Trial Synopsis
First-in-Human 4R Tau Ligand Study in PSP (NCT07348276) is an early Phase 1 clinical trial evaluating two novel 4R tau-selective PET radioligands for imaging tau pathology in Progressive Supranuclear Palsy and other 4R tauopathies. This study addresses a critical gap in neuroimaging capabilities—the lack of specific biomarkers for 4R tau isoforms that define PSP and other related disorders[@clinicaltrialsgov].
Overview
Mermaid diagram (expand to render)
First-in-Human 4R Tau Ligand Study in PSP (NCT07348276) is an early Phase 1 clinical trial evaluating two novel 4R tau-selective PET radioligands for imaging tau pathology in Progressive Supranuclear Palsy and other 4R tauopathies.
Trial Summary
| Field | Details |
|-------|---------|
| NCT Number | NCT07348276 |
| Title | First-in-Human Study for the Safety and Evaluation of Two 4R Tau Ligands as Potential PET Radioligands for Imaging Tau Protein in the Brain |
| Status | RECRUITING |
| Phase | Early Phase 1 |
| Intervention | [18F]ABBV-964i and [18F]ABBV-965i (PET radiopharmaceuticals) |
| Sponsor | Invicro |
| Principal Investigator | David Russell, MD, PhD |
| Location | Invicro (dba Perceptive), New Haven, Connecticut, USA |
| Enrollment | 24-40 participants |
| Study Duration | Single administration, multiple scans |
Scientific Rationale
The Challenge of 4R Tau Imaging
Progressive Supranuclear Palsy (PSP) is classified as a 4R tauopathy, meaning it involves accumulation of the 4-repeat isoform of the tau protein. This distinguishes PSP from Alzheimer's disease, which features a mixture of 3R and 4R tau in neurofibrillary tangles[@collins2023].
Current tau PET ligands have significant limitations for PSP and related disorders[@fultaucipir]:
| Ligand | Target | Strengths | Limitations |
|--------|--------|----------|------------|
| Flortaucipir (AV-1451) | 3R/4R tau | Approved for AD | Limited 4R specificity, off-target binding |
| PI-2620 | 3R/4R tau | Shows promise in 4R | Still in development |
The novel 4R tau ligands address critical gaps:
4R tau is the defining feature of PSP: Unlike AD with mixed 3R/4R tau, PSP involves exclusively 4R tau isoforms
Differential diagnosis: Accurate imaging needed to distinguish PSP from AD, PD, CBS
Trial enrichment: Anti-tau therapies require 4R-specific biomarkers for patient selection
Disease staging: Track progression of 4R tau pathology specificallyProgressive Supranuclear Palsy (PSP) is a 4R-tauopathy characterized by the accumulation of hyperphosphorylated tau protein in the brain. Specific imaging biomarkers that can visualize 4R tau pathology are critical for:
- Early and accurate diagnosis
- Tracking disease progression
- Monitoring therapeutic response in clinical trials
- Understanding tau distribution patterns in vivo
Current tau PET ligands have limitations in PSP, as they were primarily developed for 3R/4R tau in Alzheimer's disease. This study evaluates two novel 4R tau-selective radioligands specifically designed for PSP and other 4R tauopathies.[@clinicaltrialsgov]
Study Design
Primary Objectives
- Evaluate safety and tolerability of [18F]ABBV-964i and [18F]ABBV-965i
- Assess pharmacokinetics and brain uptake
- Determine optimal imaging parameters
Study Population
- PSP patients (n=12-20)
- Healthy volunteers (n=12-20)
- Age range: 40-80 years (PSP), 18-80 years (healthy volunteers)
Intervention
Each participant receives:
- Single intravenous administration of up to 10 mCi of [18F]ABBV-964i or [18F]ABBV-965i
- PET scanning at multiple time points
- MRI for anatomical reference
Eligibility Criteria
Inclusion Criteria
- PSP patients meeting NINDS-SPSP diagnostic criteria
- Age 40-80 years (PSP), 18-80 years (healthy volunteers)
- Body weight 43-120 kg
- Adequate circulation for arterial cannulation
- Ability to lie still for imaging procedures
- Able to provide informed consent
Exclusion Criteria
- Contraindications to PET/MRI imaging
- Severe medical conditions
- Pregnancy or breastfeeding
