title: Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs.
abstract: Coccidioidomycosis can be a chronic, systemic fungal infection requiring long-term to lifetime medication. Thus, there is a need for improved antifungal agents with greater efficacy and reduced toxicity. VT-1161 has a low affinity for mammalian cytochromes and potently inhibits fungal CYP51 with proven efficacy in murine models of central nervous system (CNS) and respiratory coccidioidomycosis. Dogs experience coccidioidomycosis similar to humans and are a useful preclinical model for naturally occurring disease. Twenty-four client-owned dogs diagnosed with respiratory coccidioidomycosis based on radiography, serology, clinical signs, and clinicopathologic abnormalities were treated with a loading dose of VT-1161 for 14 days, followed by 46 days of a lower maintenance dose. Twelve dogs received a high dose (29 mg/kg loading, 6 mg/kg maintenance) and 12 received a low dose (10 mg/kg loading, 1.6 mg/kg maintenance). Response to treatment was assessed by calculating the reduction in disease scores at exit compared to disease scores at enrollment. Overall, 20 of 24 (83%) dogs had ≥50% reduction in enrollment disease scores at exit (P< 0.001), with no difference between the high- and low-dose groups (P= 0.66). Time-weighted average plasma concentrations for the high- and low-dose groups were 39 ± 5 μg/ml and 19 ± 2 μg/ml, respectively. In this open-label study, VT-1161 was efficacious for the treatment of respiratory coccidioidomycosis in naturally infected dogs. Combined with previously reported murine data, this finding supports the further development of VT-1161 for the treatment of coccidioidomycosis in humans.
authors.affiliation: Valley Fever Center for Excellence, The University of Arizona, Tucson, Arizona, USA Lfshubit@email.arizona.edu.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Shubitz
authors.affiliation: Veterinary Specialty Center of Tucson, Tucson, Arizona, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Roy
authors.affiliation: Valley Fever Center for Excellence, The University of Arizona, Tucson, Arizona, USA.
authors.forename: Hien T
authors.initials: HT
authors.lastname: Trinh
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hoekstra
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schotzinger
authors.affiliation: Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Garvey
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003045:Coccidioides / Q000187:drug effects*; D003047:Coccidioidomycosis / Q000188:drug therapy* / Q000382:microbiology / Q000662:veterinary*; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000188:drug therapy* / Q000382:microbiology; D004285:Dogs; D005260:Female; D008297:Male; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058886:Sterol 14-Demethylase / Q000378:metabolism; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D011725:Pyridines; D013777:Tetrazoles; C000599187:VT-1161; D058886:Sterol 14-Demethylase
keywords: Coccidioides; VT-1161; antifungal agents; dogs