VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model

Abstract

c Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of <0.016 to 0.5 g/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P < 0.001) and improvement in clinical scores (P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 g/ml (or g/g), at or above the MIC against the isolate used in the model (0.5 g/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens. F ungal infections of the skin, nails, and hair by dermatophytes, yeasts, and nondermatophyte molds are a common occurrence (1-3), with an estimated worldwide prevalence of 20% to 25% (1). In a survey of ambulatory records in the United States, these infections necessitated an average of 4 million physician visits per year from 1995 to 2004 (4), and the majority of these infections were caused by dermatophytes. The worldwide distribution of causative fungi and types of infection are dependent on geography, environment, and cultural factors (1, 2). Consistent with most of Europe and the United States (1, 2), a recent retrospective study found that onychomycosis (also referred to as tinea unguium) was the most common dermatophyte infection and that the absolute number of onychomycosis cases increased 10-fold over a 40-year period (5). This increase can be partly explained by the increases of two at-risk populations, the elderly (6) and diabetics (7). The most common species causing onychomycosis in Europe and the United States are Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum (8).Current oral treatment options for superficial fungal infections include allylamines, such as terbinafine, and azole-based fungal sterol 14␣-demethylase (CYP51) inhibitors (8, 9). The azoles fall into two classes defined by the moiety that binds the heme iron within the active site of CYP51, the imidazoles (e.g., ketoconazole), which are rarely used orally due...

Major challenges and perspectives in the diagnostics and treatment of dermatophyte infections

“…These drugs show action against new cellular targets, being inhibitors of metabolic pathways different from those previously described, including glyoxylate cycle, pyrimidine and heme biosynthesis, cytochrome P450 pathway and iron metabolism, along with signal transduction pathways such as MAP and calcineurin pathway (McCarthy et al 2017). One such example may be the preparation labelled VT-1161, which is currently in clinical trials as a potential alternative solution in the treatment of onychomycosis (Garvey et al 2015;Schell et al 2017). This drug, like azole derivatives, inhibits lanosterol 14-a-demethylase present in fungal cells .…”

“…This drug, like azole derivatives, inhibits lanosterol 14-a-demethylase present in fungal cells . It has been shown to be highly effective in vitro against cells of such dermatophyte species as T. rubrum, T. mentagrophytes and E. floccosum (Garvey et al 2015). VT-1161 has been designed in such a way as to ensure selective inhibition of the aforementioned enzyme present in fungal cells, with no affinity for homologues of this protein present in human cells.…”

“…VT-1161 has been designed in such a way as to ensure selective inhibition of the aforementioned enzyme present in fungal cells, with no affinity for homologues of this protein present in human cells. In addition, preclinical studies showed that single oral doses of the preparation administered in vivo in guinea pigs led to at least 48-h plasma persistence of active compound concentrations higher than those determined as in vitro effective MIC values (Garvey et al 2015). Another preparation with a broad spectrum of activity is a compound designated as AR-12, that is, a derivative of celecoxib, which is an effective inhibitor of cyclooxygenase 2 (Cox2) (Kushwaha et al 2017).…”

Preparation, and Assessment of Antidermatophyte Activity of Miconazole–Urea Water-Soluble Film

“…In addition, they have large body surface, giving a sufficient area to do tests and hence determine the clinical as well as the mycological efficacies. Garvey et al (2015) and Long et al (2016) used a guinea pig model to assess the efficacies of various antifungals for the treatment of dermatophytosis. Accordingly, the aim of this work is to evaluate the combined effect of miconazole as an antifungal agent as well as urea as a penetration enhancer against T. rubrum in vitro and in vivo.…”

In vitroactivities of the tetrazole SHR8008 compared to itraconazole and fluconazole againstCandidaandCryptococcusspecies

“…Therefore, SHR8008 avoids toxicity and drug interactions that occur with the cross-reaction of the azole with the human cytochrome P450 enzyme(16, 17). Moreover, SHR8008 has shown promising preclinical potential in the treatment of a wide range of fungal diseases, including dermatomycosis, trypanosomiasis, mycosis, coccidiomycosis and so on(18–22). Thus, the objective of this study was to evaluate the antifungal effect of SHR8008 systematically and to compare it with the triazoles itraconazole (ITC) and fluconazole (FLC) against common fluconazole-sensitive or resistant Candida and Cryptococcus strains isolated from Chinese patients in the last 2 years by Invasive Fungal Infection Group (IFIG).…”