David A. Rodriguez, MD
Dermatology Associates/Research, Coral Gables, Florida
Disclosure: Dr. Rodriguez has served as a paid consultant to Valeant Pharmaceuticals North America LLC.
Objective: To evaluate efficacy, safety, and tolerability of efinaconazole topical solution, 10%, in patients with mild (less than or equal to 25% nail involvement) and moderate (>25% nail involvement) toenail onychomycosis. Methods: A subgroup analysis of patients, aged 18 to 70 years, randomized to receive efinaconazole topical solution, 10%, or vehicle from two identical multicenter, double-blind, vehicle-controlled, 48-week studies evaluating safety and efficacy. The primary endpoint was complete cure rate (0% clinical involvement of target toenail and both negative potassium hydroxide examination and fungal culture) at Week 52. Results: Mycologic cure rates were similar in mild and moderate onychomycosis patients treated with efinaconazole (58.2% and 55.5%, respectively), but markedly different with vehicle (25.0% and 14.1%, respectively). The primary endpoint, complete cure, was achieved in 25.8 percent of mild onychomycosis patients and 15.9 percent of moderate onychomycosis patients compared to 11.3 and 2.7 percent, respectively, with vehicle (both P<0.001). Treatment success (percent affected target toenail less than or equal to 10%) for efinaconazole was 65.7 and 40.7 percent, respectively, depending on disease severity. Adverse events associated with efinaconazole were local site reactions and clinically similar to vehicle. Conclusions: Once-daily efinaconazole topical solution, 10%, may provide a useful topical option in the treatment of mild-to-moderate onychomycosis. (J Clin Aesthet Dermatol. 2015;8(6):24–29.)
Onychomycosis is the most common nail disease in adults, representing up to 50 percent of all nail disorders and is nearly always associated with tinea pedis.[1,2] In addition, one in three people with diabetes are afflicted with onychomycosis, and diabetic individuals suffer from a much higher incidence of onychomycosis than those without; especially older patients, male patients, and those with severe nail changes. Moreover, toenail onychomycosis frequently involves several nails and can be more challenging to treat because of the nail’s slow growth rate.[4,5]
In clinical research, it is common practice to classify disease severity according to the extent of the infection involvement. Onychomycosis is often described as mild (25% or less nail involvement), moderate (26–74% involvement), and severe (more than 75% involvement).
A prospective, multicenter survey of 15,000 patients visiting physicians’ offices lead to a projected rate of onychomycosis in Canada of 6.5 percent. Of those patients diagnosed with distal lateral subungual onychomycosis (DLSO), 27.6 percent were considered mild, 39.9 percent moderate, and 32.5 percent severe. Higher prevalence rates have been suggested in the United States (13.8%), and some studies have suggested that almost half of the population may be affected by the age of 70. There are no data on the range of severity with these higher prevalence rates and little data on prognostic outcome. One study failed to demonstrate any prognostic value of the extent of nail involvement or the number of toenails involved. Patients with a history of prior infection, men, and older patients were less likely to reach clinical cure.
Numerous studies have assessed the effectiveness of antifungal drugs in treating onychomycosis. Results of two identical, 52-week, prospective, multicenter, randomized, double-blind studies in 1,655 patients (18–70 years) assessed the safety and efficacy of efinaconazole topical solution, 10%, in the treatment of onychomycosis were recently reported. The author provides a subgroup analysis of those patients who had mild (less than or equal to 25% nail involvement) and moderate (>25% nail involvement) onychomycosis.
Two multicenter, randomized, double-blind, vehicle-controlled studies designed to evaluate the efficacy, safety, and tolerability of efinaconazole topical solution, 10%, relative to its vehicle in 1,655 male and female patients aged 18 to 70 years with mild-to-moderate toenail onychomycosis.
Patients who presented with 20 to 50 percent clinical involvement of the target toenail were randomized (3:1) to apply blinded study drug once daily to the toenails for 48 weeks. Representative examples of patients with 20 and 50 percent target toenail involvement are shown in Figure 1A, Figure 1B.
Efficacy evaluation. The primary efficacy endpoint was complete cure rate (0% clinical involvement of target toenail and both negative potassium hydroxide examination and fungal culture) at Week 52. Secondary endpoints included mycologic cure, treatment success (less than or equal to 10% clinical involvement of the target toenail), and complete or almost complete cure (less than or equal to 5% clinical involvement and mycologic cure). All secondary endpoints were assessed at Week 52.
Safety evaluation. Safety assessments included monitoring and recording of adverse events (AEs) until Week 52.
The two studies included 414 patients with mild onychomycosis (less than or equal to 25% nail involvement) and 1,237 patients with moderately severe onychomycosis (>25% nail involvement). Pooled results (Observed Case, OC) are provided below.
Patients with mild onychomycosis (less than or equal to 25% target toenail involvement). At baseline, mean patient age was 50.7 years. The majority of patients (369, 89.1%) were aged <65 years with 45 aged greater than or equal to 65 years old.
Patients were predominantly male (74.9%) and Caucasian (75.4%), although a number of Asian patients were enrolled through participation of a number of Japanese sites. The mean area of target toenail involvement was 22.3 percent and the mean number of affected non-target toenails was 2.6 (Table 1, Table 2).
Diabetes was reported in 7.0 percent of patients and co-existing tinea pedis in 21.0 percent (Table 2).
Patients with moderately severe onychomycosis (>25% target toenail involvement). At baseline, mean patient age was 51.8 years. The majority of patients (1064, 86.0%) were aged <65 years with 173 aged <65 years old.
