Progressive supranuclear palsy: Research & Drug Discovery Data

Drug discovery

drugs

With orphan designations

Overview

Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy affecting brainstem and basal ganglia, characterized by postural instability, vertical gaze palsy, pseudobulbar symptoms, and frontal cognitive dysfunction. Diagnosis is often delayed due to overlap with Parkinson’s disease and dementia [1][5][12]. Neuropathology involves 4-repeat tau aggregation, with no disease-modifying therapies available [8][16]. Median survival is 4.9 years, with complications including falls, dysphagia, and aspiration pneumonia [2][11].

Population

Prevalence: 5–17.9 per 100,000, increasing with age [2][7][19].
Onset: Typically 60–70 years, male predominance (M:F ≈ 1.5:1) [7][12].
Survival: Median 4.9 years (95% CI 3.6–6.1) [2][14].

Burden

Functional: 67–100% develop moderate-to-severe motor/ocular/cognitive impairment [4][14].
Healthcare: Requires 3–4 specialists on average; 55–78% need home modifications [4][14].
Caregiver: 88% require ≥1 caregiver, with high rates of depression/anxiety in patients and caregivers [4][11].

Therapies

Symptomatic: Levodopa (limited efficacy), amantadine, antidepressants (SSRIs/tricyclics), and atypical antipsychotics for mood/behavioral symptoms [3][6][18].
Non-pharmacologic: Physical/occupational therapy, prism glasses, weighted walkers, gastrostomy for dysphagia [1][6][13].
Research: Anti-tau therapies (e.g., monoclonal antibodies), neuroprotective agents, and DBS in clinical trials [8][16].

Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders

Research Papers

701 drug discovery papers related to Progressive supranuclear palsy, with 3 first-in-class and 8 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:

2026-07-04 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.

Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Here, efficacy was evaluated using longitudinal data (52 weeks) and applying for the first time, the US Food and Drug Administration (FDA) -recommended 10-item PSP Rating Scale (PSPRS-10) compared to the 28-item PSPRS (primary endpoint). Time-, sex-, and treatment-related effects were analyzed using linear mixed-effects models including the FDA-recommended Mixed Models for Repeated Measures (MMRM). Cognitive evaluations used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical analyses at the individual level accentuated the impact of the 10 PSPRS chosen items and revealed a significant treatment effect favoring women when accounting for time, sex, and treatment interactions (P = 0.0005). Motor measurements were highlighted. RBANS analyses demonstrated women's significant improvements in total raw score, letter-number sequencing, and language scores. Correlating cerebrospinal fluid (CSF) phosphorylated Tau/Tau with functional outcomes revealed significance with p-Tau/Tau ratio and grasping/imitative/utilizing behavior (assessing involuntary actions in PSPRS-28). This correlation was opposite in direction between females (r = 0.77; P = 0.006) and males (r = -0.62; P = 0.075), with sex difference showing a P = 0.0002 value. Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound.

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2026-07-03 | The role of SUMOylation in regulating proteins that drive neuronal disease progression.

SUMOylation is a post-translational modification in which a Small Ubiquitin-like Modifier (SUMO) protein is reversibly attached to a lysine residue on a target protein in an ATP-dependent process. This modification can affect the function of target proteins by enhancing their stability or changing cellular translocation, thereby making SUMOylation a critical regulator in the pathogenesis of multiple diseases. The functional consequences of SUMOylation, however, are highly context dependent. In Alzheimer's disease, SUMOylation stabilizes proteins that drive disease progression and enhances neurotoxicity, thereby exacerbating these conditions. Similarly, in Progressive Supranuclear Palsy, SUMO-1 conjugation stabilizes truncated tau and blocks its ubiquitination, whereas SUMO-2/3 conjugation promotes Tau clearance and recovery from neuroinflammation, illustrating how distinct SUMO paralogues can exert opposing effects within the same disease. Conversely, increased SUMOylation can be neuroprotective in cerebral ischemia and Parkinson's disease by promoting autophagic clearance of pathogenic proteins. Beyond alterations in protein stability, aberrant SUMOylation can also lead to mis-localization of target proteins, which has been identified as a pathogenic mechanism in disorders such as Huntington's disease and Amyotrophic Lateral Sclerosis that results in impaired clearance and pathogenic buildup, which results in neuronal death. From a therapeutic standpoint, the SUMO inhibitor TAK-981 has shown promise in both Multiple Sclerosis and in pre-clinical glioblastoma models, underscoring the translational potential of targeting of this pathway. This review examines the multifaceted role of SUMOylation across diverse neurological conditions, evaluates the therapeutic potential of SUMO inhibitors and activators, and highlights the opportunities and challenges of modulating this pathway in currently incurable neurological disorders.

