1635. VT-1129 and VT-1161 have in vitro activity against Candida isolates from patients with chronic mucocutaneous candidiasis
Session: Poster Abstract Session: Mycology - There's a Fungus Among Us: Treatment
Friday, October 28, 2016
Room: Poster Hall
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. 14 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.

Jigar V Desai, PhD1, Timothy J Break, PhD1, Mukil Natarajan, MD2, Christina Henderson, BS3, Adrian M Zelazny, PhD3, William J Hoekstra, PhD4, Robert J Schotzinger, MD/PhD4, Edward P Garvey, PhD5 and Michail S Lionakis, MD, ScD2, (1)Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, NIAID, Bethesda, MD, (2)Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, (3)NIH Clinical Center/Department of Laboratory Medicine, Bethesda, MD, (4)Viamet Pharmaceuticals Inc., Durham, NC, (5)4505 Emperor Blvd., Viamet Pharmaceuticals Inc., Durham, NC

Disclosures:

J. V. Desai, None

T. J. Break, None

M. Natarajan, None

C. Henderson, None

A. M. Zelazny, None

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

M. S. Lionakis, None

Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.