Arrowhead Pharmaceuticals (NasdaqGS:ARWR) FY Earnings Call Presentation

TRiM BBB Platform Overview - The TRiM BBB platform facilitates subcutaneous administration for delivering siRNA to the central nervous system by crossing the blood-brain barrier[20] - The platform utilizes a TfR-targeting ligand conjugated to siRNA through a stable, non-reversible covalent linkage, ensuring stability in circulation[20] - The conjugation process is economical, using equimolar amounts of ligand and oligo, achieving a 75-80% yield consistently[26] - Cryo-EM structure shows the TRiM BBB ligand binds to the apical domain of TfR1 without interfering with endogenous Tf binding[28] Efficacy and Target Engagement - In transgenic mice expressing human Transferrin receptor, siRNA quantitation shows over 50x difference between Tg and control group, demonstrating BBB crossing[31] - Two doses of 1.5 mpk achieved ≥75% knockdown across CNS regions in mice, including deep brain[39] - In NHP, therapeutically relevant siRNA accumulation in the brain was achieved, with 0.5-1.5 µg/g across the brain on day 29[42] - ARO-MAPT achieved 70-80% MAPT mRNA reduction across all brain regions in NHP at 3 x 3 mpk, including brain stem and deep brain, with up to 85% knockdown in some cortex regions[53] Durability and Dosing - ARO-MAPT maintains ≥50% knockdown over 3 months in CNS regions in NHP, including deep brain[63] - Tau protein reduction was maintained at 50-60% up to 5 months with single 3 mpk monthly dose in NHP[67] - PK/PD modeling projects quarterly dosing of ARO-MAPT to maintain 50-70% knockdown[70]