Urolithin A for Parkinson's Disease (MUSIC Trial NCT06033890)

Urolithin A for Parkinson's Disease (MUSIC Trial NCT06033890)

Trial Overview

| Field | Value |
|-------|-------|
| NCT Number | NCT06033890 |
| Official Title | Mitophagy Induction With Urolithin A in Parkinson's Disease (MUSIC) |
| Phase | Phase 2 |
| Status | Completed |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention | Urolithin A (500mg, 1000mg) vs placebo |
| Enrollment | 200 participants (estimated) |
| Sponsor | University of Kentucky |
| Start Date | September 2024 |
| Estimated Completion | December 2026 |

Disease Target

• [Parkinson's Disease](/diseases/parkinsons-disease)
• Mitochondrial dysfunction
• Impaired mitophagy
• Dopaminergic neuron degeneration

Scientific Rationale

The Mitophagy Deficit in Parkinson's Disease

Mitochondrial dysfunction is a hallmark of Parkinson's disease pathogenesis. The PINK1/Parkin pathway, which controls mitophagy (selective autophagy of damaged mitochondria), is mutated in familial forms of PD[@liu2023]. This impairment leads to accumulation of dysfunctional mitochondria, increased oxidative stress, and ultimately dopaminergic neuron death.

Urolithin A is a gut microbiome-derived metabolite of ellagitannins (found in pomegranates, walnuts, and certain berries) that has demonstrated remarkable mitophagy-inducing properties without significant toxicity[@giron2021].

Why Urolithin A?

Urolithin A offers several advantages as a therapeutic candidate:

...

Urolithin A for Parkinson's Disease (MUSIC Trial NCT06033890)

Trial Overview

| Field | Value |
|-------|-------|
| NCT Number | NCT06033890 |
| Official Title | Mitophagy Induction With Urolithin A in Parkinson's Disease (MUSIC) |
| Phase | Phase 2 |
| Status | Completed |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention | Urolithin A (500mg, 1000mg) vs placebo |
| Enrollment | 200 participants (estimated) |
| Sponsor | University of Kentucky |
| Start Date | September 2024 |
| Estimated Completion | December 2026 |

Disease Target

• [Parkinson's Disease](/diseases/parkinsons-disease)
• Mitochondrial dysfunction
• Impaired mitophagy
• Dopaminergic neuron degeneration

Scientific Rationale

The Mitophagy Deficit in Parkinson's Disease

Mitochondrial dysfunction is a hallmark of Parkinson's disease pathogenesis. The PINK1/Parkin pathway, which controls mitophagy (selective autophagy of damaged mitochondria), is mutated in familial forms of PD[@liu2023]. This impairment leads to accumulation of dysfunctional mitochondria, increased oxidative stress, and ultimately dopaminergic neuron death.

Urolithin A is a gut microbiome-derived metabolite of ellagitannins (found in pomegranates, walnuts, and certain berries) that has demonstrated remarkable mitophagy-inducing properties without significant toxicity[@giron2021].

Why Urolithin A?

Urolithin A offers several advantages as a therapeutic candidate:

Physiological targeting: Works through the body's natural PINK1/Parkin pathway

Excellent safety profile: Already shown safe in multiple human trials

Oral bioavailability: Easy administration as a daily supplement

No known drug interactions: Can be combined with standard PD medications

Multi-target benefits: Beyond mitophagy, reduces inflammation and oxidative stress

Preclinical Evidence

The development of urolithin A for neurodegenerative disease is supported by robust preclinical data:

In PD Models:

• Increases mitophagy in dopaminergic neurons
• Reduces alpha-synuclein aggregation
• Improves mitochondrial function and ATP production
• Protects against MPTP-induced parkinsonism in mice
• Restores behavioral deficits in animal models

In AD Models (extrapolation):

• Reduces amyloid-beta and tau pathology
• Reverses cognitive deficits
• Improves memory function

The findings from Alzheimer's disease models suggest mitophagy enhancement may benefit multiple neurodegenerative conditions[@fang2017].

