274. VT-1598 Inhibits the in vitro Growth of Mucosal Candida Isolates and Protects Against Oropharyngeal Candidiasis in IL-17 Deficient Mice
Session: Poster Abstract Session: Fungus Among Us: Basic Science
Thursday, October 5, 2017
Room: Poster Hall CD
Background: Patients with chronic mucocutaneous candidiasis (CMC) often develop azole-resistant Candida infections, making treatment difficult due to lack of oral antifungal drug options. VT-1598 is a novel broad-spectrum fungal CYP51 inhibitor designed for exquisite selectivity for the fungal target versus human CYP enzymes to circumvent classic azole side effects like drug-drug interactions. We report the efficacy of VT-1598 in the treatment of oral Candida infection (including by azole-resistant strains).

Methods: The in vitro MIC values of 28 Candida species isolated from patients with CMC due to AIRE mutations were tested against VT-1598 and fluconazole (FLC), using CLSI broth microdilution M27-S4. Plasma VT-1598 levels were measured using LC-MS/MS with electrospray ionization. Tongue fungal load was determined in IL-17 deficient Act1-/- mice following sublingual C. albicans infection and once-daily oral treatment for 4 days with 25 mg/kg FLC or 3.2, 8, and 20 mg/Kg VT-1598 starting 18 hours post-infection.

Results: Among 28 Candida isolates tested (22 C. albicans, 3 C. glabrata, and 1 each of C. utilis, C. dubiliensis, and C. krusei), 10 (36%) were not susceptible to FLC, based on CLSI breakpoints (>4 mg/mL). Remarkably, all 28 isolates were highly susceptible to VT-1598 (MIC50 and MIC90, 0.06 and 0.125 mg/mL, respectively). Oral administration of VT-1598 led to mean drug levels in mouse plasma (2.0, 3.0, and 11 mg/mL at the low, mid, and high doses, respectively) that were higher than the MIC values. In vivo, VT-1598 was significantly more effective, compared to FLC, against FLC-susceptible and –resistant C. albicans, and led to elimination of fungal growth even at the lowest tested dose (3.2 mg/Kg). After a 10-day washout period from the last dose, mice treated with VT-1598 did not have mucosal fungal growth, while mice treated with FLC had tongue fungal loads similar to vehicle control.

Conclusion: VT-1598 shows in vitro activity against mucosally-derived Candida, including FLC-resistant strains. In vivo, VT-1598 achieves high plasma concentrations and eliminates viable C. albicans, even at low doses and after an extended washout period. These data indicate that VT-1598 may be a significantly improved treatment option for patients with CMC.

Timothy J Break, PhD1, Jigar V Desai, PhD2, Mukil Natarajan, MD3, Elise Ferre, PA-C, MPH4, Christina Henderson, BS5, Adrian M Zelazny, PhD5, Christopher M Yates, MS6, Oren J Cohen, MD6, Robert J Schotzinger, MD/PhD6, Edward P Garvey, PhD6 and Michail Lionakis, M.D., Sc.D.4, (1)Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, (2)Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, NIAID, NIH, Bethesda, MD, (3)Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, (4)National Institute of Allergy and Infectious Diseases, Bethesda, MD, (5)NIH Clinical Center/Department of Laboratory Medicine, Bethesda, MD, (6)Viamet Pharmaceuticals Inc., Durham, NC

Disclosures:

T. J. Break, None

J. V. Desai, None

M. Natarajan, None

E. Ferre, None

C. Henderson, None

A. M. Zelazny, None

C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee , Salary

O. J. Cohen, Viamet Pharmaceuticals, Inc.: Employee , Salary

R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Employee , Salary

E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee , Salary

M. Lionakis, Viamet Pharmaceuticals: Research support (CRADA) , Research support

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