APX001 is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis [Experimental Therapeutics]

Invasive pulmonary aspergillosis (IPA) due to Aspergillus fumigatus 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 glycosylphosphatidyl inositol (GPI)-anchored mannoproteins in fungi. We evaluated the in vitro activity of APX001A against A. fumigatus and the in vivo activity of its prodrug APX001 in an immunosuppressed mouse model of IPA. APX001A inhibited the growth of A. fumigatus with a minimum effective concentration (MEC) of 0.03 μg/ml. The use of 50 mg/kg 1-aminobenzotriazole (ABT), a suicide inhibitor of cytochrome P450 (CYP) enzymes, enhanced APX001A exposures (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 as compared to posaconazole treatment. Treatment of mice with 78 mg/kg QD, 78 mg/kg BID, or 104 mg/kg QD APX001 significantly enhanced median survival time and prolonged Day 21 post-infection overall survival when compared to placebo. Furthermore, administration of APX001 resulted in a significant reduction in lung fungal burden (4.2 to 7.6 log₁₀ conidial equivalents/gram tissue) vs 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 for invasive fungal infections.

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