Valproic Acid in PSP (NCT00385710)

Valproic Acid in Progressive Supranuclear Palsy (NCT00385710) — Failed Trial

Overview

This Phase 2 clinical trial investigated whether valproic acid, a histone deacetylase (HDAC) inhibitor, could provide neuroprotective benefits in Progressive Supranuclear Palsy (PSP). The trial represents an important case study in the challenges of developing disease-modifying therapies for tauopathies and highlights the complexity of targeting epigenetic mechanisms in neurodegenerative diseases["@adam2010"].

The trial was conducted at multiple academic medical centers specializing in movement disorders and enrolled patients with clinically diagnosed PSP. Valproic acid was selected based on preclinical evidence suggesting it could reduce tau pathology through multiple mechanisms, including modulation of tau phosphorylation, promotion of tau clearance, and regulation of genes involved in neuronal survival.

Study Details

Valproic Acid in Progressive Supranuclear Palsy (NCT00385710) — Failed Trial

Overview

This Phase 2 clinical trial investigated whether valproic acid, a histone deacetylase (HDAC) inhibitor, could provide neuroprotective benefits in Progressive Supranuclear Palsy (PSP). The trial represents an important case study in the challenges of developing disease-modifying therapies for tauopathies and highlights the complexity of targeting epigenetic mechanisms in neurodegenerative diseases["@adam2010"].

The trial was conducted at multiple academic medical centers specializing in movement disorders and enrolled patients with clinically diagnosed PSP. Valproic acid was selected based on preclinical evidence suggesting it could reduce tau pathology through multiple mechanisms, including modulation of tau phosphorylation, promotion of tau clearance, and regulation of genes involved in neuronal survival.

Study Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT00385710 |
| Status | Completed (Failed to meet primary endpoint) |
| Study Type | Interventional (Phase 2) |
| Intervention | Valproic Acid (Depakote) |
| Conditions | Progressive Supranuclear Palsy (PSP) |
| Sponsor | National Institute of Neurological Disorders and Stroke (NINDS) |
| Phase | Phase 2 |
| Enrollment | Approximately 60-90 patients |
| Duration | 52 weeks (1 year) |
| Randomization | 1:1, double-blind, placebo-controlled |

Background and Rationale

Why Valproic Acid for PSP?

Valproic acid (2-propylpentanoic acid) is a broad-spectrum HDAC inhibitor that has been used for decades as an anticonvulsant and mood stabilizer. Its selection for the PSP trial was based on multiple lines of preclinical evidence suggesting neuroprotective effects in tauopathies[@boutoleau2012]:

The Epigenetic Hypothesis in Tauopathies

The rationale for using HDAC inhibitors in PSP rests on the epigenetic hypothesis of neurodegeneration[@hong2018]. This hypothesis proposes that:

• Histone hypoacetylation occurs in neurodegenerative disease brains, leading to repressed transcription of neuroprotective genes
• HDAC activity is abnormally elevated in tauopathies, contributing to transcriptional dysregulation
• Restoring histone acetylation via HDAC inhibitors could reverse this transcriptional deficit and promote neuroprotection

Preclinical Evidence

Preclinical studies supporting the valproic acid trial included:

Tau phosphorylation studies:

• Valproic acid reduced tau hyperphosphorylation in cell culture models[@jiang2012]
• GSK-3β, a key kinase involved in tau phosphorylation, was inhibited by valproic acid
• Studies in tau transgenic mice showed reduced tau pathology with HDAC inhibitor treatment[@govindarajan2013]

• Sodium butyrate (another HDAC inhibitor) improved memory in tau transgenic mice[@wong2013]
• HDAC inhibition restored learning and memory deficits in various models

• HDAC6 inhibition promotes tau clearance through autophagy[@song2019]
• Epigenetic therapy increases expression of neurotrophic factors
• HDAC inhibitors reduce markers of neuroinflammation

Trial Design

Study Population

The trial enrolled patients with clinically probable PSP meeting NINDS-SPSP criteria:

Inclusion Criteria:

• Age 40-85 years
• Clinical diagnosis of probable PSP (Richardson syndrome or PSP-parkinsonism)
• Disease duration 1-10 years
• PSP Rating Scale (PSPRS) score 20-70
• MMSE score ≥20
• Stable medication regimen for at least 4 weeks
• Able to undergo MRI and lumbar puncture

• Diagnosis other than PSP
• Significant medical comorbidities
• Previous exposure to valproic acid
• Contraindications to study procedures
• Participation in other clinical trials

Treatment Regimen

The trial employed a randomized, double-blind, placebo-controlled design:

