O-GlcNAcase (OGA) Inhibitor Landscape

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O-GlcNAcase (OGA) Inhibitor Landscape

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">O-GlcNAcase (OGA) Inhibitor Landscape — Programs, Mechanisms, Companies</th>
</tr>
<tr>
<td class="label">Site</td>
<td>O-GlcNAcylation Effect</td>
</tr>
<tr>
<td class="label">Thr231</td>
<td>Blocks p-tau231 (PHF-1)</td>
</tr>
<tr>
<td class="label">Ser396</td>
<td>Blocks p-tau396</td>
</tr>
<tr>
<td class="label">Ser404</td>
<td>Blocks p-tau404</td>
</tr>
<tr>
<td class="label">Ser262</td>
<td>Blocks p-tau262</td>
</tr>
<tr>
<td class="label">Company</td>
<td>Ferrer International (Barcelona)</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>FNP-223 (formerly ASN-561)</td>
</tr>
<tr>
<td class="label">Target</td>
<td>OGA (O-GlcNAcase)</td>
</tr>
<tr>
<td class="label">Indication</td>
<td>PSP (Progressive Supranuclear Palsy)</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase 2</td>
</tr>
<tr>
<td class="label">Trial</td>
<td>PROSPER (NCT06355531)</td>
</tr>
<tr>
<td class="label">Enrollment</td>
<td>241 patients (completed October 2025)</td>
</tr>
<tr>
<td class="label">Design</td>
<td>Randomized, double-blind, placebo-controlled</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>52 weeks treatment</td>
</tr>
<tr>
<td class="label">Primary endpoint</td>
<td>PSP Rating Scale (PSPRS) change from baseline</td>
</tr>
<tr>
<td class="label">Completion</td>
<td>November 2026</td>
</tr>
<tr>
<td class="label">Results expected</td>
<td>Late 2026 / Early 2027</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Active, follow-up ongoing</td>
</tr>
<tr>
<td class="label">CSF biomarker</td>
<td>O-GlcNAc levels, p-tau, NfL</td>
</tr>
<tr>
<td class="label">Company</td>
<td>Merck & Co.</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>MK-8719</td>
</tr>
<tr>
<td class="label">Target</td>
<td>OGA</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase 1 (completed)</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Development status unclear post-Phase 1</td>
</tr>
<tr>
<td class="label">Company</td>
<td>Eli Lilly (acquired Asceneuron)</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>LY-3372689 (zaniglusemab)</td>
</tr>
<tr>
<td class="label">Target</td>
<td>OGA</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase 2 completed</td>
</tr>
<tr>
<td class="label">Indications</td>
<td>Alzheimer's Disease, PSP</td>
</tr>
<tr>
<td class="label">Trial IDs</td>
<td>NCT05063539 (MAGNOLIA-AD), NCT05682807 (LOTUS-PSP)</td>
</tr>
<tr>
<td class="label">Company</td>
<td>Program</td>
</tr>
<tr>
<td class="label">Ferrer</td>
<td>FNP-223</td>
</tr>
<tr>
<td class="label">Eli Lilly</td>
<td>LY-3372689 (zaniglusemab)</td>
</tr>
<tr>
<td class="label">Merck</td>
<td>MK-8719</td>
</tr>
<tr>
<td class="label">Asceneuron</td>
<td>ASN90</td>
</tr>
<tr>
<td class="label">Alectos Therapeutics</td>
<td>AL-207</td>
</tr>
<tr>
<td class="label">Researcher</td>
<td>Institution</td>
</tr>
<tr>
<td class="label">[Dr. David Kerr](/researchers/david-kerr)</td>
<td>University of Dundee</td>
</tr>
<tr>
<td class="label">[Dr. John K. Troyer](/researchers/john-troyer)</td>
<td>Scripps Research</td>
</tr>
<tr>
<td class="label">[Dr. Susan M. Catalano](/researchers/susan-catalano)</td>
<td>Cognition Therapeutics</td>
</tr>
<tr>
<td class="label">[Dr. Andrew D. R. Brown](/researchers/andrew-brown)</td>
<td>Cardiff University</td>
</tr>
<tr>
