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New oral antifungals for onychomycosis: interesting potential and the need for comparative effectiveness trials

Onychomycosis is a relatively common condition with a prevalence of 5–10% depending on the population studied. Dermatophytes, particularly Trichophyton rubrum, are the most common causative organisms. A variety of treatment options are available including topical antifungals such as efinaconazole, tavaborole, amorolfine and ciclopirox, as well as systemic antifungals such as oral terbinafine and itraconazole. Treatment for onychomycosis is associated with improved quality of life for affected patients. However, treatment may be challenging, and even the most effective topical antifungals have complete cure rates under 20%. In this issue of the BJD, Elewski et al. report on the results of a phase II randomized trial evaluating the safety of VT-1161, a novel oral antifungal, for the treatment of onychomycosis of the toenail. Among the four dosing regimens evaluated, in the intent-to-treat population, complete cure rate ranged from 32% to 42% at week 48, compared with 0% for placebo. Clinical cure ranged from 33% to 44% and mycological cure ranged from 61% to 72%. Adverse events were uncommon, with 2–6% of participants discontinuing the study drug owing to adverse events, compared with 2% for placebo. VT-1161 binds much more strongly to fungal CYP51 than to human CYP51, which may help reduce the risk of side-effects with this medication. VT-1161 has several potential advantages over current options, including once weekly dosing. While more safety data are needed from phase III and IV studies, VT-1161 may have fewer risks than terbinafine, which can be associated with rare serious liver toxicity, and itraconazole, which has frequent drug interactions and can cause or exacerbate heart failure. An important question going forward will be how new antifungals such as VT-1161 fit into current treatment paradigms for onychomycosis. In a 2017 Cochrane review of oral antifungal medications for toenail onychomycosis, 58% and 68% in the pooled terbinafine group and 46% and 52% in the pooled azole group achieved clinical cure and mycological cure, respectively. As this review did not assess complete cure, Elewski et al. estimated the complete cure rate for terbinafine using the US Food and Drug Administration summary basis of approval data to be approximately 32%. However, these comparisons may be challenging because of the different study durations and outcome definitions used in these trials. Although VT-1161 may have similar efficacy to oral terbinafine for toenail onychomycosis, there is a need for formal comparative effectiveness studies using standardized outcome parameters to determine the relative effectiveness of VT-1161 compared with standard of care oral antifungals. VT-1161 has interesting potential as a new treatment for onychomycosis; however, it will be important for future trials to establish not only whether it is efficacious, but additionally how it compares with standard of care treatments such as oral terbinafine.