The valproic acid trial (NCT00385710) in Progressive Supranuclear Palsy (PSP) represents a notable failure in the development of disease-modifying treatments for tauopathies. This page documents the trial, analyzes why [HDAC](/entities/hdac-enzymes) inhibition with valproic acid failed to provide benefit, and extracts lessons learned for future clinical trials in PSP and related disorders [1].
Trial Background
Rationale for Valproic Acid in PSP
Valproic acid (VPA) is a mood stabilizer and anticonvulsant with histone deacetylase (HDAC) inhibitor activity. The preclinical rationale for testing in PSP included:
Trial Design (NCT00385710)
Trial Results
Primary Outcome
Result: No significant difference between valproic acid and placebo
PSPRS change: Similar progression in both arms
Conclusion: Trial failed to meet primary endpoint
Secondary Outcomes
Safety Profile
Failure Analysis
Why the Trial Failed
1. Wrong Target or Pathway
HDAC inhibition may not be the right approach for PSP:
Tau pathology complexity: Acetylation is one of many post-translational modifications
HDAC isoform specificity: VPA inhibits multiple HDACs, not specifically HDAC6
Tau clearance mechanisms: May need different approach than acetylation modulation [2]
2. Insufficient Target Engagement
CNS penetration: Valproic acid brain levels may have been inadequate
HDAC inhibition: May not have achieved sufficient HDAC inhibition in brain
Duration: 12 months may be insufficient to see disease modification
3. Patient Population Issues
Diagnostic accuracy: Clinical diagnosis of PSP has limited specificity
Disease stage: Patients may have been too advanced
Heterogeneity: PSP includes multiple clinical variants
4. Trial Design Limitations
Mechanistic Insights
What We Learned About HDAC6
HDAC6 remains a valid target, but with caveats:
Subcellular localization: Cytoplasmic HDAC6 is relevant
Specificity matters: Selective HDAC6 inhibitors may work better
Combination approaches: May need more than HDAC inhibition alone
Alternative Approaches
Since valproic acid failed, other strategies are being pursued:
Lessons Learned for Future Trials
1. Target Validation
Better preclinical models: Need models with human tau
Biomarker development: Confirm target engagement before large trials
Mechanistic studies: Understand which HDAC isoforms matter
2. Patient Selection
Biomarker-enriched trials: Use tau PET or CSF markers
Early intervention: Treat patients earlier in disease course