Phase 1 Study to Assess Safety, Tolerability and Pharmacokinetics of Single and Multiple Oral Doses of APX001 and to Investigate the Effect of Food on APX001 Bioavailability

In Vitro and In Vivo Evaluation of the Antifungal Activity of APX001A/APX001 against Candida auris

“…These dose levels were chosen based upon doses successfully used in a previous animal model ( 20 ). Phase 1 studies of APX001 has demonstrated that it has a long half-life in humans (∼2.5 days) ( 26 , 27 ); however, its half-life in mice is short (1 to 1.8 h depending upon the route of administration), necessitating multiple daily doses ( 20 , 28 ). The anidulafungin dose (10 mg/kg BID i.p.…”

“…Thus, it was anticipated that this dose regimen would be effective in this model. The doses of APX001 used in this model are greater than or equal to doses that have been previously shown to be effective in animal models of candidiasis or other invasive fungal infections ( 18 , 20 , 28 ) and achieve area under the concentration-time curve (AUC) after 24 h values in mice that are severalfold (∼3) lower than the steady-state AUC 0−24 values anticipated to be used in phase 2 studies in humans ( 26 , 27 ). In the current model of disseminated C. auris infection, APX001 resulted in significantly better survival than anidulafungin.…”

Significantly Improved Pharmacokinetics Enhances In Vivo Efficacy of APX001 against Echinocandin- and Multidrug-Resistant Candida Isolates in a Mouse Model of Invasive Candidiasis

“…Potent activity of APX001A/APX001 against a broad spectrum of Candida and Aspergillus species was demonstrated by extensive in vitro susceptibility assessments, as well as some in vivo evaluations ( 1 – 7 ). A long half-life of ∼2.5 days was observed in phase 1 clinical trials with APX001, in which safety, tolerability, and pharmacokinetics (PK) in healthy human subjects were assessed ( 8 , 9 ). In comparison, a surprisingly short half-life, ranging from 1.40 to 2.75 h, was reported in a recent PK and pharmacodynamic (PD) study utilizing mouse models of invasive candidiasis ( 10 ).…”

Galactomannan Is a Biomarker of Fosmanogepix (APX001) Efficacy in Treating Experimental Invasive Pulmonary Aspergillosis

“…In that study, we administered 50 mg/kg of body weight of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) 2 h prior to fosmanogepix to extend the short half-life of MGX in mice (from a range of 1.4 to 2.75 h to 9 h). The ABT treatment also enhanced MGX exposures (area under the concentration-time curve [AUC]), more closely mimicking phase 1 clinical exposures where a long half-life was observed (half-life [t 1/2 ], 2 to 2.5 days in humans) (1,2,7). The extended half-life of MGX (administered as 78 mg/kg once a day [QD] or 104 mg/kg QD of fosmanogepix) significantly enhanced mouse survival and reduced lung fungal burden by several log conidial equivalents (CE)/gram tissue versus the untreated control.…”

“…I nvasive pulmonary aspergillosis (IPA) is a serious fungal infection affecting immunocompromised patients. Fosmanogepix (APX001) is a first-in-class antifungal prodrug that is currently in clinical development for the treatment of invasive fungal infections (1,2). Fosmanogepix is rapidly and completely metabolized by systemic phosphatases to the active moiety manogepix (MGX; previously APX001A), which targets the highly conserved fungal enzyme Gwt1.…”