Conflict of interest:
Aditya Gupta has served as consultant, speaker, and investigator for Ortho Dermatologics, a consultant for Moberg Pharma, and a speaker and principal investigator for Bausch Health. Elizabeth Cooper is an employee of Aditya Gupta and has no individual conflicts to declare.

Abstract:
Onychomycosis, a difficult-to-treat fungal nail infection, is more prevalent in the elderly. Efinaconazole 10% topical solution is a firstline therapy for onychomycosis, based on phase III trials of 12-month treatment; the slow growth of onychomycotic nails suggests a longer treatment period may increase efficacy. This is the first efficacy and safety data for a 24-month duration of efinaconazole 10% topical solution treatment for onychomycosis. Enrolled patients (N = 101) with mild to moderate distal lateral subungual onychomycosis applied efinaconazole to all affected toenails once daily for 18-24 months. Efficacy and safety were evaluated at months 6, 12, 18, and 24 (M6, M12, M18, and M24). The study is ongoing; to date, 47 patients have completed to M24. Mycological cure (MC) was 60.0% at M12, increasing to 74.2% at M24; effective cure (MC and ≤10% clinical involvement of the target toenail) was 17.8% at M12, rising to 19.4% at M24. Mild to moderate application site reactions were the only efinaconazole-related adverse events in 8 patients (7.9%). Increased age, increased severity of onychomycosis, and the presence of mixed infections (dermatophyte plus non-dermatophyte moulds) may drive a need for longer treatment durations. Although the data are interim, there is a trend of increasing efficacy beyond M12 use, without increased safety risk, even in patients >70 years of age.

Key Words:
efinaconazole, Jublia, clinical trial, onychomycosis, nail

Introduction

Onychomycosis is a chronic fungal nail infection, occurring at an estimated prevalence of 8-14% in North America.^1-3 Onychomycosis, while mainly asymptomatic, can result in reduced quality of life (cosmetic issues, pain, difficulty walking) and significant health impacts, particularly in diabetic patients and those with poor peripheral circulation (secondary skin infections, ulceration, amputation).^4-16 Traditional treatments for toenail onychomycosis have included oral agents such as terbinafine and itraconazole.¹⁷ Despite good efficacy, oral agents present the potential for a significant number of drug interactions and hepatotoxicity, which are particularly problematic for elderly patients most in need of onychomycosis treatment to maintain health and mobility.

Efinaconazole 10% topical solution (Jublia™) is approved for mild to moderate dermatophyte toenail onychomycosis.^18,19 Efinaconazole inhibits fungal lanosterol 14α-demethylase, with broad spectrum of action against dermatophytes, yeasts and non-dermatophyte moulds (NDMs).²⁰ Efinaconazole 10% solution has low surface tension, with low affinity to keratin in the nail plate,²¹ and accumulates in the nail plate and nail bed to levels well above the minimum inhibitory concentration (MIC) of dermatophytes after continuous application for 28 days.²² In phase III trials that led to the approval of efinaconazole 10% solution, the mycological (MC) and complete cure (CC) rates of 48 weeks of efinaconazole treatment were 53-55% and 15-18%, respectively, comparable to some traditional oral agents.^19,23-26 Efinaconazole has also been shown to be effective in onychomycosis patients with diabetes (CC 13%) and coexisting tinea pedis (CC 29.4%).²⁷

Despite the promising results of efinaconazole in the phase III trials, more than half of the treated patients were left with visual signs of infection in the target toenail.^23,24 It is suspected that the 48-week (12-month) treatment period may be insufficient for complete nail outgrowth, as it is noted that nail growth rates are reduced in onychomycotic compared to healthy nails.^28-31 To investigate this possibility, we present interim results of a study to assess the safety and efficacy of treatment up to 24 months with efinaconazole for mild to moderate toenail distal lateral subungual onychomycosis (DLSO).

Study Design

This phase IV, single-site, Canadian trial included patients aged 18 years or older with mild to moderate DLSO (20-50% of the toenail affected, ≤3 mm thick and ≥1 mm lowest proximal extent of infection) in a great toenail designated as the ‘target’ for evaluation. Diagnosis was confirmed visually and by dermatophyte growth in culture. Study treatment was to be applied topically on all infected toenails as well as the ‘target’ toenail, as per the approved efinaconazole monograph instructions.

The primary variables for efficacy were mycological cure, MC (negative fluorescent potassium hydroxide [KOH] microscopic examination and negative culture) and effective cure EC (MC and ≤10% clinical involvement of the target toenail). Efficacy variables were reviewed at 6, 12, 18 and 24 months.

Results

Fifty-five (55) patients were randomized 1:1 into blinded treatment groups as of April 2018: patients received either oncedaily efinaconazole for 24 months, or once-daily vehicle for 6 months followed by once-daily efinaconazole for 18 months (i.e., 24 months of total study time). From May 2018 onward, the remaining 46 patients enrolled in the study were provided with open-label topical efinaconazole daily for 24 months, for a total of 101 patients entered into the study (Figure 1). The study remains ongoing at this time. Currently, 47 patients have completed 24 months of study and are analyzed here to provide an interim assessment of long-term efficacy. Demographics of the completed patients are shown in Table 1.

Efficacy criteria were evaluated after 6, 12, 18 and 24 months (M6, M12, M18, and M24) of treatment. Good mycological success was found up to M12 (60.0%) and there appears to be an increase in MC from M12 to M24 (74.3%) during prolonged efinaconazole application (Figure 2). Effective cure also increased from M12 (17.8%) to M18 (25.5%), indicating ongoing improvement in target nails beyond the 12-month period with continued efinaconazole 10% solution use (Figures 3 & 4).

Application site reactions (11 events) occurred in 8 of 101 enrolled patients (7.9%), and were graded as mild to moderate only, with symptoms typical of previously reported application site reactions with efinaconazole: erythema, eczema, exfoliation, and pruritus. No systemic reactions occurred in association with efinaconazole. No patients reported reactions during the vehicleuse period. A majority of the reported events occurred within the first 9 months of efinaconazole 10% solution application, i.e. in the ‘labelled’ period of use. For reactions that developed after M12, two patients reported application site trauma not related to study participation, which may have predisposed them to efinaconazole reaction (Table 2 – bottom row, 2 patients). In our ongoing dataset, the long-term use of efinaconazole 10% solution does not appear to increase the risk of an application site reaction.

Discussion

The interim data presented here represents the first assessment of a 24-month efinaconazole 10% solution use period, and demonstrates increased efficacy beyond a 12-month use period, without increased risk of AEs.

