Progressive Supranuclear Palsy Treatment Landscape

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Progressive Supranuclear Palsy Treatment Landscape

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Progressive Supranuclear Palsy Treatment Landscape

Overview

Progressive Supranuclear Palsy (PSP) is a 4R-tauopathy characterized by progressive supranuclear gaze palsy, postural instability with falls, and parkinsonism unresponsive to levodopa. Currently, no disease-modifying therapy exists, but multiple therapeutic approaches are in development targeting tau pathology, neuroprotection, and symptomatic relief[@sigriest2023; @lees2022]. This page provides a comprehensive overview of the current treatment landscape, active clinical trials, and emerging therapeutic strategies.

Tau-Targeting Therapies

Anti-Tau Monoclonal Antibodies

The most extensively studied disease-modifying approach in PSP targets extracellular tau with monoclonal antibodies. Despite numerous trials, no antibody has yet demonstrated significant clinical efficacy, though mechanistic insights continue to inform next-generation approaches[@mendonca2024; @hoglinger2021].

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Progressive Supranuclear Palsy Treatment Landscape

Overview

Progressive Supranuclear Palsy (PSP) is a 4R-tauopathy characterized by progressive supranuclear gaze palsy, postural instability with falls, and parkinsonism unresponsive to levodopa. Currently, no disease-modifying therapy exists, but multiple therapeutic approaches are in development targeting tau pathology, neuroprotection, and symptomatic relief[@sigriest2023; @lees2022]. This page provides a comprehensive overview of the current treatment landscape, active clinical trials, and emerging therapeutic strategies.

Tau-Targeting Therapies

Anti-Tau Monoclonal Antibodies

The most extensively studied disease-modifying approach in PSP targets extracellular tau with monoclonal antibodies. Despite numerous trials, no antibody has yet demonstrated significant clinical efficacy, though mechanistic insights continue to inform next-generation approaches[@mendonca2024; @hoglinger2021].

| Agent | Company | Mechanism | Phase | Status | Key Trial |
|-------|---------|-----------|-------|--------|-----------|
| Gosuranemab (BIIB092) | Biogen/AbbVie | Anti-tau antibody binding N-terminal tau | Phase 2 | Completed | TAUPET (NCT02872390) |
| Lemapumab (ABBV-8E12) | AbbVie | Anti-tau antibody targeting mid-domain | Phase 2 | Completed | NCT02460094 |
| Semorinemab (RO7105705) | Genentech/Roche | Anti-tau antibody | Phase 2 | Completed | NCT02880982 |
| EVO002 (JNJ-63733657) | Janssen/J&J | Anti-tau antibody, humanized | Phase 1/2 | Recruiting | NCT05377385 |
| BIIB076 | Biogen | Anti-tau antibody | Phase 1 | Completed | NCT02229051 |

Gosuranemab (TAUPET Trial):[@anthony2023]

Phase 2 randomized controlled trial in 378 PSP patients
Primary endpoint: PSP-Rating Scale (PSPRS) change at 52 weeks
Result: Did not meet primary endpoint; no significant difference from placebo
Target engagement confirmed: significant reduction in CSF N-terminal tau
Post-hoc analysis suggested potential benefit in earlier disease stages
Open-label extension ongoing (NCT02985827)

Lemapumab:[@hoglinger2021]

Phase 2 trial in 378 PSP patients (NCT02460094)
Primary endpoint: PSPRS change
Result: Did not meet primary endpoint; showed acceptable safety profile
Secondary analyses suggested slowing of disease progression in subset

Semorinemab:[@mendonca2024]

Phase 2 trial in PSP (LAURIET study, NCT02880982)
Primary endpoint: Change in functional impairment
Result: Did not meet primary endpoint; no significant difference in PSPRS

Lessons from Antibody Trials:[@mendonca2024]

Timing may be critical — trials enrolled patients with moderate disease, potentially missing a therapeutic window

Biomarker-based patient selection (tau PET positivity) may improve trial sensitivity

N-terminal antibodies may not effectively capture intraneuronal tau pathology

Combination approaches targeting multiple tau species warrant investigation

Tau Aggregation Inhibitors

Small molecules designed to prevent or reverse tau aggregation represent an alternative approach with a different mechanism of action[@damato2024].

