NCT07217665: PSP Clinical Trial Platform - Regimen A (AADvac1)

The Progressive Supranuclear Palsy Clinical Trial Platform - Regimen A: AADvac1 (NCT07217665)

Overview

NCT07217665 is a Phase 2 clinical trial evaluating AADvac1, a tau active immunotherapy vaccine, as a treatment for [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) (PSP). This trial is part of the PSP Clinical Trial Platform (NCT07173803), a master protocol designed to efficiently evaluate multiple investigational products for PSP simultaneously[@nct].

AADvac1 targets pathological tau proteins through active immunization, stimulating the immune system to produce antibodies that bind and facilitate clearance of toxic tau species. This approach differs from passive antibody therapies by inducing long-lasting active immunity.

Trial Details

| Field | Value |
|-------|-------|
| NCT ID | NCT07217665 |
| Status | Not Yet Recruiting |
| Phase | Phase 2 |
| Sponsor | University of Pennsylvania |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Blinding | Triple (Participant, Investigator, Outcomes Assessor) |
| Estimated Enrollment | ~200 participants |
| Start Date | 2024 |
| Estimated Completion | ~2028 |

Mechanism of Action

AADvac1: Active Tau Immunotherapy

The Progressive Supranuclear Palsy Clinical Trial Platform - Regimen A: AADvac1 (NCT07217665)

Overview

NCT07217665 is a Phase 2 clinical trial evaluating AADvac1, a tau active immunotherapy vaccine, as a treatment for [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) (PSP). This trial is part of the PSP Clinical Trial Platform (NCT07173803), a master protocol designed to efficiently evaluate multiple investigational products for PSP simultaneously[@nct].

AADvac1 targets pathological tau proteins through active immunization, stimulating the immune system to produce antibodies that bind and facilitate clearance of toxic tau species. This approach differs from passive antibody therapies by inducing long-lasting active immunity.

Trial Details

| Field | Value |
|-------|-------|
| NCT ID | NCT07217665 |
| Status | Not Yet Recruiting |
| Phase | Phase 2 |
| Sponsor | University of Pennsylvania |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Blinding | Triple (Participant, Investigator, Outcomes Assessor) |
| Estimated Enrollment | ~200 participants |
| Start Date | 2024 |
| Estimated Completion | ~2028 |

Mechanism of Action

AADvac1: Active Tau Immunotherapy

AADvac1 is a first-in-class active tau vaccine developed by [Axon Neuroscience SE](https://www.axon-neuroscience.eu/)[@axon]. The vaccine consists of a synthetic tau peptide conjugated to keyhole limpet hemocyanin (KLH), designed to provoke a robust immune response against pathological tau proteins[@kovacech2022][@novak2019].

Immunological mechanism:

Target Population

AADvac1 targets patients with confirmed PSP based on the Movement Disorder Society (MDS) PSP criteria, specifically those with:

• PSP with Richardson's syndrome (PSP-RS)
• PSP with progressive gait freezing (PSP-PGF)
• Other PSP phenotypes with documented tau pathology

Why Active Immunization?

Active vaccination offers several advantages over passive antibody approaches[@zilavec2021]:

• Durable response: Single immunization series generates long-lived antibody titers
• Lower treatment burden: No repeated infusions required
• Potential for booster shots: Immune response can be boosted if titers decline
• Cost-effective: Less expensive per patient than repeated monoclonal antibody infusions

Clinical Development History

Phase 1 (Completed)

AADvac1 completed Phase 1 testing in healthy volunteers and patients with mild cognitive impairment/early Alzheimer's disease, demonstrating:

• Favorable safety profile with no dose-limiting toxicities[@novak2019]
• Robust immunogenicity with high anti-tau antibody titers
• Good tolerability with mostly mild adverse events

Phase 2 AD Trial (Zin万丈-1)

The AADvac1 Phase 2 trial in [Alzheimer's disease](/diseases/alzheimers-disease) (Zin万丈-1) provided key safety and biomarker data[@kovacech2022]:

• Showed target engagement via reduction in CSF neurogranin
• Demonstrated favorable safety in AD patients
• Biomarker evidence suggested disease modification signal
• Results informed the PSP platform trial design

Translational Rationale for PSP

The translation from AD to PSP is supported by:

• Shared tau pathology between AD and PSP (though different isoforms)
• PSP patients have higher baseline extracellular tau
• Active immunotherapy may be particularly effective in 4R-tauopathies like PSP
• Preclinical models showed efficacy in tau transgenic mice

