Arrowhead Pharmaceuticals (ARWR) Study update summary

Study design and interim results

• Phase 1/2a placebo-controlled, dose-escalating AROMAPT-SC-1001 includes healthy volunteers and people with early Alzheimer’s disease; healthy-volunteer cohorts are fully enrolled, with plans for ~64 volunteers and up to 48 patients.

• At Day 105, mean CSF total tau reductions were 40% and 69% with 2.1 and 6.4 mg/kg on Days 1, 8 and 15; 12.8 mg/kg on Days 1 and 15 achieved 73% mean reduction and 85% maximum individual reduction.

• Day 105 was 90 days after the final dose; sustained CSF tau reductions support potential dosing every three months or less frequently.

• Study endpoints include safety, pharmacokinetics, CSF total tau and plasma brain-derived tau; patient assessments include tau-PET, MRI volumetry, cognition and function.

• ARO-MAPT is designed to silence CNS MAPT expression and reduce production of all six tau isoforms; effects on brain tau tangles, cognition, function and disease progression are being studied in patients.

Safety and tolerability

• Generally well tolerated; most treatment-emergent adverse events were Grade 1 or mild, with no serious events, deaths, TEAE-related discontinuations or persistent anemia.

• No neurobehavioral adverse events were reported; common events included injection-site reactions, vessel puncture-site bruising, upper respiratory tract infection, back pain and headache.

TRiM CNS platform

• TRiM CNS links siRNA to a TfR1-targeting Fab or ligand to support subcutaneous delivery across the blood-brain barrier; infrequent dosing could avoid drug administration by lumbar puncture and enable home use.

• In monkeys, subcutaneous ARO-MAPT reduced MAPT across CNS regions, including deep brain and hippocampus; repeat dosing maintained silencing, with CSF tau knockdown of 50–60% up to four months after the last dose.

• Preclinical comparisons showed more even brain-region MAPT reduction with subcutaneous than intrathecal delivery, including in deep brain regions.

• Clinical CSF results are presented as initial proof of concept for TRiM CNS delivery and clinical validation of ARO-MAPT.