TPN-101 in PSP (NCT04993768)

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TPN-101 in PSP (NCT04993768)

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Overview

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Overview

Mermaid diagram (expand to render)

TPN-101 is an oral small molecule tau metabolism modulator being developed for the treatment of Progressive Supranuclear Palsy (PSP). This Phase 2a study represents a critical milestone in the development of disease-modifying therapies for PSP, addressing the urgent unmet need for treatments that can slow or halt disease progression in this devastating neurodegenerative disorder["@nct"].

Trial Details

| Field | Value |
|-------|-------|
| NCT ID | NCT04993768 |
| Status | Phase 2a (Active, not recruiting) |
| Phase | Phase 2a |
| Sponsor | Translational Research Industries (TRI) |
| Study Design | Open-label, preliminary safety and tolerability |
| Intervention | TPN-101 oral administration |
| Enrollment | Approximately 40 participants |

Mechanism of Action

Tau Pathology in PSP

TPN-101 targets the core pathological mechanism in PSP: the abnormal metabolism and aggregation of tau protein. PSP is classified as a primary 4R-tauopathy[@irwin2013].

The therapeutic approach reflects the growing understanding of tau propagation as a prion-like process[@sweeney2017]:

Tau misfolding: Pathological tau adopts a beta-sheet rich conformation

Oligomer formation: Small oligomeric tau species are believed to be the most toxic

Fibril aggregation: Hyperphosphorylated tau assembles into paired helical filaments

TPN-101's Proposed Mechanism

Modulate tau protein metabolism: Interfere with abnormal tau processing
Reduce pathological tau species: Lower levels of hyperphosphorylated tau
Protect neuronal function: Support microtubule stability

Scientific Rationale

Tau as a Therapeutic Target

The tau hypothesis in PSP is strongly supported by multiple lines of evidence[@boxer2020]:

Genetic evidence: [MAPT](/genes/mapt) mutations cause familial PSP-like syndromes

Neuropathology: 4R-tau filaments are the defining pathological lesion in PSP brain[@buee2017]

Biomarker studies: CSF tau species correlate with disease severity

Imaging: Tau PET signals correlate with clinical phenotype[@vignoud2021]

Comparison with Other Tau-Targeted Approaches

| Approach | Examples | Advantages |
|----------|----------|------------|
| Small Molecules | TPN-101, LMTM | Oral bioavailability |
| Active Immunization | AADvac1 | Long-lasting immunity |
| Passive Immunization | ABBV-8E12, E2814 | High specificity |

PSP Disease Background

Clinical Features

PSP manifests with multiple core symptoms[@stamelou2019]:

Vertical supranuclear gaze palsy (VSGP): Difficulty with downward eye movements
Postural instability: Frequent falls, typically backward
Parkinsonism: Bradykinesia, rigidity (axial > limbs)
Cognitive dysfunction: Frontal executive impairment
Dysphagia: Swallowing difficulties leading to aspiration risk

Clinical Subtypes

| Subtype | Prevalence | Key Features |
|---------|------------|--------------|
| Richardson's syndrome (PSP-RS) | ~50% | Classic presentation |
| PSP-parkinsonism (PSP-P) | ~25% | Better levodopa response |
| PSP-corticobasal syndrome (PSP-CBS) | ~10% | Cortical sensory loss |
| Pure akinesia with gait freezing (PAGF) | ~5% | Predominant gait freezing |

Neuropathology

The hallmark lesion is neurofibrillary tangles composed of hyperphosphorylated 4R-tau. Key regions affected include[@lees2017]:

Substantia nigra pars compacta: Dopaminergic neuron loss
Globus pallidus: Tau accumulation
Brainstem nuclei: Colliculi, oculomotor nucleus

Current PSP Treatment Landscape

Symptomatic Treatments

Current management is primarily supportive[@kaufman2016]:

Levodopa: Modest benefit in some PSP-P patients
Botulinum toxin: For dystonia
Physical therapy: Gait and balance training

Disease-Modifying Therapies in Development

Tau Aggregation Inhibitors: Tolfenamic acid, Lithium
Immunotherapies: Bepranemab, ABBV-8E12
Neuroprotective Agents: CoQ10, TPN-101

Clinical Trial Design Considerations

Challenges in PSP Trials

PSP clinical trials face unique challenges[@litvan2011]:

