Clinical effectiveness of efinaconazole 10% solution for treatment of onychomycosis with longitudinal spikes

Abstract Onychomycosis with longitudinal spikes in the nail plate has been reported to be refractory to oral drugs as with dermatophytoma. We evaluated the efficacy of 10% efinaconazole solution in the treatment of onychomycosis with longitudinal spikes. Of the 223 subjects who were enrolled in a previous study, a post‐hoc analysis of 82 subjects with longitudinal spikes was performed in this study. The opacity ratio of longitudinal spikes was decreased over time from 8.1 to 0.9 at the final assessment. In addition, the longitudinal spike disappearance rate increased early after the application to 81.7% at the final assessment. Therefore, 10% efinaconazole solution can be a first‐line drug for longitudinal spikes, which have been regarded as refractory to oral drugs.


| INTRODUC TI ON
Onychomycosis is a common disease in daily medical practice, and affects approximately 10% of the population in Japan. 1 The disease types of onychomycosis are classified by the fungal entry route; as per the Japanese guidelines, 2 they are classified into the following five types: (i) distal and lateral subungual onychomycosis (DLSO); (ii) superficial white onychomycosis; (iii) proximal subungual onychomycosis (PSO); (iv) endonyx onychomycosis; and (v) total dystrophic onychomycosis (TDO). In addition, there may be specific disease types such as onychomycosis with longitudinal spikes (yellow or white linear affected area) or onychomycosis with dermatophytoma (round circumscribed yellow or a white patch) in the nail plate. Recently, DLSO with a V-shaped affected area at the tip of the nail are called "wedge shape" in Japan.
However, it is a normal manifestation in DLSO; thus, it is different from longitudinal spikes.
In daily clinical practice, oral antifungal drugs are effective in many cases. However, longitudinal spikes or dermatophytoma have been reported to be refractory to oral drugs. [3][4][5][6] Therefore, in previous clinical trials for onychomycosis, these disease types were excluded. [7][8][9] However, after launching 10% efinaconazole solution (EFCZ) as the first topical therapeutic agent for onychomycosis in Japan, some cases with longitudinal spikes responded to EFCZ.
Using the data of the study by Iozumi et al. 10 where longitudinal spikes were not excluded, we conducted a post-hoc analysis of the efficacy of EFCZ in onychomycosis with longitudinal spikes.

| Study subjects
This was a retrospective study to investigate the data from the study conducted by Iozumi et al. 10 after the end of the observation period. An ethical review was conducted at each study site, and approval was obtained. This study was conducted in compliance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects; information on the study including its objectives was notified or disclosed, and opportunities for refusal were secured as much as possible. From the study by Iozumi et al., 10 patients who were assessed to have onychomycosis with longitudinal spikes based on the images taken at the start date of the study by both the medical expert and the investigator of the study site were included.

| Assessment and fixation of onychomycosis with longitudinal spikes
In this study, onychomycosis with a yellow or white linear affected area was defined as onychomycosis with longitudinal spikes. We defined longitudinal spike as a clinical manifestation of longitudinal linear opacity; however, the fungal histological findings, such as a dense mass of dermatophytes, were not confirmed. The medical expert evaluated whether or not the masked images of onychomycosis at the start of the study corresponded to the definition. After this, the investigator at each site assessed whether the image at the start of the study corresponded to the definition of patients at their site.
When the assessments by the medical expert and the investigator were the same, it was placed as the assessment result. If the assessments of the medical expert and the investigator were different, the two parties discussed and the agreed assessment was placed as the assessment result. When multiple longitudinal spikes were observed in the study nail, the one with a higher opacity ratio was evaluated.
The opacity ratio and width ratio of the longitudinal spike were calculated. The opacity ratio was defined by the following

| Primary end-point
The primary end-point was change in longitudinal spike opacity ratio and disappearance rate over time.

| Secondary end-points
Evaluation of the complete cure rate, mycological cure rate, and treatment success rate were for the entire infected area, not for longitudinal spikes.
Complete cure was defined as a 0% clinical involvement of the target nail, with a negative KOH examination result.
Mycological cure was defined as a negative result in the KOH examination of the target nail.
Treatment success was defined as a reduction in clinical involvement to 10% or less of the target nail.
Other secondary end-points were changes over time in the opacity area and in the decrease of the affected nail area.