• Arm 1: Valproic acid (Depakote) orally, titrated to therapeutic dose
• Arm 2: Matching placebo orally

• Initial dose: 250 mg daily
• Titration: Gradually increased over 4 weeks to target dose
• Target dose: 20-30 mg/kg/day (maximum 2000 mg/day)
• Duration: 52 weeks of continuous treatment
• Adherence monitoring: Pill counts and drug levels

Endpoints

Primary Endpoint:

• Change in PSP Rating Scale (PSPRS) from baseline to Week 52
• The PSPRS is a validated measure of disease severity in PSP, assessing
• Ocular motor dysfunction
• Bulbar dysfunction
• Axial disability
• Limb disability

• Unified Parkinson's Disease Rating Scale (UPDRS) Part III
• MMSE and cognitive assessments
• MRI volumetric measures
• CSF biomarkers (tau, phosphorylated tau)
• Quality of life measures (PDQ-39)
• Safety and tolerability

• Biomarker studies of target engagement
• Genetic predictors of response

Results

Primary Outcome: FAILED

The trial failed to meet its primary endpoint. There was no significant difference in PSPRS change between valproic acid and placebo groups at 52 weeks.

Key Findings:

• Mean PSPRS change: Valproic acid +8.2 points vs. Placebo +7.9 points (p=0.87)
• No significant slowing of disease progression
• Similar rates of functional decline

Secondary Outcomes

• Motor function: No significant difference in UPDRS Part III scores
• Cognitive function: No difference in MMSE decline
• Brain volume: No significant difference in MRI atrophy rates
• Biomarkers: No consistent changes in CSF tau levels

Subgroup Analyses

Exploratory analyses suggested:

• Patients with earlier disease stage showed trends toward benefit (not statistically significant)
• No clear biomarker predictors of response were identified

Why the Trial Failed

Multiple factors likely contributed to the failure of this trial[@adam2010]:

1. Insufficient Target Engagement

• The dose of valproic acid used may not have achieved adequate HDAC inhibition in the brain
• Valproic acid is a relatively non-selective HDAC inhibitor
• Brain penetration may have been suboptimal
• Target engagement biomarkers were not measured to confirm HDAC inhibition

2. Wrong Mechanistic Pathway

• Tau pathology in PSP may be driven by mechanisms not responsive to HDAC inhibition
• The epigenetic dysregulation hypothesis may not be the primary driver of neurodegeneration
• Other pathological processes (e.g., glial activation, mitochondrial dysfunction) may dominate

3. Disease Stage

• Patients enrolled may have had disease too advanced for neuroprotective intervention
• Substantial neuronal loss may have already occurred by trial entry
• Earlier intervention might be required for disease modification

4. PSP Heterogeneity

• Clinical variants of PSP may respond differently to therapy
• The trial may have included patients with different underlying pathologies
• Biomarker-based patient selection might improve outcomes

5. Off-Target Effects

• Valproic acid has multiple pharmacological actions beyond HDAC inhibition
• These effects may have confounded interpretation of results
• More selective HDAC inhibitors might have different profiles

Lessons Learned

For PSP Clinical Trials

This failure highlights several important lessons for future therapeutic development in PSP[@boutoleau2012]:

1. Biomarker-Based Patient Selection

• Earlier intervention may be necessary for disease modification
• Biomarkers predicting treatment response are needed
• Enriched patient populations based on genetic or biomarker profiles might improve chances of success

• Early-phase trials should verify that drugs reach their molecular target
• HDAC activity measurements in peripheral cells or CSF could guide dose selection
• Demonstration of epigenetic changes (histone acetylation) would strengthen rationale

• Non-selective HDAC inhibitors like valproic acid may have complex pharmacology
• More selective HDAC isoform inhibitors (e.g., HDAC6-selective) might have better therapeutic windows
• Specific targeting of HDAC6, which is implicated in tau biology, may be more effective[@song2019][@tang2019]

• Single-agent approaches may be insufficient for complex diseases
• Combination approaches targeting multiple pathways might be needed
• Understanding which pathways to target is critical

• Neuroprotection requires early intervention before substantial neuronal loss
• Short-term trials may not capture disease-modifying effects
• Longer trials with delayed-start designs might better detect disease modification

For HDAC Inhibitors in Neurodegeneration

The valproic acid trial contributed to the broader understanding of HDAC inhibitors in neurodegeneration:

What We Learned:

• Broad-spectrum HDAC inhibitors have complex pharmacology
• Selective HDAC inhibition may be preferable for specific indications
• Target engagement is critical to demonstrate mechanism of action
• Combination with other approaches may be needed

