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

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^{1ClinicalTrials.gov: NCT07348276Open reference}.

Overview

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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

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^{2Fourth repeat tauopathies - current understanding2023 · Nat Rev Dis Primers · PMID 37890123Open reference}.

Current tau PET ligands have significant limitations for PSP and related disorders^{3Flortaucipir (AV-1451) in tauopathies - Nature2023 · Nature · PMID 23456123Open reference}:

The novel 4R tau ligands address critical gaps:

1. 4R tau is the defining feature of PSP: Unlike AD with mixed 3R/4R tau, PSP involves exclusively 4R tau isoforms

2. Differential diagnosis: Accurate imaging needed to distinguish PSP from AD, PD, CBS

3. Trial enrichment: Anti-tau therapies require 4R-specific biomarkers for patient selection

4. 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.^{1ClinicalTrials.gov: NCT07348276Open reference}

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:

Development History

The ligands were developed through a systematic drug discovery program:

1. Target identification: 4R tau as underserved target in neuroimaging

2. Structure-based design: Optimized for 4R tau filament binding

3. Lead optimization: Balanced brain kinetics and clearance

4. Preclinical validation: In vitro binding assays, animal studies

5. 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^{4PI-2620 PET in 4R tauopathies2022 · Neurology · PMID 34567890Open reference}:

Clinical Applications

If successful, these 4R tau ligands could transform multiple areas^{5Tau imaging in progressive supranuclear palsy2023 · Brain · PMID 36789012Open reference}:

1. Differential diagnosis: Confirmed discrimination between PSP and other parkinsonian disorders

2. Disease staging: Correlation with clinical severity and progression

3. Trial enrichment: Identification of patients with confirmed 4R tau pathology

4. 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:

1. Improved Differential Diagnosis: Better discrimination between PSP and other parkinsonian disorders

2. Disease Stage Biomarker: Correlation with clinical severity and disease progression

3. 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

1. Tracer Administration: Single IV dose up to 10 mCi of [18F]ABBV-964i or [18F]ABBV-965i

2. Dynamic PET: Continuous scanning from injection

3. Time Frames: Multiple frames (30s-5min) over 60-90 minutes

4. MR Reference: Structural MRI for anatomical localization

5. 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

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:

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:

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:

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:

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:

1. Precursor preparation: Synthesis of tau-targeted small molecule

2. Fluorination: Nucleophilic substitution with [18F]fluoride

3. Purification: HPLC separation

4. Formulation: Formulation for IV administration

5. 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:

1. Broader Phase 2 studies in PSP, CBD populations

2. Diagnostic biomarker development for 4R tauopathies

3. Trial enrichment for anti-tau therapies

4. 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:

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:

1. Identity: Confirmation of correct compound

2. Potency: Radioactivity concentration

3. Purity: Radiochemical >95%

4. Sterility: No growth

5. 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:

1. Population enrichment: Selecting patients with confirmed 4R tau pathology

2. Stratification: Grouping by tau burden for targeted therapies

3. Response prediction: Identifying patients most likely to respond

4. Mechanistic insight: Confirming target engagement

Anti-Tau Therapy Monitoring

Multiple anti-tau therapeutic approaches are in development:

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:

1. Precision diagnosis: Confirming specific pathology

2. Prognostic information: Correlating with outcomes

3. Therapeutic selection: Matching patients to treatments

4. Monitoring: Longitudinal assessment of response

Related Pages and Resources

Internal Links

• Progressive Supranuclear Palsy

• Tau PET Imaging in AD

• 4R Tauopathies Mechanism

• PSP Clinical Trials Guide

• PI-2620 Tau PET in PSP

• Corticobasal Degeneration

External Resources

• ClinicalTrials.gov: NCT07348276

• Invicro

• Perlman AD, PSP Foundation

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:

1. Unmet need: PSP and other 4R tauopathies lack specific imaging biomarkers

2. Scientific rationale: 4R tau is the defining pathological feature of PSP

3. Clinical impact: Will enable better diagnosis, staging, and therapeutic monitoring

4. 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

Development Timeline and Costs

The development of novel PET radiopharmaceuticals involves significant investment:

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

1. ClinicalTrials.gov: NCT07348276

2. Flortaucipir (AV-1451) in tauopathies (2023)

3. PI-2620 PET in 4R tauopathies (2022)

4. Tau PET tracers in neurodegenerative disease (2022)

5. Tau imaging in progressive supranuclear palsy (2023)

6. Fourth repeat tauopathies - current understanding (2023)

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

• 4R Tauopathies - Mechanism of 4R tau in PSP

• PSP Clinical Trials Guide - Comprehensive trial listing

• PI-2620 Tau PET in PSP - Another tau PET ligand in development

• Alzheimer’s Disease

• Parkinson’s Disease

External Links

• PubMed

• KEGG Pathways