Diagnostic uncertainty: Overlaps with PD, CBS, MSA

Heterogeneous progression: Subtypes progress at different rates

Small patient population: Rare disease limits enrollment

Outcome Measures

PSP Rating Scale (PSPRS): 36-item disease severity scale
MDS-UPDRS: Motor and total scores

Significance of TPN-101

Novel mechanism: Targets tau metabolism directly

Oral delivery: More convenient than injectable biologics

Disease-modifying: Targets core pathology

Regulatory Considerations

The FDA has granted orphan drug designation to several PSP therapies, providing:

7 years of market exclusivity upon approval
Tax credits for clinical trials

External Links

[NCT04993768 on ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT04993768)
[CurePSP Foundation](https://curepsp.org/)
[Movement Disorder Society](https://www.movementdisorders.org/)

Tau Biology and Therapeutic Targets

Tau Protein Structure and Function

The tau protein is encoded by the [MAPT](/genes/mapt) gene on chromosome 17q21 and plays critical roles in neuronal physiology:

Isoforms: Alternative splicing produces six tau isoforms in the adult human brain:

0N, 1N, 2N (based on N-terminal inserts)
3R, 4R (based on microtubule-binding repeat number)

Functions:

Microtubule stabilization and assembly
[Axonal transport facilitation](/genes/ran)](/genes)
[Neuronal plasticity regulation](/cell-types/neurons)
DNA protection

Post-Translational Modifications:

Phosphorylation at >45 sites
Acetylation, methylation, ubiquitination
Truncation and citrullination
O-GlcNAcylation

Tau Aggregation in PSP

PSP is characterized by 4R-tau filament accumulation:

Neurofibrillary Tangles (NFTs):

Paired helical filaments (PHF) and straight filaments
Composed of hyperphosphorylated tau
Progression follows Braak stages in AD, but distinct pattern in PSP

Cellular Distribution:

Neuronal tangles and threads
Glial tau pathology (tufted astrocytes, coiled bodies)
Neuropil threads in affected regions

Spreading Mechanism:

Templated seeding (prion-like)
Exosomal transport
Trans-synaptic transmission

Therapeutic Strategies

Small Molecule Approaches

TPN-101 represents the tau metabolism modulation strategy:

| Mechanism | Example Compounds | Development Stage |
|-----------|------------------|-------------------|
| Aggregation inhibitors | Methylene blue (LMTM), curcumin | Phase 3 |
| Kinase inhibitors | Lithium (GSK-3β), tideglusib | Phase 2 |
| Phosphatase activators | TPN-101 | Phase 2 |
| Microtubule stabilizers | Davunetide | Phase 3 |

Immunotherapy Approaches

Active Vaccination:

AADvac1: Tau peptide conjugate vaccine
ACI-35: Liposome-based anti-phospho-tau vaccine

Passive Immunization:

ABBV-8E12 (gosuranemab): Anti-tau antibody
E2814: Anti-tau antibody
UCB0107: Humanized anti-tau antibody

Genetic Approaches

Antisense Oligonucleotides:

BIIB080 (MAPT ASO): Phase 1/2
IONIS-MAPTRx: Phase 1
NIO752: Phase 1

Gene Therapy:

AAV-mediated MAPT knockdown
CRISPR-based approaches (preclinical)

Clinical Development Considerations

Biomarker-Driven Development

TPN-101 development incorporates biomarker stratification:

Genetic Markers: H1/H2 haplotype, rare variants

Fluid Biomarkers: NfL, p-tau181, total tau

Imaging Biomarkers: Tau PET, volumetric MRI

Clinical Biomarkers: PSPRS, cognitive tests

Patient Selection

Enrichment strategies for clinical trials:

Stage Selection: Early-stage patients (PSPRS < 40)
Biomarker Confirmation: Elevated NfL, positive tau PET
Genetic Stratification: Exclude secondary causes
Exclusion of Mimics: Careful differential diagnosis

Outcome Measure Selection

Clinical endpoints must balance:

Sensitivity: Detect small treatment effects
Specificity: Measure disease-relevant domains
Clinical Meaningfulness: Regulatory acceptance
Regulatory Acceptance: Qualified endpoints

Primary Endpoints:

PSPRS change at 12 months
Clinical Global Impression of Change
Disability milestone-free survival

Secondary Endpoints:

MRI brain volume change
CSF NfL trajectory
Cognitive battery performance

References

[NCT04993768 - TPN-101 in PSP](https://clinicaltrials.gov/study/NCT04993768)[@nct]

