4R-Tau Targeting Therapies for PSP and CBS

SUMMARY

# 4R-Tau Targeting Therapies for PSP and CBS ## Background and Rationale This Phase II randomized, double-blind, placebo-controlled clinical trial investigates isoform-selective 4R-tau targeting therapies for Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS). These primary 4R-tauopathies represent distinct pathological entities from Alzheimer's disease, characterized by selective aggregation of four-repeat tau isoforms in neurons and glia. The pathological hallmark involves mi

METHODOLOGY NOTES

Phase 1 (Weeks 0-4): Screen 300 participants with probable PSP (MDS-PSP criteria) or CBS (Armstrong criteria) aged 40-80. Conduct comprehensive baseline assessments including neuropsychological batteries, movement disorder scales, volumetric brain MRI, and lumbar puncture for CSF biomarkers. Randomize 180 eligible participants 2:1 to mAb-4RT (15 mg/kg IV monthly) versus placebo. Phase 2 (Weeks 4-52): Administer monthly infusions with safety monitoring including vital signs, laboratory assessments, and immunogenicity panels. Conduct clinical evaluations every 8 weeks using PSP Rating Scale, CBS Functional Rating Scale, and Schwab-England Activities of Daily Living. Perform CSF sampling at weeks 12, 24, and 48 for 4R-tau quantification via liquid chromatography-tandem mass spectrometry. Phase 3 (Weeks 24, 48): Execute neuroimaging assessments including structural MRI for volumetric analysis of midbrain, superior cerebellar peduncle, and cortical regions using FreeSurfer processing. Condu