| Evaluation time points
The evaluation time points were at the start of application, weeks 12, 24, 36, 48, 60, and 72, and the final evaluation (week 72 or the date of completion of administration).
In the data to be evaluated in this study, the data from the study conducted by Iozumi et al. 10 were used for the following: • Study nail (left or right first toenail): if the right and left first toenails were affected, the one with a larger opacity area was evaluated. If the areas were the same, the right toenail was evaluated.
• Opacity area (%): the opacity area was measured by visual measurement for the percentage of the opaque area (including the area of opacity lost due to nail cutting) with the nail area assumed to be 100%.
• KOH examination: results of the target nail on the evaluation time point after the start of application.
• Fungal culture test: results of the target nail at the start of application.
• Background information: sex, age, opacity area, and causative fungal species.

| Statistical analysis
For each end-point, the number of subjects and proportion (%) were obtained for nominal variables, and summary statistics were calculated for continuous variables. The statistical analysis software R version 3.6.2 (R Core Team) was used. Missing data were imputed using the last observation carried forward method.  Table 2 shows the results of each end-point at the final assessment. Figure 2 shows changes over time in the opacity ratio of the longitudinal spike and changes in the disappearance rate of the longitudinal spike over time. The opacity ratio of the longitudinal spike was 8.1 (95% CI, 7.8-8.4) at baseline, decreasing from the early stage of treatment. It decreased to 2.5 (95% CI, 1.9-3.1) at week 24, which was approximately 30% of the baseline value, and decreased to 0.9 (95% CI, 0.4-1.3) at the final assessment (Figure 2a). The disappearance rate was 41.3% (nearly half disappeared) at week 24, and 81.7% at the final assessment (Figure 2b).

| RE SULTS
In addition to the evaluation of the longitudinal spike, changes over time in the complete cure, mycological cure, and treatment success rates of the entire opaque part of the target nail are shown in Figure 3. The complete cure rate at the final evaluation was 41.5% ( Figure 3a). The mycological cure rate and treatment success rate at the final evaluation were 69.5% and 64.6%, respectively (Figure 3b,c).
The total opacity area was 42.5% at baseline and decreased to 11.3% at the final assessment (Figure 3d,e).
Representative changes in symptoms after application of EFCZ are presented in Figure 4. Marked improvement was observed; longitudinal spike had disappeared at week 24, and onychomycosis was completely cured at week 36 (subject 1) or week 48 (subjects 2 and 3).
Subgroup analysis was performed for the primary and secondary end-points. The results are shown in Table 3. In all subgroup analyses, the disappearance rate of the longitudinal spike at the final assessment was comparable to the entire achievement rate. In addition, the rates of complete cure, mycological cure, and treatment success for the entire opacity part of the target nail were all comparable to those of the entire achievement rate.

| DISCUSS ION
Ten percent efinaconazole solution has been shown to be effective for various types of onychomycosis and has been prescribed as a treatment option for onychomycosis. In a global phase 3 study, 7 EFCZ was shown to be effective for mild to moderate DLSO. Iozumi et al. 10 evaluated the efficacy of long-term use of EFCZ for onychomycosis, including severe cases. The complete cure rate at the final evaluation was 31.1%. 10 In another study, Noguchi et al. 11 reported an efficacy rate of 65.4% in patients with an infected area exceeding 50%. In 2020, randomized controlled trials 7,12 of EFCZ with a high level of evidence were cited in the review of local treatment and device treatment for onychomycosis in the Cochrane Library. 13 In our study, the opacity ratio of the longitudinal spike de-    In conclusion, this study clarified the clinical effectiveness of EFCZ for the treatment of onychomycosis with longitudinal spikes. Since this is a multicenter study with a sample size of over 80 subjects, it will provide important findings to clarify the therapeutic effect. Although data on the efficacy of longitudinal spikes have been insufficient, the results of our study showed that EFCZ has a high therapeutic effect and can be the first-line therapy.

ACK N OWLED G M ENTS
We sincerely appreciate the cooperation of the medical staff of institutions that participated in the study. This study was funded by Kaken Pharmaceutical.