Study Design

This is a randomized, double-blind, placebo-controlled Phase 2 trial evaluating urolithin A, a natural compound that induces mitophagy (mitochondrial autophagy).

Trial Phases

| Phase | Duration | Purpose |
|-------|----------|---------|
| Screening | 4 weeks | Confirm eligibility |
| Treatment | 12 months | Randomized dosing |
| Follow-up | 2 months | Safety monitoring |

Randomization

• Ratio: 1:1:1 (500mg : 1000mg : placebo)
• Stratification: By disease duration and baseline severity
• Blinding: Double-blind - neither participants nor investigators know assignment

Molecular Mechanism

Dosing

Participants will be randomized to receive:

• Urolithin A 500mg daily
• Urolithin A 1000mg daily
• Placebo

Treatment duration: 12 months. The two dose levels allow comparison of efficacy and safety across different exposure levels.

Eligibility Criteria

Inclusion Criteria

• Age 50-80 years
• Diagnosis of Parkinson's disease (UK Brain Bank criteria)
• Disease duration 1-10 years
• Hoehn & Yahr stage 1-3
• On stable PD medication for ≥30 days
• Able to undergo MRI and PET imaging
• Willing to provide informed consent

Exclusion Criteria

• Atypical parkinsonism (PSP, CBD, MSA)
• Significant cognitive impairment (MoCA <24)
• History of significant cardiac disease
• Liver or kidney dysfunction (eGFR <60 mL/min)
• Use of mitophagy inhibitors
• Cancer within 5 years
• Previous urolithin A use
• Gastrointestinal disorders affecting absorption

Endpoints

Primary Endpoints

• Change in MDS-UPDRS (Movement Disorder Society-Unified Parkinson's Disease Rating Scale) Part III (motor) at 12 months
• Safety and tolerability (adverse events, lab values, vital signs)

Secondary Endpoints

• Change in MDS-UPDRS Parts I (non-motor), II (activities of daily living)
• Change in Montreal Cognitive Assessment (MoCA)
• PET imaging of mitochondrial function (FDG-PET)
• Blood biomarkers: NfL (neurofilament light chain), mitochondrial DNA copy number
• Motor complications (ON/OFF time, dyskinesia severity)
• Quality of life (PDQ-39)

Exploratory Endpoints

• Gut microbiome composition changes
• Inflammatory biomarkers (IL-6, TNF-alpha, CRP)
• Sleep quality (PDSS-2)
• Depression screening (BDI-II)

Current Status

Completed — results published March 2026.

The MUSIC trial has completed enrollment and follow-up. Results are expected to inform future development of urolithin A as a disease-modifying therapy for Parkinson's disease.

Trial Results

Key Findings

The Phase 2 MUSIC trial (NCT06033890) evaluated urolithin A at 500mg and 1000mg daily doses over 12 months in 200 participants with early-to-mid stage Parkinson's disease.

Primary Outcomes:

• Urolithin A was well-tolerated at both dose levels with no significant safety concerns
• No differences in MDS-UPDRS Part III motor scores between treatment and placebo groups at 12 months
• Biomarker analysis showed increased mitochondrial gene expression in muscle biopsies in the treatment arm

Interpretation

While the trial did not meet its primary motor endpoint, the results suggest potential disease-modifying activity through mitochondrial mechanisms. The biomarker findings support further investigation in earlier-stage patients or as combination therapy.

Comparison With Other Mitochondrial-Targeting Therapies

| Therapy | Mechanism | Status | Notes |
|---------|-----------|--------|-------|
| Urolithin A | Mitophagy inducer | Phase 2 (MUSIC) | Oral, excellent safety |
| CoQ10 | Electron transport chain | Phase 3 failed | Mixed results |
| GLP-1 agonists | Mitochondrial function | Phase 2/3 | Diabetes drug repurposing |
| Rapamycin | mTOR inhibition | Phase 1 | Immunosuppression concerns |
| PINK1 gene therapy | Restore mitophagy | Preclinical | Viral vector delivery |

Implications for Tauopathies

While the MUSIC trial targets Parkinson's disease (an α-synucleinopathy), the mitophagy mechanism may have broader relevance for neurodegenerative diseases including tauopathies like CBS and PSP.

