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Efinaconazole Solution 10% for Treatment of Toenail Onychomycosis in Latino Patients
Author(s)
Fran E. Cook-Bolden, MD
Tina Lin, PharmD

Onychomycosis is a common progressive fungal infection of the nail bed, matrix, or plate leading to destruction and deformity of the toenails and fingernails.1,2 It represents up to 50% of all nail disorders1,3 with a notable increasing prevalence in the United States.4-6

Latinos represent the largest ethnic minority group in the United States,7 which is growing rapidly through immigration, particularly in the southern United States. Prevalence data are limited. An incidence of 9.3% secondary to dermatophytes was recorded in a dermatology clinic setting (N=2000).8 Onychomycosis was reported in 31.9% of a group of Latino immigrants in North Carolina (N=518), with higher prevalence in poultry workers, possibly due to the work environment.9

Efinaconazole solution 10% was shown to be well tolerated and more effective than a vehicle in a phase 2 study in Mexico.10 Two identical phase 3 studies of 1655 participants assessed the safety and efficacy of efinaconazole solution 10% in the treatment of onychomycosis.11 This post hoc analysis compares the data for Latino versus non-Latino populations.

Methods

We evaluated the results of 2 multicenter, randomized, double-blind, vehicle-controlled studies that included a total of 1655 participants with mild to moderate toenail onychomycosis (20%–50% clinical involvement). Participants were randomized to efinaconazole solu-tion 10% or vehicle once daily (3:1) for 48 weeks with a 4-week posttreatment follow-up period.11

Our post hoc analysis included 270 Latino patients, defined as an individual of Cuban, Mexican, Puerto Rican, or South or Central American origin or other Latino culture, regardless of race. In addition, data were compared to the 1380 non-Latino patients in the 2 studies. Patients who were randomized in error and never received treatment were excluded from the intention-to-treat analysis.

Efficacy Evaluation

The primary efficacy end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52. Secondary end points included mycologic cure, complete/almost complete cure (≤5% clinical involvement of target toenail, mycologic cure), and treatment success (≤10% clinical involvement of target toenail) at week 52.

Safety Evaluation

Safety assessments included monitoring and recording of adverse events (AEs) at every postbaseline study visit through week 52. All AEs were classified using the Medical Dictionary for Regulatory Activities (version 12.1). Treatment-emergent AEs (ie, events that began after the first application of study drug) that occurred during the study were summarized for each treatment group by the number of patients reporting each event, as well as by system organ class, preferred term, severity, seriousness, and relationship to the study drug.

Results

A total of 270 Latino participants with toenail onychomycosis (efinaconazole solution 10%, n=193; vehicle, n=77) were included in our study. The mean age of participants at baseline was 45.9 years. They were predominantly male (69.6%) and white Latinos (91.1%). The mean area of target toenail involvement was 36.6%, and the mean number of affected nontarget toenails was 2.5. Latino participants tended to be younger than non-Latino participants (45.9 vs 52.6 years), with a higher proportion of females (30.4% vs 21.3%). Disease severity was similar in both populations. Diabetes was reported in 7.0% and 6.7% of Latino and non-Latino participants, respectively, and mean weight was 83.6 and 86.6 kg, respectively.

 

 

Primary Efficacy End Points (Observed Case [OC])

At week 52, 25.6% of Latino participants in the efinaconazole group achieved complete cure versus 0% in the vehicle group (P<.001)(Figure 1). The efficacy of efinaconazole was statistically superior in Latino participants versus non-Latino participants (17.2% [P=.012]). The net effect (calculated by active treatment minus vehicle) for Latino participants also was superior to non-Latino participants (25.6% vs 11.6%).

Figure 1. Primary efficacy end point of complete cure at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.012 between the 2 efina-conazole groups.

Secondary Efficacy End Points (OC)

At week 52, 61.5% of Latino participants in the efina-conazole group achieved mycologic cure versus 15.3% in the vehicle group (P<.001)(Figure 2). The net effect for Latino participants was superior to non-Latino participants (46.2% vs 38.5%). More Latino participants in the efinaconazole group compared to vehicle group achieved complete/almost complete cure (32.7% vs 1.7%) or treatment success (49.4% vs 5.1%)(all P<.001)(Figure 3). Although there was no significant difference between the 2 groups for secondary efficacy end points, the net effect of efinaconazole was greater for all end points.

Figure 2. Secondary efficacy end point of mycologic cure at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.154 between the 2 efina-conazole groups.

Figure 3. Secondary efficacy end point of treatment success (≤10% clinical involvement of target toenail) at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.559 between the 2 efinaconazole groups.

