The Fungal Cyp-51 Inhibitor VT-1129 is Efficacious in an Experimental Model of Cryptococcal Meningitis [PublishAheadOfPrint]

Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungal-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with C. neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28 after which mice were monitored off-therapy until day 30 or day 60, respectively, to assess survival. Fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg once daily. VT-1129 at doses of ≥ 0.3 mg/kg/day and each dose of fluconazole significantly reduced brain tissue fungal burden compared to control after both 7 and 14 days of dosing. Fungal burden was also undetectable in most mice treated with dose of ≥ 3 mg/kg/day, even ≥ 20 days after dosing had stopped in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.

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