MK-8719 is an oral O-GlcNAcase (OGA) inhibitor developed by Merck & Co. (known as MSD outside the United States and Canada). It was one of the first brain-penetrant OGA inhibitors to advance to clinical development, completing Phase 1 studies demonstrating target engagement in healthy volunteers[1][2].
MK-8719 represents Merck's entry in the tauopathy therapeutic space, targeting the same O-GlcNAcylation pathway as other OGA inhibitors (FNP-223, LY-3372689) but with distinct pharmaceutical properties designed for optimal brain penetration.
MK-8719 is a potent, selective OGA inhibitor that increases O-GlcNAcylation levels on tau protein:
The scientific foundation rests on the yin-yang hypothesis: phosphorylation and O-GlcNAcylation compete for the same serine/threonine residues on tau. By inhibiting OGA, MK-8719 shifts the balance toward protective O-GlcNAcylation[3][4].
| Field | Detail |
|---|---|
| Sponsor | Merck & Co. |
| Phase | Phase 1 (completed) |
| Subjects | Healthy volunteers |
| Design | Single ascending dose, multiple ascending dose |
| Primary endpoint | Safety, tolerability, pharmacokinetics |
| Key finding | Dose-dependent increase in CSF O-GlcNAcylation |
The Phase 1 study demonstrated:
As of early 2026, Merck has not announced Phase 2 development plans for MK-8719. Several factors may influence future development decisions:
| Property | MK-8719 | FNP-223 | LY-3372689 |
|---|---|---|---|
| Company | Merck | Ferrer | Eli Lilly |
| Brain penetration | High | Moderate | Moderate |
| Phase | Phase 1 | Phase 2 | Phase 2 |
| Indication | Not announced | PSP | AD, PSP |
| Status | On hold | Active | Active |
While MK-8719 is a small molecule OGA inhibitor, Eli Lilly's LY-3372689 (zaniglusemab) is also a small molecule OGA inhibitor that advanced further:
| Dimension | MK-8719 | LY-3372689 |
|---|---|---|
| Development stage | Phase 1 (completed) | Phase 2 (MAGNOLIA/LOTUS) |
| Company | Merck | Eli Lilly |
| Clinical trials | NCT04195312 | NCT05063539, NCT05682807 |
| Indications | Not launched | AD, PSP |
| Status | No announced Phase 2 | Active |
Merck's decision not to advance MK-8719 into Phase 2 may reflect strategic prioritization rather than efficacy concerns, as Phase 1 data demonstrated target engagement.
MK-8719 Phase 1 Study. 2020. ↩︎
Kim, C., et al. Discovery of MK-8719 as a potent brain-penetrant O-GlcNAcase inhibitor for tauopathy. Journal of Medicinal Chemistry. 2020. ↩︎
Trapps, S., et al. O-GlcNAcylation in tauopathy: From mechanisms to therapy. Nature Reviews Neurology. 2023. ↩︎
Yuzwa, S. A., et al. Increasing O-GlcNAcylation reduces pharmacologically reversible amyloid and tau pathology. Nature Chemical Biology. 2012. ↩︎
West, T., et al. Target engagement and biomarkers in OGA inhibitor trials. Alzheimer's & Dementia. 2024. ↩︎