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Review
. 2020 Oct 22;6(4):239.
doi: 10.3390/jof6040239.

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

Karen Joy Shaw  1 , Ashraf S Ibrahim  2   3
Affiliations
Review

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

Karen Joy Shaw et al. J Fungi (Basel). .

Abstract

Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by Candida, Aspergillus 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 Candida and azole-resistant Aspergillus. Manogepix is also active against pathogens that demonstrate intrinsic resistance to other drug classes, such as Scedosporium, Lomentospora prolificans, and Fusarium with variable activity against Mucorales. Fosmanogepix demonstrates significant in vivo efficacy in mouse and rabbit disseminated infection models due to C. albicans, C. glabrata, C. auris, C. tropicalis, Coccidioides immitis, and F. solani as well as pulmonary infection models of A. fumigatus, A. flavus, S. prolificans, S. apiospermum and Rhizopus arrhizus. 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.

Keywords: APX001; APX001A; Aspergillus; Candida; FMGX; Gwt1; MGX; antifungal; fosmanogepix; manogepix; rare mold.

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Conflict of interest statement

K.J.S. was an employee of Amplyx and is now an independent consultant at Hearts Consulting Group, LLC. A.S.I. has received research support to the Lundquist Institute at Harbor-UCLA Medical Center from Amplyx, Astellas, and Cidara and has served on advisory boards of Amplyx, Astellas, Cidara and Navigen.

Figures

Figure 1
Figure 1
The structures of fosmanogepix and manogepix.
Figure 2
Figure 2
The mechanism of action of manogepix. Modified from 2019 Covel et al. [26]. Gwt1 is an enzyme which catalyzes an acyl group transfer reaction, an essential part of the GPI biosynthesis pathway. This occurs in the lumen of the endoplasmic reticulum. Gwt1 catalyzes the inositol acylation of glucosaminyl phosphatidylinositol (GlcN-PI), resulting in the formation glucosaminyl(acyl)phosphatidylinositol (GlcN(acyl)PI), an intermediate in the biosynthesis of GPI anchors.
See this image and copyright information in PMC

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