Trial Design

Master Protocol Structure

NCT07217665 is conducted under the PSP Clinical Trial Platform (NCT07173803) master protocol[@nct]. Key design features:

• Shared placebo control: Single placebo group serves all active treatment arms
• Adaptive design: Interim analyses allow early stopping for futility or efficacy
• Basket of biomarkers: Core biomarker panel applied across all treatment arms
• Core outcome measures: Common PSP Rating Scale (PSPRS) as primary endpoint

Inclusion Criteria

Likely inclusion criteria for the AADvac1 regimen:

• Age 40-85 years
• Diagnosis of probable PSP (MDS criteria)
• PSP Rating Scale score 20-60
• Disease duration 1-7 years
• Stable background medications for 30 days
• No significant medical comorbidities

Exclusion Criteria

Likely exclusion criteria:

• Other neurodegenerative diseases (AD, PD, CBS)
• Significant white matter disease or vascular parkinsonism
• Contraindications to MRI
• Active autoimmune disorders
• Immunosuppressive therapy

Outcome Measures

Primary Endpoint

• Change from baseline in PSP Rating Scale (PSPRS) at 52 weeks
• The PSPRS is a validated 100-point scale measuring disease severity across:
• Mentation (7 points)
• Bulbar (7 points)
• Axial (14 points)
• Limb (14 points)
• Gait/balance (58 points)

Secondary Endpoints

| Measure | Timepoint | Purpose |
|---------|-----------|---------|
| Clinical Global Impression of Change (CGI-C) | 52 weeks | Global clinical assessment |
| Montreal Cognitive Assessment (MoCA) | 52 weeks | Cognitive function |
| Timed Up and Go Test (TUG) | 52 weeks | Mobility/balance |
| MDS-UPDRS Part III | 52 weeks | Motor examination |
|軁Quality of Life (PSP-QoL) | 52 weeks | Patient-reported outcome |

Biomarker Endpoints

• Tau PET imaging: Quantify tau burden using 4R-tau selective ligands
• CSF biomarkers: Total tau, phospho-tau (p-tau181, p-tau217), neurogranin
• Serum NfL: Neurodegeneration marker
• Anti-AADvac1 antibody titers: Confirm vaccine immunogenicity

Safety Monitoring

Adverse Event Monitoring

Comprehensive safety monitoring including:

• Solicited adverse events (injection site reactions, systemic symptoms)
• Unsolicited adverse events with causality assessment
• Serious adverse event (SAE) reporting
• Immune-related adverse events
• Clinical laboratory monitoring (hematology, chemistry, immunology)

Independent Data Monitoring

An independent Data Safety Monitoring Board (DSMB) reviews:

• Accumulating safety data at predefined intervals
• Randomized, unblinded interim analysis for efficacy/futility
• Risk-benefit assessment for trial continuation

Comparison with Other Anti-Tau Approaches

| Agent | Type | Target | Trial Status | Notes |
|-------|------|--------|--------------|-------|
| AADvac1 (NCT07217665) | Active vaccine | Tau aggregates | Not Yet Recruiting | Platform Regimen A |
| Tilavonemab (NCT02880956) | mAb | N-terminal tau | Failed Phase 2 | Did not meet primary endpoint |
| Gosuranemab (NCT02882456) | mAb | N-terminal tau | Failed Phase 2 | No efficacy signal |
| BIIB080 (NCT05348786) | ASO | MAPT mRNA | Recruiting | Tau-lowering approach |
| E2814 (NCT05615614 (DOES NOT EXIST)) | mAb | Microtubule binding region | Recruiting | Anti-aggregation |
| Bepranemab (NCT04838314) | mAb | Tau | Phase 2 | Different epitope |

Scientific Rationale

Why Target Tau in PSP

PSP is a 4R-tauopathy characterized by:

• Intraneuronal tangles composed of hyperphosphorylated 4-repeat tau isoforms
• Neuronal loss in subcortical structures (basal ganglia, brainstem)
• Progressive motor and cognitive decline

• Tau tangles correlate with clinical severity
• Extracellular tau propagation drives disease spread
• Reducing tau burden may slow disease progression

AADvac1 Advantages in PSP

Compared to passive monoclonal antibodies[@cummings2024]:

Current Status

As of early 2026, this trial is not yet recruiting. Updates will be tracked as enrollment begins.

Anticipated Timeline

| Milestone | Expected Timeframe |
|-----------|-------------------|
| IRB approval and site activation | 2025-2026 |
| First patient enrolled | 2026 Q1-Q2 |
| Enrollment completion | 2027 Q4 |
| Primary endpoint readout | 2028 Q1 |

References