In comparison to the controlled phase III populations, our participants had a much older age distribution with one-third of the patients exceeding 70 years old, in contrast to the phase III trials which restricted enrollment to 70 years or less.^23,24 Increased age is a burden for nail clearance, as there may be a decrease in peripheral circulation and slower outgrowth of toenail.^4,32-35 Figures 5 and 6 review efficacy in the elderly subset versus the younger subset; both MC and EC rates are comparable between the age population subsets to M12 (MC: 61.5% <70 years and 57.9% ≥70 years; EC: 19.2% <70 years and 15.8% ≥70 years), and MC is comparable to the phase III trials (53-55%).¹⁹ Our M12 EC data cannot be directly compared to the phase III ‘treatment success’ outcome which did not review area clearance in conjunction with mycology status. At M18, the MC and EC in all patients applying efinaconazole was 72.3% and 25.5%, respectively. It appears that there is an improvement in efficacy with longer treatment durations. Efinaconazole treatment beyond 12 months appears to benefit the <70-year-old subgroup to a greater degree than the ≥70-year-old subgroup; however, interim results at M24 suggest the ≥70-year-old subgroup may be able to achieve similar results to the younger subset when given longer periods of nail outgrowth to reach those levels. This older subset of patients is the population most in need of nonoral antifungal treatment options due to their increased use of systemic pharmaceuticals, and being able to confirm efficacy and safety for these patients is critical. In addition to efficacy, our data shows no increased safety risk from efinaconazole 10% solution application in the elderly subset.

Our population also began treatment with onychomycosis penetrating more proximally into the nail plate of the target toenail, with almost 50% of patients having a lowest proximal extent less than 3 mm at enrollment, versus a minimum of 3 mm for the phase III studies. It is expected that such increase in severity would lead to an overall longer period of outgrowth/ lower cure rate at similar time points relative to less severe populations.

The causative organisms in toenail onychomycosis in North America are generally dermatophytes, specifically Trichophyton rubrum, and to a lesser extent Trichophyton mentagrophytes. Historically, it has been difficult to detect the presence of NDMs in onychomycosis: the addition of cycloheximide to culture media inhibits growth of NDMs in favor of dermatophytes, and high rates of false negative cultures are problematic with any fungal sampling/culturing. With the advent of polymerase chain reaction (PCR) technology, it is now possible to detect NDMs as well as dermatophytes with much greater reliability in fungal samples.^36,37 In fact, studies of PCR detection of NDMs and dermatophytes in onychomycosis suggest that the prevalence of NDMs alone or in mixed infection (dermatophyte plus NDM) may be higher than originally recognized.^36,38-43 It is suspected that the lack of effective NDM removal could be a factor that restricts the efficacy of antifungal nail therapy.^39,44 A small subset of 16 enrolled patients had PCR investigation of target toenail material for the presence of NDMs prior to treatment with efinaconazole 10% solution. All of these patients were culture positive for a dermatophyte at screening; none had mixed infection by culture methods. At screening, dermatophytes were confirmed in 15 of 16 patients by PCR, and 12 of 16 also had at least one NDM found in conjunction with a dermatophyte (75%; unpublished data). Our data suggests the presence of NDMs is high in onychomycosis. Efinaconazole has been shown to be effective in mixed infections (dermatophyte and NDM) since it is fungicidal in nature and has broad spectrum activity.^19,20,45 An extended treatment time in mixed toenail infection (dermatophyte plus NDM) has been described previously, and may be required for effective treatment of mixed infection.³⁹ This long-term study of efinaconazole is well-positioned to provide further evaluation of the role of NDMs in onychomycosis, and potential for treatment with efinaconazole 10% solution. Such review of mixed infection outcomes remains a goal for this study’s future efficacy reporting.

Conclusion

Early clinical trial data indicate the increasing effectiveness and safety of efinaconazole 10% solution use beyond 12 months; application for up to 24 months appears to remain safe even for elderly patients. Review of the final data will provide increased knowledge of both clinical and mycological efficacy with long-term efinaconazole 10% solution use in onychomycosis.

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¹University of Toronto Department of Medicine, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada

Conflicts of Interest:
AKG has been a clinical trials investigator for Valeant Canada, Nuvolase, Bristol Meyers Squibb, Eli Lilly, Merck, Novartis, Janssen and Allergan. AKG has served as a speaker or consultant for Valeant Canada, Almirall, Janssen, Novartis, Sandoz, Moberg Pharma, and Bayer. CWL has been an investigator in clinical trials sponsored by Abbvie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Dermira, Galderma, Innovaderm, Janssen, Eli Lilly, Leo Pharma, Merck, MSD, Medimmune, Novartis, Pfizer, Regeneron and Xoma. CWL has acted as an advisor or speaker, or received travel support, from Abbvie, Amgen, Boehringer, Celgene, Eli Lilly, Janssen, Leo-Pharma, Merck-Serono, MSD, Novartis, Pfizer, Sandoz, and Valeant. MC is a former employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of AKG.

ABSTRACT
Tofacitinib is an oral immunosuppressant approved for the treatment of rheumatoid arthritis (RA) and is currently undergoing investigation (Phase III trials) for treating chronic plaque psoriasis. Tofacitinib inhibits Janus kinases (JAKs), which are essential for the signaling of multiple inflammatory pathways and have been implicated in the pathogenesis of RA and psoriasis. The efficacy and safety of tofacitinib in the treatment of RA and psoriasis have been demonstrated in Phase III trials. Across all studies, the efficacy of tofacitinib in alleviating symptoms of RA and psoriasis were superior to placebo. Moreover, treatment was generally well-tolerated, with the most frequently reported adverse events, for both RA and psoriasis, being nasopharyngitis and upper respiratory tract infection. As such, tofacitinib proves to be an effective therapeutic option for RA and a promising new therapy for psoriasis.

Key Words:
IL-17, interleukin-17, interleukin-17A, monoclonal antibody, chronic plaque psoriasis

Introduction

Tofacitinib (CP-690,550; trade name: Xeljanz®) is an oral immunosuppressant developed by Pfizer¹ that is currently approved for the treatment of rheumatoid arthritis (RA)^2,3 and is undergoing Phase III trials for the treatment of chronic plaque psoriasis.^4-6 Tofacitinib is a pan-Janus-activated kinase (JAK) inhibitor, which works by inhibiting JAK3, JAK1, and, to a lesser extent, JAK2.⁷ Members of the JAK family play a key role in the signaling pathways of multiple cytokines (e.g., tumour necrosis factor [TNF]), growth factors, and hormones.² Activation of these immune pathways involving JAKs have been implicated in the pathogenesis of RA^2,8 and psoriasis.⁹

Since its FDA approval in 2012, tofacitinib has demonstrated promising results in Phase III clinical trials by significantly reducing RA associated symptoms such as synovial inflammation and structural joint damage.¹⁰ Moreover, ongoing Phase III studies are demonstrating that tofacitinib could emerge as a valuable therapy for psoriasis.¹¹ The focus of this paper is to evaluate the efficacy and safety of tofacitinib in the treatment of RA and psoriasis by reviewing recent clinical trials.

