Work

VT-1129 and VT-1161 have in vitro activity against Candida isolates from patients with chronic mucocutaneous candidiasis

Year: 2016

Type: conference-abstract

Abstract: Background. Patients with inherited syndromes of chronic mucocutaneous candidiasis (CMC) frequently develop azole resistance, which makes treatment of their fungal infections challenging. VT-1129 and VT-1161 belong to a new class of antifungals that specifically target fungal cytochrome CYP51. These drugs are effective in vitro against azole-susceptible and -resistant fungal strains and in vivo in animal models of fungal disease. VT-1161 is currently in phase 2b studies of recurrent vulvovaginal candidiasis (RVVC) and onychomycosis, having successfully met proof-of-concept goals in phase 2a studies of acute VVC and tinea pedis. The drugs' long half-life, efficacy even when dosed once weekly, and decreased drug-drug interaction potential makes them attractive for patients with CMC who require long-term, often lifelong, antifungal prophylaxis. Methods. We tested the in vitro susceptibility of VT-1129, VT-1161 and azoles by CLSI broth microdilution (M27-A3) against 31 mucosal Candida strains obtained from patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. We determined the 24-hour minimum inhibitory concentration (MIC) at which 50% of strains were inhibited (MIC50). Results. Strains tested were C. albicans (20), C. glabrata (6) and 1 each of C. parapsilosis, C. krusei, C. dubliniensis, C. utilis and C. nivariensis; they were recovered from oral (21), vaginal (4), stool (3), esophageal (2) and duodenal (1) cultures. Fourteen strains were not susceptible to fluconazole based on CLSI breakpoints (MIC equal or >4 µg/mL). VT-1129 and VT-1161 showed in vitro activity against the majority of the 31 strains with MIC50 of 0.06 µg/mL and 0.03 µg/mL, respectively; only 4 and 1 strains were resistant to VT-1129 and VT-1161, respectively (MIC >16 µg/mL). VT-1129 and VT-1161 were highly potent against C. albicans (MIC50, 0.03 µg/mL) as well as non-albicans, non-glabrata Candida strains (MIC50, 0.125 and 0.06 µg/mL, respectively) and had significant activity against C. glabrata (MIC50, 0.25 and 0.125 µg/mL, respectively). Importantly, VT-1129 and VT-1161 showed in vitro activity against fluconazole-resistant strains (MIC50, 0.25 and 0.125 µg/mL, respectively). Conclusion. VT-1129 and VT-1161 have in vitro activity against mucosal Candida strains from CMC patients, including azole-resistant strains. Their efficacy in mice and patients with CMC merits investigation. Disclosures. W. J. Hoekstra, Viamet: Employee and VP, Chemistry, Salary R. J. Schotzinger, Viamet Pharmaceuticals, Inc: President and CEO, Salary E. P. Garvey, Viamet Pharmaceuticals, Inc: Director of Infectious Disease Biology, Salary.

Source: Open Forum Infectious Diseases

DOI: 10.1093/ofid/ofw172.1335