FNP-223 (Ferrer OGA Inhibitor)
Overview
<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">FNP-223 (Ferrer OGA Inhibitor)</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Trial ID</td>
<td>NCT06355531</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase 2</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Active, not recruiting</td>
</tr>
<tr>
<td class="label">Enrollment</td>
<td>220 patients (originally targeted)</td>
</tr>
<tr>
<td class="label">Sponsor</td>
<td>Ferrer Internacional S.A.</td>
</tr>
<tr>
<td class="label">Start Date</td>
<td>July 2024</td>
</tr>
<tr>
<td class="label">Completion Date</td>
<td>November 2026</td>
</tr>
<tr>
<td class="label">Sites</td>
<td>44 sites across EU, UK, and US</td>
</tr>
<tr>
<td class="label">Primary Endpoint</td>
<td>Change from baseline to week 52 in PSPRS (Progressive Supranuclear Palsy Rating Scale)</td>
</tr>
<tr>
<td class="label">Secondary Endpoints</td>
<td>Safety, tolerability, pharmacokinetics</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Company</td>
</tr>
<tr>
<td class="label">FNP-223</td>
<td>Ferrer</td>
</tr>
<tr>
<td class="label">LY3372689</td>
<td>Eli Lilly</td>
</tr>
<tr>
<td class="label">ASN90</td>
<td>Asceneuron</td>
</tr>
<tr>
<td class="label">MK-8719</td>
<td>Merck</td>
</tr>
</table>
FNP-223 is an oral O-GlcNAcase (OGA) inhibitor developed by Ferrer Internacional S.A., a Spanish pharmaceutical company. It is being evaluated in the PROSPER Phase 2 clinical trial for the treatment of progressive supranuclear palsy (PSP), a 4R-tauopathy characterized by tau protein aggregation in the brain[@prosper][@ferrer].
FNP-223 represents a novel disease-modifying approach that targets tau pathology through modulation of tau post-translational modifications, specifically by increasing O-GlcNAcylation which competes with pathological phosphorylation[@oglcnacylation2024].
Background: O-GlcNAcylation and Tau Pathology
O-GlcNAcylation is a post-translational modification where O-linked N-acetylglucosamine (O-GlcNAc) is added to serine and threonine residues on proteins, including tau. This modification is increasingly recognized as a key regulatory mechanism that competes with pathological phosphorylation[@oglcnacylation2024][@tau2025]:
- Physiological role: O-GlcNAcylation regulates protein function, stability, and localization
- Tau relationship: O-GlcNAcylation of tau at specific sites competes with phosphorylation at the same serine/threonine residues
- Key insight: O-GlcNAcylation at Thr231, Ser396, and Ser400 inhibits tau aggregation
- Disease context: In PSP and other tauopathies, tau is hyperphosphorylated at these same sites, leading to neurofibrillary tangle formation
The scientific rationale follows the "yin-yang" hypothesis: phosphorylation and O-GlcNAcylation compete for the same residues. By inhibiting OGA, FNP-223 shifts the balance toward protective O-GlcNAcylation, potentially reducing pathological tau phosphorylation and aggregation[@thiametg][@yu2017].
Mechanism of Action
FNP-223 is a potent, selective OGA inhibitor that increases O-GlcNAcylation levels on tau protein:
- Target: O-GlcNAcase (OGA) — the enzyme that removes O-GlcNAc from proteins
- Mechanism: Inhibiting OGA increases tau O-GlcNAcylation at pathological sites
- Effect: O-GlcNAcylated tau is less prone to pathological phosphorylation and aggregation
- Outcome: Potential disease modification by reducing toxic tau species
The OGA inhibitor approach offers several advantages over other tau-targeted strategies:
Oral bioavailability: Small molecule can be taken orally, improving patient convenience
Direct mechanism: Targets the fundamental yin-yang relationship between phosphorylation and O-GlcNAcylation
BBB penetration: Designed to cross the blood-brain barrier
4R-tau specificity: Particularly relevant for 4R-tauopathies like PSP where tau isoform balance is disruptedMermaid diagram (expand to render)
PROSPER Phase 2 Trial
Trial Design
The PROSPER trial (NCT06355531) is a Phase 2 clinical trial evaluating FNP-223 in patients with Progressive Supranuclear Palsy[@prosper]:
The PROSPER trial is specifically designed for PSP, making it one of the largest dedicated PSP trials:
- Patient population: Clinically diagnosed PSP patients
- Duration: 52-week treatment period
- Enrollment completed: October 2025 (2 months ahead of schedule)
- Results expected: Late 2026 / early 2027
Why PSP Specifically?
