O-GlcNAcylation is a 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.
OGA (O-GlcNAcase) removes O-GlcNAc from proteins. Inhibiting OGA increases O-GlcNAcylation, thereby:
This is a fundamentally different mechanism from anti-tau antibodies (which clear existing aggregates) or ASOs (which reduce total tau production).
| Field | Detail |
|---|---|
| Company | Ferrer International (Barcelona) |
| Drug | FNP-223 (formerly ASN-561) |
| Target | OGA (O-GlcNAcase) |
| Indication | PSP (Progressive Supranuclear Palsy) |
| Phase | Phase 2 |
| Trial | PROSPER (NCT05649734) |
| Enrollment | 220 patients (completed recruitment) |
| Design | Randomized, double-blind, placebo-controlled |
| Duration | 52 weeks treatment |
| Primary endpoint | PSP Rating Scale (PSPRS) change from baseline |
| Results expected | 2026 |
| CSF biomarker | O-GlcNAc levels, p-tau, NfL |
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.
| Field | Detail |
|---|---|
| Company | Merck & Co. |
| Drug | MK-8719 |
| Target | OGA |
| Phase | Phase 1 (completed) |
| Status | Development status unclear post-Phase 1 |
| Field | Detail |
|---|---|
| Company | Eli Lilly (acquired from Asceneuron) |
| Drug | LY-3372689 (zaniglusemab) |
| Target | OGA |
| Phase | Phase 2 |
| Indications | PSP, AD |
| Trial | LOTUS (PSP), MAGNOLIA (AD) |
| Company | Program | Stage | Notes |
|---|---|---|---|
| Ferrer | FNP-223 | Phase 2 (PSP) | PROSPER trial, 220 patients |
| Eli Lilly | LY-3372689 | Phase 2 (PSP, AD) | Acquired from Asceneuron |
| Merck | MK-8719 | Phase 1 completed | Status unclear |
| Alectos Therapeutics | Preclinical OGA | Preclinical | Early-stage, Vancouver |
| Research needed: additional companies |
To be populated: PIs of PROSPER trial, OGA biology experts, key academic labs
| Approach | Mechanism | Advantages | Disadvantages |
|---|---|---|---|
| OGA inhibitors | Increase O-GlcNAcylation → reduce p-tau | Oral, brain-penetrant, upstream of phosphorylation | New MOA, limited clinical data |
| Anti-tau antibodies | Clear extracellular/aggregated tau | Proven platform, multiple in clinic | IV/SC, may not reach intracellular tau |
| Tau ASOs | Reduce total tau production | Gene-level, potentially disease-modifying | Intrathecal, total tau reduction may have side effects |
| Kinase inhibitors | Block tau phosphorylation directly | Direct mechanism | Off-target kinase effects, selectivity challenge |
| Tau vaccines | Active immunization against tau | Long-lasting, one-time | Immune response variability |