Buntanetap (formerly PD-01) is an oral small molecule inhibitor of 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.
| 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 |
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
Buntanetap is a novel oral small molecule that inhibits alpha-synuclein aggregation through multiple 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 autophagy
Alpha-synuclein aggregation is considered a central pathogenic mechanism in Parkinson's disease. The formation of toxic oligomers and fibrils leads to neuronal dysfunction and death in dopaminergic neurons of the substantia nigra. Buntanetap's intracellular mechanism addresses this root cause directly.
Unlike antibody-based approaches (e.g., 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.
- 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
- 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
- Change from baseline in MDS-UPDRS Part 3 (motor) score at Week 52
- 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)
- Neuroimaging (DAT-SPECT) substudy
- Blood biomarker analysis
- Pharmacokinetic sampling
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
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
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
The Phase 3 trial aims to confirm:
- Clinically meaningful motor symptom improvement
- Disease modification (slowed progression)
- Non-motor symptom benefits
- Sustained safety profile
Based on Phase 1 and Phase 2 data, buntanetap has demonstrated:
- Mild gastrointestinal symptoms (nausea, dyspepsia)
- Headache
- Dizziness
- 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
The buntanetap Phase 3 trial represents several important milestones:
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.
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
Success would have implications for other synucleinopathies:
| 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
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 for current enrollment status