VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model
Authors: E. P. Garvey, W. J. Hoekstra, W. R. Moore, R. J. Schotzinger, L. Long, and M. A. Ghannoum
Publication Year: 2015
Fungal 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 14α-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 to poor systemic side effect profiles, and the triazoles (e.g., itraconazole). These heterocycles greatly aid in the potency of inhibiting fungal CYP51 but are relatively nonselective and can lead to inhibition of off-target human CYPs, often manifested as side effects. Although allylamines and azoles are efficacious for a large number of dermatophyte infections, there remains room for improvement in efficacy and safety, particularly for more difficult-to-treat infections such as onychomycosis. In randomized controlled trials of onychomycosis, complete cure rates reflecting both mycological and clinical cures for terbinafine and itraconazole range from approximately 35 to 50% (10). Moreover, both drug classes carry safety warnings pertaining to liver toxicity (11, 12) and drug-drug interactions (13), with a small but significant percentage of more serious side effects (14,–16). As a consequence, many patients choose not to pursue oral therapy.
Given the need for improved efficacy and a better safety profile, the lack of new oral therapies under development is striking. It has been 18 years since the last new oral drug (terbinafine) was approved by the FDA for the treatment of onychomycosis. Additionally, since 1996, only three phase 2 studies of new oral therapies have been reported (ravuconazole , posaconazole , and albaconazole ). Although these studies were successful in demonstrating efficacy, complete cure rates were similar to current standard-of-care therapies (17,–19), and no further clinical studies on these agents have been reported.
We recently described a novel fungal CYP51 inhibitor, VT-1161 (Fig. 1), that uses a tetrazole to bind the heme iron within the enzyme’s active site (20). The tetrazole was critical in establishing greater selectivity for fungal CYP51 versus off-target human CYPs while retaining high potency for the fungal CYP51 target. The potency of VT-1161 against Candida albicans CYP51 in a cellular assay was ≤0.5 nM compared to in vitro 50% inhibitory concentration (IC50) values of ∼100 μM or greater against human CYP51 and key xenobiotic-metabolizing CYPs present in human liver microsomes (e.g., CYP2C9, -2C19, and -3A4) (21). VT-1161 has also demonstrated potent intrinsic activity against the dermatophyte T. rubrum (20). In this study, we show that in vitro, the antifungal activity of VT-1161 translated into potent activity in the oral treatment of dermatophytosis in a guinea pig model, and that the efficacy of VT-1161 was statistically equivalent whether dosed once daily or once weekly.
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