Tofacitinib for Rheumatoid Arthritis

Phase III Trials

Six Phase III trials (belonging to the Oral Rheumatoid Arthritis triaLs [ORAL] series) have been conducted to assess the efficacy of tofacitinib in the treatment of RA in various patient groups.^12-17 A summary of the details from each Phase III trial and two long-term open extension trials¹⁸ can be found in Table 1. Three primary efficacy outcomes were similar between the five Phase III trials: 1) American College of Rheumatology (ACR) 20 ( ≥20% reduction in the number of both tender and swollen joints and ≥20% improvement in three of five other criteria: the patient’s assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician) response criteria; 2) changes from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI; range of score 0-3, “no difficulty” to “unable to do”); and 3) percentage of patients with Disease Activity Score for 28 joint counts based on erythrocyte sedimentation rate (DAS28-4 [ESR]) of less than 2.6 (range 0-9.4). The sixth trial (ORAL Start) used the primary efficacy outcome of ARC 70 response and the modified total Sharp score (mTSS) from baseline. In the groups receiving tofacitinib treatment, ARC 20 or 70 (for the ORAL Start trial) response rates and the HAQ-DI scores were significantly higher compared to the placebo groups. Most studies also showed significant changes from baseline in the DAS28-4 (ESR) score in the tofacitinib group(s) compared to placebo and the ORAL Start trials showed that the change in mTSS from baseline was significantly smaller in the tofacitinib groups. The most common adverse event (AE) throughout the studies was upper respiratory tract infection. During the first 3 months of tofacitinib therapy, significant decreases in neutrophil counts and increases in low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol counts were observed compared to placebo groups. Safety and tolerability data for these studies are summarized in Table 2.

Data from Phase II and Phase III Trials

A study using pooled data from tofacitinib Phase II, Phase III and long-term extension studies was conducted to determine the rate of infection and all-cause mortality across studies in patients receiving tofacitinib monotherapy or tofacitinib in conjunction with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs).¹⁹ The overall rate of serious infection in 4,789 patients was 3.09 events per 100 patientyears, with the overall rates of mortality and infection being similar in the tofacitinib groups and groups being treated with biological agents. A recent Phase II randomized control study was conducted to test the efficacy of tofacitinib monotherapy vs. placebo for the treatment of RA in Japanese patients.²⁰ Similar to the Phase III ORAL studies, dose-dependent decreases were observed in neutrophil and platelet counts, with a significant increase in low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and total cholesterol levels compare to placebo groups.²⁰ The significant decrease in neutrophil counts led to moderate-severe neutropenia in seven patients that was not life threatening.²⁰ Furthermore, 23.3% of patients across all groups had a decrease in absolute lymphocyte counts, however, this did not lead to an increase in severe infections.²⁰ Of note, RA patients from Asia may be at increased risk for herpes zoster when undergoing tofacitinib treatment. An open-label, longterm extension study of tofacitinib in Japanese patients reported herpes zoster in 19.3% of patients,²¹ while analysis of tofacitinib patients from the worldwide clinical program identified Asia as an enrollment center to be an independent risk factor for developing herpes zoster.²²

Another study conducted using data from the Phase III trial ORAL Step assessed patient-reported outcomes for tofacitinib.²³ Patients reported improvements in patient global assessment of disease activity (p<0.0001) and the physical and mental component of the Short Form 36 Health Survey version 2 scores (p<0.05) for both tofacitinib doses compared with placebo. Furthermore, improvements were more frequently reported by tofacitinib treated patients vs. placebo for pain (p<0.0001). The results are consistent with recently published data from the ORAL Solo trial, demonstrating statistically significant improvements in pain, Medical Outcome Survey (MOS) for Physical and Mental health, and Functional Assessment of Chronic Illness Therapy-Fatigue in patients receiving tofacitinib (5 mg or 10 mg) vs. placebo (p<0.0001 for all).²⁴

A systematic review of randomized Phase II and III controlled trials concluded that tofacitinib, at dosages of 5 mg and 10 mg twice daily, is effective in patients with active RA who show an inadequate response to methotrexate or DMARDs.²⁵ The ACR 20 response rates were significantly higher in the tofacitinib 5 mg and 10 mg groups than in the placebo groups in all studies. Moreover, the safety outcomes did not differ between the tofacitinib groups and placebo groups, with the exception of infection in the tofacitinib 10 mg group.

A systematic review of randomized Phase II and III controlled trials concluded that tofacitinib, at dosages of 5 mg and 10 mg twice daily, is effective in patients with active RA who show an inadequate response to methotrexate or DMARDs.²⁵ The ACR 20 response rates were significantly higher in the tofacitinib 5 mg and 10 mg groups than in the placebo groups in all studies. Moreover, the safety outcomes did not differ between the tofacitinib groups and placebo groups, with the exception of infection in the tofacitinib 10 mg group.

A meta-analysis of 10 randomized controlled studies evaluating the efficacy and safety of tofacitinib in patients with active RA showed that tofacitinib, at dosages of 5 mg and 10 mg twice daily, in combination with methotrexate, was the most effective therapy for active RA and was not associated with a significant risk for withdrawal due to AEs.²⁶

From an economic/societal perspective, studies conducted in Korea²⁷ and Brazil²⁸ showed that incorporating tofacitinib into the treatment regime or as a first-line therapy for patients with moderate to severe RA is a cost-effective alternative to the current standard of care.

Tofacitinib for Psoriasis

Phase II Trials (NCT00678210)

A 12 week, Phase IIb multicenter, randomized, double-blind, parallel-group, placebo-controlled trial was conducted to evaluate the efficacy and safety of various doses of oral tofacitinib (2 mg, 5 mg, or 15 mg twice daily) in 197 patients with moderate-tosevere psoriasis.²⁹ At week 12, Psoriasis Area and Severity Index 75 (PASI 75; the percentage of patients who have achieved a 75% or more reduction in their PASI score from baseline) responses were observed in 25% (2 mg; p<0.001), 40.8% (5 mg; p<0.0001), and 66.7% (15 mg; p<0.0001) of the patients in the tofacitinib groups compared with 2% in the placebo group. The most common AEs were upper respiratory tract infections, nasopharyngitis, and headache. Moreover, mild dose-dependent decreases in hemoglobin and neutrophil counts, and increased total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol occurred over the duration of treatment compared to placebo.²⁹ In this same study cohort, outcome questionnaires were completed by the patient³⁰ and showed that treatment with tofacitinib resulted in significant, dose-dependent improvements in several patient-reported outcomes compared with placebo. In the same study cohort, the efficacy of tofacitinib was evaluated in four body regions (head and neck, upper limbs, trunk, and lower limbs).³¹ Mean improvements in PASI 75 and body surface area (BSA) values were significantly improved with tofacitinib vs. placebo across all four body regions.

Data from the Phase IIb trial was also used to elucidate the correlation between pruritus (a severe and bothersome symptom of psoriasis which is not assessed by the PASI or Physician’s Global Assessment [PGA] rating of ‘clear’ or ‘almost clear’ using a 5-point scale: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe)³² and the clinical signs of psoriasis (erythema, induration and scaling).³³ This study showed that tofacitinib acts directly to improve patient-reported pruritus and this effect is independent from improvements in clinician-reported psoriasis severity signs.