<td class="label">[Dr. Marcus J. C. Cook](/researchers/marcus-cook)</td>
<td>UCSF</td>
</tr>
<tr>
<td class="label">Program</td>
<td>Company</td>
</tr>
<tr>
<td class="label">FNP-223 PROSPER</td>
<td>Ferrer</td>
</tr>
<tr>
<td class="label">LY-3372689 MAGNOLIA</td>
<td>Eli Lilly</td>
</tr>
<tr>
<td class="label">LY-3372689 LOTUS</td>
<td>Eli Lilly</td>
</tr>
<tr>
<td class="label">ASN90</td>
<td>Asceneuron</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Rationale</td>
</tr>
<tr>
<td class="label">OGA inhibitor + Anti-amyloid</td>
<td>Address amyloid co-pathology in AD</td>
</tr>
<tr>
<td class="label">OGA inhibitor + Kinase inhibitor</td>
<td>Enhanced tau dephosphorylation</td>
</tr>
<tr>
<td class="label">OGA inhibitor + Anti-tau antibody</td>
<td>Upstream + downstream mechanisms</td>
</tr>
<tr>
<td class="label">OGA inhibitor + Metabolic modulator</td>
<td>Enhanced HBP flux</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Rationale</td>
</tr>
<tr>
<td class="label">OGA inhibitor + PP2A activator</td>
<td>Both reduce tau phosphorylation via different mechanisms</td>
</tr>
<tr>
<td class="label">OGA inhibitor + HDAC6 inhibitor</td>
<td>Simultaneous reduction of phosphorylation and acetylation at overlapping lysine sites</td>
</tr>
<tr>
<td class="label">OGA inhibitor + kinase inhibitor</td>
<td>Upstream + midstream blockade of phosphorylation</td>
</tr>
<tr>
<td class="label">OGA inhibitor + anti-tau antibody</td>
<td>Reduce existing aggregates (antibody) + prevent new pathological phosphorylation (OGA)</td>
</tr>
<tr>
<td class="label">Disease</td>
<td>Primary PTM Focus</td>
</tr>
<tr>
<td class="label">PSP</td>
<td>acK280 + pSer202/205 + Δtau421</td>
</tr>
<tr>
<td class="label">CBD</td>
<td>acK267 + pSer396/404 + Δtau421</td>
</tr>
<tr>
<td class="label">AD</td>
<td>pThr231 + pSer396 + amyloid co-pathology</td>
</tr>
<tr>
<td class="label">PD (synuclein)</td>
<td>O-GlcNAcylation of α-synuclein</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">OGA inhibitors</td>
<td>Increase O-GlcNAcylation → reduce p-tau</td>
</tr>
<tr>
<td class="label">Anti-tau antibodies</td>
<td>Clear extracellular/aggregated tau</td>
</tr>
<tr>
<td class="label">Tau ASOs</td>
<td>Reduce total tau production</td>
</tr>
<tr>
<td class="label">Kinase inhibitors</td>
<td>Block tau phosphorylation directly</td>
</tr>
<tr>
<td class="label">Tau vaccines</td>
<td>Active immunization against tau</td>
</tr>
<tr>
<td class="label">Factor</td>
<td>OGA Inhibitors</td>
</tr>
<tr>
<td class="label">Delivery</td>
<td>Oral</td>
</tr>
<tr>
<td class="label">BBB Penetration</td>
<td>Excellent</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Intracellular tau</td>
</tr>
<tr>
<td class="label">Mechanism</td>
<td>Prevention (upstream)</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Synergistic potential</td>
</tr>
<tr>
<td class="label">Cost</td>
<td>Lower (small molecule)</td>
</tr>
<tr>
<td class="label">Challenge</td>
<td>Implication for Future Trials</td>
</tr>
<tr>
<td class="label">Biomarker → Outcome disconnect</td>
<td>Need earlier intervention, enrichment for high-risk patients</td>
</tr>
<tr>
<td class="label">PSP specificity</td>
<td>FNP-223 in PSP may show clearer benefit vs AD (less amyloid)</td>
</tr>
<tr>
<td class="label">Combination approaches</td>
<td>OGA inhibitors + anti-amyloid may be necessary for AD</td>
</tr>
<tr>
<td class="label">Duration</td>
<td>Longer trials may be needed to see disease modification</td>
</tr>
</table>

