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[1].
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.
| 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 |
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[2].
Current tau PET ligands have significant limitations for PSP and related disorders[3]:
| 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:
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:
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.[1:1]
Each participant receives:
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 |
The ligands were developed through a systematic drug discovery program:
Tau PET imaging has transformed our understanding of Alzheimer's disease, but 4R tauopathies remain challenging[4]:
| Condition | Tau Isoforms | Available Ligands |
|---|---|---|
| Alzheimer's Disease | 3R + 4R | Multiple (approved) |
| PSP | 4R only | Limited |
| CBD | 4R only | Limited |
| CGT | 3R only | Limited |
If successful, these 4R tau ligands could transform multiple areas[5]:
Beyond clinical use, 4R tau ligands enable:
If successful, these 4R tau ligands could provide:
| 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 |
The first FDA-approved tau PET ligand for Alzheimer's disease:
Developed by Piramal/Coviant:
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 |
For a diagnostic biomarker like tau PET ligands, FDA approval requires demonstration of:
Location: New Haven, Connecticut, USA
Contact:
The trial is conducted at Invicro, a specialized imaging contract research organization (CRO) with:
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.
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 |
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 |
Key preclinical studies included:
Preclinical animal studies established:
| Species | Findings | Translation Relevance |
|---|---|---|
| Rodent | Brain uptake, clearance | Dose selection |
| Non-human primate | Regional distribution | Human analog |
The use of Fluorine-18 provides several advantages for PET imaging:
The synthesis of [18F]ABBV-964i and [18F]ABBV-965i involves:
Radiation dosimetry is a key safety consideration:
Positive results from this trial could enable:
4R tau PET imaging complements other therapeutic development:
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> |
Key stability parameters for radiopharmaceuticals:
Each batch requires QC testing before release:
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:
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:
The development of 4R tau PET ligands represents progress toward personalized medicine in neurodegenerative diseases:
This first-in-human study of 4R tau-selective PET ligands represents an important step forward in neuroimaging of neurodegenerative diseases:
This trial represents a significant milestone in several ways:
For Patients:
For Clinicians:
For Researchers:
For Industry:
| 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 |
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.
Fourth repeat tauopathies - current understanding. Nat Rev Dis Primers. 2023. ↩︎
Flortaucipir (AV-1451) in tauopathies - Nature. Nature. 2023. ↩︎
PI-2620 PET in 4R tauopathies. Neurology. 2022. ↩︎
Tau imaging in progressive supranuclear palsy. Brain. 2023. ↩︎