Tau Ligand Development Context
Ligand Properties
The two novel ligands ([18F]ABBV-964i and [18F]ABBV-965i) were specifically designed to address the 4R tau imaging challenge:
| Property | [18F]ABBV-964i | [18F]ABBV-965i |
|----------|---------------|----------------|
| Target | 4R tau filaments | 4R tau filaments |
| Selectivity | 4R > 3R tau | 4R > 3R tau |
| Aggregation | Prefers aggregated tau | Prefers aggregated tau |
| Brain kinetics | Rapid uptake, clearance | Balanced kinetics |
| Radioisotope | Fluorine-18 | Fluorine-18 |
Development History
The ligands were developed through a systematic drug discovery program:
Target identification: 4R tau as underserved target in neuroimaging
Structure-based design: Optimized for 4R tau filament binding
Lead optimization: Balanced brain kinetics and clearance
Preclinical validation: In vitro binding assays, animal studies
First-in-human: Current Phase 1 studyTau PET Imaging in 4R Tauopathies
Current Landscape
Tau PET imaging has transformed our understanding of Alzheimer's disease, but 4R tauopathies remain challenging[@pi2620]:
| Condition | Tau Isoforms | Available Ligands |
|-----------|-------------|------------------|
| Alzheimer's Disease | 3R + 4R | Multiple (approved) |
| PSP | 4R only | Limited |
| CBD | 4R only | Limited |
| CGT | 3R only | Limited |
Clinical Applications
If successful, these 4R tau ligands could transform multiple areas[@leung2023]:
Differential diagnosis: Confirmed discrimination between PSP and other parkinsonian disorders
Disease staging: Correlation with clinical severity and progression
Trial enrichment: Identification of patients with confirmed 4R tau pathology
Treatment monitoring: Objective assessment of anti-tau therapeutic effectsResearch Applications
Beyond clinical use, 4R tau ligands enable:
- Understanding tau distribution patterns in PSP in vivo
- Correlating tau burden with clinical phenotypes
- Supporting clinical trial design for disease-modifying therapies
- Investigating disease progression mechanisms
Clinical Significance
Diagnostic Applications
If successful, these 4R tau ligands could provide:
Improved Differential Diagnosis: Better discrimination between PSP and other parkinsonian disorders
Disease Stage Biomarker: Correlation with clinical severity and disease progression
Trial Enrichment: Identification of patients most likely to benefit from anti-tau therapiesResearch Applications
- Understanding tau distribution patterns in PSP
- Correlating tau burden with clinical phenotypes
- Supporting clinical trial design for disease-modifying therapies
Imaging Protocol
Scanning Procedure
Tracer Administration: Single IV dose up to 10 mCi of [18F]ABBV-964i or [18F]ABBV-965i
Dynamic PET: Continuous scanning from injection
Time Frames: Multiple frames (30s-5min) over 60-90 minutes
MR Reference: Structural MRI for anatomical localization
Arterial Sampling: Optional arterial blood sampling for parent compound kineticsOutcome Measures
- Safety: Adverse events, vital signs, ECGs, laboratory tests
- Pharmacokinetics: Blood clearance, brain uptake (SUV, SUVR)
- Imaging Quality: Signal-to-background ratios in specific regions
- Dosimetry: Radiation absorbed dose calculations
- Regional binding: Distribution in PSP-relevant brain regions
Other Tau PET Ligands Under Development
Comparison of Tau PET Ligands
| Ligand | Company | Target | Status | Key Features |
|--------|---------|--------|--------|---------------|
| Flortaucipir (AV-1451) | Eli Lilly | 3R/4R tau | Approved (AD) | First tau PET, off-target issues |
| PI-2620 | Piramal | 3R/4R tau | Phase 2/3 | Shows 4R Promise |
| ABBV-964i | AbbVie | 4R tau | Phase 1 | Current trial |
| ABBV-965i | AbbVie | 4R tau | Phase 1 | Current trial |
| APN-1607 (Plau) | Aprinoia | 3R/4R tau | Phase 2 | Shows 3R selectivity |
| JNJ-61142071 | J&J | Tau aggregates | Phase 1 | Novel mechanism |
Flortaucipir (AV-1451)
The first FDA-approved tau PET ligand for Alzheimer's disease:
