Overview
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clinical_trials_bunt_0["Trial Details"]
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clinical_trials_bunt_1["Key Information"]
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clinical_trials_bunt_2["Study Design"]
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clinical_trials_bunt_3["Mechanism of Action"]
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clinical_trials_bunt_4["Primary Mechanisms"]
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...Overview
Mermaid diagram (expand to render)
Buntanetap (formerly PD-01) is an oral small molecule inhibitor of [alpha-synuclein](/proteins/alpha-synuclein) aggregation being developed by Annovis Bio for the treatment of Parkinson's disease and other synucleinopathies. The Phase 3 trial (NCT07284784) represents a pivotal study to evaluate the efficacy and safety of buntanetap in patients with early to mid-stage Parkinson's disease["sunrisepd"][annovis2024].
This trial follows the successful completion of the SUNRISE-PD Phase 2 study, which demonstrated target engagement through CSF biomarker changes and a favorable safety profile.
Trial Details
| Parameter | Value |
|-----------|-------|
| NCT Number | NCT07284784 |
| Trial Name | Buntanetap Phase 3 PD Trial |
| Phase | Phase 3 |
| Status | Recruiting |
| Sponsor | Annovis Bio, Inc. |
| Indication | Parkinson's Disease |
| Intervention | Buntanetap mesylate (oral) |
| Comparator | Placebo |
| Study Start | 2024 |
| Estimated Completion | 2026 |
| Enrollment | ~600 patients |
Study Design
The trial employs a randomized, double-blind, placebo-controlled design:
- Allocation: Randomized (1:1 ratio)
- Intervention: Buntanetap oral tablets
- Control: Matching placebo tablets
- Duration: 52 weeks treatment period
- Follow-up: 4-week safety follow-up
Mechanism of Action
Buntanetap is a novel oral small molecule that inhibits alpha-synuclein aggregation through multiple mechanisms:
Primary Mechanisms
Monomer Binding: Buntanetap binds to soluble alpha-synuclein monomers at the NAC (Non-Aβ Component) region
Conformational Blockade: Prevents the conformational change to beta-sheet rich oligomers
Oligomer Inhibition: Blocks formation of toxic soluble oligomers
Fibril Prevention: Prevents fibril extension and Lewy body formation
Autophagy Enhancement: Promotes clearance of existing aggregates through autophagyTherapeutic Rationale
Alpha-synuclein aggregation is considered a central pathogenic mechanism in [Parkinson's disease](/diseases/parkinsons-disease). The formation of toxic oligomers and fibrils leads to neuronal dysfunction and death in dopaminergic neurons of the [substantia nigra](/brain-regions/substantia-nigra). Buntanetap's intracellular mechanism addresses this root cause directly.
Unlike antibody-based approaches (e.g., [prasinezumab](/therapeutics/prasinezumab)) that target extracellular alpha-synuclein, buntanetap's small molecule design allows it to penetrate neurons and target intracellular aggregation where the majority of pathology occurs.
Inclusion Criteria
- Age 40-80 years
- Diagnosis of idiopathic Parkinson's disease (UK Brain Bank criteria)
- Disease duration 1-10 years
- Hoehn & Yahr stage 1-3
- On stable dopaminergic therapy for ≥4 weeks
- MDS-UPDRS Part 3 score ≥10
- MMSE score ≥24
- Able to swallow tablets
- Willing to comply with study procedures
Exclusion Criteria
- Atypical parkinsonism (PSP, MSA, CBS)
- Significant cognitive impairment (MMSE <24)
- History of stroke or significant neurological disease
- Active malignancy
- Severe medical conditions
- Prior alpha-synuclein immunotherapy
- Known hypersensitivity to buntanetap
- Pregnancy or breastfeeding
Endpoints
Primary Endpoint
- Change from baseline in MDS-UPDRS Part 3 (motor) score at Week 52
Secondary Endpoints
MDS-UPDRS Parts 1-2 (non-motor experiences of daily living)
MDS-UPDRS Part 4 (motor complications)
Patient Global Impression of Change (PGIC)
Clinical Global Impression of Change (CGIC)
CSF alpha-synuclein oligomer levels (biomarker subgroup)
Time to onset of motor complications
Quality of life (PDQ-39)Exploratory Endpoints
- Neuroimaging (DAT-SPECT) substudy
- Blood biomarker analysis
- Pharmacokinetic sampling
Study Population
Target Population
Early to mid-stage Parkinson's disease patients who meet the following criteria:
- Demonstrated ability to complete motor assessments OFF medication
- On stable PD medication regimen