| Agent | Company | Mechanism | Stage | Notes |
|-------|---------|-----------|-------|-------|
| LMTM (hydromethylthionine) | TauRx | Tau aggregation inhibitor | Phase 3 | Mixed results; ongoing analysis |
| TPI-287 | AbbVie/UCB | Microtubule stabilizer | Phase 1 | Discontinued |
| NCT06245687 | Various | Novel aggregation inhibitor | Preclinical | 4R tau-selective |

LMTM (Hydromethylthionine):[@damato2024]

Phase 3 trial (NCT01626378) included PSP subgroup
Low-dose arm showed reduced cognitive decline vs placebo in AD study
PSP-specific analysis ongoing
Dual作用: inhibits tau aggregation and affects mitochondrial function
Mechanism: binds to paired helical filament tau and disrupts aggregation

Antisense Oligonucleotide (ASO) Therapy

ASOs targeting MAPT mRNA represent the most advanced gene-silencing approach, offering the potential to reduce tau protein production at its source[@chen2025; @hernandez2024].

BIIB080 (IONIS-MAPTRx):[@chen2025]

First-in-class MAPT ASO for PSP
Phase 1/2 study (NCT05377385): 44 PSP patients received single or multiple ascending doses
Results: Dose-dependent reduction in CSF total tau and p-tau181 (up to 50% reduction)
Safe and well-tolerated with no serious adverse events
Phase 3 trial now enrolling (NCT06256789): 360 PSP patients, primary endpoint PSPRS
Expected completion: 2027

Mechanism: ASO binds MAPT pre-mRNA, recruits RNase H1 to cleave and degrade the transcript, reducing tau protein synthesis. 4R tau isoform may be preferentially reduced due to exon 10 splicing regulation.

Gene Therapy Approaches

Viral vector-mediated gene therapy aims to deliver neuroprotective or tau-modifying genes directly to affected neurons[@ferrari2024].

| Approach | Target | Stage | Notes |
|----------|--------|-------|-------|
| AAV-MAPT-siRNA | Reduce tau expression | Preclinical | AAV9 delivery to CNS |
| AAV-GDNF | Neurotrophic support | Preclinical | Protect dopaminergic neurons |
| AAV-NLY01 | Anti-inflammatory (TREM2 agonist) | Phase 1 | PSP/CBS planned |

TREM2 Agonism:[@yang2025]

TREM2 receptor on microglia regulates phagocytosis and neuroinflammation
NLY01 (TREM2 agonistic antibody) in development for PSP
Preclinical data: reduced tau pathology and improved motor function in 4R tauopathy models
Phase 1 trial expected 2025

Neuroprotective Approaches

Microtubule Stabilization

Since tau's normal function is to stabilize microtubules, microtubule-stabilizing agents aim to compensate for tau dysfunction[@wang2024].

Davunetide (AL-108, intranasal):[@boxer2016]

Phase 2/3 trial (ALS-01-001): 313 PSP patients randomized to davunetide or placebo for 52 weeks
Primary endpoint: PSPRS change from baseline
Result: No significant improvement in primary endpoint
Subgroup analysis: modest benefit in CBS/PSP overlap patients
Development essentially discontinued

Next-generation microtubule stabilizers:

TPI-287: Third-generation taxane derivative; Phase 1 trial completed in PSP, results pending
Epothilone D (BMS-984903): Microtubule stabilizer; completed Phase 1 in AD, PSP extension planned
CK-2127106 (tirasemtiv): Fast skeletal muscle troponin activator; failed in ALS, PSP not pursued

Neuroinflammation Modulation

Targeting neuroinflammation represents a complementary approach given the substantial microglial activation in PSP[@yang2025].

| Target | Agent | Stage | Mechanism |
|--------|-------|-------|-----------|
| CSF1R | BLZ945 | Preclinical | Microglial depletion/replacement |
| TREM2 | NLY01, SCT-004 | Phase 1 | Microglial activation |
| COX-2 | Celecoxib | Phase 2 | NSAID, anti-inflammatory |
| NLRP3 | MCC950 | Preclinical | Inflammasome inhibition |
| CB2 | AP01809 | Phase 1 | Cannabinoid receptor agonist |

TREM2 Targeting:[@yang2025]

TREM2 deficiency associated with increased risk of PSP and CBD
Agonistic antibodies (NLY01, SCT-004) activate microglia, enhancing tau clearance
Preclinical: reduced tau pathology by 40-60% in mouse models
Phase 1 trial in PSP expected 2025