Phase III Trials

A summary of the details for the Phase III psoriasis trials can be found in Table 3. The most common AEs were nasopharyngitis and upper respiratory tract infection. Safety and tolerability data for these studies are summarized in Table 4. Laboratory findings were similar to those reported for tofacitinib for the treatment of RA. Two additional Phase III trials are undergoing clinical investigation: NCT01163253 (OPT Extend) is in the process of recruiting participants and is a long-term open label extension study available to patients enrolled in a qualifying clinical study, while NCT01815424 has been concluded and investigated the efficacy of tofacitinib 5 mg and 10 mg in Asian patients; results have not yet been published.

Treatment Withdrawal & Retreatment Study (NCT01186744)

A Phase III, randomized, double-blind, parallel-group study was conducted to evaluate the efficacy of tofacitinib in three phases of treatment (OPT Retreatment).⁵ At the end of the initial treatment, patients were classified as treatment responders if they achieved both PASI 75 response and a PGA rating of ‘clear’ or ‘almost clear’. Responders entered the treatment-withdrawal period, and were re-randomized to placebo or their previous dose of tofacitinib. Patients who relapsed (defined as >50% reduction in the PASI improvement from baseline to week 24) entered the retreatment period. All remaining patients continued in the treatmentwithdrawal period before entering the retreatment period. In the retreatment period, patients who received placebo during treatment withdrawal were retreated with the same dose of tofacitinib that they received during the initial treatment period. After initial treatment, 33.5% and 55.2% of patients achieved both PASI 75 and PGA responses with tofacitinib 5 mg and 10 mg, respectively, and were eligible to enter the treatment withdrawal phase. At the end of the withdrawal period, a greater number of patients receiving tofacitinib 5 mg (56.2%) and 10 mg (62.3%) maintained a PASI 75 response compared to patients who were switched to placebo (23.3%, p=0.008 and 26.1% p<0.0001). Moreover, 92.3% and 93.0% of patients receiving tofacitinib 5 mg and 10 mg, respectively, did not relapse compared with 32.8% and 42.9% of those who were switched to placebo. At the end of the retreatment period, 63.0% and 73.8% of patients who continued to receive tofacitinib 5 mg and 10 mg during the treatmentwithdrawal period regained or maintained a PASI 75 response and 66.7% and 64.3% regained or maintained a PGA response. Moreover, 48.0% and 72.5% of the patients treated with placebo during the treatment-withdrawal period regained or maintained a PASI 75 response, and 52.0% and 64.2% regained or maintained a PGA response after 16 weeks of retreatment with tofacitinib 5 mg or 10 mg, respectively.

Pivotal Trials (NCT01276639 & NCT01309737)

Two similarly designed Phase III studies (OPT Pivotal 1, n=901 and OPT Pivotal 2, n=960) were conducted to evaluate the efficacy and safety of tofacitinib 5 mg and 10 mg twice daily.⁴ At Week 16, higher PASI 75 rates were observed in both tofacitinib groups vs. placebo (OPT Pivotal 1: 39.9%, 59.2% and 6.2% for tofacitinib 5 mg and 10 mg, and placebo; OPT Pivotal 2: 46.0%, 59.6% and 11.4%; all p<0.0001). Moreover, higher PGA ratings were seen in patients receiving tofacitinib 5 mg and 10 mg vs. placebo (OPT Pivotal 1: 41.9% and 59.2% vs 9.0%; OPT Pivotal 2: 46.0% and 59.1% vs. 10.9%; all p<0.0001).

Tofacitinib vs. Etanercept (NCT01241591)

A Phase III, randomized, multicenter, double-dummy, placebocontrolled trial compared the non-inferiority of tofacitinib with etanercept (50 mg) subcutaneously twice weekly or placebo (OPT Compare).⁶ At week 12, a greater number of patients receiving active treatment (39.5% for tofacitinib 5 mg, 63.6% for tofacitinib 10 mg, and 58.8% for etanercept) achieved PASI 75 responses compared to placebo (5.6%, p<0.0001 for all treatments vs. placebo). Moreover, a PGA response was achieved by 47.1%, 68.2%, 66.3%, and 15.0% of the patients in the tofacitinib 5 mg, 10 mg, etanercept and placebo groups (p<0.0001 for all treatments vs. placebo).

Conclusion

Numerous Phase II and Phase III trials have shown that tofacitinib is safe and effective in alleviating RA symptoms, relieving pain, and improving physical and mental health, either when used as monotherapy in patients who show inadequate responses to TNF inhibitors, methotrexate or DMARDs, or as combination therapy with methotrexate or DMARDs. In addition, tofacitinib has been shown to be effective in the treatment of chronic plaque psoriasis in Phase II and III clinical trials, with continuous therapy resulting in better treatment prognosis than intermittent therapy. Efficacy of tofacitinib was comparable to etanercept and superior to placebo in improving the clinical symptoms of psoriasis. Moreover, tofacitinib was also shown to improve pruritus, a common and troublesome symptom of psoriasis not typically assessed in clinical studies. These studies provide support for tofacitinib as an innovative and valuable oral systemic therapy for the treatment of RA and psoriasis.

