Arrowhead Pharmaceuticals (ARWR) Corporate presentation summary

Disease background and rationale

• Tau protein aggregation is a key driver in tauopathies, including Alzheimer's disease, leading to neurodegeneration through hyperphosphorylation and neurofibrillary tangle formation.

• Tauopathies encompass about 20 neurodegenerative diseases, with Alzheimer's, FTLD, PSP, and familial FTLD-MAPT among the major types.

• Tau pathology, rather than amyloid, correlates with cognitive decline in Alzheimer's, and tau reduction may offer broader benefits and improved safety over anti-amyloid therapies.

TRIM™ platform and delivery technology

• The TRIM™ platform uses modular RNAi chemistry, targeting ligands, and stabilization/linker chemistries to enhance pharmacokinetics and maximize activity.

• The platform enables productive RNAi delivery to multiple tissue types, including CNS, with strong clinical validation in extrahepatic tissues.

• TRIM™ BBB platform allows subcutaneous siRNA administration, crossing the blood-brain barrier via a TfR-targeting ligand without interfering with endogenous transferrin binding.

Preclinical efficacy and pharmacodynamics

• In transgenic mouse models, the TRIM™ BBB platform achieves over 50x siRNA delivery to the brain compared to controls, with dose-dependent MAPT mRNA reduction across CNS regions.

• MAPT mRNA knockdown translates to reduced phospho-tau pathology, with significant reductions in AT8-positive tau in treated animals.

• Subcutaneous administration in non-human primates (NHP) achieves uniform and deep MAPT mRNA knockdown (70-80%, up to 85% in cortex) across all brain regions, including deep brain and brainstem.

• Knockdown is observed across all major CNS cell types and is durable for at least 3 months post-dosing.