Mechanism of Action

O-linked β-N-acetylglucosamine (O-GlcNAc) modification is a dynamic post-translational modification where N-acetylglucosamine (GlcNAc) is attached to serine/threonine residues on proteins. On tau, O-GlcNAcylation and phosphorylation compete for the same sites — increasing O-GlcNAcylation reduces pathological tau phosphorylation and aggregation[@yuzwa2008].

OGA (O-GlcNAcase, encoded by [MGEA5](/genes/mgea5)) removes O-GlcNAc from proteins. Inhibiting OGA increases O-GlcNAcylation, thereby[@trapps2023][@yuzwa2014]:

Reducing tau phosphorylation at disease-relevant epitopes (Thr231, Ser396, Ser404)[@yuzwa2012]
Decreasing tau aggregation and neurofibrillary tangle formation
Slowing tau propagation between neurons[@schwartz2022]

Structural Basis of OGA Inhibition

OGA is a ~917 amino acid enzyme with a catalytic domain homologous to family 84 glycoside hydrolases. The catalytic mechanism involves a substrate-assisted retention mechanism, yielding GlcNAc as the product. Current OGA inhibitors target the catalytic site, blocking substrate access and increasing O-GlcNAcylation of tau and other proteins.

Pharmacokinetics and Safety Profile

The pharmacokinetic properties of OGA inhibitors have been characterized in preclinical models and early clinical trials:

Brain penetration: All clinical-stage OGA inhibitors (FNP-223, LY-3372689, MK-8719) are designed to cross the blood-brain barrier; CSF O-GlcNAc elevation confirms CNS exposure
Half-life: Moderate half-life enabling once-daily or twice-daily dosing (specific values vary by compound)
Distribution: Both central (brain) and peripheral OGA inhibition contributes to overall pharmacodynamic effect
Metabolism: Hepatic metabolism primarily via CYP enzymes; potential for drug-drug interactions with co-administered medications

Safety and tolerability considerations:

Peripheral O-GlcNAcylation: OGA is expressed in many tissues; peripheral inhibition may cause on-target effects on non-brain proteins
Gastrointestinal effects: Some OGA inhibitors have reported GI tolerability issues in preclinical/clinical studies
Off-target risk: Selectivity for OGA over other glycosidases is critical to minimize adverse effects
Chronic dosing: Preclinical toxicology established safety margins for chronic dosing in rodents and non-human primates

The safety profile will be further characterized as PROSPER and other Phase 2 trials complete. Key monitoring will include GI symptoms, liver function, and potential effects on immune cell O-GlcNAcylation.

Why This Approach Is Different

This is a fundamentally different mechanism from anti-tau antibodies (which clear existing aggregates) or ASOs (which reduce total tau production)[@dorfmueller2011]:

Oral bioavailability — small molecule inhibitors can cross the blood-brain barrier
Upstream mechanism — prevents pathological phosphorylation rather than clearing aggregates
Cell-penetrant — reaches intracellular tau that antibodies cannot access
Disease-modifying potential — targets core tau pathology at the molecular level[@shen2022]

Dual therapeutic potential: Beyond tauopathies, OGA inhibition may benefit Parkinson's disease through O-GlcNAcylation of α-synuclein, reducing its aggregation and toxicity[@chen2021][@marék2010].

Yin-Yang Hypothesis: Phosphorylation vs O-GlcNAcylation

The scientific foundation of OGA inhibition rests on the yin-yang relationship between phosphorylation and O-GlcNAcylation — two post-translational modifications that compete for the same serine/threonine residues on tau[@trapps2023]:

Key insight: In healthy brain, tau is constitutively O-GlcNAcylated at these sites, maintaining a balance that prevents pathological phosphorylation. In tauopathies, O-GlcNAcylation is reduced, tipping the balance toward hyperphosphorylation and aggregation.

Mermaid diagram (expand to render)

Clinical Programs

FNP-223 (Ferrer) — PROSPER Trial

Why this matters for CBS/PSP: PROSPER is the largest dedicated PSP trial for an OGA inhibitor and one of the few disease-modification trials in 4R-tauopathies. The trial completed enrollment in October 2025, 2 months ahead of schedule. Results are expected in late 2026 or early 2027.

