Therapeutic Potential of Fosmanogepix (APX001) for Intra-abdominal Candidiasis: from Lesion Penetration to Efficacy in a Mouse Model
- 18 March 2021
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 65 (4)
- https://doi.org/10.1128/aac.02476-20
Abstract
Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated form of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug resistant breakthrough infections are common in some institutions despite the use of echinocandins as first line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in Phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological property and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in infected liver tissues in a clinically relevant IAC mouse model due to C. albicans. Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed absolute drug quantitation were employed to evaluate drug penetration into liver abscess lesions both spatially and quantitatively. The partitioning of MGX into lesions occurred slowly after a single dose; however robust accumulation in the lesion was achieved after 3 days of repeated dosing. Associated with this drug penetration pattern, reduction in fungal burden and clearance in the liver were observed in mice receiving the multi-day FMGX regimen. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC.Funding Information
- Amplyx (Research contract)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI109025)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (S10 OD023524-01, S10 OD018072-01)
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