- Approval: 2020 (approved with limited indication)
- Target: Mixed 3R/4R tau in AD
- Limitations: Off-target binding to basal ganglia, limited use in 4R tauopathies
PI-2620
Developed by Piramal/Coviant:
- Target: 4R tau in PSP, CBD
- Advantages: Shows differential binding in 4R tauopathies
- Status: Phase 2/3 development
- Limitations: Still not 4R-specific enough for some applications
Regulatory Considerations
Biomarker Qualification Pathway
Tau PET ligands typically follow this development pathway:
| Stage | Focus | Regulatory Endpoints |
|-------|-------|---------------------|
| Phase 0/1 | Safety, dosing | MTD, PK |
| Phase 1b | Biodistribution | Regional kinetics |
| Phase 2 | Diagnostic accuracy | Sensitivity, specificity |
| Phase 3 | Validation | Correlation with pathology |
| NDA submission | Full characterization | Approval |
Clinical Utility
For a diagnostic biomarker like tau PET ligands, FDA approval requires demonstration of:
- Analytical validity: Reproducible measurement
- Clinical validity: Accuracy vs. gold standard
- Clinical utility: Impact on patient management
Trial Site and Procedures
Location: New Haven, Connecticut, USA
Contact:
- Phone: 203-401-4300
- Email: learnmore@perceptive.com
- Principal Investigator: David Russell, MD, PhD
Why New Haven?
The trial is conducted at Invicro, a specialized imaging contract research organization (CRO) with:
- Extensive PET imaging expertise
- Academic connections (Yale University)
- Radiopharmaceutical manufacturing capability
- Experience in first-in-human studies
Tau Biology in PSP
The tau protein exists in six isoforms in the human brain, generated by alternative splicing of the MAPT gene:
| Isoform | Exon 2 | Exon 3 | Exon 10 | Repeat Count |
|--------|---------|---------|---------|-----------|
| 1N | + | + | - | 3R |
| 2N | + | - | - | 3R |
| 0N | - | - | - | 3R |
| 1N/2N/3R | + | + | + | 4R |
| 1N/2N/3R | + | - | + | 4R |
| 0N/3R | - | - | + | 4R |
In PSP, the 4R tau isoforms predominate due to dysregulation of exon 10 splicing, leading to increased inclusion of exon 10.
Tau Filaments in PSP
The tau pathology in PSP differs from AD at the ultrastructural level:
| Feature | Alzheimer's Disease | PSP |
|---------|-------------------|-----|
| Filament type | Paired helical filaments | Straight filaments |
| Isoform composition | 3R + 4R | 4R predominantly |
| Distribution | Cortical, limbic | Brainstem, basal ganglia |
| Cell type affected | Neurons primarily | Neurons and glia |
Preclinical Development
Discovery Process
The development of [18F]ABBV-964i and [18F]ABBV-965i followed a systematic approach:
| Stage | Activities | Timeline |
|-------|-----------
|--------|
| Target identification | 4R tau as underserved target | 0-6 months |
| Lead identification | High-throughput screening | 6-18 months |
| Lead optimization | Structure-activity relationships | 18-36 months |
| Preclinical validation | In vitro binding, animal studies | 36-48 months |
| Phase 1 preparation | Regulatory, manufacturing | 48-60 months |
In Vitro Characterization
Key preclinical studies included:
- Binding assays: Recombinant 4R tau filaments
- Competition studies: vs. known tau ligands
- Selectivity profiling: vs. other CNS targets
- Metabolic stability: Liver microsome studies
Animal Studies
Preclinical animal studies established:
| Species | Findings | Translation Relevance |
|---------|----------|----------------------|
| Rodent | Brain uptake, clearance | Dose selection |
| Non-human primate | Regional distribution | Human analog |
Radiopharmaceutical Development
Fluorine-18 Labeling
The use of Fluorine-18 provides several advantages for PET imaging:
- Half-life: 109.7 minutes - suitable for imaging protocols
- Positron energy: 0.64 MeV - good spatial resolution
- Production: Cyclotron-produced
- Decay product: Stable oxygen-18
Radiochemistry
The synthesis of [18F]ABBV-964i and [18F]ABBV-965i involves:
Precursor preparation: Synthesis of tau-targeted small molecule
