Reduction to individual pre-dose Levels 0.8 Maintained at 50–60% t-tau normalized Mean + SE
Slide 30: BBB Platform Achieves Uniform Reduction Across the Brain
BBB Platform Achieves Uniform Reduction Across the Brain MAPT mRNA Reduction in NHP Brain Regions by IT MAPT mRNA Reduction in NHP Brain Regions by SC Intrathecal Administration: Subcutaneous Administration: • Minimal mRNA reduction in deep brain regions. • Even mRNA reduction across brain regions,
Slide 31: TfR1 BBB siRNA Delivery Platform Improves Homogeneity of Brain Distribution
TfR1 BBB siRNA Delivery Platform Improves Homogeneity of Brain Distribution versus IT Administered ASO (without a lumbar puncture) TfR1-ligand Conjugated siRNA – NHPs Non-shuttled ASO – Humans Administration: Distribution: Capillary Network Administration: Distribution: CSF Flow IV/SC • Homogenous d
Slide 32: Clinical Study Update from AROMAPT-SC-1001
ARO-MAPT Phase 1/2a Study Clinical Data Update Clinical Study Update from AROMAPT-SC-1001 James Hamilton MD, MBA Chief Medical Officer and Head of R&D
Slide 33: AROMAPT-SC-1001: Phase 1 Study in Healthy Volunteers and AD Patients
AROMAPT-SC-1001: Phase 1 Study in Healthy Volunteers and Patients with Alzheimer’s Disease (AD) Cohort A1 (2.1 mg/kg ARO-MAPT) (n=8) Single dose at Day 1; No LP Part 1A NHV (6 Active : 2 Placebo) Part 1B NHV (6 Active : 2 Placebo) Cohort A2 (2.1 mg/kg ARO-MAPT, D1/8/15) (n=8) Part 2 AD Patients (12
Slide 34: AD Cohort Patient Population
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
Slide 35: AROMAPT-SC-1001: Sites Open in UK, Canada, AU, and NZ
AROMAPT-SC-1001: Sites Open in UK, Canada, AU, and NZ NHV (Part 1a and Part 1b) Early Alzheimer’s Disease (Part 2) UK Canada NHV Enrollment Completed in NZ (August 2026) New Australia Zealand 35
Slide 36: Key Endpoints
Key Endpoints NHVs 1° Safety • CSF total tau (t-tau) • Plasma brain-derived (BD) tau AD Subjects: 2° Pharmacokinetics • Plasma and CSF Biomarkers • Tau-PET SUVR change • MRI Brain volumetry Exploratory • Cognitive and functional scores • CDR-SB, ADAS-Cog13, ADCS-ADL CSF = cerebrospinal fluid; BD = b
Slide 37: Baseline NHV Characteristics
Baseline NHV Characteristics 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) Blac
Slide 38: Loading Dose of ARO-MAPT Achieved CSF tau reduction of Up to 85%
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. 38
Slide 39: Consistent individual response to ARO-MAPT
Consistent individual response to ARO-MAPT, maximal individual response of 85% 39
Slide 40: ARO-MAPT Demonstrates a Favorable Safety Profile
ARO-MAPT Demonstrates a Favorable Safety Profile N of Subjects with Treatment-Emergent AEs Placebo ARO-MAPT Part 1A ARO-MAPT Part 1B Characteristic (N=15) (N=30) (N=12) ARO-MAPT was well Overall tolerated in normal Any TEAEs, n (%) 8 (53.3) 27 (90.0) 10 (83.3) healthy volunteers. Serious TEAEs, n (%
Slide 41: Next Steps
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 41
Slide 42: Conclusions
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 d
Slide 43: Key Takeaways
ARO-MAPT Phase 1/2a Study Clinical Data Update Key Takeaways Chris Anzalone, Ph.D. President and CEO
Slide 44: Key Takeaways
Key Takeaways A major scientific breakthrough: Clinically validated delivery across the blood- brain barrier that overcomes central obstacles of CNS siRNA medicines Simple treatment: Subcutaneous administration eliminates the need for spinal injections, making treatment more practical for large pati
Slide 45: TRiM Platforms Drive Robust Pipeline for Multiple Tissue Types
TRiM Platforms Drive Robust Pipeline for Multiple Tissue Types Skeletal Cardio- Liver Lung CNS Adipose Ocular Muscle myocyte Strong Deep lung Mid clinical Early Early Preclinical Preclinical clinical clinical stage clinical clinical stage stage validation validation stage stage Arrowhead now has cli
Slide 46: Multiple "firsts" in 2026
Multiple “firsts” in 2026 In less than 12 months, Arrowhead further solidified its position as the leading RNAi innovator with the following “firsts” 1 Clinical PoC for brain delivery of siRNA after subcutaneous injection 2 Clinical PoC for silencing two genes with a single RNAi molecule 3 Clinical
Slide 47: Questions? Answers.
“oN Questions? () Answers. Pharmaceuticals