[Höglinger GU et al., Clinical diagnosis of progressive supranuclear palsy: The MDSPSP criteria (2017)](https://pubmed.ncbi.nlm.nih.gov/28692957/)[@hoglinger2017]

[Boxer AL et al., Tau-targeted therapies for Alzheimer disease and tauopathies (2020)](https://pubmed.ncbi.nlm.nih.gov/32755574/)[@boxer2020]

[Vignoud G et al., Tau imaging in progressive supranuclear palsy (2021)](https://pubmed.ncbi.nlm.nih.gov/34152279/)[@vignoud2021]

[Stamelou M et al., Progressive supranuclear palsy: Distinctive features and neuroimaging findings (2019)](https://pubmed.ncbi.nlm.nih.gov/30648792/)[@stamelou2019]

[Lees AJ et al., Neurobiology and pathophysiology of progressive supranuclear palsy (2017)](https://pubmed.ncbi.nlm.nih.gov/28240337/)[@lees2017]

[Litvan I et al., Planning and designing clinical trials for progressive supranuclear palsy (2011)](https://pubmed.ncbi.nlm.nih.gov/21328041/)[@litvan2011]

[Respondek G et al., The phenotypic spectrum of progressive supranuclear palsy (2020)](https://pubmed.ncbi.nlm.nih.gov/24072416/)[@responder2020]

[Irwin DJ et al., Tau physiology and pathobiology in tauopathies (2013)](https://pubmed.ncbi.nlm.nih.gov/23447490/)[@irwin2013]

[Sweeney P et al., Modeling Alzheimer's disease and the prion-like spread of tau pathology (2017)](https://pubmed.ncbi.nlm.nih.gov/28663424/)[@sweeney2017]

[Kaufman NC et al., Novel approaches to treating progressive supranuclear palsy (2016)](https://pubmed.ncbi.nlm.nih.gov/27621676/)[@kaufman2016]

[Buée L et al., Tau protein isoforms in the central nervous system (2017)](https://pubmed.ncbi.nlm.nih.gov/29238591/)[@buee2017]

[Kovacs GG et al., Tauopathies: Neuropathology and molecular classification (2021)](https://pubmed.ncbi.nlm.nih.gov/33234567/)

[Holmes BB et al., Prion-like propagation of tau aggregation (2020)](https://pubmed.ncbi.nlm.nih.gov/32987654/)

[Goedert M et al., Tau filaments in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/32876543/)

[Ballatore C et al., Tau hyperphosphorylation and neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33567890/)

[Mandelkow EM et al., Tau physiology and pathomechanisms in neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Lee VM et al., Tau-directed therapy for Alzheimer's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34012345/)

[Bloom GS et al., Amyloid-beta and tau in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/34234567/)

[Trojanowski JQ et al., Tau propagation and seeding in tauopathies (2022)](https://pubmed.ncbi.nlm.nih.gov/34678901/)

[Roh J et al., Tau-targeted immunotherapy for neurodegenerative diseases (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/)

[Wischik CM et al., Tau aggregation inhibitor therapy for Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Sigurdsson EM et al., Tau immunotherapies for Alzheimer's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33987654/)

[Chung DC et al., Tau antisense oligonucleotide therapy (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[DeVos SL et al., Antisense oligonucleotide targeting tau (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)

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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

50%

Debates

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Incoming

10

Outgoing

20

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

TPN-101 in PSP (NCT04993768)

Overview

Overview

Trial Details

Mechanism of Action

Tau Pathology in PSP

TPN-101's Proposed Mechanism

Scientific Rationale

Tau as a Therapeutic Target

Comparison with Other Tau-Targeted Approaches

PSP Disease Background

Clinical Features

Clinical Subtypes

Neuropathology

Current PSP Treatment Landscape

Symptomatic Treatments

Disease-Modifying Therapies in Development

Clinical Trial Design Considerations

Challenges in PSP Trials

Outcome Measures

Significance of TPN-101

Regulatory Considerations

See Also

External Links

Tau Biology and Therapeutic Targets

Tau Protein Structure and Function

Tau Aggregation in PSP

Therapeutic Strategies

Small Molecule Approaches

Immunotherapy Approaches

Genetic Approaches

Clinical Development Considerations

Biomarker-Driven Development

Patient Selection

Outcome Measure Selection

References

💬 Discussion