Buntanetap Phase 3 Parkinson's Disease Trial (NCT07284784)

Overview

Overview

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

Key Information

| 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

Therapeutic 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

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:

Safety 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