Safety

Adverse event rates were higher in the efinaconazole group than the vehicle group (65.3% vs 54.4%) and were similar in both populations; they were generally mild (61.8% vs 54.5%) or moderate (35.3% vs 45.5%) in severity, not related to study medication (96.8% vs 98.0%), and resolved without sequelae. Only 3 Latino participants (1.6%) discontinued efinaconazole treatment compared to 29 (2.8%) in the non-Latino population.

 

 

Comment

With the continued growth of the Latino population in the United States and likely higher prevalence of onychomycosis,9 this post hoc analysis provides important insights into treatment of onychomycosis in this patient population.

Efinaconazole solution 10% was significantly more effective than vehicle in the Latino population (P<.001) and also appeared significantly more effective than the non-Latino population across the 2 phase 3 studies (P=.012). Interestingly, complete cure rates (25.6%) were identical to those reported in the phase 2 study of Mexican patients treated with efinaconazole for 36 weeks.10 Specific data with other topical therapies, such as tavaborole, in Latino patients are not available. One phase 3 study of tavaborole for onychomycosis included 89 Mexican patients (15% of the total study population), but complete cure rates for the overall active treatment group were higher in a second phase 3 study (6.5% vs 9.1%) that did not include participants outside the United States or Canada.12

It is not clear why phase 3 efficacy results with efinaconazole appear better in the Latino population. There are a number of predisposing factors for onychomycosis that are important treatment considerations in Latinos. Obesity is an important factor in the development of onychomycosis,13 with more than 42% of Latino adults in the United States reportedly obese compared to 32.6% of non-Latino adults.14 Obese patients reportedly have shown a poorer response to efinaconazole treatment15; however, in our analysis, the mean weight of the 2 subpopulations was similar at baseline. Diabetes also is associated with an increased risk for onychomycosis16,17 and may be a more important issue in Latinos perhaps due to differences in health care access, social and cultural factors, and/or genetics, as well as the greater incidence of obesity. Prior reports suggest the efficacy of efinaconazole is not substantially influenced by the presence of diabetes,18 and in our 2 subpopulations, baseline incidence of coexisting diabetes was similar. These factors are unlikely to account for the better treatment success seen in our analysis. Efinaconazole has been reported to be more effective in females,19 though the reasons are less clear. The higher proportion of female Latinos (30.4% vs 21.3%) in our study may have had an impact on the results reported, though this baseline characteristic cannot be considered in isolation.

When considering the net effect (active minus vehicle), the apparent benefits of efinaconazole in Latino patients with onychomycosis were more marked. Vehicle complete cure rates at week 52 were 0% compared with 5.6% of non-Latino participants. Vehicle cure rates in randomized controlled trials of toenail onychomycosis are relatively low and appear to be independent of the study characteristics.20 Vehicle cure rates of 2 topical treatments—efinaconazole and tavaborole—reported in their 2 respective phase 3 studies were 3.3% and 5.5% for efinaconzole11 and 0.5% and 1.5% for tavaborole.12 It has been suggested that the higher results seen with the efinaconazole vehicle relate to the formulation, though there is no reason to expect it to perform differently in a Latino population. It also has been suggested that baseline disease severity might impact vehicle treatment outcome.20 In our analysis, the percentage affected nail at baseline was higher in the Latino participants treated with vehicle (38.9% vs 36.2%).

Although the overall level of AEs was similar in Latino versus non-Latino participants treated with efinaconazole, events were generally milder in the Latino subpopulation and fewer participants discontinued because of AEs.

Our study had a number of limitations. A study period of 52 weeks may be too brief to evaluate clinical cure in onychomycosis, as continued improvement could occur with either longer treatment or follow-up. Also, the pivotal studies were not set up to specifically study Latino participants; the demographics and study disposition may not be representative of the general Latino population.

Conclusion

Once-daily treatment with efinaconazole solution 10% may provide a useful topical option in the treatment of Latino patients with toenail onychomycosis.

Acknowledgment

The authors would like to thank Brian Bulley, MSc (Konic Limited, West Sussex, United Kingdom), for medical writing support. Valeant Pharmaceuticals North America LLC funded Konic Limited’s activities pertaining to this manuscript. Dr. Cook-Bolden did not receive funding or any form of compensation for authorship of this publication.

