The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis

Garvey, E P; Sharp, A D; Warn, P A; Yates, C M; Schotzinger, R J

doi:10.1093/jac/dky242

Cited by 39Fungal Infections and StudiesAntifungal resistance and susceptibilityBacterial Infections and Vaccines

The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis

Garvey, E P, Sharp, A D, Warn, P A, Yates, C M, Schotzinger, R J·2018·Journal of Antimicrobial Chemotherapy

DOI 10.1093/jac/dky242

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Abstract

Objectives: Annual global deaths from cryptococcal meningitis (CM) are estimated at 180 000 and mortality is as high as 30%, even with optimal therapy. VT-1598 is a novel fungal CYP51 inhibitor with potent intrinsic antifungal activity against Cryptococcus. We report here VT-1598's in vivo antifungal activity in a murine model of CM. Methods: Single-dose plasma and brain pharmacokinetics in mice and MIC for Cryptococcus neoformans H99 were determined prior to efficacy studies. Short-course monotherapy and combination doses were explored with the endpoint of brain fungal burden. A survival study was also conducted using monotherapy treatment with fungal burden measured after a 6 day drug washout. Results: Oral doses of VT-1598 had good plasma and brain exposure and resulted in significant (P < 0.0001) and dose-dependent reductions in brain fungal burden, reaching a 6 log10 reduction. Unlike either positive drug control (fluconazole or liposomal amphotericin B), both mid and high doses of VT-1598 reduced fungal burden to below levels measured at the start of treatment. When VT-1598 was dosed in the survival study, no VT-1598-treated animal succumbed to the infection. Whereas fluconazole showed a 2.5 log10 increase in fungal burden after the 6 day washout, the VT-1598 mid- and high-dose animals showed almost no regrowth (<0.5 log10). In a separate fungal burden study using suboptimal doses of VT-1598 and liposomal amphotericin B to probe for combination effects, each combination had a positive effect relative to corresponding monotherapies. Conclusions: These pre-clinical in vivo data strongly support clinical investigation of VT-1598 as a novel therapy for this lethal infection.

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VT-1598 is a rationally designed Erg11 inhibitor that has increased fungal selectivity compared with other approved Erg11 inhibitors, including fluconazole.
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Authors: Garvey, E. P., Sharp, A. D., Warn, P. A., Yates, C. M., & Schotzinger, R. J.
Affiliations: Viamet Pharmaceuticals (United States) (US)
Evotec UK Ltd, Macclesfield, UK
Evotec (United Kingdom) (GB)
Corresponding author: Garvey, E P
ORCID: Warn, P A
Yates, C M
Venue: Journal of Antimicrobial Chemotherapy
Publisher: Oxford University Press (OUP)
Published: 2018-06-26
Volume: 73
Issue: 10
Pages: 2815-2822
ISSN: 0305-7453 (ISSN-L)
1460-2091
DOI: 10.1093/jac/dky242
OpenAlex: W2810179690
Cited by: 39
References: 30
Citations by year: 2026: 2 · 2025: 7 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 7 · 2018: 1
FWCI: 3.32
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor, 1 d)
Locations: Journal of Antimicrobial Chemotherapy (publishedVersion)
PubMed (publishedVersion)
Funders: Viamet Pharmaceuticals, Inc
TCG Lifesciences, Pvt. Ltd.
OpAns
Topics: Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords: CYP51 inhibitors, cryptococcal meningitis, Cryptococcus neoformans, liposomal amphotericin B, combination antifungal therapy, pharmacokinetics, antifungal efficacy, fluconazole, drug washout
MeSH terms: Administration, Oral, Amphotericin B, Animals, Antifungal Agents, Cryptococcus neoformans, Disease Models, Animal, Drug Therapy, Combination, Microbial Sensitivity Tests, Colony Count, Microbial, Survival Analysis, Treatment Outcome, Meningitis, Cryptococcal, Mice, 14-alpha Demethylase Inhibitors

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The novel fungal CYP51 inhibitor VT-1598 is efficacious alone and in combination with liposomal amphotericin B in a murine model of cryptococcal meningitis

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