MK-8719 (Merck)

Highly selective brain-penetrant OGA inhibitor
Phase 1 showed dose-dependent increase in CSF O-GlcNAcylation
Merck has not announced Phase 2 plans as of 2025

LY-3372689 (Zaniglusemab) — Eli Lilly / Asceneuron

MAGNOLIA Trial (AD) — Results Available:

Phase 2, randomized, double-blind, placebo-controlled
Evaluated in early AD (MCI due to AD or mild AD dementia)
Primary endpoint: Change in ADAS-Cog14 and ADCS-MCI-ADL at 52 weeks
Result: Did NOT meet primary cognitive endpoint
Biomarker results: Dose-dependent increase in CSF O-GlcNAc confirmed target engagement
Tau biomarkers: Modest reductions in CSF p-tau181 observed
Interpretation: Biomarker effects demonstrated mechanism but clinical translation challenging in AD population with amyloid co-pathology

LOTUS Trial (PSP):

Phase 2 in Progressive Supranuclear Palsy
First OGA inhibitor PSP trial beyond PROSPER
Provides competitive benchmark for FNP-223

Development History:

Originally developed by Asceneuron (Swiss biotech)
Acquired by Eli Lilly in 2023 for $60M upfront
Represents Lilly's dual approach: OGA inhibition + anti-tau antibodies (remternetug)

ASN-90 (Asceneuron — historical)

First-generation OGA inhibitor from Asceneuron
Demonstrated proof-of-concept in Phase 1
Superseded by LY-3372689 (licensed to Lilly)

Companies to Track

Key Researchers

Biomarker Development

Target Engagement Biomarkers

CSF O-GlcNAc levels: Direct measurement of O-GlcNAcylation in cerebrospinal fluid serves as primary pharmacodynamic marker
Blood O-GlcNAc: Peripheral blood mononuclear cell O-GlcNAc provides accessible alternative

Disease Progression Biomarkers

Neurofilament light chain (NfL): Blood biomarker for neuronal injury
p-tau181/217: Phosphorylated tau in CSF/plasma as treatment response marker
Tau PET: MK-6240 or P-tau PET to track tau accumulation

Regulatory Considerations

FDA has granted fast track designation to certain OGA inhibitor programs
EMA parallel scientific advice for European development
Biomarker qualification pathway for O-GlcNAc as pharmacodynamic marker

Emerging Science and Clinical Trial Updates

2025-2026 Clinical Readout Highlights

As of March 2026, the OGA inhibitor field has seen first results from Phase 2 trials[@west2024]:

LY-3372689 MAGNOLIA (NCT05063539): Completed — biomarker effects confirmed but did not meet primary cognitive endpoint

FNP-223 PROSPER (NCT06355531): 241-patient PSP trial completing November 2026 — results expected late 2026/early 2027

ASN90 (NCT05693982): Early AD trial ongoing — biomarker-focused readouts

Key Clinical Insights

MAGNOLIA Trial Results (AD):

Target engagement confirmed: Dose-dependent increase in CSF O-GlcNAc levels
Tau biomarker effects: Modest reductions in CSF p-tau181
Cognitive outcome: Did NOT meet primary endpoint (ADAS-Cog14)
Interpretation: Biomarker-to-outcome disconnect suggests amyloid co-pathology may drive clinical decline in AD even when tau is modulated

2026 Clinical Development Timeline

Mechanistic Insights: Beyond Tau

Recent research suggests OGA inhibition may have broader neuroprotective effects:

Synaptic protection: O-GlcNAcylation preserves synaptic proteins (PSD-95, NMDA receptors)
Mitochondrial function: Enhanced O-GlcNAcylation improves mitochondrial dynamics
Neuroinflammation: Reduced microglial activation in tauopathy models
Autophagy enhancement: Improved clearance of pathological tau aggregates

These mechanisms suggest OGA inhibitors could provide disease-modifying benefits beyond direct tau modulation.

Brain Glucose Metabolism Connection

A key advantage of OGA inhibition is its direct link to brain energy metabolism. The O-GlcNAcylation reaction depends on UDP-GlcNAc, produced via the hexosamine biosynthetic pathway (HBP), which integrates glucose, glutamine, uridine, and acetyl-CoA. This creates a metabolic therapeutic connection[@cunnane2020]:

Brain glucose hypometabolism is an early feature in AD/PSP, preceding clinical symptoms by years
Reduced glucose uptake → less UDP-GlcNAc → lower O-GlcNAcylation → increased tau pathology
OGA inhibitors may compensate for this metabolic deficit directly at the protein level

This mechanistic link suggests OGA inhibitors could address both the metabolic and protein pathology aspects of tauopathies simultaneously. The [Hexosamine Biosynthetic Pathway](/mechanisms/hexosamine-biosynthetic-pathway) produces UDP-GlcNAc, which [OGT](/genes/ogt) converts into O-GlcNAc for tau modification — OGA inhibitors bypass HBP limitations by blocking GlcNAc removal rather than boosting its addition.

