Therapeutic Potential of Fosmanogepix (APX001) for Intra-abdominal Candidiasis: from Lesion Penetration to Efficacy in a Mouse Model

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.

Holotoxin A1 from Apostichopus japonicus inhibited oropharyngeal and intra‐abdominal candidiasis by inducing oxidative damage in Candida albicans

“…The mouse model of intra-abdominal candidiasis was performed as described previously (Lee et al, 2021). Briefly, 21 female CD1 mice (4-6 weeks old) were infected intraperitoneally with 100 μl cell suspension prepared in sterile stool matrix containing 2 Â 10 7 CFU of C. albicans on day 0.…”

“…The prevalence of intraabdominal candidiasis was about 4.7 per 1000 (Azim et al, 2017). The intra-abdominal candidiasis models are widely used to investigate the virulence mechanisms of C. albicans (Ashizawa et al, 2019) and to evaluate the therapeutic effects of antifungal agents for systematic fungal infection (Lee et al, 2020(Lee et al, , 2021. In this study, we found that holotoxin A 1 showed potent therapeutic effects in intra-abdominal candidiasis by decreasing the fungal burden in liver, spleen and kidney without signs of systemic toxicities, suggesting holotoxin A 1 as a promising candidate for the treatment of intra-abdominal candidiasis.…”

Novel Therapeutic Approaches to Invasive Candidiasis: Considerations for the Clinician

“… 72 , 73 In a murine model of IAC, repeated doses of fosmanogepix could achieve good penetration in liver abscesses after 3 days and its efficacy in reducing liver fungal burden was superior to that of micafungin. 74 The penetration of fosmanogepix into the CNS was analyzed in one rabbit model of C. albicans IC and one murine model of C. auris IC. 73 , 75 In rabbits, the CNS tissue / plasma concentration ratio was 1 and fosmanogepix treatment achieved significant reduction in CNS fungal burden ( C. albicans ) for concentrations ranging from 25 to 100 mg/kg bid.…”

Antifungal Development and the Urgency of Minimizing the Impact of Fungal Diseases on Public Health

“…This enzyme is responsible for adding an acyl group to the inositol unit of glucosaminyl phosphatidylinositol (GlcN-PI), a key step in the biosynthesis of GPI anchors . The active compound of fosmanogepix, manogepix, has broad spectrum activity, including antifungal effects against Candida spp., Cryptococcus spp., Aspergillus spp., Fusarium spp., Scedosporium spp., and L. prolificans . − Fosmanogepix can reach the central nervous system, which places this drug as potential candidate to fight cryptococcal meningitis. ,,, A recent study in mice demonstrated that fosmanogepix is synergistic with amphotericin B against invasive pulmonary aspergillosis, invasive mucormycosis, and invasive fusariosis …”