- No significant comorbidities that would interfere with trial participation
Sample Size Justification
The sample size of ~600 patients (300 per arm) is based on:
- Expected effect size of 3-4 points on MDS-UPDRS Part 3
- Power of 80% at α = 0.05
- Assumed 15-20% dropout rate
Results and Outcomes
Phase 2 Reference (SUNRISE-PD)
The Phase 2 SUNRISE-PD trial (NCT05126590) established:
- Safety: Good tolerability with no serious adverse events related to buntanetap
- Target Engagement: Dose-dependent reduction in CSF alpha-synuclein oligomers
- Efficacy Signal: Trend toward improved MDS-UPDRS scores vs. placebo
- Dosing: Established optimal dose for Phase 3
Phase 3 Expectations
The Phase 3 trial aims to confirm:
Clinically meaningful motor symptom improvement
Disease modification (slowed progression)
Non-motor symptom benefits
Sustained safety profileSafety Profile
Based on Phase 1 and Phase 2 data, buntanetap has demonstrated:
Common Adverse Events
- Mild gastrointestinal symptoms (nausea, dyspepsia)
- Headache
- Dizziness
Notable Findings
- No dose-limiting toxicities
- No significant laboratory abnormalities
- No QT prolongation
- No drug-drug interactions with standard PD medications
Contraindications and Precautions
- Known hypersensitivity to buntanetap
- Severe hepatic impairment (dose adjustment may be needed)
- No significant renal dose adjustment required
Clinical Significance
The buntanetap Phase 3 trial represents several important milestones:
Disease Modification
If successful, buntanetap would be the first oral disease-modifying therapy targeting alpha-synuclein aggregation, addressing the root cause of Parkinson's disease rather than just symptoms.
Novel Mechanism
The small molecule oral approach offers advantages over antibody therapies:
- Intracellular targeting
- Better blood-brain barrier penetration
- Oral administration (vs. IV infusion)
- Lower cost and better accessibility
Synucleinopathy Treatment
Success would have implications for other synucleinopathies:
- [Multiple System Atrophy](/diseases/multiple-system-atrophy)
- [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies)
- Pure Autonomic Failure
Comparison to Other PD Therapies
| Therapy | Type | Route | Phase | Target |
|---------|------|-------|-------|--------|
| Buntanetap | Small molecule | Oral | Phase 3 | Alpha-synuclein aggregation |
| Prasinezumab | Antibody | IV | Phase 2 | Alpha-synuclein (extracellular) |
| Cinpanemab | Antibody | IV | Phase 2 | Alpha-synuclein (N-terminal) |
| Exenatide | GLP-1 agonist | Injection | Phase 3 | Neuroprotection |
| LRRK2 inhibitors | Small molecule | Oral | Phase 2 | LRRK2 kinase |
Challenges and Considerations
- Effect Size: Need for clinically meaningful improvements
- Biomarkers: Validation of CSF alpha-synuclein as predictive biomarker
- Patient Selection: Optimal timing of intervention (early vs. advanced disease)
- Combination Therapy: Potential for use with standard dopaminergic therapies
- Long-term Safety: Extended follow-up needed post-approval
Current Status
As of the latest available information, the Phase 3 trial is:
- Status: Recruiting
- Locations: Multiple sites in US, Europe, and potentially other regions
- Updates: Check [ClinicalTrials.gov NCT07284784](https://clinicaltrials.gov/NCT07284784) for current enrollment status
See Also
- [Buntanetap (PD-01) — Therapeutic Profile](/therapeutics/buntanetap)
- [Alpha-Synuclein Aggregation Pathway](/mechanisms/alpha-synuclein)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alpha-Synuclein Immunotherapy](/therapeutics/alpha-synuclein-aggregation-inhibitors)
- [Synucleinopathies](/mechanisms/synucleinopathies)
- [SUNRISE-PD Phase 2 Trial](/clinical-trials/sunrise-pd-phase-2)
External Links
- [ClinicalTrials.gov: NCT07284784](https://clinicaltrials.gov/NCT07284784)
- [Annovis Bio](https://www.annovisbio.com)
- [Michael J. Fox Foundation](https://www.michaeljfox.org)
- [Parkinson's Foundation](https://www.parkinson.org)
References
[SUNRISE-PD Phase 2 Trial Results (2024)](https://clinicaltrials.gov/NCT05126590)
[Annovis Bio Phase 3 Trial Announcement (2024)](https://www.annovisbio.com)
[Kalia et al., Alpha-synuclein biology and therapeutics (2023)](https://pubmed.ncbi.nlm.nih.gov/37081497/)
[Brundin et al., Therapeutic targets for progressive Parkinson's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28628284/)
[Schapira et al., Rotenone, pesticide, and Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31153816/)