In Vitro Activity of Manogepix against Multidrug-Resistant and Panresistant Candida auris from the New York Outbreak

Abstract

An ongoing Candida auris outbreak in the New York metropolitan area is the largest recorded to date in North America. Laboratory surveillance revealed NY C. auris isolates are resistant to fluconazole, with variable resistance to other currently used broad-spectrum antifungal drugs, and that several isolates are pan-resistant. Thus, there is an urgent need for new drugs with a novel mechanism of action to combat the resistance challenge. Manogepix (MGX) is a first-in-class agent that targets the fungal Gwt1 enzyme. The prodrug, fosmanogepix, is currently in Phase 2 clinical development for the treatment of fungal infections. We evaluated the susceptibility of 200 New York C. auris isolates to MGX and 10 comparator drugs using CLSI methodology. MGX demonstrated lower MICs than comparators (MIC50 and MIC90 0.03 mg/L; range 0.004-0.06 mg/L). The local ECV (epidemiological cutoff value) for MGX indicated all C. auris isolates were within the population of wild-type (WT) strains; 0.06 mg/L defines the Upper-Limit of Wild-Type (UL-WT). MGX was 8-32-fold more active than the echinocandins, 16-64-fold more active than the azoles, and 64-fold more active than amphotericin B. No differences were found in the MGX or comparators' MIC50, MIC90, or geometric mean (GM) values when subsets of clinical, surveillance, and environmental isolates were evaluated. The range of MGX MIC values for six C. auris pan-resistant isolates was 0.008-0.015 mg/L, and the median and mode MIC values were 0.015 mg/L, demonstrating that MGX retains activity against these isolates. These data support further clinical evaluation of fosmanogepix for the treatment of C. auris infections, including highly resistant isolates.

Novel antifungal agents in clinical trials

“…Among 16 C. auris isolates from Europe and Asia, fosmanogepix demonstrated a minimum inhibitory concentration (MIC) required to inhibit growth of 90% of organisms (MIC 90 ) value that was 8-fold lower than that of anidulafungin, the next most active agent. Highly potent in vitro activity was also observed in six pan-resistant C. auris isolates from New York (MIC range 0.008 µg/mL to 0.015 µg/mL) 6 . Furthermore, in a neutropenic mouse model of disseminated C. auris , treatment with fosmanogepix led to significantly improved survival and decreased fungal burden in brain tissue as compared to anidulafungin 5 .…”

The Neosartorya fischeri Antifungal Protein 2 (NFAP2): A New Potential Weapon against Multidrug-Resistant Candida auris Biofilms

“…Thus, biofilms serve as a continuous source of C. auris -related candidaemia [ 8 ]. Currently, several novel antifungal drugs are under development against C. auris , including ibrexafungerp [ 19 ], manogepix [ 20 ], VT-1598 [ 21 ], and rezafungin [ 22 ] and they may represent potential treatment options in the near future. However, considering the increasing number of multidrug-resistant C. auris isolates, new and alternative therapeutic strategies are needed to prevent and eliminate the growth of C. auris biofilms from indwelling devices.…”

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

“…Fosmanogepix (APX001) is currently in Phase II trials for invasive fungal infections. Both fosmanogepix and manogepix (APX001A) are currently under investigation and proofs of their in vivo efficacy against C. auris infection accumulate [ 105 , 106 , 107 , 108 , 109 ]. When analyzing its chemical structure, it appeared that APX001A displayed protonable nitrogen moieties (primary amine and pyridine) coupled with a lipophilic benzyl group.…”