References

1. Tofacitinib. Drugs R D. 2010;10(4):271-84.
2. Lundquist LM, Cole SW, Sikes ML. Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop. 2014 Sep;18;5(4):504-11.
3. Xeljanz® (tofacitinib citrate) tablet [Prescribing information]; revised February 2016. Pfizer Laboratories, New York, NY. Available from: http://labeling.pfizer.com/ShowLabeling.aspx?id=959. Accessed January 15, 2017.
4. Papp KA, Menter MA, Abe M, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015 Oct;173(4):949-61.
5. Bissonnette R, Iversen L, Sofen H, et al. Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial. Br J Dermatol. 2015 May;172(5):1395-406.
6. Bachelez H, van de Kerkhof PC, Strohal R, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet. 2015 Aug 08;386(9993):552-61.
7. Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011 Apr 01;186(7):4234-43.
8. Malemud CJ. Intracellular signaling pathways in rheumatoid arthritis. J Clin Cell Immunol. 2013 Aug 19;4:160.
9. Palanivel JA, Macbeth AE, Chetty NC, et al. An insight into JAK-STAT signalling in dermatology. Clin Exp Dermatol. 2014 Jun;39(4):513-8.
10. Bannwarth B, Kostine M, Poursac N. A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis. Expert Opin Drug Metab Toxicol. 2013 Jun;9(6):753-61.
11. Chang BY, Zhao F, He X, et al. JAK3 inhibition significantly attenuates psoriasiform skin inflammation in CD18 mutant PL/J mice. J Immunol. 2009 Aug 01;183(3):2183-92.
12. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012 Aug 09;367(6): 495-507.
13. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013 Feb 09;381(9865):451-60.
14. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012 Aug 09;367(6): 508-19.
15. Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013 Aug 20;159(4):253-61.
16. van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013 Mar;65(3):559-70.
17. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014 Jun 19;370(25):2377-86.
18. Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014 May;41(5):837-52.
19. Cohen S, Radominski SC, Gomez-Reino JJ, et al. Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014 Nov;66(11):2924-37.
20. Tanaka Y, Takeuchi T, Yamanaka H, et al. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol. 2015 Jul;25(4):514-21.
21. Yamanaka H, Tanaka Y, Takeuchi T, et al. Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study. Arthritis Res Ther. 2016 Jan 28;18:34.
22. Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014 Oct;66(10):2675-84.
23. Strand V, Burmester GR, Zerbini CA, et al. Tofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: patientreported outcomes from a phase III trial. Arthritis Care Res (Hoboken). 2015 Apr;67(4):475-83.
24. Strand V, Kremer J, Wallenstein G, et al. Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs. Arthritis Res Ther. 2015 Nov 04;17:307.
25. Song GG, Bae SC, Lee YH. Efficacy and safety of tofacitinib for active rheumatoid arthritis with an inadequate response to methotrexate or disease-modifying antirheumatic drugs: a meta-analysis of randomized controlled trials. Korean J Intern Med. 2014 Sep;29(5):656-63.
26. Lee YH, Bae SC, Song GG. Comparative efficacy and safety of tofacitinib, with or without methotrexate, in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Rheumatol Int. 2015 Dec;35(12):1965-74.
27. Lee MY, Park SK, Park SY, et al. Cost-effectiveness of tofacitinib in the treatment of moderate to severe rheumatoid arthritis in South Korea. Clin Ther. 2015 Aug;37(8):1662-76 e2.
28. Ferreira CN, Rufino CS, Santana CF, et al. Assessment of tofacitinib for rheumatoid arthritis from the perspective of the Brazilian healthcare system. Value Health. 2015 Nov;18(7):A646.
29. Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012 Sep;167(3):668-77.
30. Mamolo C, Harness J, Tan H, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, improves patient-reported outcomes in a phase 2b, randomized, double-blind, placebo-controlled study in patients with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol. 2014 Feb;28(2):192-203.
31. Menter A, Papp KA, Tan H, et al. Efficacy of tofacitinib, an oral janus kinase inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in different body regions. J Drugs Dermatol. 2014 Mar;13(3):252-6.
32. Globe D, Bayliss MS, Harrison DJ. The impact of itch symptoms in psoriasis: results from physician interviews and patient focus groups. Health Qual Life Outcomes. 2009 Jul 06;7:62.
33. Bushmakin AG, Mamolo C, Cappelleri JC, et al. The relationship between pruritus and the clinical signs of psoriasis in patients receiving tofacitinib. J Dermatolog Treat. 2015 Feb;26(1):19-22.

Conflict of interest disclosure:
None reported.

ABSTRACT
Efinaconazole 10% nail solution is a novel topical antifungal drug for the treatment of onychomycosis. Two Phase III trials were completed using efinaconazole 10% nail solution, where 17.8% and 15.2% of patients achieved complete cure, and 55.2% and 53.4%
achieved mycological cure. Several post hoc analyses were carried out using data from Phase III trials to determine the efficacy of efinaconazole with respect to disease duration, disease progression, and comorbidities of diabetes or tinea pedis with onychomycosis.
Efinaconazole produced higher efficacy rates with patients presenting onychomycosis in a small portion of the toenail (≤25%) for a shorter duration of time ( concurrent treatment, efficacy of efinaconazole increased from 16.1% to 29.4%, suggesting combination therapy improved results. Most interestingly, there was no difference in efinaconazole efficacy between diabetic and non-diabetic groups, indicating efinaconazole could be a safe and effective form of treatment for diabetics. Overall, efinaconazole 10% nail solution shows potential as an antifungal therapy for the treatment of onychomycosis.

Key Words:
antifungal agent, efinaconazole, fungal nail infection, Jublia^®, onychomycosis, topical triazole

Introduction

Onychomycosis is a fungal infection of the nail unit caused
by dermatophytes, yeasts, and nondermatophyte molds.¹
Onychomycosis affects toenails more frequently than fingernails
and accounts for 50% of nail disease.^2,3 Although this infection
can be perceived as merely a cosmetic issue of thickening and
discoloration of the nail plate, onychomycosis can result in
numerous side effects that can impede the use of shoes and make
walking difficult in general, leading to decreased quality of life.^4,5
Additional risks include bacterial infections, foot ulcers, and
gangrene.⁶ As a commonly occurring disease, it affects 2-13% of
the general population, with prevalence of up to 50% in patients
aged 70 years or higher.⁷ Along with advanced age, there are
several other risk factors including diabetes, peripheral arterial
disease, immunosuppression, and other pre-existing nail diseases
like psoriasis.⁸ Due to an increased chance of comorbidity with
onychomycosis, most recent investigational interests have focused
on topical antifungals, which have a lower risk of adverse effects
and drug-drug interactions.

The goal of onychomycosis treatment is restoring the nail to a
normal appearance and complete eradication of fungus. This
can be difficult to achieve as the nail plate acts as a barrier for
topical treatments, and poor circulation in the elderly can prevent
systemic treatments from reaching their target. Although some
therapies can result in complete clinical and mycological cure, the
rates are low (35-50%), and risk of relapse is high (10-53%).⁹
Currently, there are five classes of drugs approved for the
treatment of onychomycosis: allylamines, azoles, morpholines,
hydroxypyridinones, and benzoxaboroles.^10,11 Historically,
systemic therapies have been the most effective, with the oral
allylamine terbinafine being the current gold standard with a
complete cure rate of 38% and mycological cure rate of 74%.^12,13
The recommended dose of terbinafine for toenail onychomycosis
is 250 mg daily for 12 weeks. Patients who are high risk for adverse
effects from oral antifungals are prescribed topical agents. In the
US there are three topical therapies approved for the treatment
of onychomycosis: ciclopirox 8% nail solution, tavaborole 5%
solution, and efinaconazole 10% solution. Given the challenges of
transungual delivery, there is a need for novel topical antifungals
that can increase penetrance, are potent, and carry minimal side
effects.