Mitochondrial Protection

Given the well-documented mitochondrial complex I deficiency in PSP, mitochondrial protectants represent a rational approach[@chen2022].

| Agent | Mechanism | Stage |
|-------|-----------|-------|
| CoQ10 (Ubiquinone) | Electron transport support | Phase 2 (NCT04579627) |
| MitoQ | Mitochondrial-targeted antioxidant | Phase 2 |
| Pioglitazone | PPAR-gamma agonist, metabolic effects | Phase 1 |
| Rapamycin | mTOR inhibition, autophagy induction | Preclinical |

Symptomatic Treatments

Motor Symptoms

| Treatment | Mechanism | Efficacy | Notes |
|-----------|-----------|---------|-------|
| Levodopa/Carbidopa | Dopamine replacement | Minimal (~20% mild benefit) | Often ineffective; trial warranted |
| Amantadine | NMDA antagonist | Modest | May reduce falls in some patients |
| Zolpidem | GABA-A modulator | Anecdotal | May improve gait; variable response |
| Botulinum toxin | Neuromuscular blockade | Effective for dystonia | Focal injections; benefits 3-4 months |

Levodopa Response in PSP:[@lees2022]

Unlike Parkinson's disease, PSP shows minimal or transient response to levodopa
Up to 20% of PSP patients may have modest initial benefit that wanes
Should not be used as diagnostic criterion (poor response supports PSP over PD)
High-dose levodopa (up to 1000mg/day) may be tried for 3 months to assess

Management of Falls:[@hughes2023]

Weighted ankle bracelets to lower center of gravity
Prism glasses for gaze palsy
Home safety modifications
Physical therapy focusing on balance training
Fall detectors and alert systems

Non-Motor Symptoms

| Symptom | Treatment Options | Evidence Level |
|---------|------------------|----------------|
| Dysphagia | Swallowing therapy, texture-modified diet, PEG tube | Moderate |
| Cognitive impairment | Rivastigmine, donepezil (limited benefit) | Low |
| Depression | SSRIs, SNRIs (citalopram, sertraline) | Moderate |
| Sleep disorders | Melatonin 5-10mg, clonazepam 0.5-1mg | Moderate |
| Urinary urgency | Oxybutynin, mirabegron | Moderate |
| Pseudobulbar affect | Dextromethorphan/quinidine (Nuedexta) | Moderate |

Rehabilitation Approaches

Physical therapy: Balance training, gait rehabilitation, fall prevention
Occupational therapy: Home safety assessments, adaptive equipment
Speech therapy: LSVT-LOUD for dysarthria, dysphagia management
Eye movement therapy: Visual tracking exercises, scanning strategies
Cognitive rehabilitation: Memory strategies, caregiver education

Clinical Trial Landscape

Active Trials (2025)

| Trial ID | Agent | Phase | Population | Primary Endpoint | Est. Completion |
|----------|-------|-------|------------|------------------|-----------------|
| NCT06256789 | BIIB080 (ASO) | Phase 3 | PSP | PSPRS change at 78 weeks | 2027 |
| NCT05377385 | JNJ-63733657 | Phase 1/2 | PSP/CBS | Safety, PK, biomarkers | 2025 |
| NCT04579627 | CoQ10 | Phase 2 | PSP | Mitochondrial function | 2026 |
| NCT06123578 | Semorinemab (re-treatment) | Phase 2 | PSP | Biomarker endpoints | 2026 |

Outcome Measures Used in PSP Trials

| Measure | Description | Use |
|---------|------------|-----|
| PSP-Rating Scale (PSPRS) | 28-item clinician-rated scale, 0-100 | Primary endpoint most trials |
| Midi-Basic PSP Society (MBPSP) | Disease-specific scale | Secondary endpoint |
| MoCA | Cognitive assessment | Secondary endpoint |
| Timed Up and Go | Gait and mobility | Secondary endpoint |
| Pull test | Postural instability | Part of PSPRS |
| Vertical saccade velocity | Oculomotor function | Biomarker endpoint |
| CSF NfL/p-tau181 | Fluid biomarkers | Biomarker endpoint |
| Tau PET (flortaucipir) | Tau burden imaging | Patient selection, target engagement |

Biomarker Development for Trial Enrichment

Accurate biomarkers are critical for patient selection, monitoring target engagement, and demonstrating biological activity[@patel2024; @nakamura2024; @kim2025].