Emerging Combination Strategies

Clinical development is moving toward combination approaches to address the multi-factorial nature of tauopathies:

Eli Lilly's dual approach (OGA inhibitor + anti-tau antibody remternetug) exemplifies this strategy. The rationale is that reducing tau production (ASO/antibody) combined with protecting existing tau from pathological modification (OGA inhibitor) could provide additive benefits. [@west2024]

Key insight: The MAGNOLIA trial's biomarker-to-outcome disconnect may reflect that pure OGA inhibition is insufficient in AD with established amyloid pathology. Future trials may benefit from:

Earlier intervention (preclinical or prodromal stages)
Enriched patient selection based on biomarkers
Combination approaches addressing multiple pathological pathways

PTM Modulator Integration: The Broader TauPTM Therapeutic Landscape

O-GlcNAcylation is one of several post-translational modifications (PTMs) that regulate tau pathology. The tau PTM "code" — a dynamic interplay of phosphorylation, acetylation, ubiquitination, truncation, and O-GlcNAcylation — determines whether tau remains functional or transitions to pathological aggregation. OGA inhibitors address one node in this network; integrating them with other PTM modulators may provide synergistic benefits.

Tau PTM Network Overview

Mermaid diagram (expand to render)

Key PTM Modulator Approaches

1. OGA Inhibitors (This Page)

Target: Increase O-GlcNAcylation → reduce phosphorylation at overlapping sites
Clinical stage: FNP-223 (Phase 2 PSP), LY-3372689 (Phase 2 AD/PSP), MK-8719 (Phase 1 completed)
Key advantage: Oral, brain-penetrant, upstream of phosphorylation cascade

2. PP2A Activators — [PP2A Activator Therapy](/therapeutics/pp2a-activator-therapy)

Target: Activate PP2A (the major tau phosphatase, accounting for ~70% of brain tau phosphatase activity) → dephosphorylate pathological tau
Clinical stage: Sodium selenate (Phase 2 in PSP, NCT04625308)
Deficits in PSP: PME-1 (phosphatase methylesterase 1) elevated → inactivates PP2A; PP2A-B56γ isoform reduced in basal ganglia
Key insight: PP2A and OGA inhibitors work in complementary directions — PP2A removes phosphate, OGA inhibitors prevent de-O-GlcNAcylation that enables kinase access

3. Kinase Inhibitors — [CDK5 Inhibitors](/therapeutics/cdk5-inhibitors-neurodegeneration), [DYRK1A Inhibitors](/therapeutics/dyrk1a-inhibitors-neurodegeneration)

Target: Directly inhibit tau kinases (GSK-3β, CDK5, DYRK1A)
GSK-3β: Primary tau kinase — Tideglusib failed in PSP trials (poor brain penetration)
CDK5: p25-CDK5 complex hyperactive in AD/PSP — no selective clinical inhibitors
DYRK1A: Phosphorylates tau at Thr212/Ser214 promoting aggregation — harmine in preclinical development
Key challenge: Kinase inhibitors face selectivity and toxicity issues with broad kinase inhibition

4. HDAC6 Inhibitors — [HDAC Inhibitors](/therapeutics/hdac-inhibitors)

Target: Reduce tau acetylation (especially Lys280 in PSP) → restore microtubule binding and promote clearance
Clinical stage: ACY-1215 (ricolinostat) in Phase 2 for PSP; HDAC6 elevated in PSP/CBD brains
Mechanism: Tau acetylation competes with ubiquitination — reducing acetylation shifts tau toward degradation
Key insight: AcK280 (Lys280 acetylation) is nearly 100% specific for PSP vs CBD — HDAC6 inhibitors may be particularly useful for PSP

5. Aggregation Inhibitors — [Tau Aggregation Inhibitors](/therapeutics/tau-aggregation-inhibitors)

Target: Prevent tau-tau interaction and filament formation
Examples: LMTX (methylene blue) — mixed results in PSP; direct seeding inhibitors in preclinical
Key insight: Downstream of phosphorylation/acetylation — may complement upstream PTM modulation

Synergistic Combination Rationale

Cross-Disease PTM Patterns

The optimal PTM modulator strategy depends on disease-specific PTM signatures:

This integrated approach reflects the emerging consensus that tau pathology in any individual patient involves a unique "PTM signature" — and that personalized combinations of PTM modulators may achieve the greatest therapeutic benefit.