References
  1. Scher RK, Coppa LM. Advances in the diagnosis and treatment of onychomycosis. Hosp Med. 1998;34:11-20.
  2. Crissey JT. Common dermatophyte infections. a simple diagnostic test and current management. Postgrad Med. 1998;103:191-192, 197-200, 205.
  3. Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol. 2000;43:244-248.
  4. Scher RK, Rich P, Pariser D, et al. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013;32(2, suppl 1):S2-S4.
  5. Kumar S, Kimball AB. New antifungal therapies for the treatment of onychomycosis. Expert Opin Investig Drugs. 2009;18:727-734.
  6. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.
  7. Census 2010: 50 million Latinos. Hispanics account for more than half of nation’s growth in past decade. Pew Hispanic Center website. http://pewhispanic.org/files/reports/140.pdf. Published March 24, 2011. Accessed November 22, 2016.
  8. Sanchez MR. Cutaneous diseases in Latinos. Dermatol Clin. 2002;21:689-697.
  9. Pichardo-Geisinger R, Mun˜oz-Ali D, Arcury TA, et al. Dermatologist-diagnosed skin diseases among immigrant Latino poultry processors and other manual workers in North Carolina, USA. Int J Dermatol. 2013;52:1342-1348.
  10. Tschen EH, Bucko AD, Oizumi N, et al. Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study. J Drugs Dermatol. 2013;12:186-192.
  11. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600-608.
  12. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015;73:62-69.
  13. Chan MK, Chong LY. A prospective epidemiology survey of foot disease in Hong Kong. J Am Podiatr Med Assoc. 2002;92:450-456.
  14. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of Obesity Among Adults: United States, 2011-2012. Hyattsville, MD: National Center for Health Statistics, 2013. NCHS data brief, no. 131.
  15. Elewski BE, Tosti A. Risk factors and comorbidities for onychomycosis: implications for treatment with topical therapy. J Clin Aesthet Dermatol. 2015;8:38-42.
  16. Tosti A, Hay R, Arenas-Guzmán R. Patients at risk of onychomycosis–risk factor identification and active prevention. J Eur Acad Dermatol Venereol. 2005;19(suppl 1):13-16.
  17. Sigurgeirsson B, Steingrímsson O. Risk factors associated with onychomycosis. J Eur Acad Dermatol Venereol. 2004;18:48-51.
  18. Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014;13:1186-1190.
  19. Rosen T. Evaluation of gender as a clinically relevant outcome variable in the treatment of onychomycosis with efinaconazole topical solution 10%. Cutis. 2015;96:197-201.
  20. Gupta AK, Paquet M. Placebo cure rates in the treatment of onychomycosis. J Am Podiatr Med Assoc. 2014;104:277-282.
Article PDF
CT099004286.PDF
Author and Disclosure Information

Dr. Cook-Bolden is from Skin Specialty Dermatology, New York, New York. Dr. Lin is from Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey.

Dr. Cook-Bolden was a principle investigator in the study and has served as an advisory board member, researcher, and speaker for Valeant Pharmaceuticals North America LLC. Dr. Lin is an employee and shareholder of Valeant Pharmaceuticals North America LLC.

Correspondence: Fran E. Cook-Bolden, MD, Skin Specialty Dermatology, 150 E 58th St, New York, NY 10155 (skinspecialtydermatology@gmail.com).

Issue
Cutis - 99(4)
Publications
Cutis
MDedge Dermatology
Topics
Hair & Nails
Page Number
286-289
Sections
Original Research
Author(s)
Fran E. Cook-Bolden, MD
Tina Lin, PharmD
Author(s)
Fran E. Cook-Bolden, MD
Tina Lin, PharmD
Author and Disclosure Information

Dr. Cook-Bolden is from Skin Specialty Dermatology, New York, New York. Dr. Lin is from Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey.

Dr. Cook-Bolden was a principle investigator in the study and has served as an advisory board member, researcher, and speaker for Valeant Pharmaceuticals North America LLC. Dr. Lin is an employee and shareholder of Valeant Pharmaceuticals North America LLC.

Correspondence: Fran E. Cook-Bolden, MD, Skin Specialty Dermatology, 150 E 58th St, New York, NY 10155 (skinspecialtydermatology@gmail.com).

Author and Disclosure Information

Dr. Cook-Bolden is from Skin Specialty Dermatology, New York, New York. Dr. Lin is from Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey.

Dr. Cook-Bolden was a principle investigator in the study and has served as an advisory board member, researcher, and speaker for Valeant Pharmaceuticals North America LLC. Dr. Lin is an employee and shareholder of Valeant Pharmaceuticals North America LLC.

Correspondence: Fran E. Cook-Bolden, MD, Skin Specialty Dermatology, 150 E 58th St, New York, NY 10155 (skinspecialtydermatology@gmail.com).

