In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017

Abstract

Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e., Candida (except Candida krusei), Aspergillus, and hardto-treat molds, including Fusarium and Scedosporium. In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 (1.8%) Cryptococcus neoformans var. grubii isolates, 14.7% were Aspergillus spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC 50 , 0.008 g/ml; MIC 90 , 0.06 g/ml) was the most active agent tested against Candida sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC 90 values were 16-to 64-fold higher. Similarly, APX001A (MIC 50 , 0.25 g/ml; MIC 90 , 0.5 g/ml) was Ն8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii. Against Aspergillus spp., AXP001A (50% minimal effective concentration [MEC 50 ], 0.015 g/ml; MEC 90 , 0.03 g/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (Ͼ98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Scedosporium spp. (MEC values, 0.015 to 0.06 g/ml). APX001A demonstrated potent in vitro activity against recent fungal isolates, including echinocandin-and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.

Fungal Cell Wall: Emerging Antifungals and Drug Resistance

“…(Stevens, 2000; Cordeiro et al, 2006), while a recent study described strong in vitro activity of echinocandins against Coccidioides immitis (Thompson et al, 2017). The data presented in this table are based on the references: Aguilar-Zapata et al (2015); Arendrup et al (2018a); Shaw et al (2018); Castanheira et al (2012); Goldberg et al (2000); Hage et al (2011); Hector et al (1990); Lamoth and Alexander (2015); Li and Rinaldi (1999); Nakai et al (2003); Pfaller et al (2019); Thompson et al (2017); Viriyakosol et al (2019); Zhao et al (2018) .…”

Antifungal Therapy: New and Evolving Therapies

“…• Manogepix (APX001A and formerly E1210) is an oral and IV broad-spectrum antifungal targeting the highly conserved fungal enzyme Gwt1. [109][110][111][112] Inhibition of Gwt1 blocks the inositol acylation of glycosylphosphatidylinositol-anchored proteins and compromises fungal wall integrity. Manogepix is active against most pathogenic fungi such as Candida spp.…”

“…(including caspofungin-resistant strains but not C. krusei), C. neoformans, Aspergillus spp., Scedosporium spp., and other rare molds. 109,110 While awaiting further improvement in our options to treat invasive fungal infections, a good understanding of the clinically relevant features of antifungals, which drive their use in terms of drug selection and management, is crucial for improving the prognosis of infected patients.…”

New Approaches for Cryptococcosis Treatment

“…The APX001A MIC ranged from 0.03 to 2 µg/mL for 48 Cryptococcus spp. clinical isolates in vitro [61,62], and demonstrated in vitro synergism with FLC [62]. APX001 alone or in combination with FLC decreased the fungal burden in the lungs and brain using cryptococcal meningitis murine model [62].…”