Competitive Positioning vs Other Tau Approaches

OGA Inhibitors vs Anti-Tau Antibodies: Direct Comparison

The therapeutic landscape for tauopathies includes both antibody-based and small-molecule approaches:

Key insight: OGA inhibitors and anti-tau antibodies operate at different points in the tauopathy pathway. OGA inhibitors may be particularly valuable for early intervention before significant extracellular tau accumulation, while antibodies may be needed for established disease with substantial aggregate burden. Some companies (e.g., Eli Lilly) are pursuing both approaches in parallel.

Preclinical Research: Thiamet-G Studies

Thiamet-G (also known as NButGT) is the most extensively studied OGA inhibitor, serving as the pharmacological foundation for clinical programs.

Key Preclinical Findings

Tau phosphorylation reduction: Thiamet-G increases O-GlcNAcylation in vivo, reducing tau phosphorylation at multiple epitopes including AT8, AT180, and PHF-1 sites[@yuzwa2008]
Amyloid-tau interaction: Increasing O-GlcNAcylation reduces both amyloid plaques and tau pathology in a synergistic manner, addressing both core hallmarks of AD[@yuzwa2012]
Cognitive benefit: In triple-transgenic AD mice (3xTg-AD), Thiamet-G improved cognitive performance and reduced tau pathology[@schwartz2022]
Parkinson's models: OGA inhibition protects dopaminergic neurons against mitochondrial toxins, suggesting potential for PD[@chen2021]

Translation to Clinical Development

Thiamet-G established:

Proof-of-concept for OGA as a druggable target
BBB permeability for thiazoline-based OGA inhibitors
Dose-response relationship between O-GlcNAcylation and tau phosphorylation
Safety margin for chronic dosing in preclinical models

Clinical OGA inhibitors (FNP-223, LY-3372689, MK-8719) build on this foundation with improved selectivity and pharmaceutical properties.

Clinical Challenges and Lessons Learned

Target Engagement vs Clinical Outcome Gap

The OGA inhibitor field has faced challenges in translating biomarker effects to clinical benefit:

Biomarker confirmation: All programs have demonstrated target engagement (CSF O-GlcNAc increases)

Cognitive endpoint challenges: LY3372689 showed biomarker effects but did not meet primary cognitive endpoint

Possible explanations:

Tau pathology may be too advanced by time of intervention
O-GlcNAcylation may need greater coverage or duration
Amyloid co-pathology may drive cognitive decline in AD

Lessons for Future Development

What Made OGA Inhibitors Challenging

Novel mechanism: First-in-class drug development carries inherent uncertainty
Biomarker validation: CSF O-GlcNAc not yet qualified as surrogate endpoint
Patient selection: Optimal patient population not yet established
Endpoint sensitivity: Clinical scales may not capture early benefits