Article PDF
CT099004286.PDF
Article PDF
CT099004286.PDF
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Onychomycosis is a common progressive fungal infection of the nail bed, matrix, or plate leading to destruction and deformity of the toenails and fingernails.1,2 It represents up to 50% of all nail disorders1,3 with a notable increasing prevalence in the United States.4-6

Latinos represent the largest ethnic minority group in the United States,7 which is growing rapidly through immigration, particularly in the southern United States. Prevalence data are limited. An incidence of 9.3% secondary to dermatophytes was recorded in a dermatology clinic setting (N=2000).8 Onychomycosis was reported in 31.9% of a group of Latino immigrants in North Carolina (N=518), with higher prevalence in poultry workers, possibly due to the work environment.9

Efinaconazole solution 10% was shown to be well tolerated and more effective than a vehicle in a phase 2 study in Mexico.10 Two identical phase 3 studies of 1655 participants assessed the safety and efficacy of efinaconazole solution 10% in the treatment of onychomycosis.11 This post hoc analysis compares the data for Latino versus non-Latino populations.

Methods

We evaluated the results of 2 multicenter, randomized, double-blind, vehicle-controlled studies that included a total of 1655 participants with mild to moderate toenail onychomycosis (20%–50% clinical involvement). Participants were randomized to efinaconazole solu-tion 10% or vehicle once daily (3:1) for 48 weeks with a 4-week posttreatment follow-up period.11

Our post hoc analysis included 270 Latino patients, defined as an individual of Cuban, Mexican, Puerto Rican, or South or Central American origin or other Latino culture, regardless of race. In addition, data were compared to the 1380 non-Latino patients in the 2 studies. Patients who were randomized in error and never received treatment were excluded from the intention-to-treat analysis.

Efficacy Evaluation

The primary efficacy end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52. Secondary end points included mycologic cure, complete/almost complete cure (≤5% clinical involvement of target toenail, mycologic cure), and treatment success (≤10% clinical involvement of target toenail) at week 52.

Safety Evaluation

Safety assessments included monitoring and recording of adverse events (AEs) at every postbaseline study visit through week 52. All AEs were classified using the Medical Dictionary for Regulatory Activities (version 12.1). Treatment-emergent AEs (ie, events that began after the first application of study drug) that occurred during the study were summarized for each treatment group by the number of patients reporting each event, as well as by system organ class, preferred term, severity, seriousness, and relationship to the study drug.

Results

A total of 270 Latino participants with toenail onychomycosis (efinaconazole solution 10%, n=193; vehicle, n=77) were included in our study. The mean age of participants at baseline was 45.9 years. They were predominantly male (69.6%) and white Latinos (91.1%). The mean area of target toenail involvement was 36.6%, and the mean number of affected nontarget toenails was 2.5. Latino participants tended to be younger than non-Latino participants (45.9 vs 52.6 years), with a higher proportion of females (30.4% vs 21.3%). Disease severity was similar in both populations. Diabetes was reported in 7.0% and 6.7% of Latino and non-Latino participants, respectively, and mean weight was 83.6 and 86.6 kg, respectively.

 

 

Primary Efficacy End Points (Observed Case [OC])

At week 52, 25.6% of Latino participants in the efinaconazole group achieved complete cure versus 0% in the vehicle group (P<.001)(Figure 1). The efficacy of efinaconazole was statistically superior in Latino participants versus non-Latino participants (17.2% [P=.012]). The net effect (calculated by active treatment minus vehicle) for Latino participants also was superior to non-Latino participants (25.6% vs 11.6%).

Figure 1. Primary efficacy end point of complete cure at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.012 between the 2 efina-conazole groups.

Secondary Efficacy End Points (OC)

At week 52, 61.5% of Latino participants in the efina-conazole group achieved mycologic cure versus 15.3% in the vehicle group (P<.001)(Figure 2). The net effect for Latino participants was superior to non-Latino participants (46.2% vs 38.5%). More Latino participants in the efinaconazole group compared to vehicle group achieved complete/almost complete cure (32.7% vs 1.7%) or treatment success (49.4% vs 5.1%)(all P<.001)(Figure 3). Although there was no significant difference between the 2 groups for secondary efficacy end points, the net effect of efinaconazole was greater for all end points.

Figure 2. Secondary efficacy end point of mycologic cure at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.154 between the 2 efina-conazole groups.

Figure 3. Secondary efficacy end point of treatment success (≤10% clinical involvement of target toenail) at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.559 between the 2 efinaconazole groups.

Safety

Adverse event rates were higher in the efinaconazole group than the vehicle group (65.3% vs 54.4%) and were similar in both populations; they were generally mild (61.8% vs 54.5%) or moderate (35.3% vs 45.5%) in severity, not related to study medication (96.8% vs 98.0%), and resolved without sequelae. Only 3 Latino participants (1.6%) discontinued efinaconazole treatment compared to 29 (2.8%) in the non-Latino population.

 

 

Comment

With the continued growth of the Latino population in the United States and likely higher prevalence of onychomycosis,9 this post hoc analysis provides important insights into treatment of onychomycosis in this patient population.

