Arrowhead Pharmaceuticals, Inc. · NASDAQ:ARWR
Arrowhead Pharmaceuticals — RNA Leaders USA Congress 2025
25 slides from Arrowhead Pharmaceuticals's conference presentation, Sep 10, 2025
Slide 1: siRNA for Neurodegenerative Diseases
siRNA for Neurodegenerative Diseases Christine Esau, Ph.D., RNA Leaders USA Congress 2025 September 10, 2025
Slide 2: 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 3: Breaking the Mold of Medicine with RNA Interference
Breaking the Mold of Medicine with RNA Interference Arrowhead Pharmaceuticals is an RNAi therapeutics platform company with a broad pipeline of wholly owned and partnered product candidates on track for its first commercial launch in 2025. • Plozasiran for familial chylomicronemia syndrome US FDA PD
Slide 4: Arrowhead's Targeted RNAi Molecule (TRiM) Platform: The Broadest and Most Versatile in the Field
Arrowhead’s Targeted RNAi Molecule (TRiM ) Platform: The Broadest and Most Versatile in the Field TRiM also has rules and algorithms to optimize siRNA sequence and modification patterns Characterized by depth & duration of effect Activity • Ability to unlock previously undruggable targets To maximiz
Slide 5: TRiM Platform Enables Delivery to Seven Target Tissues
TRiMTM Platform Enables Delivery to Seven Target Tissues Skeletal Cardio- Liver Lung CNS Adipose Ocular Muscle myocyte Strong Deep lung Early Early Early Preclinical Preclinical clinical clinical clinical clinical clinical Stage Stage validation validation stage stage stage (RAGE) Systemic Delivery
Slide 6: Neurodegenerative Diseases Are an Enormous Burden Uniquely Addressable by RNA Therapeutics
Neurodegenerative Diseases Are an Enormous Burden Uniquely Addressable by RNA Therapeutics SOD1 (ALS) TDP-43 proteinopathies Over 50 million neurodegeneration patients • Amyotrophic Lateral Sclerosis (ALS) worldwide1 and few disease modifying therapies • Fronto-temporal dementia (FTD) Tauopathies •
Slide 7: CNS Portfolio Programs
CNS Portfolio Programs Program Indication Stage Product Rights ARO-ATXN2 (IT) Spinocerebellar Ataxia 2 Phase 1 Sarepta ARO-MAPT (SC) Alzheimer’s disease & Tauopathies CTA Filed Arrowhead ARO-HTT (SC) Huntington’s disease Preclinical Sarepta ARO-SNCA (SC) Parkinson’s disease & Synucleinopathies Precl
Slide 8: Next Gen. CNS-Targeting TRiM Platform via Subcutaneous Administration
Next Gen. CNS-Targeting TRiM Platform via Subcutaneous Administration We Have Developed an Optimized Systemic Delivery Platform for CNS Linker • Ligand-driven delivery via noninvasive BBB penetration and cellular uptake in brain tissue • Effective and durable reduction in expression levels of therap
Slide 9: TRiM CNS-SC Platform Leverages Noninvasive TfR1-Binding for CNS Delivery
TRiM CNS-SC Platform Leverages Noninvasive TfR1-Binding for CNS Delivery Blood • TfR1 highly H+ Recycling Tfr1 (high pH) enriched in Fe2+ Tfr1 (low pH) endothelium of Fe3+ Apo-Tf (-Fe) the blood-brain Endothelial Cell EE barrier (BBB) holo-Tf (+Fe) • Fast kinetics of Proton pump internalization LE/L
Slide 10: TRiM CNS-SC Platform's TfR1-Binding Does Not Interfere with Binding of Endogenous Ligand
TRiM CNS-SC Platform’s TfR1-Binding Does Not Interfere with Binding of Endogenous Ligand Helical Apical Tf Protease Like Transferrin (up to 4 mg/mL in serum) occludes helical and protease like domains Front Immunol. 2021; 12: 607692. 10
Slide 11: TRiM CNS-SC Platform Demonstrated to Achieve BBB Penetration in Mouse
TRiM CNS-SC Platform Demonstrated to Achieve BBB Penetration in Mouse siRNA Visualization in Hippocampus siRNA Concentration in Half Brain WT Mouse B-hTFR1 Mouse SC, 1.5 mpk, D1 Sac 24 h post-dose 56x 100 Relative Concentration 80 60 40 20 10 8 6 siRNA signal in red 4 SC, 1.5 mpk, D1; 2 24 h post-do
Slide 12: TRiM CNS-SC Platform Achieves Improved Delivery to Deep Brain Region
TRiM CNS-SC Platform Achieves Improved Delivery to Deep Brain Region siRNA Concentrations in siRNA Concentrations in NHP Brain Regions by IT NHP Brain Regions by SC IT, 15 mg, D1 SC, 3 x 3 mpk, qw: Sac D29 D1, D8, D15 Sac D29 5 25 Relative Concentration 21.6 Relative Concentration 20 4 3.6 < 2x 3.3
Slide 13: TRiM CNS Delivery Platforms Show Different Knockdown Profiles in Deep Brain Regions in NHP