Cross-Disease Potential

Mitochondrial dysfunction is implicated in multiple neurodegenerative conditions:

• Alzheimer's disease: Mitophagy declines with age, amyloid-beta impairs mitophagy
• Progressive supranuclear palsy: Tau pathology associated with mitochondrial deficits
• Corticobasal degeneration: Similar mitochondrial dysfunction patterns

If urolithin A proves effective in PD, similar trials could be designed for tauopathies.

Relevance to This Patient

Relevance: LOW for atypical parkinsonism (CBS/PSP)

While urolithin A's mitophagy-enhancing mechanism is theoretically relevant to neurodegenerative diseases, the trial specifically enrolls Parkinson's disease patients (an α-synucleinopathy).

Given this patient:

• Alpha-synuclein NEGATIVE (SAA confirmed)
• Likely tauopathy (CBS/PSP)

The anti-tau therapies (E2814, BIIB080, bepranemab) are more directly relevant. However, urolithin A could be considered as an adjunct therapy given its:

• Excellent safety profile
• Potential mitochondrial benefits
• Easy oral administration
• No known drug interactions

ClinicalTrials.gov Link

[NCT06033890](https://clinicaltrials.gov/study/NCT06033890)

Related Pages

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Mitochondrial Dysfunction in PD](/mechanisms/mitochondrial-dysfunction-parkinsons)
• [PINK1/Parkin Pathway](/mechanisms/pink1-parkin-pathway)
• [Mitophagy in Neurodegeneration](/mechanisms/mitophagy-neurodegeneration)
• [Urolithin A Supplements](/therapeutics/urolithin-a-supplements)
• [Natural Compounds in Neuroprotection](/therapeutics/natural-compounds-neuroprotection)

References

[Liu J, et al, Urolithin A induces mitophagy and improves mitochondrial function in Parkinson's disease models (2023)](https://pubmed.ncbi.nlm.nih.gov/37148123/)

[Andreux M, et al, Urolithin A improves muscle strength and endurance in humans: A randomized controlled trial (2022)](https://pubmed.ncbi.nlm.nih.gov/36564321/)

[Music Trial Study Group, Rationale and design of the MUSIC trial: Urolithin A in Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38764218/)

[Giron C, et al, Urolithin A: A mitophagy activator for healthy aging (2021)](https://pubmed.ncbi.nlm.nih.gov/34079153/)

[Fang EF, et al, Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28250456/)

Detailed Pharmacological Profile

Pharmacokinetics

Urolithin A has been extensively studied in human trials:

| Property | Value | Notes |
|----------|-------|-------|
| Oral bioavailability | ~30-40% | Variable based on gut microbiome |
| Peak plasma time | 6-8 hours | Delayed by food |
| Elimination half-life | 16-20 hours | Supports daily dosing |
| Protein binding | Low-moderate | <60% bound |
| Tissue distribution | Wide | Muscle, brain demonstrated |
| Metabolism | Phase I/II | Gut microbiome influences |
| Excretion | Fecal (80%), urinary (20%) | Minimal renal elimination |

Mechanism Details

PINK1/Parkin Pathway Activation

Urolithin A activates mitophagy through the PINK1/Parkin pathway:

Mitochondrial damage detection: Impaired mitochondria lose membrane potential

PINK1 accumulation: Stabilized on outer mitochondrial membrane

Parkin recruitment: PINK1 phosphorylates and activates Parkin

Ubiquitination: Parkin adds ubiquitin chains to mitochondrial proteins

Autophagy receptor binding: p62, OPTN, NDP52 recognize ubiquitin

Phagosome formation: LC3-positive autophagosome engulfs mitochondria

Lysosomal fusion: Damaged mitochondria degraded and recycled

Comparison With Other Mitophagy Inducers

| Compound | Mechanism | Evidence Level | Status |
|----------|-----------|---------------|--------|
| Urolithin A | PINK1/Parkin | Phase 2 | Most advanced |
| Rapamycin | mTOR inhibition | Preclinical | Toxicity concerns |
| Trehalose | Autophagy induction | Preclinical | Unclear mechanism |
| Metformin | AMPK activation | Observational | Not designed for CNS |
| Resveratrol | SIRT1 activation | Mixed | Poor bioavailability |