Efinaconazole solution 10% was significantly more effective than vehicle in the Latino population (P<.001) and also appeared significantly more effective than the non-Latino population across the 2 phase 3 studies (P=.012). Interestingly, complete cure rates (25.6%) were identical to those reported in the phase 2 study of Mexican patients treated with efinaconazole for 36 weeks.10 Specific data with other topical therapies, such as tavaborole, in Latino patients are not available. One phase 3 study of tavaborole for onychomycosis included 89 Mexican patients (15% of the total study population), but complete cure rates for the overall active treatment group were higher in a second phase 3 study (6.5% vs 9.1%) that did not include participants outside the United States or Canada.12

It is not clear why phase 3 efficacy results with efinaconazole appear better in the Latino population. There are a number of predisposing factors for onychomycosis that are important treatment considerations in Latinos. Obesity is an important factor in the development of onychomycosis,13 with more than 42% of Latino adults in the United States reportedly obese compared to 32.6% of non-Latino adults.14 Obese patients reportedly have shown a poorer response to efinaconazole treatment15; however, in our analysis, the mean weight of the 2 subpopulations was similar at baseline. Diabetes also is associated with an increased risk for onychomycosis16,17 and may be a more important issue in Latinos perhaps due to differences in health care access, social and cultural factors, and/or genetics, as well as the greater incidence of obesity. Prior reports suggest the efficacy of efinaconazole is not substantially influenced by the presence of diabetes,18 and in our 2 subpopulations, baseline incidence of coexisting diabetes was similar. These factors are unlikely to account for the better treatment success seen in our analysis. Efinaconazole has been reported to be more effective in females,19 though the reasons are less clear. The higher proportion of female Latinos (30.4% vs 21.3%) in our study may have had an impact on the results reported, though this baseline characteristic cannot be considered in isolation.

When considering the net effect (active minus vehicle), the apparent benefits of efinaconazole in Latino patients with onychomycosis were more marked. Vehicle complete cure rates at week 52 were 0% compared with 5.6% of non-Latino participants. Vehicle cure rates in randomized controlled trials of toenail onychomycosis are relatively low and appear to be independent of the study characteristics.20 Vehicle cure rates of 2 topical treatments—efinaconazole and tavaborole—reported in their 2 respective phase 3 studies were 3.3% and 5.5% for efinaconzole11 and 0.5% and 1.5% for tavaborole.12 It has been suggested that the higher results seen with the efinaconazole vehicle relate to the formulation, though there is no reason to expect it to perform differently in a Latino population. It also has been suggested that baseline disease severity might impact vehicle treatment outcome.20 In our analysis, the percentage affected nail at baseline was higher in the Latino participants treated with vehicle (38.9% vs 36.2%).

Although the overall level of AEs was similar in Latino versus non-Latino participants treated with efinaconazole, events were generally milder in the Latino subpopulation and fewer participants discontinued because of AEs.

Our study had a number of limitations. A study period of 52 weeks may be too brief to evaluate clinical cure in onychomycosis, as continued improvement could occur with either longer treatment or follow-up. Also, the pivotal studies were not set up to specifically study Latino participants; the demographics and study disposition may not be representative of the general Latino population.

Conclusion

Once-daily treatment with efinaconazole solution 10% may provide a useful topical option in the treatment of Latino patients with toenail onychomycosis.

Acknowledgment

The authors would like to thank Brian Bulley, MSc (Konic Limited, West Sussex, United Kingdom), for medical writing support. Valeant Pharmaceuticals North America LLC funded Konic Limited’s activities pertaining to this manuscript. Dr. Cook-Bolden did not receive funding or any form of compensation for authorship of this publication.

Onychomycosis is a common progressive fungal infection of the nail bed, matrix, or plate leading to destruction and deformity of the toenails and fingernails.1,2 It represents up to 50% of all nail disorders1,3 with a notable increasing prevalence in the United States.4-6

Latinos represent the largest ethnic minority group in the United States,7 which is growing rapidly through immigration, particularly in the southern United States. Prevalence data are limited. An incidence of 9.3% secondary to dermatophytes was recorded in a dermatology clinic setting (N=2000).8 Onychomycosis was reported in 31.9% of a group of Latino immigrants in North Carolina (N=518), with higher prevalence in poultry workers, possibly due to the work environment.9

Efinaconazole solution 10% was shown to be well tolerated and more effective than a vehicle in a phase 2 study in Mexico.10 Two identical phase 3 studies of 1655 participants assessed the safety and efficacy of efinaconazole solution 10% in the treatment of onychomycosis.11 This post hoc analysis compares the data for Latino versus non-Latino populations.

