In vitro activity of manogepix against Candida spp. displaying elevated echinocandin MIC results

ABSTRACT Fosmanogepix is the prodrug of manogepix, an antifungal agent with a novel mechanism of action targeting the cell wall anchoring protein Gwt1. Fosmanogepix is currently in a Phase 3 clinical trial for the treatment of candidemia and invasive candidiasis (CIC). Echinocandins are first-line recommendations for empiric treatment of CIC, but resistance rates are rising, particularly in Candida glabrata . Given its unique mechanism of action, manogepix might retain activity against Candida spp. isolates that are non-susceptible to echinocandins, although supporting data are limited. Here, we collected 129 Candida spp. isolates from worldwide surveillance testing between 2017 and 2024 that were either resistant or non-wild type (WT) to ≥1 echinocandin when applying the Clinical and Laboratory Standards Institute breakpoints or epidemiological cutoff values. Isolates included 74 C. glabrata , 19 C. albicans , 14 C. auris , 14 C. tropicalis , 3 C. dubliniensis , 2 C. guilliermondii , and 1 each of C. krusei , C. lusitaniae , and C. parapsilosis . Sequencing of the gene encoding the echinocandin target was performed in all isolates and 75/129 (58.1%) had ≥1 alteration in a hotspot region of FKS1 and/or FKS2. Manogepix maintained low minimum inhibitory concentrations (MICs) across all isolates with only one C. auris isolate with a MIC above the prior WT-upper limit-defined value of 0.03 mg/L. This isolate had an alteration in Tac1B but wild-type Gwt1. All isolates were WT for amphotericin B and fluconazole resistance varied depending on species from 0% to 100%. The continued clinical development of manogepix for the treatment of CIC is warranted, including against resistant isolates based on these data.