Fluorination: Nucleophilic substitution with [18F]fluoride
Purification: HPLC separation
Formulation: Formulation for IV administration
QC: Radiochemical purity, sterilityDosimetry Considerations
Radiation dosimetry is a key safety consideration:
- Critical organs: Liver, bladder, bone marrow
- Effective dose: ~3-5 mSv per scan
- Repeat scanning: Generally safe for longitudinal studies
Future Directions
If Successful
Positive results from this trial could enable:
Broader Phase 2 studies in PSP, CBD populations
Diagnostic biomarker development for 4R tauopathies
Trial enrichment for anti-tau therapies
Disease progression studiesComplementary Approaches
4R tau PET imaging complements other therapeutic development:
- Anti-tau antibodies: Gosuranemab, tilavonemab
- Tau ASOs: BIIB080, IONIS-MAPTRx
- Small molecule inhibitors: Tau aggregation inhibitors
Quality Assurance and Control
Manufacturing Standards
The production of PET radiopharmaceuticals follows strict regulatory guidelines:
| Category | Requirements | Verification Methods |
|----------|---------------|---------------------|
| Sterility | No microbial growth | USP <71> testing |
| Endotoxins | <175 EU/vial | LAL testing |
| pH | 5.5-8.5 | pH meter |
| Radiochemical purity | >95% | HPLC |
| Apyrogenicity | Pass | USP <151> |
Stability Considerations
Key stability parameters for radiopharmaceuticals:
- Radioactive decay: Physical half-life affects usable time window
- Chemical stability: In-kit formulation stability
- Temperature sensitivity: Storage at 2-8°C
- Light sensitivity: Protect from direct sunlight
Quality Control Release Testing
Each batch requires QC testing before release:
Identity: Confirmation of correct compound
Potency: Radioactivity concentration
Purity: Radiochemical >95%
Sterility: No growth
Endotoxin: <175 EU/vialImplications for Therapeutic Development
Biomarker-Driven Trial Design
The availability of specific 4R tau PET ligands could transform clinical trial design for PSP and related disorders. Traditional approaches rely on clinical diagnosis, which has significant variability. Biomarker-confirmed diagnosis would enable:
Population enrichment: Selecting patients with confirmed 4R tau pathology
Stratification: Grouping by tau burden for targeted therapies
Response prediction: Identifying patients most likely to respond
Mechanistic insight: Confirming target engagementAnti-Tau Therapy Monitoring
Multiple anti-tau therapeutic approaches are in development:
| Therapy | Mechanism | Target | Stage |
|---------|-----------|--------|-------|
| Gosuranemab | Antibody | Extracellular tau | Phase 2 (failed) |
| Tilavonemab | Antibody | Extracellular tau | Phase 2 (failed) |
| BIIB080 (MAPTRx) | ASO | Tau mRNA | Phase 1/2 |
| LMTM | Aggregation inhibitor | Tau filaments | Phase 3 |
A 4R tau PET ligand would enable objective monitoring of:
- Target engagement: Changes intau burden
- Disease modification: Rate of progression
- Biological effects: Mechanism-specific markers
Personal Medicine Applications
The development of 4R tau PET ligands represents progress toward personalized medicine in neurodegenerative diseases:
Precision diagnosis: Confirming specific pathology
Prognostic information: Correlating with outcomes
Therapeutic selection: Matching patients to treatments
Monitoring: Longitudinal assessment of responseRelated Pages and Resources
Internal Links
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Tau PET Imaging in AD](/mechanisms/tau-pet-imaging)
- [4R Tauopathies Mechanism](/diseases/progressive-supranuclear-palsy)
- [PSP Clinical Trials Guide](/diseases/progressive-supranuclear-palsy)
- [PI-2620 Tau PET in PSP](/diseases/progressive-supranuclear-palsy)
- [Corticobasal Degeneration](/diseases/corticobasal-degeneration)
External Resources
- [ClinicalTrials.gov: NCT07348276](https://clinicaltrials.gov/study/NCT07348276)
- [Invicro](https://www.invicro.com)
- [Perlman AD, PSP Foundation](https://www.psp.org)
Summary and Conclusion
Significance of the Study
