Fosmanogepix: A comprehensive review of its origin, mechanism, antifungal efficacy, and resistance (Review).

The escalating burden of invasive fungal infections, compounded by rising antifungal resistance and evolving pathogen epidemiology, underscores the urgent need for novel agents. There is a requirement for these novel agents to combine broad-spectrum activity with >90% oral bioavailability and a 48% acceptable safety profile. Fosmanogepix, an N-phosphonooxymethylene prodrug of manogepix (APX001A), is a first-in-class glycosylphosphatidylinositol (GPI)-anchored wall transfer protein 1 (Gwt1) inhibitor in Phase III clinical trials for invasive fungal infections. It is a potent inhibitor of the fungal enzyme Gwt1, which blocks GPI-anchored protein maturation and disrupts cell wall integrity. Manogepix has broad in vitro activity against yeasts and molds, including drug-resistant and intrinsically resistant pathogens. Fosmanogepix shows notable in vivo efficacy in mouse and rabbit models of disseminated candidiasis, coccidioidomycosis, fusariosis, pulmonary aspergillosis, scedosporiosis and mucormycosis. Clinical trials have demonstrated high oral bioavailability (90%), allowing seamless intravenous-to-oral switching. Favorable drug-drug interaction, tolerability and effective tissue distribution profiles make fosmanogepix an attractive option for treating invasive fungal infections. However, emerging resistance mechanisms, including Gwt1 target mutations (such as V162A/V163A), efflux pump overexpression mediated by transcription factor mutations (Tac1B, Tac1, Pdr1), and calcineurin-dependent calcium signaling activation, pose potential threats to its long-term clinical utility. The present narrative review summarized published findings on fosmanogepix, encompassing its origin, mechanism of action, antifungal efficacy, resistance mechanisms, and combination strategies through in vitro, in vivo, and clinical investigations.