Methods

We evaluated the results of 2 multicenter, randomized, double-blind, vehicle-controlled studies that included a total of 1655 participants with mild to moderate toenail onychomycosis (20%–50% clinical involvement). Participants were randomized to efinaconazole solu-tion 10% or vehicle once daily (3:1) for 48 weeks with a 4-week posttreatment follow-up period.11

Our post hoc analysis included 270 Latino patients, defined as an individual of Cuban, Mexican, Puerto Rican, or South or Central American origin or other Latino culture, regardless of race. In addition, data were compared to the 1380 non-Latino patients in the 2 studies. Patients who were randomized in error and never received treatment were excluded from the intention-to-treat analysis.

Efficacy Evaluation

The primary efficacy end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52. Secondary end points included mycologic cure, complete/almost complete cure (≤5% clinical involvement of target toenail, mycologic cure), and treatment success (≤10% clinical involvement of target toenail) at week 52.

Safety Evaluation

Safety assessments included monitoring and recording of adverse events (AEs) at every postbaseline study visit through week 52. All AEs were classified using the Medical Dictionary for Regulatory Activities (version 12.1). Treatment-emergent AEs (ie, events that began after the first application of study drug) that occurred during the study were summarized for each treatment group by the number of patients reporting each event, as well as by system organ class, preferred term, severity, seriousness, and relationship to the study drug.

Results

A total of 270 Latino participants with toenail onychomycosis (efinaconazole solution 10%, n=193; vehicle, n=77) were included in our study. The mean age of participants at baseline was 45.9 years. They were predominantly male (69.6%) and white Latinos (91.1%). The mean area of target toenail involvement was 36.6%, and the mean number of affected nontarget toenails was 2.5. Latino participants tended to be younger than non-Latino participants (45.9 vs 52.6 years), with a higher proportion of females (30.4% vs 21.3%). Disease severity was similar in both populations. Diabetes was reported in 7.0% and 6.7% of Latino and non-Latino participants, respectively, and mean weight was 83.6 and 86.6 kg, respectively.

 

 

Primary Efficacy End Points (Observed Case [OC])

At week 52, 25.6% of Latino participants in the efinaconazole group achieved complete cure versus 0% in the vehicle group (P<.001)(Figure 1). The efficacy of efinaconazole was statistically superior in Latino participants versus non-Latino participants (17.2% [P=.012]). The net effect (calculated by active treatment minus vehicle) for Latino participants also was superior to non-Latino participants (25.6% vs 11.6%).

Figure 1. Primary efficacy end point of complete cure at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.012 between the 2 efina-conazole groups.

Secondary Efficacy End Points (OC)

At week 52, 61.5% of Latino participants in the efina-conazole group achieved mycologic cure versus 15.3% in the vehicle group (P<.001)(Figure 2). The net effect for Latino participants was superior to non-Latino participants (46.2% vs 38.5%). More Latino participants in the efinaconazole group compared to vehicle group achieved complete/almost complete cure (32.7% vs 1.7%) or treatment success (49.4% vs 5.1%)(all P<.001)(Figure 3). Although there was no significant difference between the 2 groups for secondary efficacy end points, the net effect of efinaconazole was greater for all end points.

Figure 2. Secondary efficacy end point of mycologic cure at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.154 between the 2 efina-conazole groups.

Figure 3. Secondary efficacy end point of treatment success (≤10% clinical involvement of target toenail) at week 52 (intention-to-treat pooled data) for Latino and non-Latino subpopulations. Asterisk indicates P<.001 vs vehicle; dagger, P=.559 between the 2 efinaconazole groups.

Safety

Adverse event rates were higher in the efinaconazole group than the vehicle group (65.3% vs 54.4%) and were similar in both populations; they were generally mild (61.8% vs 54.5%) or moderate (35.3% vs 45.5%) in severity, not related to study medication (96.8% vs 98.0%), and resolved without sequelae. Only 3 Latino participants (1.6%) discontinued efinaconazole treatment compared to 29 (2.8%) in the non-Latino population.

 

 

Comment

With the continued growth of the Latino population in the United States and likely higher prevalence of onychomycosis,9 this post hoc analysis provides important insights into treatment of onychomycosis in this patient population.