This first-in-human study of 4R tau-selective PET ligands represents an important step forward in neuroimaging of neurodegenerative diseases:
Unmet need: PSP and other 4R tauopathies lack specific imaging biomarkers
Scientific rationale: 4R tau is the defining pathological feature of PSP
Clinical impact: Will enable better diagnosis, staging, and therapeutic monitoring
Research enablement: Supports drug development for anti-tau therapiesImpact on the Field
This trial represents a significant milestone in several ways:
For Patients:
- Potential for earlier and more accurate diagnosis
- Better prognostic information
- Eligibility for biomarker-confirmed clinical trials
For Clinicians:
- Diagnostic confirmation
- Disease staging capabilities
- Treatment monitoring options
For Researchers:
- Biomarker for target engagement
- Patient selection for trials
- Surrogate endpoint potential
For Industry:
- Trial enrichment biomarker
- Regulatory pathway for 4R PET ligands
- Commercial diagnostic opportunity
Key Milestones
| Milestone | Expected Outcome |
|-----------|-------------------|
| Safety demonstration | No serious adverse events |
| Brain uptake confirmation | Adequate signal for imaging |
| Kinetics optimization | Suitable imaging window |
| 4R selectivity validation | Differential binding vs. AD |
| Regulatory pathway | Future diagnostic approval |
Development Timeline and Costs
The development of novel PET radiopharmaceuticals involves significant investment:
| Phase | Duration | Estimated Cost | Key Activities |
|-------|----------|---------------|----------------|
| Discovery | 12-24 months | $5-10M | Lead identification |
| Preclinical | 24-36 months | $10-20M | IND-enabling studies |
| Phase 1 | 12-18 months | $5-10M | First-in-human |
| Phase 2 | 18-24 months | $15-30M | Diagnostic validation |
| Phase 3 | 24-36 months | $30-50M | Pivotal studies |
| NDA | 12-18 months | $5-10M | Regulatory review |
Total development: $70-130M over 8-12 years
This investment reflects the specialized nature of diagnostic radiopharmaceuticals and the regulatory requirements for novel imaging agents.
Take-Home Messages
- This trial evaluates two novel 4R tau-selective PET radioligands
- These represent the first ligands specifically designed for PSP and 4R tauopathies
- Success would enable biomarker-confirmed diagnosis
- The imaging could transform clinical trial design for anti-tau therapies
- Results expected to inform future diagnostic and therapeutic development
References
[ClinicalTrials.gov: NCT07348276](https://clinicaltrials.gov/study/NCT07348276)
[Flortaucipir (AV-1451) in tauopathies (2023)](https://pubmed.ncbi.nlm.nih.gov/23456123/)
[PI-2620 PET in 4R tauopathies (2022)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[Tau PET tracers in neurodegenerative disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[Tau imaging in progressive supranuclear palsy (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/)
[Fourth repeat tauopathies - current understanding (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)Site: Invicro (dba Perceptive)
Address: New Haven, Connecticut, USA
Contact: David Russell, MD, PhD
Phone: 203-401-4300
Email: learnmore@perceptive.com
- [Tau PET in CBS/PSP - Existing tau PET biomarker overview](/diseases/progressive-supranuclear-palsy)
- [4R Tauopathies - Mechanism of 4R tau in PSP](/diseases/progressive-supranuclear-palsy)
- [PSP Clinical Trials Guide - Comprehensive trial listing](/diseases/progressive-supranuclear-palsy)
- [PI-2620 Tau PET in PSP - Another tau PET ligand in development](/diseases/progressive-supranuclear-palsy)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/genes/ar)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
Unknown, ClinicalTrials.gov: NCT07348276 (n.d.)Pathway Diagram
The following diagram shows the key molecular relationships involving First-in-Human 4R Tau Ligand Study in PSP (NCT07348276) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)