Efinaconazole 10% Topical Solution: Case Review of Onychomycosis Patients Who Were Completely Cured at Week 24

Abstract

Background

Clinical studies with topical onychomycosis agents typically involve daily application over 48 weeks. Some patients are cured earlier; however, individual data are limited.

Objective

The aim of this study was to assess baseline demographics/disposition of onychomycosis patients completely cured at week 24 following daily efinaconazole treatment.

Methods

We conducted a week-24 case review of 2 identical, multicenter, randomized, double-blind, vehicle-controlled studies on 1,655 patients with mild-to-moderate onychomycosis. Patients were randomized (3:1) to efinaconazole 10% solution or vehicle, once daily for 48 weeks, with a 4-week post-treatment follow-up. Complete cure was defined as 0% clinical involvement of the target toenail and mycological cure (negative KOH examination and fungal culture).

Results

Overall, 19 patients had clear nails (0% clinical involvement) at week 24, and 13 (68%) were completely cured. Patients were predominantly younger (17/19 aged <65 years), female (12/19), and with recent disease (6/12). No patient had disease recurrence over the subsequent 28 weeks. Complete cure appeared independent of baseline severity. Two patients with moderate disease had clear nails by week 12, and 1 experienced recurrence.

Conclusions

Efinaconazole 10% topical solution has been shown to be an effective and well-tolerated treatment for onychomycosis. Our case review highlights that some patients (typically those having faster growing, shorter nails) might expect complete cure within 24 weeks. Continued treatment appears to prevent recurrence.

Introduction

Onychomycosis is the most common nail disease in adults, representing up to 50% of all nail disorders and showing a tendency to both greater target toenail involvement and spread to non-target toenails with increasing disease duration [1, 2, 3, 4]. Yet, there are limited data on true progression in individuals, many of whom have suffered for years before seeking treatment. We still do not fully appreciate why some patients respond to treatment and others do not. It has been suggested that greater non-target toenail involvement could result in a reduced treatment efficacy [5]. However, 1 study failed to demonstrate any prognostic value of the extent of nail involvement or the number of toenails involved [6]. Post hoc analyses of 2 efinaconazole phase 3 studies reported greater complete cure rates in mild onychomycosis [7], females [8], and patients with more recent disease, or where no other toenails were involved [3]; however, the impact of a 48-week controlled treatment regimen is unclear.

Our objective was to evaluate those patients in these 2 studies who were completely cured within 12–24 weeks and to provide additional insights into our understanding of the disease and treatment outcomes.

Methods

We conducted a case review of 2 multicenter, randomized, double-blind, vehicle-controlled phase 3 studies to evaluate the efficacy, safety, and tolerability of efinaconazole 10% topical solution relative to its vehicle in 1,655 male and female patients aged 18–70 years with mild-to-moderate toenail onychomycosis (20–50% clinical involvement of the target toenail).

Patients were randomized (3:1) to apply blinded study drug or vehicle once daily to the toenails for 48 weeks, with a 4-week post-treatment follow-up. These trials were registered with ClinicalTrials.gov (Nos. NCT01008033 and NCT01007708), and phase 3 data have been published elsewhere [9].

The primary end point was complete cure rate (0% clinical involvement of target toenail and both negative potassium hydroxide [KOH] examination and fungal culture), and it was assessed at weeks 12, 24, 36, 48, and at follow-up (week 52). In addition, all investigational centers obtained close-up photographs of the patients' target toenail at baseline. At selected centers, additional photographs were obtained at weeks 24 and 52.

Data was evaluated from those patients who were completely cured at weeks 12 and 24. Additional data was reviewed for patients who had clear nails at week 24 but were not mycologic cures.

Results

Overall, 13 patients treated with efinaconazole were completely cured at week 24 (evaluable patients, n = 12; see Fig. 1 for representative baseline photographs and Fig. 2 for baseline and week-24 photographs), compared with 4 patients treated with vehicle (pooled data, observed case, p = 0.818). One additional patient treated with efinaconazole who had a baseline disease severity of 45% affected target toenail was a complete cure at week 12. However, this patient experienced a relapse (20% target toenail involvement at week 24) but was again completely cured with ongoing treatment by week 48. None of the patients who were cured by week 24 relapsed while being treated with efinaconazole through week 48, or during the 4-week follow-up. Two of the vehicle-cures relapsed at week 36; 1 was completely cured with ongoing treatment at week 52, and the other patient continued to have some active nail involvement.

Fig. 1.

Representative baseline photographs of the target toenails of patients who were completely cured with efinaconazole at week 24, indicating investigator-assessed disease severity.

Fig. 2.

Representative baseline and week 24 photographs of the target toenails for 2 patients treated with efinaconazole. a A 34-year-old Caucasian obese female with 50% nail involvement at baseline, co-existing diabetes and tinea pedis, a disease duration of 25 years, and 2 non-target toenails involved. The patient had a clear nail at week 24. b A 50-year-old Caucasian obese male with 25% nail involvement at baseline, a disease duration of 28 years, and 5 non-target toenails involved. The patient was completely cured at week 24.

A clear target toenail (0% affected target toenail, without mycologic cure) was observed in 19 patients treated with efinaconazole at week 24, compared with 5 patients treated with vehicle (pooled data, observed case, p = 0.561).

While all patients treated with vehicle who were completely cured had mild disease, half of the patients who were cured with efinaconazole had moderate disease (>25% target toenail involvement).