Efinaconazole 10% solution is a novel topical antifungal of the
azole class that was US FDA approved for the treatment of toenail
onychomycosis in June 2014.¹⁴ Efinaconazole has demonstrated
a broad spectrum of activity against dermatophytes and yeasts
in vitro,¹⁵ and has uniquely low keratin affinity, allowing drug
release from keratin and enhanced penetration through the nail
plate compared to ciclopirox and amorolfine.¹⁶ Due to the unique
formulation of efinaconazole, both transungual and subungual
routes of delivery are achieved as the drug penetrates through
the nail plate into the underlying nail bed, as well as via spreading
around and under the nail plate through the air gap to reach
the fungal infection.^17,18 Recently, a human cadaver nail study
demonstrated that efinaconazole is able to penetrate the nail
even in the presence of nail polish,¹⁹ which may be a potential
advantage for patients concerned with hiding nail abnormalities
while at the same time using a topical treatment. Efinaconazole
works by inhibiting the synthesis of ergosterol, an essential
structural component of fungal cell membranes.^20,21 Its inhibition
results in a loss of cell membrane integrity, thus preventing fungal
cell growth.^20,21

Previously, two identical, randomized, double-blind, vehiclecontrolled
Phase III studies were performed using 1655
patients with mild to moderate toenail onychomycosis.²² The
treatment course was once daily application of efinaconazole
10% nail solution to the affected toenail and underside, as well
as surrounding skin, for 48 weeks followed by a 4 week washout
period.23 At week 52, 17.8% and 15.2% of patients achieved
complete cure, and 55.2% and 53.4% achieved mycological cure.²⁴
Interestingly, female patients demonstrated higher efficacies than
males (27.1% vs 15.8%, respectively, P=0.001), where the only
notable difference between genders were mean weight (73.3 kg
and 90.2 kg).²² Further subgroup analyses were completed using
Phase III data to elucidate the differences in treatment efficacy
in patients with concurrent tinea pedis or diabetes, as well as
duration and severity of disease.^25-28

Clinical Efficacy

Consistent with previous findings,²⁹ 21.3% (352/1655) of
patients from Phase III clinical trials reported onychomycosis
with concurrent tinea pedis, and 61.1% (215/352) underwent
concomitant treatment for tinea pedis with an investigatorapproved
topical antifungal.^26,30 Butenafine, luliconazole, and
ketoconazole were the most commonly used topical antifungal
agents for tinea pedis treatment; used by 64, 52, and 23 patients,
respectively.³⁰ With concomitant treatment of onychomycosis
(efinaconazole) and tinea pedis, complete and mycological cure
rates were 29.4% and 56.2%, respectively (7.8% and 26.6%
vehicle, P=0.003 and P<0.001, respectively). When tinea pedis
was left untreated, complete and mycological cure rates were
16.1% and 45.2% (0% and 12.5% vehicle, P=0.045 and P=0.007,
respectively). Efinaconazole treatment was superior to all vehicle
outcomes, and concurrent treatment for tinea pedis was superior
to untreated tinea pedis measures. Moreover, patients treated with
efinaconazole achieved a higher complete or almost complete
cure and higher treatment success, compared with vehicle (data
summarized in Table 1). Complete or almost complete cure was
defined as ≤5% clinical involvement of the target toenail plus
mycologic cure. Treatment success was defined as ≤10% clinical
involvement of the target toenail.

Of the 1655 patients from Phase III clinical trials, 112 patients
had coexistent onychomycosis and diabetes.²⁵ Only patients
whose diabetes was under control (N=96) were included in the
study. Diabetic (N=69) and non-diabetic (N=993) patients had
similar efficacies when treated with efinaconazole, with complete
cure rates of 13% and 18.8%, respectively and mycological
cure rates of 56.5% and 56.3%, respectively. These values were
significantly higher than vehicle (N=27) for complete cure (3.7%
and 4.7%, P P=0.016, and approximately 17.4%, P<0.001) for diabetic and
non-diabetic patients, respectively. Moreover, patients receiving
efinaconazole treatment had greater success achieving complete
or almost complete cures as well as treatment success at
week 52 (data summarized in Table 2). All secondary endpoints
were identical to those defined above.

Of all patients (1655) from Phase III trials, 1526 were categorized
based on disease duration: 5 years (770 patients).²⁷ Complete cure rates of
42.6%, 17.1%, and 16.2% were observed in efinaconazole-treated
patients with 5 years disease duration,
respectively. Complete cure rates with efinaconazole treatment
were significantly improved over vehicle for patients with baseline
disease durations of 1-5 years (17.1% vs. 4.4%, P<0.001) and >5
years (16.2% vs. 2.5%, P<0.001), however, this was not the case
for patients presenting with onychomycosis for vs. 16.7%, not significant). It is possible that non-significance
may be due to the small sample size (N=33 efinaconazole).
Furthermore, 66.0%, 59.0%, and 53.8% of patients achieved
mycological cure with disease duration of 5 years, respectively. Similar to complete cure, the latter two
durations were significantly different from vehicle (P <0.001).
Lastly, while not significant for any duration, patients receiving
efinaconazole treatment did show numerically higher complete
or almost complete cure rates, as well as treatment success, for
disease durations of 5 years (Figure 3). All secondary endpoints are identical to those
defined above.

Figure 1.Summary of cure rates for patients with baseline disease duration of 27

While cure rates are numerically higher for all efficacy outcomes, efinaconazole cure rates were not significantly greater than vehicle.

Figure 2.Summary of cure rates for patients with baseline disease duration of 1-5 years with efinaconazole.²⁷

^*

Figure 3.Summary of cure rates for patients with baseline disease duration of >5 years with efinaconazole.²⁷

^*P

Finally, effectiveness of efinaconazole based on disease severity
was measured using 414 patients with mild onychomycosis
(≤25% nail involvement), and 1237 patients with moderately
severe onychomycosis (>25% nail involvement).²⁸ Patients
presenting with mild onychomycosis had complete and
mycological cure rates of 25.8% and 58.2%, respectively, which are
significantly higher than vehicle cure rates of 11.3% (P=0.006)
and 25.0% (P<0.001), respectively. Patients with moderately
severe onychomycosis had complete and mycological cure rates
of 15.9% and 55.6%, respectively, again demonstrating significant
improvement over vehicle cure rates of 2.7% and 14.1% (P<0.001
for both), respectively. Moreover, all patients with efinaconazole
treatment had significantly higher complete or almost complete
cure rates and treatment success compare to vehicle (summarized
in Table 3, P to those defined above.

^a P<0.01; ^b P

Discussion

The data from two Phase III clinical trials have been analyzed and
the efficacy of efinaconazole with respect to concurrent treatment
for tinea pedis, diabetic patients, disease duration, and severity
of disease shows promise. Efficacies were highest among patients
with less severe (≤25% nail involvement) and shorter disease
duration.

Efinaconazole treatment was more effective than vehicle for the
treatment of onychomycosis with or without concurrent treatment
of tinea pedis. Since one-third of onychomycosis patients also
have tinea pedis, it is recommended that patients are examined
for concomitant dermatomycoses, and treatment for both fungal
infections (if present) be sought, as pathogens that cause tinea
pedis can also lead to onychomycosis.^29,30 Although concurrent
treatment for tinea pedis and onychomycosis (efinaconazole)
improved complete cure rates from 16.1% to 29.4%, there was
no information about the severity of tinea pedis, or the success
of tinea pedis treatment. Therefore, further testing would need
to be completed to confirm whether combination therapy could
increase treatment efficacy of both fungal infections.

