TY - JOUR
T1 - The fungal cyp51 inhibitor vt-1129 is efficacious in an experimental model of cryptococcal meningitis
AU - Wiederhold, Nathan P.
AU - Najvar, Laura K.
AU - Garvey, Edward P.
AU - Brand, Stephen R.
AU - Xu, Xin
AU - Ottinger, Elizabeth A.
AU - Alimardanov, Asaf
AU - Cradock, Jim
AU - Behnke, Mark
AU - Hoekstra, William J.
AU - Schotzinger, Robert J.
AU - Jaramillo, Rosie
AU - Olivo, Marcos
AU - Kirkpatrick, William R.
AU - Patterson, Thomas F.
N1 - Funding Information:
We thank Cyprotex US for analysis of the plasma and brain tissue concentrations of VT-1129. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E and the National Center for Advancing Translational Sciences. N.P.W. has received research support to the UT Health San Antonio from Astellas, bioMérieux, Cidara, F2G, Merck, Pfizer, and Viamet and has served on advisory boards for Merck, Astellas, Toyama, and Viamet and as a speaker for Gilead. T.F.P. has received research grants to UT Health San Antonio from Astellas, Merck, and Revolution Medicines and has served as a consultant for Astellas, Gilead, Merck, Pfizer, Revolution Medicines, Toyama, Viamet, and Scynexis. L.K.N. has received travel support from Viamet Pharmaceuticals, Inc. E.P.G., W.J.H., and R.J.S. are employees of Viamet Pharmaceuticals, Inc. S.R.B. was an employee at Viamet Pharmaceuticals, Inc., at the time of the study and is now an employee at Mycovia Pharmaceuticals, Inc.
Funding Information:
N.P.W. has received research support to the UT Health San Antonio from Astellas, bioMérieux, Cidara, F2G, Merck, Pfizer, and Viamet and has served on advisory boards for Merck, Astellas, Toyama, and Viamet and as a speaker for Gilead. T.F.P. has received research grants to UT Health San Antonio from Astellas, Merck, and Revolution Medicines and has served as a consultant for Astellas, Gilead, Merck, Pfizer, Revolution Medicines, Toyama, Viamet, and Scynexis. L.K.N. has received travel support from Viamet Pharmaceuticals, Inc. E.P.G., W.J.H., and R.J.S. are employees of Viamet Pharmaceuticals, Inc. S.R.B. was an employee at Viamet Pharmaceuticals, Inc., at the time of the study and is now an employee at Mycovia Pharmaceuticals, Inc.
Funding Information:
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E and the National Center for Advancing Translational Sciences.
Publisher Copyright:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/9
Y1 - 2018/9
N2 - Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungus-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy of VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with Cryptococcus neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and the fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28, after which mice were monitored off therapy until day 30 or day 60, respectively, to assess survival. The fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg of body weight once daily. VT-1129 at doses of 0.3 mg/kg/day and each dose of fluconazole significantly reduced the brain tissue fungal burden compared to that in the control after both 7 and 14 days of dosing. The fungal burden was also undetectable in most mice treated with a dose of 3 mg/kg/day, even 20 days after dosing had stopped, in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.
AB - Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungus-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy of VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with Cryptococcus neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and the fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28, after which mice were monitored off therapy until day 30 or day 60, respectively, to assess survival. The fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg of body weight once daily. VT-1129 at doses of 0.3 mg/kg/day and each dose of fluconazole significantly reduced the brain tissue fungal burden compared to that in the control after both 7 and 14 days of dosing. The fungal burden was also undetectable in most mice treated with a dose of 3 mg/kg/day, even 20 days after dosing had stopped, in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.
KW - Cryptococcal meningitis
KW - Cryptococcus neoformans
KW - In vivo efficacy
KW - VT-1129
UR - http://www.scopus.com/inward/record.url?scp=85052200335&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052200335&partnerID=8YFLogxK
U2 - 10.1128/AAC.01071-1
DO - 10.1128/AAC.01071-1
M3 - Article
C2 - 29987152
AN - SCOPUS:85052200335
SN - 0066-4804
VL - 62
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 9
M1 - e01071-18
ER -