Methods: The in vivo activity of SCY-078 was assessed against a wild type (WT) and two azole-resistant A. fumigatus strains in neutropenic ICR mice. Five groups of mice (6/group) were infected IV into the lateral tail vein. Antifungal therapy was initiated 5 hours post infection and maintained for 7 days. SCY-078 was administered orally as a loading dose of 15/mg/kg or 20 mg/kg followed by BID maintenance doses of 7.5 or 10 mg/kg, respectively. Caspofungin (CSP) and amphotericin B (AMB) were administered QD by intraperitoneal injection (IP) at doses of 5 mg/kg and 10 mg/kg, respectively. The primary endpoint was survival at day 14, secondary endpoints were changes in fungal kidney burden and serum galactomannan index (GM). Pharmacokinetic analysis was conducted on blood samples at Day 7.
Results: SCY-078 was well tolerated at all doses. Treatment with SCY-078 at 15 mg/kg/day and 20 mg/kg/day significantly increased mean survival in all strains (P ≤ 0.003). SCY-078 also resulted in significant reductions in fungal kidney burden (p<0.05) and serum GM levels (p<0.005) in all strains. Primary and secondary efficacy endpoints were also met in the groups treated with IP administration of CSP or AMB. Plasma levels of SCY-078 ranged from ≈15-20 μM*hr (AUC0-12) with Cmaxranging from ≈ 1-1.6 µg/mL for the two dose groups.
Conclusion: SCY-078 demonstrated potent activity against WT and azole-resistant strains of A. fumigatus in a murine model of invasive aspergillosis. The exposure needed to achieve efficacy is in line with efficacious exposures reported in the invasive candidiasis models. These results support further development of SCY-078 as an oral treatment for IA infections.
D. Angulo, Scynexis, Inc: Employee , Salary
K. Holden, Evotec (UK) Ltd.: Employee , Salary
P. Warn, Evotec (UK) Ltd.: Employee , Salary
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