Efinaconazole solution 10% was significantly more effective than vehicle in the Latino population (P<.001) and also appeared significantly more effective than the non-Latino population across the 2 phase 3 studies (P=.012). Interestingly, complete cure rates (25.6%) were identical to those reported in the phase 2 study of Mexican patients treated with efinaconazole for 36 weeks.10 Specific data with other topical therapies, such as tavaborole, in Latino patients are not available. One phase 3 study of tavaborole for onychomycosis included 89 Mexican patients (15% of the total study population), but complete cure rates for the overall active treatment group were higher in a second phase 3 study (6.5% vs 9.1%) that did not include participants outside the United States or Canada.12

It is not clear why phase 3 efficacy results with efinaconazole appear better in the Latino population. There are a number of predisposing factors for onychomycosis that are important treatment considerations in Latinos. Obesity is an important factor in the development of onychomycosis,13 with more than 42% of Latino adults in the United States reportedly obese compared to 32.6% of non-Latino adults.14 Obese patients reportedly have shown a poorer response to efinaconazole treatment15; however, in our analysis, the mean weight of the 2 subpopulations was similar at baseline. Diabetes also is associated with an increased risk for onychomycosis16,17 and may be a more important issue in Latinos perhaps due to differences in health care access, social and cultural factors, and/or genetics, as well as the greater incidence of obesity. Prior reports suggest the efficacy of efinaconazole is not substantially influenced by the presence of diabetes,18 and in our 2 subpopulations, baseline incidence of coexisting diabetes was similar. These factors are unlikely to account for the better treatment success seen in our analysis. Efinaconazole has been reported to be more effective in females,19 though the reasons are less clear. The higher proportion of female Latinos (30.4% vs 21.3%) in our study may have had an impact on the results reported, though this baseline characteristic cannot be considered in isolation.

When considering the net effect (active minus vehicle), the apparent benefits of efinaconazole in Latino patients with onychomycosis were more marked. Vehicle complete cure rates at week 52 were 0% compared with 5.6% of non-Latino participants. Vehicle cure rates in randomized controlled trials of toenail onychomycosis are relatively low and appear to be independent of the study characteristics.20 Vehicle cure rates of 2 topical treatments—efinaconazole and tavaborole—reported in their 2 respective phase 3 studies were 3.3% and 5.5% for efinaconzole11 and 0.5% and 1.5% for tavaborole.12 It has been suggested that the higher results seen with the efinaconazole vehicle relate to the formulation, though there is no reason to expect it to perform differently in a Latino population. It also has been suggested that baseline disease severity might impact vehicle treatment outcome.20 In our analysis, the percentage affected nail at baseline was higher in the Latino participants treated with vehicle (38.9% vs 36.2%).

Although the overall level of AEs was similar in Latino versus non-Latino participants treated with efinaconazole, events were generally milder in the Latino subpopulation and fewer participants discontinued because of AEs.

Our study had a number of limitations. A study period of 52 weeks may be too brief to evaluate clinical cure in onychomycosis, as continued improvement could occur with either longer treatment or follow-up. Also, the pivotal studies were not set up to specifically study Latino participants; the demographics and study disposition may not be representative of the general Latino population.

Conclusion

Once-daily treatment with efinaconazole solution 10% may provide a useful topical option in the treatment of Latino patients with toenail onychomycosis.

Acknowledgment

The authors would like to thank Brian Bulley, MSc (Konic Limited, West Sussex, United Kingdom), for medical writing support. Valeant Pharmaceuticals North America LLC funded Konic Limited’s activities pertaining to this manuscript. Dr. Cook-Bolden did not receive funding or any form of compensation for authorship of this publication.

