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Therapeutic Potential of Fosmanogepix (APX001) for Intra-abdominal Candidiasis: from Lesion Penetration to Efficacy
Annie Lee1, Ning Wang1, Claire L Carter1
1Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.
Abstract:
Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated forms 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 properties and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in liver tissues in a clinically relevant IAC mouse model infected with Candida 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 multiday 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.
Insights
Fosmanogepix (FMGX) shows promise for treating difficult intra-abdominal candidiasis. Repeated dosing led to significant fungal reduction in mice, outperforming micafungin.
Area of Science:
- Mycology
- Pharmacology
- Infectious Diseases
Background:
- Intra-abdominal candidiasis (IAC) is a common invasive fungal infection.
- Treatment failure and drug resistance are significant challenges with current therapies like echinocandins.
- Fosmanogepix (FMGX) is a novel antifungal prodrug with oral and IV administration potential.
Purpose of the Study:
- To evaluate the drug penetration and efficacy of FMGX's active moiety, manogepix (MGX), in liver tissues for IAC.
- To assess FMGX's therapeutic potential against Candida albicans in a relevant IAC mouse model.
Main Methods:
- Utilized a clinically relevant IAC mouse model infected with Candida albicans.
- Employed Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) for spatial drug quantitation.
- Used laser capture microdissection (LCM)-directed absolute drug quantitation to assess MGX penetration into liver abscess lesions.
Main Results:
- MGX penetration into liver lesions was slow after a single dose but robust after 3 days of repeated FMGX dosing.
- Multiday FMGX treatment resulted in significant reduction in fungal burden and clearance in the liver.
- Micafungin showed only marginal reduction in fungal burden after 4 days of treatment.
Conclusions:
- FMGX demonstrates promising therapeutic potential for intra-abdominal candidiasis.
- The drug's efficacy is linked to achieving robust accumulation in liver lesions through repeated dosing.
- FMGX represents a potential new treatment option for challenging IAC cases.
