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Efficacy and Safety of VT-1161 in a Randomized, Double-Blinded, Placebo-Controlled Phase 2 Study of Four Oral Dosing Regimens in the Treatment of Patients with Moderate-to-Severe Distal-Lateral Subungual Onychomycosis (DLSO)

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Introduction

Current therapies for onychomycosis are inadequate due to the low efficacy of topical products or poor safety profile of oral therapies, which often require monitoring of liver transaminases.  VT-1161 is a novel inhibitor of cytochrome P51 (CYP51), with nearly 2000-fold greater selectivity for fungal CYP51, and minimal activity against off-target human CYPs. It exhibits favorable oral pharmacokinetics with sustained plasma and nail concentrations combined with an excellent safety profile.  VT-1161 has demonstrated potent activity against Trichophyton rubrum, T. mentagrophytes, and yeast.

Objective:

We report the final results of RENOVATE, a Phase. 2b study to evaluate the efficacy and safety of oral VT-1161 in patients with toenail onychomycosis

Methods;

The study enrolled 259 patients (18-70 years) with a clinical diagnosis of moderate to severe distal lateral subungual onychomycosis (DLSO) defined as having 25% to 75% nail involvement at baseline and positive KOH and culture for dermatophytes, performed at a central laboratory. Patients had at least 2 mm clear nail measured from the proximal nail fold and a nail thickness of no greater than 3 mm measured at the distal end.  Patients who were breast feeding, pregnant or intended to become pregnant were excluded.  Those who received systemic antifungal therapy for 3 months, or a topical applied to their toenail or feet for 1 month prior to entry were also excluded.

Treatment:

Patients received 300 or 600 mg oral VT-1161 or matching placebo once-weekly for either 10 or 22 weeks, following 14-days of a daily loading dose.

Clinical Assessment:

The percent nail involvement of the target toenail was assessed by the Principal Investigator (PI) at each clinic visit.

Mycological Assessment:

Dermatophyte infection was assessed by KOH wet mount microscopy and culture of the subungual debris in the target toenail; both conducted at the central mycology Lab.

Efficacy Endpoints and Assessments:

The primary efficacy endpoint was the proportion of patients with complete cure at Week 48, defined as both clinical cure (0% nail involvement) and mycological cure (negative KOH stain and negative culture).  The secondary endpoints were complete cure at Week 60, mycological and clinical cure at Week 48 and/or 60. Efficacy assessment are presented for 259 patients in the intent to treat (ITT) population defined as all patients who were randomized.

Safety Assessment: 

Adverse events (AE) were collected as reported by patients as well as by any clinically significant changes in blood chemistry. ECGs performed at each visit.

Statistics:

Study was designed to provide >90% power to show a treatment difference of 25% between active treatment and placebo in complete cure rates at Week 48 (Fisher's exact test, two-sided alpha=0.05; assuming 5% of placebo patients are completely cured)

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