Fosmanogepix (DB15183): A Comprehensive Monograph on a First-in-Class Investigational Antifungal Agent

Executive Summary

Fosmanogepix is an investigational, first-in-class antifungal agent that represents a potentially transformative advancement in the treatment of invasive fungal infections (IFIs). As a water-soluble N-phosphonooxymethylene prodrug, fosmanogepix is rapidly and completely converted in vivo to its active moiety, manogepix. The therapeutic action of manogepix is derived from a novel mechanism: the specific inhibition of the fungal enzyme Gwt1 (Glycosylphosphatidylinositol-anchored Wall protein Transfer 1). This enzyme is essential for an early step in the biosynthesis of GPI anchors, which are required to attach critical mannoproteins to the fungal cell wall. By disrupting this pathway, manogepix compromises fungal cell wall integrity, inhibits virulence factors such as hyphal and biofilm formation, and ultimately leads to fungal cell death.

The clinical promise of fosmanogepix is underscored by its broad spectrum of activity. In vitro and in vivo studies have demonstrated potent activity against a wide array of clinically significant yeasts and molds. This includes common pathogens such as Candida and Aspergillus species, as well as difficult-to-treat, multidrug-resistant organisms like Candida auris, echinocandin-resistant Candida, and azole-resistant Aspergillus. Furthermore, it has shown activity against rare molds that are often intrinsically resistant to standard therapies, including species of Fusarium, Scedosporium, and Lomentospora prolificans.