P-1115. COT-832, a Novel Polyene Macrolide Antifungal (II): <i>In Vivo</i> Fungicidal Efficacy against <i>Aspergillus fumigatus</i> and <i>Candida albicans</i> in Mice and Rats Infection Models

Abstract Background A novel antifungal compound, COT-832 was created by SHIONOGI through modifying Amphotericin B (AmB). Marketed AmB formulations are often discontinued in clinical use due to nephrotoxicity. In this study, we investigated in vivo efficacy of COT-832 against Aspergillus fumigatus (A. fumigatus) and Candida albicans (C. albicans) in mice and rats infection models in comparison with those of Fungizone (FGZ) and AmBisome (L-AMB) at each human clinically equivalent dose (CED) in AUC. Methods CED; Mice (male ICR mice): FGZ;2.2 mg/kg, L-AMB; 7 mg/kg, Rats (Crl:CD(SD)): L-AMB; 8 mg/kg, cf. COT-832; 4 mg/kg showed the safety level similar to L-AMB at CED in a rat 2-week toxicology study. Systemic candidiasis in mice and rats: Conidia of C. albicans were intravenously administered (iv) in immunosuppressed mice. At 2, 24, and 48 hours (h) in mice, 48h in rats post-infection, each compound was administered (iv). Fungal burden in kidney was quantified at 24h post-treatment. Invasive pulmonary aspergillosis in rats: 104 conidia of A. fumigatus were inoculated intranasally in immunosuppressed rats. At 24h post-infection, each compound was administered (iv). A. fumigatus 18S rRNA in lung was quantified at 24h post-treatment. Results Systemic candidiasis in mice: FGZ at CED; immediate death when treatment was initiated at 24 and 48h post-infection. L-AMB at CED; fungistatic when initiated at 24h post-infection. COT-832; fungicidal at 3 mg/kg when initiated at 24h post-infection. Systemic candidiasis in rats: COT-832 at 2 mg/kg showed fungistatic efficacy comparable to L-AMB at CED, and COT-832 at 4 mg/kg showed 1-log down fungicidal efficacy from initial. Invasive pulmonary aspergillosis in rats: COT-832 at 2 mg/kg showed comparable efficacy to L-AMB at CED, and COT-832 at 4 mg/kg showed further 1-log down fungicidal efficacy. Conclusion In our rodent infection models, COT-832 showed more potent fungicidal effects in systemic candidiasis and invasive pulmonary aspergillosis at a dose with similar safety level to that of L-AMB at a clinically equivalent dose. These results suggest that COT-832 can be a novel antifungal active pharmaceutical ingredient to exhibit potent in vivo efficacy with less safety concerns than L-AMB. Disclosures Yuri Nishiyama, MS, Shionogi &amp; Co., Ltd.: employee Hideki Maki, PhD, Shionogi &amp; Co., Ltd.: employee|Shionogi &amp; Co., Ltd.: employee Osamu Yoshida, n/a, Shionogi &amp; Co., Ltd.: employee Yasushi Hasegawa, n/a, Shionogi &amp; Co., Ltd.: employee Yuuta Ukai, MSc, Shionogi &amp; Co., Ltd.: employee Tamio Fukushima, n/a, Shionogi &amp; Co., Ltd.: employee