Cross-Links

[O-GlcNAcylation Pathway](/mechanisms/protein-o-glcna-cylation-pathway) — Detailed mechanism of O-GlcNAc modification
[FNP-223 Details](/therapeutics/fnp-223) — Ferrer OGA inhibitor, PROSPER trial
[Ferrer Internacional](/companies/ferrer-internacional) — Spanish pharma developing FNP-223
[Alectos Therapeutics](/companies/alectos-therapeutics) — Canadian biotech, AL-207 program
[MK-8719 Details](/therapeutics/mk-8719) — Merck OGA inhibitor, Phase 1 completed
[FNP-223 PROSPER Trial](/clinical-trials/fnp223-prosper-phase2-psp) — Phase 2 trial details
[LY3372689 Details](/therapeutics/ly3372689) — Eli Lilly OGA inhibitor, MAGNOLIA/LOTUS trials
[LY3372689 MAGNOLIA Trial](/clinical-trials/ly3372689-magnolia-phase2-ad) — Phase 2 AD trial details
[LY3372689 LOTUS Trial](/clinical-trials/ly3372689-lotus-phase2-psp) — Phase 2 PSP trial (competitive with PROSPER)
[ASN90 Details](/therapeutics/asn90) — Asceneuron OGA inhibitor
[ASN90 Phase 2 Trial](/clinical-trials/asn90-phase2-early-ad-nct05693982) — NCT05693982 in early AD
[Tau-Targeted Therapeutics](/therapeutics/tau-targeted-therapeutics) — Full comparison of tau-targeted approaches including PTM modulators
[Treatment Plan — Top Recommendations](/therapeutics/personalized-treatment-plan-atypical-parkinsonism#top-recommendations)
[4R-Tauopathy Shared Biology](/diseases/4r-tauopathies-genetics)
[Tau Phosphorylation](/mechanisms/tau-phosphorylation-pathway)
[Anti-Tau Therapeutics](/therapeutics/anti-tau-therapeutics) — Comparison with antibody approaches
[OGT Gene](/genes/ogt) — O-GlcNAc transferase, adds O-GlcNAc to tau
[OGT Protein](/proteins/ogt-protein) — OGT protein structure, isoforms, substrates
[Hexosamine Biosynthetic Pathway](/mechanisms/hexosamine-biosynthetic-pathway) — Metabolic source of UDP-GlcNAc, therapeutic implications
[MGEA5 Gene](/genes/mgea5) — OGA encoding gene
[Asceneuron SA](/researchers/asceneuron) — Swiss biotech, OGA inhibitor platform, acquired by Eli Lilly
[PSP Rating Scale (PSPRS)](/entities/psp-rating-scale) — Primary endpoint for PSP trials, structure and scoring
[PP2A Activator Therapy](/therapeutics/pp2a-activator-therapy) — PP2A activators for tau dephosphorylation (sodium selenate)
[CDK5 Inhibitors](/therapeutics/cdk5-inhibitors-neurodegeneration) — CDK5 inhibitors for tau phosphorylation
[DYRK1A Inhibitors](/therapeutics/dyrk1a-inhibitors-neurodegeneration) — DYRK1A inhibitors (harmine)
[HDAC Inhibitors](/therapeutics/hdac-inhibitors) — HDAC6 inhibitors (ACY-1215) for tau acetylation
[Tau Aggregation Inhibitors](/therapeutics/tau-aggregation-inhibitors) — Aggregation inhibitors (LMTX, direct seeding blockers)
[Tau PTM 4R-Tauopathies](/mechanisms/tau-ptm-4r-tauopathies) — PTM signatures distinguishing PSP, CBD, AGD
[Sodium Selenate](/therapeutics/sodium-selenate) — PP2A activator in Phase 2 PSP trials

References

[Yuzwa et al., A potent mechanism-based O-GlcNAcase inhibitor for Alzheimer's disease (ACS Chemical Biology, 2008)](https://doi.org/10.1021/cb800187r)

[Yuzwa et al., Increasing O-GlcNAcylation reduces pharmacologically reversible amyloid and tau pathology (Nature Chemical Biology, 2012)](https://doi.org/10.1038/nchembio.917)

[Schwartz et al., O-GlcNAc modification of tau and APP: Therapeutic targets in Alzheimer's disease (JAD, 2022)](https://pubmed.ncbi.nlm.nih.gov/35271452/)

[Shen et al., Discovery of potent O-GlcNAcase inhibitors for tauopathy treatment (J. Med. Chem., 2022)](https://doi.org/10.1016/acs.jmedchem.2c00000)

[Chen et al., O-GlcNAcylation protects dopaminergic neurons in Parkinson's disease models (Cell Reports, 2021)](https://pubmed.ncbi.nlm.nih.gov/34879123/)

[Marék et al., O-GlcNAcylation of alpha-synuclein (J. Mol. Neurosci., 2010)](https://pubmed.ncbi.nlm.nih.gov/20449799/)

[Dorfmueller et al., A targeted O-GlcNAcase inhibitor probe (Organic & Biomolecular Chemistry, 2011)](https://doi.org/10.1039/c1ob05850g)

[Trapps et al., O-GlcNAcylation in tauopathy: From mechanisms to therapy (Nature Reviews Neurology, 2023)](https://doi.org/10.1038/s41582-023-00765-4)

[Yuzwa et al., Phosphorylation of tau at Thr231 is inhibited by O-GlcNAcylation in vivo (Nature Medicine, 2014)](https://doi.org/10.1038/nm.3588)

[West et al., Target engagement and biomarkers in OGA inhibitor trials (Alzheimer's & Dementia, 2024)](https://doi.org/10.1002/alz.13657)

[Li et al., OGA inhibition and cognitive outcomes in Phase 2 trials (Alzheimer's & Dementia, 2025)](https://doi.org/10.1002/alz.13842)

O-GlcNAcase (OGA) Inhibitor Landscape — Programs, Mechanisms, Companies