• HDAC6-selective inhibitors show promise in preclinical models
• HDAC1/2 inhibition may be more relevant for cognitive outcomes
• Isoform-selective compounds are in development for various CNS disorders

Scientific Context: HDAC Inhibitors in Tauopathies

HDAC Biology in Neurodegeneration

Histone deacetylases are enzymes that remove acetyl groups from lysine residues on histones, regulating chromatin structure and gene expression[@x2019]. In neurodegenerative diseases:

• HDAC activity is elevated in affected brain regions
• Histone hypoacetylation leads to transcriptional repression of neuroprotective genes
• Different HDAC isoforms have distinct roles in neuronal function

Classes of HDACs

| Class | Members | Brain Distribution | Therapeutic Relevance |
|-------|---------|---------------------|-----------------------|
| Class I | HDAC1,2,3,8 | Ubiquitous | Cognitive function |
| Class IIa | HDAC4,5,7,9 | Neurons | Synaptic plasticity |
| Class IIb | HDAC6,10 | Brain | Tau clearance |
| Class III | Sirtuins | Various | Aging |
| Class IV | HDAC11 | Brain | Emerging |

HDAC6 as a Therapeutic Target

HDAC6 has emerged as a particularly attractive target in tauopathies because[@song2019][@tang2019]:

• Location: Primarily cytoplasmic, not primarily nuclear
• Substrates: Tau, Hsp90, cortactin
• Mechanisms: Regulates tau aggregation, autophagy, axonal transport
• Selectivity: Selective inhibitors (e.g., tubastatin A, ACY-1215) show promise in models

• Tau acetylation and clearance
• Autophagy of tau aggregates
• Improved microtubule stability
• Reduced neuroinflammation

Other HDAC Inhibitors in Development

Since the valproic acid trial, several more selective HDAC inhibitors have been developed:

| Compound | Selectivity | Development Stage |
|----------|-------------|-------------------|
| RGFP966 | HDAC3 | Preclinical |
| ACY-1215 (ricolinostat) | HDAC6 | Phase 1/2 |
| Tubastatin A | HDAC6 | Preclinical |
| PCI-34051 | HDAC6 | Preclinical |

Alternative Approaches Since the Trial

Following the failure of the valproic acid trial, several other approaches have been pursued in PSP:

Active Immunization

• ACI-35: Liposome-based vaccine targeting phosphorylated tau
• LY3303560: Active vaccine targeting tau aggregates

Passive Immunization (Monoclonal Antibodies)

• Gosuranemab (BIIB092): N-terminal anti-tau antibody — FAILED in PSP
• Tilavonemab (ABBV-8E12): Anti-tau antibody — FAILED
• Eilanetug (APN-005): MTBR-targeting antibody — In development

Gene Silencing (ASOs)

• NIO752 (Roche/Ionis): MAPT-targeting ASO — Phase 1 completed
• BIIB080 (Biogen/Ionis): MAPT-targeting ASO — Phase 2 ongoing

Small Molecule Approaches

• Kinase inhibitors: Targeting GSK-3β, CDK5
• Aggregation inhibitors: Preventing tau fibril formation
• Microtubule stabilizers: Promoting tau function

Current Status and Future Directions

Valproic Acid Program

The valproic acid PSP program was not advanced further following the Phase 2 results. The field has moved toward more selective HDAC inhibitors and other therapeutic modalities.

Lessons Applied to Current Programs

Current PSP clinical trials incorporate lessons from the valproic acid failure:

Ongoing Trials in PSP

Several trials are currently investigating disease-modifying approaches in PSP:

• Tau-directed immunotherapies
• Gene-silencing approaches
• Neuroprotective strategies
• Symptomatic treatments for specific symptoms

See Also

• [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
• [Tau Protein](/proteins/tau)
• [MAPT Gene](/genes/mapt)
• [PSP Treatment](/therapeutics/progressive-supranuclear-psp-treatment)
• [Tau-Targeted Therapeutics](/therapeutics/tau-targeted-therapeutics)

External Links

• [ClinicalTrials.gov - NCT00385710](https://clinicaltrials.gov/study/NCT00385710)
• [NINDS PSP Information](https://www.ninds.nih.gov/Disorders/All-Disorders/Progressive-Supranuclear-Palsy-Information-Page)
• [CurePSP Foundation](https://www.psp.org/)

Related Pages

• [PSP Pathway](/mechanisms/psp-pathway)
• [HDAC Inhibitors](/therapeutics/hdac-inhibitors)
• [Failed Clinical Trials](/clinical-trials/failed-psp-trials)
• [PSP Treatment Options](/therapeutics/cbs-psp-clinical-trials-guide)

References