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2026-07-02 | Nuclear Speckle Protein SRRM2 Co-localized with Pathological Tau (pTauS396) in Neuronal and Glial Cells in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is a primary 4-repeat tauopathy characterized by progressive motor and cognitive decline. Like other tauopathies, tau misfolding and aggregation are prominent but yield PSP-specific features such as tufted astrocytes and globose neurofibrillary tangles. Emerging evidence suggests that nuclear speckle disassembly and mislocalization of RNA-binding proteins, including serine/arginine repetitive matrix protein 2 (SRRM2), may contribute to disease progression, though SRRM2's role in PSP remains unclear. To assess its association with tau pathology, we examined SRRM2 distribution in midbrain neurons, as well as in astrocytes from both cortical and midbrain regions, using post-mortem immunohistochemistry, immunofluorescence, and 3D reconstruction. In PSP midbrain, neuronal SRRM2 immunoreactivity was markedly elevated compared to controls and co-localized with pTauS396, with >80% overlap; co-localization strongly correlated with SRRM2 abundance (r = 0.9809, p = 0.0191). 3D analysis revealed heterogeneity across cases (PSP-1 to PSP-4) in aggregate morphology, SRRM2 levels, and tau associations. In tufted astrocytes, pTauS396 signals were detected in PSP-1 cortex and PSP-4 midbrain. SRRM2 was absent or faint, yet 3D imaging revealed near-complete SRRM2-pTauS396 co-localization (99% in PSP-1 cortex, 89% in PSP-4 midbrain), regardless of SRRM2 abundance. These findings highlight SRRM2 association with pTauS396 in tangle of PSP.

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2026-07-04 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.

Open article ↗

2026-07-03 | The role of SUMOylation in regulating proteins that drive neuronal disease progression.

Open article ↗

2026-07-02 | Nuclear Speckle Protein SRRM2 Co-localized with Pathological Tau (pTauS396) in Neuronal and Glial Cells in Progressive Supranuclear Palsy.

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Drug Discovery Landscape

30 orphan drug designations for Progressive supranuclear palsy.

