A Phase II, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study to Evaluate the Efficacy and Safety of VT-1161 Oral Tablets in the Treatment of Patients With Distal and Lateral Subungual Onychomycosis of the Toenail

B. Elewski; S. Brand; T. Degenhardt; S. Curelop; R. Pollak; R. Schotzinger; A. Tavakkol

Disclosures

The British Journal of Dermatology. 2021;184(2):270-280. 

In This Article

Abstract and Introduction

Abstract

Background: Onychomycosis is a fungal disease that affects the fingernails and toenails and is predominantly caused by dermatophytes. VT-1161 is a novel inhibitor of fungal CYP51 through the inhibition of lanosterol demethylase, and has demonstrated potent activity against Trichophyton rubrum and Trichophyton mentagrophytes.

Objectives: To evaluate the safety and efficacy of four dosing regimens of orally administered VT-1161 compared with placebo in patients with moderate-to-severe distal and lateral subungual onychomycosis of the toenail.

Methods: This was a phase II, randomized, double-blind, placebo-controlled, multicentre study (ClinicalTrials.gov identifier NCT02267356). Patients aged 18–70 years (n = 259) who had 25–75% mycotic involvement were randomized to five treatment groups. They received 300 mg VT-1161 as a 2-week daily dose, followed by a once-weekly dose for either 10 or 22 weeks, or 600 mg VT-1161 as a 2-week daily dose, followed by a once-weekly dose for either 10 or 22 weeks. All treatments were followed by a nontreatment period of 36 weeks. A matching placebo arm was included.

Results: In the intent-to-treat population, at week 48 the complete cure rates were 0% in the placebo group and ranged from 32% to 42% in the VT-1161 treatment groups (P < 0·001 vs. placebo). VT-1161 was well tolerated, with no evidence of an adverse effect on liver function or QT intervals.

Conclusions: VT-1161 treatment led to high nail clearance rates and a favourable safety profile. VT-1161 exhibits characteristics that appear promising for the treatment of this chronic and difficult-to-treat condition and warrants further evaluation in larger studies.

Introduction

Onychomycosis is a common fungal disease of the nail, affecting 2–13% of the population in the developed world.[1–7] It remains difficult to treat, partly due to the inherent characteristics of the nail including slow growth, the impermeable nail plate, and the sequestration of pathogens between the nailbed and plate. Topical treatments alone are generally less effective than oral therapies because of insufficient nail plate penetration.[2,8,9] Reported clinical cure rates at week 52 for more recently US Food and Drug Administration (FDA)-approved agents, tavaborole and efinaconazole, were approximately 9% and 18%, respectively.[10–12] Oral antifungal drugs are believed to be more effective. The prescribing information for terbinafine reports 38% of cases with complete cure at week 48,[13] whereas approximately 14% of patients receiving itraconazole achieved the same outcome.[14] While topical drugs are generally considered safe, orally administered agents such as terbinafine can exhibit more serious side-effects including rash, taste disturbance, vision disturbance and liver toxicity.[15–17]

VT-1161 is a new molecular entity targeting inhibition of the lanosterol demethylase (CYP51) enzyme, the enzyme required for the production of ergosterol, a key membrane lipid vital for fungal survival. However, while all currently available molecules of the azole class contain an imidazole or triazole group as part of their molecular structure, VT-1161 contains a tetrazole group with reduced metal-binding affinity, and improved selectivity by binding more than 2000-fold more tightly to fungal CYP51 than to human CYP51, thus reducing the potential for side-effects that are known for the azole class.

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