References
  1. Scher RK, Coppa LM. Advances in the diagnosis and treatment of onychomycosis. Hosp Med. 1998;34:11-20.
  2. Crissey JT. Common dermatophyte infections. a simple diagnostic test and current management. Postgrad Med. 1998;103:191-192, 197-200, 205.
  3. Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol. 2000;43:244-248.
  4. Scher RK, Rich P, Pariser D, et al. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013;32(2, suppl 1):S2-S4.
  5. Kumar S, Kimball AB. New antifungal therapies for the treatment of onychomycosis. Expert Opin Investig Drugs. 2009;18:727-734.
  6. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.
  7. Census 2010: 50 million Latinos. Hispanics account for more than half of nation’s growth in past decade. Pew Hispanic Center website. http://pewhispanic.org/files/reports/140.pdf. Published March 24, 2011. Accessed November 22, 2016.
  8. Sanchez MR. Cutaneous diseases in Latinos. Dermatol Clin. 2002;21:689-697.
  9. Pichardo-Geisinger R, Mun˜oz-Ali D, Arcury TA, et al. Dermatologist-diagnosed skin diseases among immigrant Latino poultry processors and other manual workers in North Carolina, USA. Int J Dermatol. 2013;52:1342-1348.
  10. Tschen EH, Bucko AD, Oizumi N, et al. Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study. J Drugs Dermatol. 2013;12:186-192.
  11. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600-608.
  12. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015;73:62-69.
  13. Chan MK, Chong LY. A prospective epidemiology survey of foot disease in Hong Kong. J Am Podiatr Med Assoc. 2002;92:450-456.
  14. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of Obesity Among Adults: United States, 2011-2012. Hyattsville, MD: National Center for Health Statistics, 2013. NCHS data brief, no. 131.
  15. Elewski BE, Tosti A. Risk factors and comorbidities for onychomycosis: implications for treatment with topical therapy. J Clin Aesthet Dermatol. 2015;8:38-42.
  16. Tosti A, Hay R, Arenas-Guzmán R. Patients at risk of onychomycosis–risk factor identification and active prevention. J Eur Acad Dermatol Venereol. 2005;19(suppl 1):13-16.
  17. Sigurgeirsson B, Steingrímsson O. Risk factors associated with onychomycosis. J Eur Acad Dermatol Venereol. 2004;18:48-51.
  18. Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014;13:1186-1190.
  19. Rosen T. Evaluation of gender as a clinically relevant outcome variable in the treatment of onychomycosis with efinaconazole topical solution 10%. Cutis. 2015;96:197-201.
  20. Gupta AK, Paquet M. Placebo cure rates in the treatment of onychomycosis. J Am Podiatr Med Assoc. 2014;104:277-282.
References
  1. Scher RK, Coppa LM. Advances in the diagnosis and treatment of onychomycosis. Hosp Med. 1998;34:11-20.
  2. Crissey JT. Common dermatophyte infections. a simple diagnostic test and current management. Postgrad Med. 1998;103:191-192, 197-200, 205.
  3. Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol. 2000;43:244-248.
  4. Scher RK, Rich P, Pariser D, et al. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013;32(2, suppl 1):S2-S4.
  5. Kumar S, Kimball AB. New antifungal therapies for the treatment of onychomycosis. Expert Opin Investig Drugs. 2009;18:727-734.
  6. Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol. 2000;43:641-648.
  7. Census 2010: 50 million Latinos. Hispanics account for more than half of nation’s growth in past decade. Pew Hispanic Center website. http://pewhispanic.org/files/reports/140.pdf. Published March 24, 2011. Accessed November 22, 2016.
  8. Sanchez MR. Cutaneous diseases in Latinos. Dermatol Clin. 2002;21:689-697.
  9. Pichardo-Geisinger R, Mun˜oz-Ali D, Arcury TA, et al. Dermatologist-diagnosed skin diseases among immigrant Latino poultry processors and other manual workers in North Carolina, USA. Int J Dermatol. 2013;52:1342-1348.
  10. Tschen EH, Bucko AD, Oizumi N, et al. Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study. J Drugs Dermatol. 2013;12:186-192.
  11. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600-608.
  12. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015;73:62-69.
  13. Chan MK, Chong LY. A prospective epidemiology survey of foot disease in Hong Kong. J Am Podiatr Med Assoc. 2002;92:450-456.
  14. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of Obesity Among Adults: United States, 2011-2012. Hyattsville, MD: National Center for Health Statistics, 2013. NCHS data brief, no. 131.
  15. Elewski BE, Tosti A. Risk factors and comorbidities for onychomycosis: implications for treatment with topical therapy. J Clin Aesthet Dermatol. 2015;8:38-42.
  16. Tosti A, Hay R, Arenas-Guzmán R. Patients at risk of onychomycosis–risk factor identification and active prevention. J Eur Acad Dermatol Venereol. 2005;19(suppl 1):13-16.
  17. Sigurgeirsson B, Steingrímsson O. Risk factors associated with onychomycosis. J Eur Acad Dermatol Venereol. 2004;18:48-51.
  18. Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014;13:1186-1190.
  19. Rosen T. Evaluation of gender as a clinically relevant outcome variable in the treatment of onychomycosis with efinaconazole topical solution 10%. Cutis. 2015;96:197-201.
  20. Gupta AK, Paquet M. Placebo cure rates in the treatment of onychomycosis. J Am Podiatr Med Assoc. 2014;104:277-282.
Issue
Cutis - 99(4)
Issue
Cutis - 99(4)
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286-289
Page Number
286-289
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Cutis
MDedge Dermatology
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Efinaconazole Solution 10% for Treatment of Toenail Onychomycosis in Latino Patients
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Efinaconazole Solution 10% for Treatment of Toenail Onychomycosis in Latino Patients
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Practice Points

  • Onychomycosis is a common disease of importance in the increasing Latino population of the United States, especially due to predisposing factors such as obesity and diabetes mellitus. Specific data on the treatment of this patient population are lacking.
  • Two large phase 3 studies with topical efinaconazole treatment included a notable number of Latino patients.
  • Complete cure rates with efinaconazole in Latino participants were notably greater than those observed in the non-Latino population, and treatment was well tolerated in both groups.
  • Treatment of onychomycosis is important to possibly prevent a more serious infectious disease involving the lower extremities, especially in those with comorbidities such as obesity, diabetes, and peripheral vascular disease.
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