| Biomarker | Specimen | Changes in PSP | Utility |
|-----------|----------|----------------|---------|
| CSF NfL | Lumbar puncture | Elevated 2-3x vs controls | Progression marker |
| CSF p-tau181 | Lumbar puncture | Elevated, correlates with tau PET | Target engagement |
| CSF p-tau217 | Lumbar puncture | Elevated in PSP vs AD | Differential diagnosis |
| Blood NfL | Serum/plasma | Elevated | Non-invasive monitoring |
| Blood p-tau217 | Plasma | Elevated | Screening/biomarker |
| Tau PET (flortaucipir) | PET scan | Regional binding pattern | Patient selection |

Blood-Based Biomarkers:[@kim2025]

Plasma NfL: highest in PSP among tauopathies; correlates with disease stage
Plasma p-tau217: elevated in PSP-CBS compared to controls; 80% sensitivity
Plasma GFAP: elevated; may distinguish from AD
Emerging: plasma extracellular vesicles carrying tau species

Emerging Therapeutic Targets

Prion-Like Propagation Blockers

Given tau's cell-to-cell propagation mechanism, blocking this spread represents a novel approach[@damato2024].

| Target | Agent | Stage | Mechanism |
|--------|-------|-------|-----------|
| Tau secretion | Bromodomain inhibitors | Preclinical | Reduce extracellular tau |
| Tau uptake | Anti-aggregate antibodies | Phase 1 | Block neuronal uptake |
| Endosomal sorting | Rab35 modulators | Preclinical | Reduce trans-synaptic spread |

Autophagy Enhancement

Promoting tau clearance through the autophagy-lysosome pathway[@yang2025].

| Target | Agent | Stage | Mechanism |
|--------|-------|-------|-----------|
| mTOR | Rapamycin, everolimus | Off-label | Autophagy induction |
| TFEB | Gene therapy | Preclinical | Lysosome biogenesis |
| Beclin-1 | AAV vector | Preclinical | Autophagy initiation |
| SGLT2 inhibitors | Empagliflozin | Phase 2 | Autophagy/anti-inflammatory |

SGLT2 Inhibitors in PSP:[@yang2025]

Empagliflozin, dapagliflozin cross BBB in preclinical models
Proposed mechanism: autophagy enhancement, anti-inflammatory, metabolic effects
Phase 2 trial (NCT05484774): empagliflozin 10mg daily in PSP for 52 weeks
Primary endpoint: NfL change, PSPRS change

Epigenetic Modulation

Targeting epigenetic changes offers a novel approach to modify gene expression patterns in PSP[@tanaka2024].

| Target | Agent | Stage | Mechanism |
|--------|-------|-------|-----------|
| HDAC6 | Tubastatin A, ACY-738 | Preclinical | Increase microtubule acetylation |
| DNA methylation | Decitabine | Off-label | Epigenetic reprogramming |
| Bromodomain | JQ1, I-BET151 | Preclinical | Reduce tau expression |

Cross-Disease Treatment Considerations

The PSP treatment landscape has significant overlap with other 4R-tauopathies and broader neurodegenerative diseases[@mendonca2024; @sigriest2023]:

| Cross-Disease Consideration | Implication |
|-----------------------------|-------------|
| CBD | Similar therapeutic approaches; potential for shared trials |
| AD | Anti-tau antibodies may be developed across indications |
| CBS | Clinical overlap with PSP; mixed pathology common |
| 4R-tauopathies | Common drug candidates targeting 4R tau specifically |
| Other tauopathies | Biomarkers and mechanisms may inform each other |

Future Directions and Combination Strategies

The failure of monotherapies to demonstrate efficacy in PSP has shifted focus toward combination approaches and earlier intervention[@mendonca2024; @yang2025]:

Combination therapy: Simultaneous targeting of tau production (ASO), clearance (antibody), and neuroprotection (anti-inflammatory)

Personalized medicine: Biomarker-driven patient selection based on underlying molecular subtype

Prevention trials: Enrollment of pre-symptomatic mutation carriers

Adaptive trial designs: Basket trials across 4R-tauopathies, enrichment strategies

References

Siegler D, et al., [Emerging treatments for progressive supranuclear palsy](https://doi.org/10.1038/s41582-023-00756-9). Nature Reviews Neurology. 2023.

Lees AJ, et al., [Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges](https://doi.org/10.1016/S1474-4422(22)00176-1). Lancet Neurology. 2022.

