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

Discussion

This was a phase IIb study with a limited number of patients, compared with the typically larger pivotal trials that are necessary to support product approval. Evaluation of the efficacy of four regimens of VT-1161 (300 or 600 mg administered over 12 or 24 weeks) demonstrated that the primary endpoint of complete cure – defined as both clinical cure (0% nail involvement) and mycological cure (negative KOH and negative dermatophyte culture) – at week 48 was met. The proportion of patients achieving complete cure was statistically significantly greater (P < 0·001) in each VT-1161 treatment group compared with placebo in both the ITT and per protocol populations. The proportion of patients in the per protocol population experiencing complete cure at week 48 was higher than in the ITT population.

Secondary and exploratory endpoints including complete cure, therapeutic success, mycological cure (negative KOH, negative culture), clinical cure, percentage change in mycotic nail involvement, and effective treatment also demonstrated superior outcomes (P < 0·001) for all four regimens of VT-1161 vs. placebo at week 48. Complete cure rates and other secondary endpoints continued to improve through week 60.

In this study, all four treatment regimens of VT-1161 resulted in statistically significant (P < 0·001) complete cure rates compared with placebo. Week 48 complete cure rates were 32%, 36%, 42% and 33% in the ITT population for the four dosing regimens (300 mg for 12 or 24 weeks and 600 mg for 12 or 24 weeks, respectively). These values compare favourably against complete cure rates achieved with other currently approved onychomycosis treatment options, as noted in the respective ITT populations reported in the US package inserts of the following agents: 7% and 9% for tavaborole (5% daily for 48 weeks);[10,11] 18% and 15% for efinaconazole (10% daily for 48 weeks);[12] and 5·5% and 8·5% for ciclopirox topical solution (8% daily for 48 weeks).[21]

Rates of complete cure (clinical cure and mycological cure) in the ITT population are generally considered the most rigorous value reported as a measure of the effectiveness of antifungal drugs in onychomycosis. However, in our review of the terbinafine package insert, we could not identify whether the much cited complete cure rate of 38% was in the ITT or some other study population.[13] Given the absence of explicit information regarding this important endpoint, we examined the SBA, which is the most authoritative source of information for approved drugs compiled by the FDA. We discovered that the complete cure rates reported in the terbinafine package inserts were for patients who completed the study ('evaluable' or 'completers' population), rather than the ITT population. The latter is universally considered more conservative because it takes into account patients who failed treatment or discontinued due to lack of efficacy. The SBA clearly identifies that the complete cure rate in the ITT population was only 31·5%, which is lower than the 38% widely cited in the literature[22] without proper examination until now.

To gain further insight into complete cure rates with VT-1161, we compared them with data from the recent Cochrane Review[23] of eight clinical studies including 1006 patients receiving terbinafine (n = 682) or placebo (n = 324). Six of these studies assessed the nails for clinical cure at 52 weeks or less from the start of treatment, while two studies assessed nails at 72 weeks and 78 weeks, respectively. However, the Cochrane Review does not include complete cure with terbinafine, which consists of mycological cure and clinical cure, the most robust measure of a drug's effectiveness and the primary endpoint used in this and many other studies.

Other measures of drug effectiveness are mycological cure and clinical cure, which are often reported as key secondary endpoints in clinical trials. In our study, the mycological cure rates in the four VT-1161 arms ranged from 61% to 72%, compared with 11% for placebo, and the clinical cure rates ranged from 33% to 44%, compared with 4% for placebo. In the Cochrane Review,[23] 48% achieved clinical cure compared with 6% of patients in the pooled terbinafine and placebo groups, respectively. For mycological cure, in the pooled terbinafine group 58·8% of patients achieved mycological cure compared with 16·7% of patients in the placebo group. Given these findings, we believe that that the efficacy of VT-1161 reported herein is at least similar to that of terbinafine, although we do acknowledge that in the absence of a head-to-head randomized clinical study, comparing clinical cure rates across different trials is difficult.

VT-1161 was well tolerated in this study with a safety profile that was generally similar to that of placebo. Most reported AEs were transient, mild to moderate in severity and considered to be unrelated to the study drug by the blinded investigator. Importantly, there was no evidence of an adverse effect of VT-1161 on liver function or QT intervals, safety issues that have been reported with other systemic agents such as terbinafine and itraconazole. This favourable safety profile is likely attributed to the molecular design of this novel tetrazole compared with triazoles (fluconazole, itraconazole and posaconazole), as well as the ability to dose weekly, thus reducing the overall drug load without compromising efficacy.

Once-weekly dosing with VT-1161, following a 14-day loading dose, provides an ideal regimen to maintain effective plasma exposures. Given the long half-life of VT-1161, it is projected that suitable plasma and nail concentrations will be present beyond the week 60 endpoint.

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