Human Safety Data

Urolithin A has been tested in multiple human trials with excellent tolerability:

• Phase 1: Single ascending dose up to 2000mg - no serious adverse events
• Phase 1: Multiple dose (500mg daily for 4 weeks) - well tolerated
• Phase 2 (sarcopenia): 500mg daily for 6 months - safe and well-tolerated
• Phase 2 (PD - MUSIC): Currently enrolling, monitoring safety

Common side effects (mild, transient):

• Gastrointestinal: nausea, bloating, diarrhea (uncommon)
• Headache (rare)
• Fatigue (rare)

No significant drug interactions identified to date.

Therapeutic Implications

For Parkinson's Disease

If the MUSIC trial demonstrates efficacy, urolithin A could become:

First disease-modifying therapy: Targeting the underlying mitochondrial dysfunction

Adjunct to dopaminergic therapy: Enhancing benefit of levodopa

Prevention strategy: Potential use in at-risk populations (RBD, LRKK2 carriers)

Combination component: Partnered with other neuroprotective agents

Broader Neurodegeneration Applications

The mechanism has relevance beyond PD:

Alzheimer's Disease:

• Mitophagy decline is an early event in AD
• Amyloid and tau pathology impairs mitophagy
• Enhancement may reduce protein burden

Huntington's Disease:

• Mutant huntingtin impairs mitochondrial function
• May help clear mutant protein aggregates

Amyotrophic Lateral Sclerosis:

• Mitochondrial dysfunction is a key feature
• May protect motor neurons

Tauopathies (PSP, CBD):

• Mitochondrial deficits in tauopathy brains
• Mitophagy enhancement could complement anti-tau approaches

Challenges and Limitations

Gut microbiome variability: Response may vary based on individual microbiome

Delayed onset: Effects may take months to become apparent

Modest effect size: May provide neuroprotection rather than dramatic improvement

Not a cure: Would need to be combined with other approaches

Current Research Landscape

Ongoing Trials

| Trial ID | Phase | Condition | Status |
|----------|-------|-----------|--------|
| NCT06033890 | Phase 2 | Parkinson's disease | Completed |
| NCT05564138 | Phase 2 | Sarcopenia | Completed |
| NCT05309490 | Phase 1 | Healthy aging | Completed |

Planned/Related Trials

• Phase 3 trial in AD (potential 2026 start)
• Combination trial with GLP-1 agonists
• Prevention trial in RBD patients

Patient Perspectives

Who Might Benefit Most?

Based on preclinical data, patients with:

• Early-to-mid stage PD (Hoehn & Yahr 1-3)
• Evidence of mitochondrial dysfunction on FDG-PET
• Rapid progression despite optimal medical therapy
• Family history suggestive of mitochondrial susceptibility

Practical Considerations

Benefits:

• Oral administration - convenient
• Excellent safety profile
• Over-the-counter availability in some countries
• No significant drug interactions

Limitations:

• Not yet proven effective for PD
• May require 3-6 months to see effects
• Variable response based on gut microbiome
• Not covered by insurance in most regions

Comparison With Standard Treatments

| Factor | Levodopa/Carbidopa | Deep Brain Stimulation | Urolithin A |
|--------|-------------------|----------------------|-------------|
| Efficacy | Symptomatic (strong) | Symptomatic (strong) | Disease-modifying (unknown) |
| Mechanism | Dopamine replacement | Electrical modulation | Mitochondrial enhancement |
| Invasiveness | Non-invasive | Surgical | Non-invasive |
| Cost | Generic available | High | Not covered |

Conclusion

The MUSIC trial represents an important step toward developing disease-modifying treatments for Parkinson's disease. Urolithin's unique mechanism of action targeting mitophagy addresses a fundamental pathological process in PD.

While results are pending, the strong preclinical data and excellent human safety profile make urolithin A one of the most promising candidates in the neurodegenerative disease-modifying pipeline.