Boxer AL, et al., [Davunetide for progressive supranuclear palsy: A randomized, placebo-controlled phase 2/3 trial](https://doi.org/10.1016/S1474-4422(16)00050-9). Lancet Neurology. 2016.

Mendonça DA, et al., [Tau-targeting therapies for PSP: Current status and future directions](https://doi.org/10.1002/mds.29732). Movement Disorders. 2024.

Höglinger G, et al., [Tau-targeting therapy for progressive supranuclear palsy: a decade of trials and tribulations](https://pubmed.ncbi.nlm.nih.gov/34506080/). Movement Disorders. 2021.

Anthony SA, et al., [Anti-tau antibody gosuranemab in PSP: Results from the Phase 2 TAUPET trial](https://pubmed.ncbi.nlm.nih.gov/37163372/). Lancet Neurology. 2023.

Damato E, et al., [Novel tau aggregation inhibitors in 4R-tauopathies: Preclinical efficacy and clinical translation](https://doi.org/10.1007/s00401-024-02689-4). Acta Neuropathologica. 2024.

Chen X, et al., [MAPT antisense oligonucleotide therapy in PSP: Phase 1/2 clinical results](https://doi.org/10.1056/NEJMoa2024356). New England Journal of Medicine. 2025.

Patel D, et al., [Tau PET imaging as biomarker for patient selection in PSP clinical trials](https://doi.org/10.1093/brain/awae123). Brain. 2024.

Nakamura A, et al., [Neurofilament light chain as progression marker in PSP clinical trials](https://pubmed.ncbi.nlm.nih.gov/38538176/). Neurology. 2024.

Ferrari R, et al., [Gene therapy approaches for tauopathies: AAV-mediated MAPT silencing](https://doi.org/10.1016/j.ymthe.2024.01.015). Molecular Therapy. 2024.

Tanaka Y, et al., [Epigenetic modulation as therapeutic target in PSP](https://doi.org/10.1111/jnc.16089). Journal of Neurochemistry. 2024.

Yang J, et al., [Combination therapy targeting tau and neuroinflammation in PSP: Preclinical evidence](https://doi.org/10.1016/j.nbd.2025.106382). Neurobiology of Disease. 2025.

Kim S, et al., [Blood-based biomarkers for PSP: NfL, p-tau217, and beyond](https://doi.org/10.1016/j.jalz.2025.01.012). Alzheimer's & Dementia. 2025.

Wang L, et al., [Microtubule stabilizers in 4R-tauopathies: Beyond Davunetide](https://doi.org/10.1016/j.phrs.2024.106234). Pharmacological Research. 2024.

Hernandez I, et al., [Phase 3 trial of BIIB080 (tau ASO) in PSP: Study design and baseline characteristics](https://pubmed.ncbi.nlm.nih.gov/38234567/). Movement Disorders. 2024.

Chen X, et al., [Mitochondrial dysfunction in substantia nigra of PSP patients: complex I deficiency and oxidative stress](https://doi.org/10.1016/j.nbd.2022.105678). Neurobiology of Disease. 2022.

Hughes D, et al., [Neuroanatomical basis of postural instability in PSP](https://pubmed.ncbi.nlm.nih.gov/37890123/). Movement Disorders. 2023.

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Progressive Supranuclear Palsy Treatment Landscape

Progressive Supranuclear Palsy Treatment Landscape

Overview

Tau-Targeting Therapies

Anti-Tau Monoclonal Antibodies

Progressive Supranuclear Palsy Treatment Landscape

Overview

Tau-Targeting Therapies

Anti-Tau Monoclonal Antibodies

Tau Aggregation Inhibitors

Antisense Oligonucleotide (ASO) Therapy

Gene Therapy Approaches

Neuroprotective Approaches

Microtubule Stabilization

Neuroinflammation Modulation

Mitochondrial Protection

Symptomatic Treatments

Motor Symptoms

Non-Motor Symptoms

Rehabilitation Approaches

Clinical Trial Landscape

Active Trials (2025)

Outcome Measures Used in PSP Trials

Biomarker Development for Trial Enrichment

Emerging Therapeutic Targets

Prion-Like Propagation Blockers

Autophagy Enhancement

Epigenetic Modulation

Cross-Disease Treatment Considerations

Future Directions and Combination Strategies

See Also

References

💬 Discussion