The Novel Fungal Cyp51 Inhibitor VT-1598 is Efficacious in Experimental Models of Central Nervous System Coccidioidomycosis Caused by Coccidioides posadasii and Coccidioides immitis [PublishAheadOfPrint]

Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungal-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of CNS coccidioidomycosis caused C. posadasii and C. immitis. Infection was introduced via intracranial inoculation, and therapy began 48 hours post-inoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 hours post-treatment in the fungal burden studies, and on the days the mice succumbed to infection or at the pre-specified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT-1598 resulted in significant improvements in survival in mice infected with either species. In addition, fungal burden was significantly reduced in the fungal burden studies. Plasma concentrations 48 hours after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week wash-out. Whereas fungal burden remained suppressed after a 2-week wash-out in the C. immitis model, higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.

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