Onychomycosis in diabetic patients is extremely difficult to treat
with traditional antifungals due to hyperglycemia and problematic
foot hygiene.³¹ Moreover, onychomycosis left untreated poses a
significant risk for further complications that can potentially lead
to loss of limb.^32,33 The findings that the efficacy of efinaconazole
was comparable between diabetic and non-diabetic patients
and cure rates for both groups were significantly higher than
respective vehicle groups, indicate that diabetics can now receive
safe and effective treatment for onychomycosis.

In summary, good responders to efinaconazole treatment are
more likely to be patients with mild (≤25% clinical toenail
involvement) onychomycosis and have a low number of nontarget
nail involvement,²⁸ with early or baseline onychomycosis
(27 who receive concurrent
treatment for tinea pedis (if present),^26,30 are female,²² and weigh
22 Most interestingly, whether patients were diabetic
or non-diabetic had no effect on the efficacy of efinaconazole
treatment.

Efinaconazole 10% topical solution is an effective topical
treatment for onychomycosis with favorable clinical and
mycological efficacies, low risk of drug-drug interactions, and a
minimal side effect profile.³⁴ With complete cure rates of 17.8%
and 15.2%,^22,34 and a favorable safety profile, efinaconazole also
looks promising for use in children and in combination therapy.
Moreover, since levels of efinaconazole reach a steady state in
the nail after 2 weeks of daily application, and remain at high
concentrations well above the minimum inhibitory concentration
for dermatophytes for at least 2 weeks off therapy,³⁵ it is possible
that efinaconazole may be used twice weekly as a maintenance
regime. This strategy may be considered after the completion of
the 48 week treatment period in order to prevent relapse; however,
maintenance studies have yet to be conducted. Taken together,
efinaconazole 10% topical solution is an easy to use, safe, and
effective therapy for the treatment of onychomycosis.

References

1. Scher RK, Rich P, Pariser D, et al. The epidemiology, etiology, and pathophysiology of onychomycosis. Semin Cutan Med Surg. 2013 Jun;32(2 Suppl 1):S2-4.
2. 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 Aug;43(2 Pt 1):244-8.
3. Faergemann J, Baran R. Epidemiology, clinical presentation and diagnosis of onychomycosis. Br J Dermatol. 2003 Sep;149 Suppl 65:1-4.
4. Elewski BE. The effect of toenail onychomycosis on patient quality of life. Int J Dermatol. 1997 Oct;36(10):754-6.
5. Lubeck DP, Gause D, Schein JR, et al. A health-related quality of life measure for use in patients with onychomycosis: a validation study. Qual Life Res. 1999 8(1-2):121-9.
6. LaSenna CE, Tosti A. Patient considerations in the management of toe onychomycosis – role of efinaconazole. Patient Prefer Adherence. 2015 9:887-91.
7. Tabara K, Szewczyk AE, Bienias W, et al. Amorolfine vs. ciclopirox – lacquers for the treatment of onychomycosis. Postepy Dermatol Alergol. 2015 Feb;32(1):40-5.
8. Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis–risk factor identification and active prevention. J Eur Acad Dermatol Venereol. 2005 Sep;19(Suppl 1):13-6.
9. Epstein E. How often does oral treatment of toenail onychomycosis produce a disease-free nail? An analysis of published data. Arch Dermatol. 1998 Dec;134(12):1551-4.
10. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
11. Markham A. Tavaborole: first global approval. Drugs. 2014 Sep;74(13):1555-8.
12. LamisilÆ (terbinafine hydrochloride) tablets [Prescribing information]; revised
    August 2016. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Available
    at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/
    files/Lamisil_tablets.pdf. Accessed September 26, 2016.
13. Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol. 2013 Sep-Oct;31(5):544-54.
14. 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 Apr;68(4):600-8.
15. Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.
16. Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014 Jul;58(7):3837-42.
17. Gupta AK, Pillai R. The presence of an air gap between the nail plate and nail bed in onychomycosis patients: treatment implications for topical therapy. J Drugs Dermatol. 2015 Aug;14(8):859-63.
18. Gupta AK, Simpson FC. Routes of drug delivery into the nail apparatus: Implications for the efficacy of topical nail solutions in onychomycosis. J Dermatolog Treat. 2016 27(1):2-4.
19. Zeichner JA, Stein Gold L, Korotzer A. Penetration of ((14)C)-efinaconazole topical solution, 10%, does not appear to be influenced by nail polish. J Clin Aesthet Dermatol. 2014 Sep;7(9):34-6.
20. Rodriguez RJ, Low C, Bottema CD, et al. Multiple functions for sterols in Saccharomyces cerevisiae. Biochim Biophys Acta. 1985 Dec 4;837(3):336-43.
21. Parks LW, Smith SJ, Crowley JH. Biochemical and physiological effects of sterol alterations in yeast–a review. Lipids. 1995 Mar;30(3):227-30.
22. Gupta AK, Elewski BE, Sugarman JL, et al. The efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials. J Drugs Dermatol. 2014 Jul;13(7):815-20.
23. JUBLIA® (efinaconazole) topical solution, 10% [Prescribing information]; revised July 2014. Valeant Pharmaceuticals North America LLC, Bridgewater, NJ. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf. Accessed September 26, 2016.
24. Lipner SR, Scher RK. Efinaconazole in the treatment of onychomycosis. Infect
    Drug Resist. 2015 8:163-72.
25. Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of
    toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014
    Oct;13(10):1186-90.
26. Lipner SR, Scher RK. Management of onychomycosis and co-existing tinea
    pedis. J Drugs Dermatol. 2015 May;14(5):492-4.
27. Rich P. Efinaconazole topical solution, 10%: the benefits of treating
    onychomycosis early. J Drugs Dermatol. 2015 Jan;14(1):58-62.
28. Rodriguez DA. Efinaconazole topical solution, 10%, for the treatment of mild and
    moderate toenail onychomycosis. J Clin Aesthet Dermatol. 2015 Jun;8(6):24-9.
29. Szepietowski JC, Reich A, Garlowska E, et al, Onychomycosis Epidemiology Study
    Group. Factors influencing coexistence of toenail onychomycosis with tinea
    pedis and other dermatomycoses: a survey of 2761 patients. Arch Dermatol. 2006
    Oct;142(10):1279-84.
30. Markinson B, Caldwell B. Efinaconazole topical solution, 10% efficacy in patients
    with onychomycosis and coexisting tinea pedis. J Am Podiatr Med Assoc. 2015
    Sep;105(5):407-11.
31. Tan JS, Joseph WS. Common fungal infections of the feet in patients with diabetes mellitus. Drugs Aging. 2004 21(2):101-12.
32. Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatol. 2000 Jul-Aug;10(5):379-84.
33. Papini M, Cicoletti M, Fabrizi V, et al. Skin and nail mycoses in patients with diabetic foot. G Ital Dermatol Venereol. 2013 Dec;148(6):603-8.
34. Lipner SR, Scher RK. Efinaconazole 10% topical solution for the topical treatment of onychomycosis of the toenail. Expert Rev Clin Pharmacol. 2015 8(6):719-31.
35. Sakamoto M, Sugimoto N, Kawabata H, et al. Transungual delivery of efinaconazole: its deposition in the nail of onychomycosis patients and in vitro fungicidal activity in human nails. J Drugs Dermatol. 2014 Nov;13(11):1388-92.

