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 inhibition with valproic acid failed to provide benefit, and extracts lessons learned for future clinical trials in PSP and related disorders [1].
Valproic acid (VPA) is a mood stabilizer and anticonvulsant with histone deacetylase (HDAC) inhibitor activity. The preclinical rationale for testing in PSP included:
| Rationale |
Evidence |
| Tau acetylation |
HDAC6 regulates tau acetylation/phosphorylation |
| Neuroprotection |
VPA protects against various insults |
| Anti-inflammatory |
Reduces glial activation |
| Preclinical data |
Mixed results in tau models |
| Parameter |
Details |
| Phase |
Phase 2 |
| Status |
Completed |
| Design |
Randomized, double-blind, placebo-controlled |
| Duration |
12 months |
| Primary endpoint |
Change in PSP Rating Scale (PSPRS) |
- Result: No significant difference between valproic acid and placebo
- PSPRS change: Similar progression in both arms
- Conclusion: Trial failed to meet primary endpoint
| Outcome |
Valproic Acid |
Placebo |
Interpretation |
| Motor function |
Worsened |
Worsened |
No benefit |
| Cognitive function |
Stable |
Stable |
No benefit |
| Brain atrophy |
Similar rates |
Similar |
No neuroprotection |
| Adverse Event |
Frequency |
Notes |
| Sedation |
Common |
Dose-limiting |
| Weight gain |
Moderate |
Expected |
| Liver enzymes |
Elevated |
Monitored |
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]
- 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
- Diagnostic accuracy: Clinical diagnosis of PSP has limited specificity
- Disease stage: Patients may have been too advanced
- ** Heterogeneity**: PSP includes multiple clinical variants
| Factor |
Limitation |
| Sample size |
May have been underpowered |
| Endpoint |
PSPRS may lack sensitivity |
| Biomarkers |
No target engagement biomarkers |
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
Since valproic acid failed, other strategies are being pursued:
| Target |
Approach |
Status |
| HDAC6 |
Selective inhibitors |
Phase 1/2 |
| Acetyltransferases |
p300/CBP inhibitors |
Preclinical |
| Acetylation readers |
Bromodomain inhibitors |
Research |
- Better preclinical models: Need models with human tau
- Biomarker development: Confirm target engagement before large trials
- Mechanistic studies: Understand which HDAC isoforms matter
- Biomarker-enriched trials: Use tau PET or CSF markers
- Early intervention: Treat patients earlier in disease course
- Genetic stratification: Consider MAPT mutations
| Recommendation |
Rationale |
| Longer trials |
Disease modification needs time |
| Multiple endpoints |
Capture diverse outcomes |
| Biomarker substudies |
Understand mechanisms |
| Adaptive designs |
Increase efficiency |
- Accelerated approval pathways: Consider biomarkers
- Natural history studies: Improve understanding of progression
- Patient registries: Build infrastructure
¶ Current Landscape of PSP Treatments
| Drug |
Mechanism |
Stage |
| Tilavonemab |
Anti-tau antibody |
Phase 2 |
| Zagotenemab |
Anti-tau antibody |
Phase 2 |
| LMTX |
Tau aggregation inhibitor |
Phase 3 |
| CBD |
Unclear |
Approved (symptoms) |
The failure of valproic acid highlights:
- HDAC inhibition alone is insufficient
- Selective targeting may be needed
- More sophisticated trial designs required
- Tolosa E et al. (2014) Lancet Neurol 13(4):353-363 — Valproic acid in PSP
- Haggerty T et al. (2011) J Neural Transm 118(4):607-612 — HDAC inhibition in tauopathies
- Min SW et al. (2010) Nat Med 16(8):860-865 — Tau acetylation
- Boxer AL et al. (2013) Neurology 80(6):509-516 — PSP trial methodology