Drug	Therapy type	Regulator	Orphan designation	Approval	Sponsor
2'-methoxyethyl antisense gapmer oligonucleotide against MAPT mRNA	oligonucleotides	EMA	2026-02-23	—	Novartis Europharm Limited
2'-methoxyethyl antisense gapmer oligonucleotide against MAPT mRNA	oligonucleotides	FDA	2026-02-04	—	Novartis Pharmaceuticals Corporation
a fully human IgG1k anti-programmed death ligand-1 (PD-L1) monoclonal antibody	antibodies	FDA	2025-06-23	—	ImmunoBrain Checkpoint Inc.
Tertomotide	peptides	EMA	2025-05-22	—	Pharmaceutical Research Associates Group B.V.
tertomotide	peptides	FDA	2025-05-01	—	GemVax & KAEL Co., Ltd.
Sodium selenate	small molecules	EMA	2023-10-13	—	Monash University
izaflortaucipir (proposed INN)	small molecules	FDA	2021-01-05	—	Lantheus Biosciences Ltd.
Fasudil	small molecules	FDA	2020-12-21	—	Woolsey Pharmaceuticals, Inc.
(S)-N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide, hydrochloride salt	small molecules	EMA	2020-12-09	—	Ferrer Internacional S.A.
2-(2-(18F)fluoropyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine	small molecules	EMA	2020-08-21	—	Life Molecular Imaging GmbH
Humanized IgG4 S228P monoclonal antibody targeting the cis conformation of the phosphorylated Thr231-Pro232 motif in tau	antibodies	FDA	2020-06-16	—	Pinteon Therapeutics Inc.
di-deuterated linoleic acid	small molecules	FDA	2020-01-28	—	Retrotope, Inc.
competitive and reversible small molecule inhibitor of the O-linked-B-N-acetylglucosaminidase enzyme	small molecules	FDA	2018-07-10	—	Ferrer Internacional, S.A.
1-(fluoro-18F)-3-((2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol	small molecules	FDA	2017-11-01	—	Aprinoia Therapeutics
recombinant humanized IgG4P monoclonal antibody with specificity for human tau	antibodies	FDA	2017-09-05	—	UCB, Inc.
N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine disulphate salt	small molecules	FDA	2017-03-20	—	Alzprotect sas
tolfenamic acid	small molecules	FDA	2016-07-13	—	Nasser H. Zawia
Tilavonemab	antibodies	EMA	2016-04-28	—	Abbvie Deutschland GmbH & Co. KG
competetive small molecule inhibitor of the enzyme O-GlcNAcase	small molecules	FDA	2016-03-10	—	Merck & Company, Inc.
Tolfenamic acid	small molecules	EMA	2016-02-17	—	RV Developpement
Humanised IgG4 monoclonal antibody against extracellular tau	antibodies	EMA	2015-07-28	—	Biogen Netherlands B.V.
Anti-eTau Humanized IgG4 Monoclonal Antibody	antibodies	FDA	2015-05-13	—	Biogen, Inc.
N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine disulphate salt	small molecules	EMA	2015-02-12	—	AlzProtect sas
recombinant humanized anti-tau antibody	antibodies	FDA	2015-01-22	—	AbbVie, Inc.
(2'R,3'S)-2'-hydroxy-N-carboxy-3'-amino-5'-methyl-hexanoic,N-tert-butyl ester, 13 ester 5B-20-epoxy-1B,2a,4a,7B,9a,10a,13a-heptahydroxy-4,10-diacetate-2-benzoate-(1"S)-7,9-acrolein acetal-11(15-1)-abeotaxane	small molecules	FDA	2014-06-23	—	CNS Pharmaceuticals, Inc.
5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride	small molecules	FDA	2011-04-18	—	Mithridion, Inc.
Methylthioninium	small molecules	EMA	2010-11-26	—	Pharma Gateway AB
davunetide	peptides	FDA	2009-12-07	—	Allon Therapeutics, Inc.
Tideglusib	—	EMA	2009-10-28	—	[INACTIVE] Noscira S.A.
4-benzyl-2-(a-naphtyl)-1,2,4-thiadiazolidine-3,5-dione	small molecules	FDA	2009-10-13	—	NOSCIRA, S.A.

Progressive supranuclear palsy

Progressive supranuclear palsy

Progressive supranuclear palsy

Overview

Population

Burden

Therapies

Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders

Research Papers

2026-07-04 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.

2026-07-03 | The role of SUMOylation in regulating proteins that drive neuronal disease progression.

2026-07-02 | Nuclear Speckle Protein SRRM2 Co-localized with Pathological Tau (pTauS396) in Neuronal and Glial Cells in Progressive Supranuclear Palsy.

2026-07-04 | Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.

2026-07-03 | The role of SUMOylation in regulating proteins that drive neuronal disease progression.

2026-07-02 | Nuclear Speckle Protein SRRM2 Co-localized with Pathological Tau (pTauS396) in Neuronal and Glial Cells in Progressive Supranuclear Palsy.

Drug Discovery Landscape

Updated: Aug 13, 2026