A phase II, randomized, double-blind, placebo-controlled, parallel group, dose-ranging study to investigate the efficacy and safety of 4 dose regimens of oral albaconazole in patients with distal subungual onychomycosis

Sigurgeirsson, Bárður; Rossem, Koen van; Malahias, Steven; Raterink, Kerry

doi:10.1016/j.jaad.2013.03.021

Cited by 42 publications

(19 citation statements)

References 18 publications

(10 reference statements)

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“…For a variety of reasons, three groups of antifungal compounds — the aminocandins 60,61 , sordarins (which inhibit protein synthesis by stabilizing the ribosome–elongation factor 2 (Ef2) complex) 62 and icofungipen (which is an isoleucyl-tRNA synthesis inhibitor) 63 — have received little recent developmental attention, and a broad-spectrum triazole, albaconazole 64 , is now only studied for its use in treating superficial fungal infections, whereas before it was considered a potential compound for the treatment of systemic fungal diseases 65 . Therefore, these compounds are not emphasized in this Review.…”

Section: New Agents In Developmentmentioning

confidence: 99%

The antifungal pipeline: a reality check

Perfect

2017

Nat Rev Drug Discov

634

575

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Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies — polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) — in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes.

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Section: New Agents In Developmentmentioning

confidence: 99%

The antifungal pipeline: a reality check

Perfect

2017

Nat Rev Drug Discov

634

575

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“…Treatment‐related adverse effects occurred in < 3% of patients and were mild to moderate. The most common adverse effects were headache, nausea, diarrhoea and a transient and mild increase in liver enzymes . The weekly dosing schedule of albaconazole has the potential to improve compliance, particularly as longer courses of antifungal therapy may be required for some patients.…”

Section: Treatmentsmentioning

confidence: 99%

British Association of Dermatologists' guidelines for the management of onychomycosis 2014

et al. 2014

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“…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 [17], posaconazole [18], and albaconazole [19]). Although these studies were successful in demonstrating efficacy, complete cure rates were similar to current standard-of-care therapies (17)(18)(19), and no further clinical studies on these agents have been reported.…”

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confidence: 99%

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

Garvey

Hoekstra

Moore

et al. 2015

Antimicrob Agents Chemother

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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...

show abstract

A phase II, randomized, double-blind, placebo-controlled, parallel group, dose-ranging study to investigate the efficacy and safety of 4 dose regimens of oral albaconazole in patients with distal subungual onychomycosis

Cited by 42 publications

References 18 publications

The antifungal pipeline: a reality check

The antifungal pipeline: a reality check

British Association of Dermatologists' guidelines for the management of onychomycosis 2014

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

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