Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections

Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by <i>Candida, Aspergillus</i> and rare molds. Fosmanogepix is the N-phosphonooxymethylene prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1. Manogepix demonstrates broad spectrum in vitro activity against yeasts and molds, including difficult to treat pathogens. Because of its novel mechanism of action, manogepix retains potency against many resistant strains including echinocandin-resistant <i>Candida</i> and azole-resistant <i>Aspergillus.</i> Manogepix is also active against pathogens that demonstrate intrinsic resistance to other drug classes, such as <i>Scedosporium</i><i>,</i> <i>Lomentospora</i> <i>prolificans</i>, and <i>Fusarium</i> with variable activity against Mucorales. Fosmanogepix demonstrates significant in vivo efficacy in mouse and rabbit disseminated infection models due to <i>C. albicans, C. glabrata, C.</i> <i>auris</i><i>, C. tropicalis, Coccidioides</i> <i>immitis</i><i>,</i> and <i>F.</i> <i>solani</i> as well as pulmonary infection models of <i>A. fumigatus, A. flavus, S.</i> <i>prolificans</i><i>, S.</i> <i>apiospermum</i> and <i>Rhizopus</i> <i>arrhizus</i><i>.</i> Clinical trials demonstrated high oral bioavailability (>90%), enabling switching between fosmanogepix intravenous and oral formulations without compromising blood levels. Favorable drug-drug interaction, tolerability, and wide tissue distribution profiles are observed making fosmanogepix an attractive option for the treatment of invasive fungal infections. This systematic review summarizes the findings of published data on fosmanogepix.