The mean age of patients who were completely cured at week 24 was 49.4 years (Table 1). Equal numbers of male and female patients were completely cured, and 1 patient was Hispanic/Latino. The majority were Caucasian (67%) and overweight (75%). Only 2 patients had no other toenail involvement (mean non-target toenail involvement = 2.3), and only 4 reported recent disease (≤1 year). Coexisting diabetes was not common (2 patients only, 16.7%), and tinea pedis was reported in 4 patients (33.3%) of the study (of which 2 were treated). Trichphyton rubrum was the predisposing organism in 8 patients (66.7%), while the other 5 patients cultured T. mentagrophytes as the primary organism.

Table 1.

Baseline demographics of patients treated with efinaconazole who were completely cured at week 24 (grey)

Patient reference	Affected target toenail, %	Age, years	Gender	Hispanic	Race	BMI	Diabetes present	Tinea pedis	Organism	Non-target toenails	Disease duration, years	Country
102–014	25	52	F	N	W	26	N	N	T. rubrum	4	1	Canada
113–040	20	54	F	N	W	23	N	N	T. rubrum	4	15	Canada
113–050	40	57	M	N	W	29	N	N	T. rubrum	3	10	Canada
124–070	25	68	F	N	W	25	N	N	T. rubrum	3	1	USA
135–010	20	61	M	N	W	27	Y	N	T. rubrum	2	3	Canada
163–029	20	40	F	N	A	19	N	N	T. menta	2	?	Japan
167–017	20	58	F	N	A	18	N	Y	T. menta	1	?	Japan
170–006	20	69	F	N	A	26	N	N	T. menta	3	1	Japan
172–009	25	30	F	N	A	21	N	Y/T	T. menta	0	0	Japan
191–006	50	50	F	N	A	21	N	Y/T	T. rubrum	1	0	Japan
215–004	30	32	F	N	W	30	N	N	T. rubrum	5	10	USA
223–001	40	54	M	N	W	32	N	N	T. rubrum	4	39	USA
223–003	20	57	M	N	W	27	N	N	T. rubrum	4	6	USA
227–034	45	29	M	Y	W	28	N	N	T. rubrum	3	2	USA
227–039	50	34	F	N	W	37	Y	Y	T. rubrum	2	25	USA
227–057	20	46	F	N	W	39	N	N	T. rubrum	5	5	USA
229–009	50	57	M	N	W	27	N	N	T. menta	1	3	Canada
240–036	25	50	M	N	W	31	N	N	T. rubrum	5	28	USA
244–030	35	38	F	Y	W	31	N	N	T. rubrum	0	0	USA

The remaining patients had clear nails, without mycologic cure. One patient was completely cured at week 12 but relapsed by week 24 (dark grey). Y/N, yes/no; W/A, White/Asian; T., Trichphyton; menta, mentagrophytes; T, treated.

Discussion

Data from post hoc analyses of clinical trials suggest that female patients, younger patients, and those with milder disease (including a baseline disease duration of ≤1 year and no other toenail involvement) are likely to benefit most from topical therapy with efinaconazole [3, 6, 7, 8].

In our analysis, we looked at the profile of patients who were completely cured at week 24 following efinaconazole therapy. An equal number of male and female patients achieved complete cure; seemingly independent of disease severity, disease duration, and the involvement of other toenails, although the females tended to have more recent disease and less non-target toenail involvement. The mean age was comparable to that in the 2 phase 3 pivotal studies, although on average, the female patients were younger. This finding is consistent with the overall efficacy data in the 2 phase 3 studies.

A limited number of patients treated with vehicle were also completely cured at week 24; however, relapse was not uncommon, and their onychomycosis was considered mild. While it is not clear why the vehicle demonstrated some efficacy in these studies, placebo efficacy is not uncommon in onychomycosis studies. Here it may relate to the excipients in the vehicle formulation, and repeated trimming of the nail may also have played an important role.

There are some limitations to our evaluation. We only considered a limited number of variables and focused on those patients who were completely cured at week 24. It also represents a small group of patients. It may be worth evaluating the 57 patients who were completely cured at week 36 (compared with 8 on vehicle, p = 0.021) to see if patterns begin to emerge as a significant divergence between active and vehicle was apparent by that time.

Our data presented here suggest that it is not possible to predict treatment outcome in onychomycosis with efinaconazole, or that there are other factors involved in achieving complete cure that we have not considered. However, younger, white females with more recent disease may be easier to treat successfully. Although the studies were not set up to study relapse/recurrence, it is noteworthy that all patients who were completely cured at week 24 remained completely cured by week 48 and also through the 4-week follow-up period. In addition, it should be emphasized that although recommended treatment of onychomycosis with topical therapy typically extends beyond 1 year until complete cure is achieved and the toenail grows out completely, some patients do achieve cure much earlier.

Conclusion

Efinaconazole 10% topical solution has been shown to be an effective and well-tolerated treatment for toenail onychomycosis. Our case review highlights that some patients (typically younger females with recent disease who likely have faster growing, shorter nails) might expect to achieve complete cure within 24 weeks, with resultant cost benefits.

Statement of Ethics

All patients gave written informed consent, and permission was obtained to use the photos.

Disclosure Statement

Dr. Elewski is an investigator for Amgen, AbbVie, Boehringer Ingelheim, Celgene, Incyte, Lilly, Merck, Novan, Novartis, Pfixer, Viamet and Valeant, and a consultant for Anacor, Celgene, Lilly, Novartis, Pfizer, and Valeant. Dr. Tosti is a consultant for Valeant, a speaker for PharmaDerm, and receives author royalties from the Springer Verlag/Taylor & Francis. Tina Lin is an employee of Valeant.

Funding Sources

The original pivotal studies were funded by Valeant Pharmaceuticals. The authors of this case review did not obtain any reimbursement for their time in its preparation.