1638. Investigational CYP51 Inhibitors VT-1161 and VT-1129 Show Strong Activity In Vitro Against Candida krusei
Session: Poster Abstract Session: Mycology - There's a Fungus Among Us: Treatment
Friday, October 28, 2016
Room: Poster Hall
Posters
  • Viamet VT-1129 VT-1161 Poster IDWeek 2016.pdf (268.5 kB)
  • Background:  Candida krusei is the fifth most common Candida species recovered from clinical specimens in the U.S. and worldwide.  At Duke University Hospital it was responsible for ~4 % (96/2560) of blood stream infections between 1992 and 2013, and has increased to 6-10% over the past decade (2002-2013).  C. krusei is intrinsically resistant to fluconazole, and the emergence of voriconazole resistance following exposure to fluconazole is a pressing concern.  VT-1161 and VT-1129 represent a new generation of fungal CYP51 inhibitors, and are both highly selective and potent against Candida species, including azole- and echinocandin-resistant isolates.   In Phase 1 and 2 clinical trials, VT-1161 has achieved plasma concentrations of up to 10 µg/mL with an excellent safety profile.  Preclinical data for VT-1129 predict similar safety and PK profiles.

    Methods:  In vitro activities of VT-1129, VT-1161, fluconazole, voriconazole, anidulafungin, caspofungin, and micafungin were concurrently determined for 50 C. krusei blood isolates.  Broth microdilution testing was performed using the Clinical and Laboratory Standards Institute M27-A3/S4 method. Stock solutions of VT-1161 and VT-1129 were prepared in DMSO; endpoints were recorded at 24 and 48 hours and were defined as ≥50% growth inhibition compared to drug-free controls.  

    Results:  At 24 hours, all 50 isolates were inhibited by VT-1129 and VT-1161 at concentrations of ≤ 2µg/mL.  MICs at which 90% of isolates were inhibited by these compounds were 1 and 0.5µg/mL, respectively.

    Conclusion: VT-1161 and VT-1129 MICs for clinically and/or in vitro resistant C. krusei isolates were at least 5-fold below achievable human plasma levels for VT-1161.  VT-1161 and VT-1129 show significant promise for the treatment of C. krusei infections. 

    Table 1.  C. krusei (N=50) MIC (µg/mL)

    VT-1129

    VT-1161

    Fluconazole

    Voriconazole

    Anidulafungin

    Caspofungin

    Micafungin

    Range

    ≤0.015-2

    ≤0.015-1

    16-128

    ≤0.015-4

    ≤0.015-0.12

    0.03-0.25

    ≤0.015-0.25

    Geometric mean

    0.344

    0.164

    34.297

    0.234

    0.032

    0.090

    0.055

    Median

    0.5

    0.25

    32

    0.25

    0.03

    0.12

    0.06

    Mode

    1

    0.5

    32

    0.25

    0.03

    0.12

    0.06

    MIC50

    0.5

    0.25

    32

    0.25

    0.03

    0.12

    0.06

    MIC90

    1

    0.5

    64

    0.5

    0.03

    0.12

    0.12

    Barbara D. Alexander, MD, MHS, FIDSA1,2, Wiley a. Schell, MS3, Alexander Jones, B.S.2, William J Hoekstra, PhD4, Robert J Schotzinger, MD/PhD4 and Edward P Garvey, PhD5, (1)Division of Infectious Diseases, Duke University Medical Center, Durham, NC, (2)Duke University, Durham, NC, (3)Duke University Medical Center, Durham, NC, (4)Viamet Pharmaceuticals Inc., Durham, NC, (5)4505 Emperor Blvd., Viamet Pharmaceuticals Inc., Durham, NC

    Disclosures:

    B. D. Alexander, Viamet Pharmaceuticals, Inc.: Investigator , Research support

    W. A. Schell, None

    A. Jones, None

    W. J. Hoekstra, Viamet Pharmaceuticals: Employee , Salary

    R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: President and CEO , Salary

    E. P. Garvey, Viamet Pharmaceuticals, Inc: Director of Infectious Disease Biology , Salary

    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.