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.
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].
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.
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]
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]
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]
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]
Since tau's normal function is to stabilize microtubules, microtubule-stabilizing agents aim to compensate for tau dysfunction[@wang2024].
Davunetide (AL-108, intranasal):[@boxer2016]
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]
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 |
| 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]
| 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 |
| 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 |
| 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 |
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]
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 |
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]
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 |
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 |
The failure of monotherapies to demonstrate efficacy in PSP has shifted focus toward combination approaches and earlier intervention[@mendonca2024; @yang2025]: