Anti-Tau Therapy Failure Mechanism in PSP — Why Clinical Trials Have Not Succeeded

SUMMARY

# Anti-Tau Therapy Failure Mechanism in PSP — Why Clinical Trials Have Not Succeeded ## Background and Rationale This experiment addresses a critical therapeutic failure in neurodegeneration: why anti-tau therapies have consistently failed in Progressive Supranuclear Palsy (PSP) clinical trials despite compelling preclinical rationale. Multiple high-profile trials including gosuranemab (ABBV-8E12) in the TANGOS study and tilavonemab have failed to demonstrate clinical efficacy in PSP patients, d

METHODOLOGY NOTES

**Phase 1: Patient Cohort Assembly and Characterization (Months 1-6)** • Recruit 200 PSP patients from completed anti-tau trials (gosuranemab, tilavonemab) and 100 treatment-naive PSP patients • Collect comprehensive clinical data: PSP-RS scores, MDS-UPDRS-III, SEADL, CGI-S at baseline and follow-up timepoints • Perform detailed neuropathological analysis on available autopsy samples (n=50) with tau burden quantification • Conduct CSF biomarker analysis: total tau, phospho-tau (pT181, pT217, pT231), neurofilament light, and MTBR-tau243 • Analyze plasma biomarkers using Simoa platform for tau species and neuroinflammatory markers **Phase 2: Pharmacokinetic and Target Engagement Analysis (Months 4-10)** • Measure antibody concentrations in CSF and plasma samples using validated ELISA assays • Assess blood-brain barrier penetration ratios for each therapeutic antibody • Quantify tau target engagement using proximity ligation assays and tau conformation-specific antibodies • Evaluate anti