Patients were predominantly male (78.0%) and Caucasian (75.9%), although a substantial number of Asian patients were enrolled through participation of a number of Japanese sites. The mean area of target toenail involvement was 41.3 percent and the mean number of affected non-target toenails was 2.8 (Table 1, Table 2).
Diabetes was reported in 6.7 percent of patients and co-existing tinea pedis in 18.4 percent (Table 2).
Primary efficacy endpoint (OC). At Week 52, 25.8 percent of patients with mild onychomycosis had a complete cure on efinaconazole compared with 11.3 percent on vehicle (P=0.006). Complete cure rates in the younger population (<65 years) were lower (25.6% versus 27.6%), although the difference was not significant (P=0.761).
Almost 16 percent (15.9%) of the moderate onychomycosis patients were completely cured at Week 52, compared to only 2.7 percent on vehicle (P<0.001). Complete cure rates in the younger population (<65 years) were higher (16.4% versus 12.6%), although the difference was not significant (P=0.349).
In those patients with mild onychomycosis, complete cure rates became significant compared to vehicle at Week 36 (Figure 2). Efinaconazole topical solution, 10%, was significantly more effective than vehicle from Week 48 (Figure 3).
The difference in efficacy in the mild and moderate onychomycosis patients treated with efinaconazole topical solution, 10%, was also significant (Figure 4).
The number of non-target toenails involved could also be considered as indicative of disease severity; however, the results were less clear with complete cure rates being highest when the number of non-target toenails was 0 (28.3%), 2 (22.3%), or 5 (20.1%).
Supportive and secondary efficacy endpoints (OC). At Week 52, 58.2 percent of patients with mild onychomycosis and 55.6 percent with moderate onychomycosis achieved mycologic cure on efinaconazole compared with 25.0 and 14.1 percent on vehicle (both P<0.001). Mycologic cure became significant versus vehicle at Week 12 in the mild onychomycosis patients and at Week 24 in the moderately severe patients.
Also, more patients achieved a complete or almost complete cure on efinaconazole (37.5% and 24.3%, mild and moderate onychomycosis respectively) compared to vehicle (17.5% and 4.9%) at Week 52, and 65.7 and 40.7 percent of patients (mild and moderate onychomycosis, respectively) were considered treatment successes at Week 52 (less than or equal to 10% affected target toenail) compared to 37.8 and 12.1 percent on vehicle (Figure 5).
Safety. Overall safety data has already been reported. Efinaconazole AE rates were similar to vehicle. Adverse events were generally mild or moderate in severity (>95% of patients), not related to study medication, and resolved without sequelae. The rate of discontinuation as a result of AEs was low. In patients with moderate disease severity, AE rates tended to be higher, with more patients treated with efinaconazole (3.2% versus 1.0% in the milder patients) discontinuing because of AEs (Table 3). Most common treatment emergent AEs were application site vesicles and dermatitis.
The use of topical antifungal treatment of onychomycosis has often been restricted to mild disease. In this respect, the results seen with efinaconazole topical solution, 10%, are impressive. It is not surprising that complete cure rates were higher in those patients with milder disease, and at the end of the study more than a quarter of patients were complete cures. Although the proportion of younger patients in the mild group was greater, complete cure rates were not significantly influenced by age, with the older patients tending to do a little better. This suggests that the younger patients in this group do not influence the results seen in the milder patients.
Almost two-thirds of patients with mild onychomycosis were considered treatment successes by Week 52, with an average improvement of at least 50 percent in their target toenail involvement.
Complete cure rates in the moderate group were also not significantly influenced by age, although here the younger patients tended to do better. Overall, more than 40 percent of those patients considered to be suffering from moderately severe disease were considered treatment successes by Week 52.
Interestingly, there was little difference in mycologic cure at study end in mild or moderately severe patients treated with efinaconazole topical solution, 10%, although mycologic cure was achieved quicker in the milder patients. A marked difference in mycologic cure was noted in the vehicle groups in favor of the milder patients. Mycologic cure is the only consistently defined efficacy parameter reported in toenail onychomycosis studies. It is often considered the main treatment goal, with complete cure occurring somewhat later as the nail grows out. Indeed, in this subgroup analysis the differences seen with the vehicle groups translated to very low complete cure rates at Week 52.
Although one study failed to show any prognostic value in the degree of nail involvement,7 disease severity is an obvious predictive factor in the potential efficacy of any drug. The author was able to show that complete cure rates were higher in mild onychomycosis patients treated with efinaconazole topical solution, 10%. In patients with more severe onychomycosis, the reduced rate of growth and increased thickness of the nail may be a factor in reduced efficacy. However, when comparing the trajectories of the complete cure curves for active treatment in mild and moderate onychomycosis (Figure 3), it might just be that the more severe patients require a longer treatment course. The 12-month duration of the studies may not have allowed for full regrowth of the nail, despite mycologic cure. Indeed, continued improvement in cure rates in onychomycosis patients with longer treatment courses have been noted by other investigators.
It has been suggested that greater non-target nail involvement could result in reduced treatment efficacy. The data from the author’s analysis are less clear and more supportive of the view that the number of toenails involved is not predictive of outcome.
Efinaconazole topical solution, 10%, is well-tolerated. In the author’s analysis, application site reactions were more common in the moderately severe patient population. Although rates were still low, it is probable that compromised skin barrier function and inflammation play a role.
Based on this subgroup analysis, once-daily efinaconazole topical solution, 10%, may provide a useful topical option in the treatment of both mild and moderate onychomycosis.
The author acknowledges Brian Bulley, MSc, of Inergy Limited for medical writing support. Valeant Pharmaceuticals North America LLC funded Inergy’s activities pertaining to this manuscript.
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