Abstract
ABSTRACTSCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis. In vitro susceptibilities by broth microdilution, antifungal carryover, and time-kill dynamics were determined for three reference (ATCC) strains (Candida albicans 90028, Candida parapsilosis 90018, and Candida tropicalis 750), a quality-control (QC) strain (Candida krusei 6258), and four other strains (C. albicans MYA-2732, 64124, and 76485 and Candida glabrata 90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16 times the MIC80, and FLU and VRC were evaluated at 4× MIC80. The time to reach 50%, 90%, and 99.9% reduction in the number of CFUs from the starting inoculum was determined. Net change in the number of CFU per milliliter was used to determine 50% and 90% effective concentrations and maximum effect (EC50, EC90, and Emax, respectively). The SCY-078 MIC range was between 0.0625 and 1 μg/ml and generally similar to that of CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against seven isolates at ≥4× MIC (kill of ≥3 log10) and achieved a 1.7-log10 reduction in CFU count/milliliter against C. albicans 90028. CASP behaved similarly against each isolate and achieved a 1.5-log10 reduction in the number of CFU/milliliter against C. albicans 90028. Reductions of 50% in CFU count/milliliter were achieved rapidly (1 to 2.8 h); fungicidal endpoints were reached at 12.1 to 21.8 h at ≥4× MIC. EC90 was reached at ∼5× MIC at each time point to 24 h. The EC50 and EC90 values were generally similar (8 to 24 h). Time-kill behavior of CASP was similar to that of SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity against Candida spp. and behaved comparably to CASP.
Highlights
SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis
In vitro susceptibilities are summarized for three Candida reference strains (C. albicans 90028, C. parapsilosis 90018, and C. tropicalis 750) and five other isolates of Candida spp. to SCY-078, caspofungin, fluconazole, and voriconazole (Table 1)
Antifungal activity typically increased with concentration and incubation time, with maximal responses generally occurring at the highest drug concentrations following 24-h incubations. These results indicate that SCY-078 produces fungicidal activity based on concentration and time of exposure, consistent with the pharmacokinetic/pharmacodynamic (PK/PD) parameter of the area under the concentration-time curve (AUC)/MIC
Summary
SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis. SCY-078 was fungicidal against seven isolates at Ն4ϫ MIC (kill of Ն3 log10) and achieved a 1.7log reduction in CFU count/milliliter against C. albicans 90028. Treatment options for candidiasis are generally restricted to antifungals belonging to the polyene, triazole, and echinocandin classes of drugs. These agents demonstrate high levels of antifungal activity, their use can be hampered by toxicity, poor tolerability, or a narrow activity spectrum. SCY-078 retains in vitro activity against both azole-resistant and the majority of echinocandin-resistant strains of Candida species [9, 10], indicating that its mechanism of action is not markedly affected by key resistance mechanisms or mutations associated with traditional targets
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