P-1194. Activity of manogepix against mould isolates collected from the US in 2023

TL;DR

Manogepix shows strong in vitro activity against various US mould isolates, including those resistant to other antifungal drugs.

Contribution

The study evaluates the effectiveness of manogepix against a diverse set of clinical mould isolates from 2023 in the US.

Findings

Manogepix had significantly lower MEC90 values than azoles for Aspergillus fumigatus and Aspergillus niger.

Manogepix showed potent activity against Fusarium and Scedosporium/Lomentospora isolates with high MICs to other agents.

Manogepix MECs for Zygomycota were comparable to other antifungal agents.

Abstract

Manogepix (MGX) is a novel agent targeting the fungal Gwt1 enzyme. This agent is undergoing phase 3 clinical trials for invasive candidiasis and mould infections. Here, we assessed the in vitro activity of MGX against US mould isolates from invasive infections.

A total of 94 mould isolates from 12 hospitals in 2023 were tested. Confirmatory identification was performed by MALDI-TOF or 28S sequencing. Isolates were tested by reference broth microdilution method according to CLSI guidelines against MGX, voriconazole (VRC), posaconazole (POS), isavuconazole (ISA), and amphotericin B (AMB). Susceptible, nonsusceptible (NS), wildtype (WT), or nonwildtype (NWT) isolates were identified applying CLSI breakpoints or epidemiological cutoff values (ECV). No breakpoints or ECVs are available for MGX.

27 mould species and 11 genera were represented (Figure 1). Source of infection was varied (Figure 2). For 44 Aspergillus fumigatus (AFUM), MGX MEC90 was 0.03 mg/L, 16 to 32-fold lower than MIC90 for azoles (Table 1). 6.8% of AFUM were NS to ISA and 11.4% NS to VRC. For VRC-NS AFUM (n = 5), MGX MECs were 0.008 – 0.03 mg/L. For 9 Aspergillus niger species complex (ANSC), MGX MECs were 0.004-0.015 mg/L, 64 to 500-fold lower than MIC for azoles. All ANSC isolates were WT to VRC and ISA. For 9 Fusarium spp., MGX MECs were 0.004 – 0.03 mg/L while all azoles had limited activity (MICs ≥ 4 mg/L). For 5 Scedosporium/Lomentospora, MGX MECs were 0.008 to 0.03 mg/L, comparator agent MICs were >500-fold higher. For the 8 Zygomycota (5 Rhizopus spp., 2 Mucor spp., and 1 Lichtheimia), MGX MECs ranged from 0.25 to 4 mg/L, which was similar to other comparators.

MGX has potent in vitro activity against mould isolates collected from invasive infections as part of a worldwide surveillance program. MGX has low MECs for challenging moulds including azole-R or azole-NWT Aspergillus spp. and Fusarium spp. and Scedosporium/Lomentospora spp. with elevated MICs to other agents. MGX is a promising novel antifungal agent for the treatment of invasive mould infections, including those caused by resistant isolates and warrants further development for clinical use.

Marisa Winkler, MD, PhD, Basilea: Advisor/Consultant|Basilea: Grant/Research Support|GSK: Advisor/Consultant|GSK: Grant/Research Support|Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pulmocide: Advisor/Consultant|Pulmocide: Grant/Research Support Mariana Castanheira, PhD, Melinta Therapeutics: Advisor/Consultant|Melinta Therapeutics: Grant/Research Support

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