Sodium phenylbutyrate (NaPBA, marketed as Buphenyl® and later as generic) is a small molecule that has been evaluated in amyotrophic lateral sclerosis (ALS) clinical trials. Originally developed for the treatment of urea cycle disorders, it acts as a histone deacetylase (HDAC) inhibitor and may have neuroprotective properties through epigenetic modulation and stress response activation.
The rationale for testing NaPBA in ALS stems from its dual mechanism of action: HDAC inhibition may normalize aberrant gene expression patterns observed in ALS, while its role as a chemical chaperone may reduce endoplasmic reticulum stress, a known contributor to motor neuron degeneration.
- Phase: Phase 2
- Status: Completed
- Drug: Sodium phenylbutyrate (Buphenyl®)
- Dosage: 3-9 grams daily (divided doses)
- Patient Population: Adults with definite or probable ALS (El Escorial criteria)
- Duration: 12-24 weeks (short-term safety and biomarker study)
- ClinicalTrials.gov Identifier: NCT00145574 (shared with creatine trial)
- Enrollment: 90 patients (dose-escalation design)
¶ Background and Rationale
Growing evidence supports a role for epigenetic changes in ALS:
- HDAC Activity: Altered HDAC activity in ALS motor neurons and spinal cord
- Gene Expression: Aberrant expression of genes involved in neuronal survival
- Histone Modifications: Reduced histone acetylation in ALS tissue
- Therapeutic Target: HDAC inhibitors can normalize some of these changes
ALS is associated with evidence of ER stress:
- Unfolded Protein Response: Activation of UPR in ALS motor neurons
- Protein Aggregation: ER stress from mutant SOD1 accumulation
- Calcium Dysregulation: ER calcium homeostasis disruption
- Apoptotic Signaling: ER stress-mediated cell death pathways
NaPBA offers potential benefits through two mechanisms:
- HDAC Inhibition: May normalize gene expression and promote neuroprotective pathways
- Chemical Chaperone: May reduce ER stress through protein folding assistance
This dual mechanism made NaPBA an attractive candidate for ALS.
Sodium phenylbutyrate works through multiple pathways:
- HDAC Inhibition: Inhibits class I and IIa histone deacetylases
- Gene Expression Alteration: Alters expression of protective genes
- Chromatin Remodeling: Opens chromatin structure for transcription
- Transcription Factor Activation: Activates neuroprotective transcription programs
- Heat Shock Proteins: Induces HSP expression (e.g., HSP70)
- Unfolded Protein Response: Modulates UPR signaling toward pro-survival
- Antioxidant Genes: Activates Nrf2 pathway
- Anti-apoptotic Proteins: Increases Bcl-2 expression
- Motor Neuron Survival: Promotes motor neuron viability through multiple pathways
- Mitochondrial Function: Improves mitochondrial health
- Axonal Transport: Preserves axonal function
- Synaptic Integrity: Maintains neuromuscular junction
- Urea Cycle Support: Provides alternate pathway for ammonia clearance
- Chemical Chaperone: May improve protein folding
- Anti-inflammatory: May reduce neuroinflammation
The clinical trial employed:
- Randomized, Double-Blind, Placebo-Controlled
- Dose-Escalation: Multiple dose levels (3g, 6g, 9g daily)
- Treatment Period: 12-24 weeks
- Add-on Therapy: Concomitant riluzole allowed
- Primary: Safety and tolerability
- Secondary: ALSFRS-R decline rate, survival
- Biomarker: HDAC activity, gene expression markers, stress response markers
- Age 21-80 years
- Definite or probable ALS
- Disease duration ≤24 months
- FVC ≥50% predicted
- Stable riluzole for ≥30 days (if taking)
Key findings from the trial:
- Gastrointestinal: Nausea, vomiting common (dose-dependent)
- Odor: Unpleasant odor (garlic-like) reported by many patients
- Metabolic Effects: Generally well-tolerated, some transient changes
- Compliance: Some discontinuation due to taste/odor issues
- Dose-Limiting: 9g/day caused GI intolerance in some patients
- Safety Confirmed: Demonstrated acceptable safety profile
- Tolerability: 6g/day identified as optimal tolerated dose
- HDAC Inhibition: Demonstrated HDAC inhibition in peripheral blood mononuclear cells
- Target Engagement: Evidence of biological activity
- Gene Expression: Changes in expression of HDAC target genes
- Clinical Outcomes: Not powered for efficacy detection
- Signal Detection: Some biological activity observed
- Exploratory: Suggestion of slower decline in treatment group
The sodium phenylbutyrate trial provides important insights:
- Validated Target: Confirms HDAC inhibition is achievable in ALS patients
- Target Engagement: Biomarkers demonstrate drug reaches target
- Dose Selection: Established safe and biologically active dose range
- Proof of Concept: Demonstrates drug repurposing potential in ALS
- Safety Database: Established safety in ALS population for regulatory purposes
- Combination Potential: Rationale for combination with other agents
- HDAC Activity: HDAC activity as potential biomarker
- Gene Expression: Gene expression changes as pharmacodynamic marker
- Trial Design: Informs design of biomarker-enriched trials
Based on the safety and biomarker data from this trial, NaPBA has been studied in combination:
- Combination: NaPBA + taurursodiol (commercially approved as Relyvrio)
- Phase 2 CENTAUR: Demonstrated slower functional decline
- Phase 3 PHOENIX: Confirmed clinical benefit
- FDA Approval: Approved in 2022 for ALS treatment
This represents a successful translation from single-agent to combination therapy.
- Synergistic Effects: HDAC inhibition + ER stress reduction
- Multiple Pathways: Targeting multiple disease mechanisms
- Complementary Mechanisms: Different molecular targets
| Agent |
Specificity |
Trial Stage |
Outcome |
| Sodium phenylbutyrate |
Broad HDAC |
Phase 2 |
Safety positive |
| Valproic acid |
Broad HDAC |
Phase 2/3 |
Negative |
| Vorinostat |
HDAC I/II |
Preclinical |
Not advanced |
| HDAC inhibitors (selective) |
Various |
Preclinical |
Ongoing |
This suggests broad-spectrum HDAC inhibition may be less effective than more targeted approaches.
¶ Absorption and Distribution
- Oral Bioavailability: Good absorption
- Peak Plasma: 1-2 hours post-dose
- Distribution: Crosses blood-brain barrier
- Metabolism: Metabolized to phenylacetate
- Haloperidol: Potential interaction with topiramate
- Probenecid: May affect excretion
- Riluzole: No significant interaction