APX001 Is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis

• Published in: Antimicrobial agents and chemotherapy 2019-02, Vol.63 (2)
• Main Authors: Gebremariam, Teclegiorgis, Alkhazraji, Sondus, Alqarihi, Abdullah, Jeon, Heewon H, Gu, Yiyou, Kapoor, Mili, Shaw, Karen J, Ibrahim, Ashraf S
• Format: Article
• Language: English
• Subjects: Aminopyridines; Aminopyridines - pharmacology; Aminopyridines - therapeutic use; Animals; Antifungal Agents; Antifungal Agents - pharmacology; Antifungal Agents - therapeutic use; Disease Models, Animal; Experimental Therapeutics; Fungal Proteins - genetics; Fungal Proteins - metabolism; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Invasive Pulmonary Aspergillosis - drug therapy; Invasive Pulmonary Aspergillosis - microbiology; Isoxazoles; Isoxazoles - pharmacology; Isoxazoles - therapeutic use; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Triazoles - therapeutic use
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01713-18

Invasive pulmonary aspergillosis (IPA) due to is a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high, and new treatments are needed. The novel antifungal APX001A targets the conserved Gwt1 enzyme required for the localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the activity of APX001A against and the activity of its prodrug APX001 in an immunosuppressed mouse model of IPA. APX001A inhibited the growth of with a minimum effective concentration of 0.03 μg/ml. The use of 50 mg/kg 1-aminobenzotriazole (ABT), a suicide inhibitor of cytochrome P450 enzymes, enhanced APX001A exposures (area under the time-concentration curve [AUC]) 16- to 18-fold and enhanced serum half-life from ∼1 to 9 h, more closely mimicking human pharmacokinetics. We evaluated the efficacy of APX001 (with ABT) in treating murine IPA compared to posaconazole treatment. Treatment of mice with 78 mg/kg once daily (QD), 78 mg/kg twice daily, or 104 mg/kg QD APX001 significantly enhanced the median survival time and prolonged day 21 postinfection overall survival compared to the placebo. Furthermore, administration of APX001 resulted in a significant reduction in lung fungal burden (4.2 to 7.6 log conidial equivalents/g of tissue) versus the untreated control and resolved the infection, as judged by histopathological examination. The observed survival and tissue clearance were comparable to a clinically relevant posaconazole dose. These results warrant the continued development of APX001 as a broad-spectrum, first-in-class treatment of invasive fungal infections.