First-in-Human 4R Tau Ligand Study in PSP (NCT07348276)

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First-in-Human 4R Tau Ligand Study in PSP (NCT07348276)

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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

...

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 specifically

Progressive 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 study

Tau 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 effects

Research 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 therapies

Research 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 kinetics

Outcome 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

Invicro (Perceptive Informatics)

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

Tau Isoforms and 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, sterility

Dosimetry 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 studies

Complementary 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/vial

Implications 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 engagement

Anti-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 response

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 therapies

Impact 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

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📗 Cite This Artifact

First-in-Human 4R Tau Ligand Study in PSP (NCT07348276)

Trial Synopsis

Overview

Trial Synopsis

Overview

Trial Summary

Scientific Rationale

The Challenge of 4R Tau Imaging

Study Design

Primary Objectives

Study Population

Intervention

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Tau Ligand Development Context

Ligand Properties

Development History

Tau PET Imaging in 4R Tauopathies

Current Landscape

Clinical Applications

Research Applications

Clinical Significance

Diagnostic Applications

Research Applications

Imaging Protocol

Scanning Procedure

Outcome Measures

Other Tau PET Ligands Under Development

Comparison of Tau PET Ligands

Flortaucipir (AV-1451)

PI-2620

Regulatory Considerations

Biomarker Qualification Pathway

Clinical Utility

Trial Site and Procedures

Invicro (Perceptive Informatics)

Why New Haven?

Tau Biology in PSP

Tau Isoforms and PSP

Tau Filaments in PSP

Preclinical Development

Discovery Process

In Vitro Characterization

Animal Studies

Radiopharmaceutical Development

Fluorine-18 Labeling

Radiochemistry

Dosimetry Considerations

Future Directions

If Successful

Complementary Approaches

Quality Assurance and Control

Manufacturing Standards

Stability Considerations

Quality Control Release Testing

Implications for Therapeutic Development

Biomarker-Driven Trial Design

Anti-Tau Therapy Monitoring

Personal Medicine Applications

Related Pages and Resources

Internal Links

External Resources

Summary and Conclusion

Significance of the Study

Impact on the Field

Key Milestones

Development Timeline and Costs

Take-Home Messages

References

External Links

References

Pathway Diagram

💬 Discussion