PSP represents an ideal indication for OGA inhibitors:
4R-tauopathy: PSP is characterized by elevated 4R-tau, which may be particularly sensitive to O-GlcNAcylation effects
Unmet need: No approved disease-modifying treatments for PSP
Clear diagnosis: PSP has relatively well-defined clinical criteria compared to other tauopathies
Target engagement: CSF and PET biomarkers can measure OGA inhibition and tau changesComparison to Other OGA Inhibitors
FNP-223 competes with other OGA inhibitors in development, with key differences:
Key differentiators for FNP-223:
- PSP-specific trial (others focus on AD)
- Large 241-patient enrollment
- 44 international sites providing diverse patient population
- Results expected in late 2026/early 2027
Safety Profile
Based on available information, FNP-223 has demonstrated:
- Acceptable tolerability in preclinical studies
- Brain-penetrant properties following oral administration
- Dose-dependent pharmacokinetics supporting once-daily dosing
- Completed enrollment with no major safety signals reported
The 52-week treatment duration allows for assessment of both short-term tolerability and longer-term safety signals. Based on the LY3372689 clinical experience, OGA inhibitors have shown generally manageable safety profiles, with CSF biomarker data confirming target engagement.
Current Status and Next Steps
As of March 2026, the PROSPER trial is actively following patients with completion expected in November 2026. All 220 patients have been enrolled and are in the treatment or follow-up phase. Results are expected to be announced in late 2026 or early 2027.
Anticipated Results and Future Directions
The neurology community awaits PROSPER results with cautious optimism:
- Q4 2026: Topline results announcement expected
- 2027: Full publication of primary and secondary outcomes
- 2027-2028: Potential regulatory submissions if positive results
If successful, FNP-223 could become the first disease-modifying therapy for PSP, representing a major breakthrough for 4R-tauopathies.
If PROSPER results are positive, FNP-223 could become a first-in-class disease-modifying therapy for PSP, potentially expanding to other 4R-tauopathies including corticobasal degeneration (CBD).
Cross-References
- [OGA Inhibition Mechanism](/mechanisms/oga-inhibition-tau)
- [OGA Inhibition and Tau Pathway](/mechanisms/protein-o-glcna-cylation-pathway)
- [Tau Small-Molecule Therapeutics](/therapeutics/tau-small-molecules)
- [Tau Therapeutics Pipeline](/therapeutics/tau-therapeutics-pipeline)
- [PROSPER Trial](/clinical-trials/fnp223-psp-prosper)
- [PSP Treatment Plan](/therapeutics/personalized-treatment-plan-atypical-parkinsonism)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
References
[PROSPER Phase 2 Trial (NCT06355531)](https://clinicaltrials.gov/study/NCT06355531)
[Ferrer pipeline](https://www.ferrer.com/en)
[O-GlcNAcylation and tau in AD (Nature Reviews Neurology, 2024)](https://doi.org/10.1038/s41582-024-00850-3)
[Tau post-translational modifications (Cell, 2025)](https://doi.org/10.1016/j.cell.2025.01.010)
[Thiamet-G OGA inhibitor mechanism (Nature Chemical Biology, 2008)](https://pubmed.ncbi.nlm.nih.gov/18713746/)
[Yu et al., OGA inhibitor increases tau O-GlcNAcylation (JAD, 2017)](https://pubmed.ncbi.nlm.nih.gov/28767890/)Pathway Diagram
The following diagram shows the key molecular relationships involving FNP-223 (Ferrer OGA Inhibitor) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)