TRiM CNS Delivery Platforms Show Different Knockdown Profiles in Deep Brain Regions in NHP MAPT mRNA Reduction in MAPT mRNA Reduction in NHP Brain Regions by IT NHP Brain Regions by SC SC, 3 x 3 mpk, qw: IT, 15 mg, D1 D1, 8, 15 Sac D85 Sac D99 1.75 Ligand-siRNA 1.75 Ligand-siRNA PBS aCSF Conjugate C
Slide 14: Toxic Tau Protein Aggregation: Key Driver in Tauopathies Including Alzheimer's Disease
Toxic Tau Protein Aggregation: Key Driver in Tauopathies Including Alzheimer’s Disease Tau Protein: • Encoded by the MAPT gene • Abundant in neurons, where it promotes stabilization of microtubules in axons • Intrinsically disordered and subject to many post-translational modifications • Hyperphosph
Slide 15: ARO-MAPT SC for Alzheimer's Disease
ARO-MAPT SC for Alzheimer’s Disease Amyloid Plaque Precedes Tau Pathology • In Alzheimer’s disease, Tau neurofibrillary in Alzheimer’s Disease tangle pathology but not amyloid predicts cognitive decline • Anti-amyloid therapies have shown minimal Tau reduction, are less effective in patients with hi
Slide 16: ARO-MAPT SC Achieves Deep Knockdown of MAPT mRNA Throughout the CNS
ARO-MAPT SC Achieves Deep Knockdown of MAPT mRNA Throughout the CNS with Subcutaneous Administration MAPT mRNA in NHP RNAscope for MAPT mRNA in Hippocampus 1.5 aCSF Control 1.0 MAPT mRNA (Relative to Control) 0.5 0.0 3 x 3mg/kg oc Po a Sp al c T am s ed e al or er us ta ex au n Sp ina ord ala us ot
Slide 17: MAPT mRNA Reduction Translates into Long-Lasting Tau Protein Reduction in NHP
MAPT mRNA Reduction Translates into Long-Lasting Tau Protein Reduction After ARO-MAPT SC Treatment in NHP MAPT/Tau Reduction in NHP MAPT mRNA/Tau protein 1.00 Relative to Control Hippocampus mRNA Frontal Cortex mRNA 0.75 Hippocampus protein 0.50 Frontal Cortex protein 0.25 0.00 1 8 15 29 43 99 Study
Slide 18: PK/PD Modeling Projects Sustained Tau Inhibition with Quarterly Dosing of ARO-MAPT SC
PK/PD Modeling Projects Sustained Tau Inhibition with Quarterly Dosing of ARO-MAPT SC ARO-MAPT-SC 3x3 mg/kg Q1W SC NHP Tissue Conc.Conc. vs Tau mRNA Level NHP Tissue vs Tau mRNA Level with ARO-MAPT-SC 3x3 Q3MQ1W mg/kg SCSC with Q3M SC 150 Tau mRNA (% of Control) 100 Tau mRNA (% of Control) Mean CNS
Slide 19: Sustained Inhibition of Tau Protein After Repeat Dosing in NHP
Sustained Inhibition of Tau Protein After Repeat Dosing in NHP MAPT mRNA in NHP Tissues Study Day 156 1.5 7 x 3 mg MAPT siRNA/kg administered subcutaneously 3 weekly loading doses + monthly maintenance Study Design: MAPT mRNA levels relative to control 1.0 Study Day: 1 8 15 43 71 99 127 156 Intrathe
Slide 20: Tau Protein Reduction in Cerebrospinal Fluid Follows Reduction in CNS Tissues
M r Tau Protein Reduction in Cerebrospinal Fluid Follows Reduction 0.0 in CNS Tissues la s te en al s Pu ex lC x d or ipp Pon pu te or ul da t m or or C ed am au ta lC M C oc in 65% Reduction in CSF Tau Protein after Four Months Repeat Dosing in NHP ta ra Sp on po Tau Protein in CSF Fr H m ic ac Te
Slide 21: ARO-MAPT SC Program Status
ARO-MAPT SC Program Status • siRNA targeting of MAPT has potential to treat most common (Alzheimer’s) and rare forms of neurodegeneration caused by tauopathy • Systemically delivered ARO-MAPT showed potent and long-lasting MAPT suppression in NHP, with potential for monthly or less frequent dosing •
Slide 22: ARO-MAPT-SC-1001 Phase 1/2a Clinical Study in Patients with Early Alzheimer's Disease
ARO-MAPT-SC-1001 Phase 1/2a Clinical Study in Patients with Early Alzheimer’s Disease † Primary Endpoint Key Exploratory Endpoints Sites Safety and • CSF t-tau, p-tau217, p-tau 181, New Zealand tolerability of MTBR tau (CTA submitted ARO-MAPT-SC 9/2/2025) • Plasma p-tau 217 Australia • Functional Te
Slide 23: Key Takeaways
Key Takeaways Expanding portfolio in neurodegenerative diseases, targeting well- validated, difficult to drug disease-causing proteins • First intrathecal clinical program underway for SCA2 • MAPT CTA filed Two CNS TRiM delivery platforms with compelling preclinical data • Intrathecal – Preferential
Slide 24: Arrowhead Teamwork
Arrowhead Teamwork • Discovery Chemistry • Corporate headquarters • Discovery Biology • Clinical & Regulatory • Toxicology • CNS Discovery Biology • CMC • Discovery Chemistry • GMP • Translational Genetics Manufacturing & Data Sciences • Clinical & Regulatory 24
Slide 25: Thank You!
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