Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis

Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. The gepix Gwt1 inhibitors are a new class of antifungal drugs. Cryptococcal Meningitis (CM) is uniformly fatal if not treated, and treatment options are limited. We previously reported on the activity of APX2096, the prodrug of the novel Gwt1 inhibitor APX2039, in a mouse model of CM. Here, we investigated the efficacy of APX2039 in mouse and rabbit models of CM. In the mouse model, the controls had a mean lung fungal burden of 5.95 log(10) CFU/g, whereas those in the fluconazole-, amphotericin B-, and APX2039-treated mice were 3.56, 4.59, and 1.50 log(10) CFU/g, respectively. In the brain, the control mean fungal burden was 7.97 log(10) CFU/g, while the burdens were 4.64, 7.16, and 1.44 log(10) CFU/g for treatment with fluconazole, amphotericin B, and APX2039, respectively. In the rabbit model of CM, the oral administration of APX2039 at 50 mg/kg of body weight twice a day (BID) resulted in a rapid decrease in the cerebrospinal fluid (CSF) fungal burden, and the burden was below the limit of detection by day 10 postinfection. The effective fungicidal activity (EFA) was -0.66 log(10) CFU/mL/day, decreasing from an average of 4.75 log(10) CFU/mL to 0 CFU/mL, over 8 days of therapy, comparing favorably with good clinical outcomes in humans associated with reductions of the CSF fungal burden of -0.4 log(10) CFU/mL/day, and, remarkably, 2-fold the EFA of amphotericin B deoxycholate in this model (-0.33 log(10) CFU/mL/day). A total drug exposure of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) of 25 to 50 mg center dot h/L of APX2039 resulted in near-maximal antifungal activity. These data support the further preclinical and clinical evaluation of APX2039 as a new oral fungicidal monotherapy for the treatment of CM. IMPORTANCE Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. The gepix Gwt1 inhibitors are a new class of antifungal drugs. Here, we demonstrated the efficacy of APX2039, the second member of the gepix class, in rabbit and mouse models of cryptococcal meningitis. We also analyzed the drug levels in the blood and cerebrospinal fluid in the highly predictive rabbit model and built a mathematical model to describe the behavior of the drug with respect to the elimination of the fungal pathogen. We demonstrated that the oral administration of APX2039 resulted in a rapid decrease in the CSF fungal burden, with an effective fungicidal activity of -0.66 log(10) CFU/mL/day, comparing favorably with good clinical outcomes in humans associated with reductions of -0.4 log(10) CFU/mL/day. The drug APX2039 had good penetration of the central nervous system and is an excellent candidate for future clinical testing in humans for the treatment of CM.

Automated summary

Cryptococcal meningitis (CM) is a global fungal disease with high morbidity and mortality. The gepix Gwt1 inhibitors are a new class of antifungal drugs. This study demonstrated the efficacy of APX2039, a novel Gwt1 inhibitor, in mouse and rabbit models of CM. APX2039 showed rapid and significant reduction of the fungal burden in both models, with favorable antifungal activity compared to current treatment options. The drug also had good penetration into the central nervous system. These results support further evaluation of APX2039 as a potential oral monotherapy for CM.