¹Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Conflict of interest:
Aditya Gupta has been a clinical trials investigator for Valeant Canada, Nuvolase, Bristol Meyers Squibb, Eli Lilly, Merck, Novartis, Janssen and Allergan; and has served as a speaker or consultant for Valeant Canada, Janssen, Novartis, Sandoz, Moberg Pharma, and Bayer. Catherine Studholme is an employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of Aditya Gupta.

ABSTRACT
Adalimumab (Humira®) is a novel therapy approved by the US Food and Drug Administration, Health Canada, and the European Commission for the treatment of hidradenitis suppurativa (HS). Results of two Phase III trials of adalimumab demonstrate significantly higher efficacies compared to placebo. Primary efficacy outcome of 50% reduction in abscess and inflammatory nodule count was seen in 41.8% and 58.9% of participants receiving adalimumab in PIONEER I and PIONEER II studies, respectively, showing substantial improvement compared with placebo groups in both trials (26.0% and 27.6%, respectively). Although the significance of secondary efficacy measures of adalimumab every week treatment (EW) was not consistent between PIONEER I and PIONEER II studies, participants achieving abscess and inflammatory nodule counts of 0, 1, or 2 were significant (EW 51.8%) compared to placebo (32.2%) in the PIONEER II trial. Participants also demonstrated a marked decrease in skin pain measurements from baseline between EW patients (45.7%) and placebo (20.7%) in the PIONEER II trial. Modified Sartorius scores were decreased from baseline in both PIONEER I (-24.4) and PIONEER II (-28.9) trials versus placebo (-15.7 and -9.5, respectively). Adverse events were mild to moderate and comparable between all treatment groups including placebo. Taken together, these data conclude that treatment of HS with adalimumab is a safe and effective therapy resulting in a significant decrease in abscess and inflammatory nodule counts within the first 12 weeks of treatment.

Key Words:
adalimumab, hidradenitis suppurativa, immune modulators, tumor necrosis factor-alpha inhibitor

Introduction

Hidradenitis suppurativa (HS), also known as acne inversa, is a severe and chronic inflammatory disease resulting from occlusion and rupture of hair follicles followed by an overreaction of the immune response.^1,2 This results in painful inflammation and abscess formation, which can lead to sinus tract development and scarring, as seen in the later stages of HS.^1,2 This affliction is generally located in areas where skin-skin contact occurs, but has been observed on atypical areas such as the ears, back, and chest.³ Although the exact etiology of HS remains unknown, prevalence is reported to range from 1%-4%.^4-7 There is a lack of regulatory body-approved drugs for the treatment of HS,
leaving surgery as the established treatment option for severe disease; however, surgery is associated with a high risk of HS recurrence.^8,9 Therefore, there is an unmet need to find safe and effective therapeutic options for the treatment of HS.

Adalimumab (Humira®) is a human monoclonal antibody that binds to and neutralizes tumor necrosis factor-alpha (TNF-α).¹⁰ It has been shown to be effective at treating inflammatory conditions, including rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, and psoriasis.^11,12 Since these diseases all involve overreaction of the immune system resulting in inflammation, adalimumab has been used off-label for the treatment of HS for several years.^13, Adalimumab is now the first and only approved drug for the treatment of HS by the US Food and Drug Administration (FDA), Health Canada, and the EU’s European Commission. A Phase II clinical trial was initially completed to analyze the safety and efficacy of adalimumab for the treatment of HS, which showed promising results.¹⁴ The findings from further analysis through two Phase III trials have
recently been released, and are summarized herein.

Clinical Efficacy

Phase II Trial (NCT00918255)

A parallel, randomized, double-blind, Phase II clinical trial to assess the safety and efficacy of adalimumab in the treatment of HS was completed.¹⁵ One hundred and fifty-four participants (110 female and 44 male) were measured at baseline. Participants were randomized into three treatment arms: placebo (N = 51), adalimumab every week (EW; subcutaneous [SC] dose of 160 mg week 0, 80 mg week 2, 40 mg weekly from weeks 4-15; N = 51), or adalimumab every other week (EOW; SC 80 mg week 0, 40 mg every other week from weeks 1-15; N = 51). Average age of participants was 36.3 years and all efficacy measures were completed at week 16. Participants in the EW treatment group achieved statistically higher clinical response (17.6%), compared to EOW (9.6%) and placebo (3.9%) groups (P = 0.022; CochranMantel-Haenszel
method). Clinical response was defined as a 2 point reduction or score of 0, 1, or 2 using the Physician’s Global Assessment. The EW treatment group also had significant
improvement in secondary efficacies of decreased inflammatory nodules and plaques (P = 0.019; analysis of covariance [ANCOVA] method), clinical response at week 12 (P = 0.020; Cochran-Mantel-Haenszel method), and Modified Sartorius Scale (P = 0.014; van Elteren test) compared to placebo. The EOW treatment group did not exhibit a significant increase in efficacy compared to placebo. Adverse events were comparable between treatment groups; reported in 71% of EW, 64% of EOW, and 59% of placebo participants.

Phase III Trials

Two Phase III randomized, double-blind clinical trials to assess the safety and efficacy of adalimumab in the treatment of patients with moderate-severe HS were recently completed.^16,17 The severity of HS was defined using Hurley Staging: Stage I characterized by single or multiple abscess formations without
sinus tracts or scarring; Stage II characterized by one or more recurrent abscesses with tract formation and scars; and Stage III characterized by abscesses covering an extended area with numerous interconnected tracts and diffuse or near diffuse involvement. Inclusion criteria included adults 18-99 years of age with a diagnosis of HS for at least one year and the presence of at least two areas exhibiting HS lesions with at least one categorized as Hurley Stage II or Stage III, stable HS for at least 60 days prior to screening and baseline visits, previous inadequate response to other HS treatments, and total abscess and inflammatory nodule (AN) count of ≥3 at baseline.

PIONEER I Trial (NCT01468207)

Three hundred and seven participants (196 female and 111 male)
were measured at baseline. The participants were randomized
into the placebo or adalimumab EW (SC 160 mg week 0,
80 mg week 2, and 40 mg weeks 4-12) treatment group for weeks
0-12. The average age of placebo (N = 154) and EW (N = 153)
participants was 37.8, and 36.2 years, respectively. All efficacy
measures were completed at the end of week 12, and results of
primary efficacy measures are summarized in Figure 1. Clinical
response was significantly increased in the EW treatment group
compared to placebo (P = 0.003). Moreover, the clinical response
was significantly greater in participants with Hurley Stage II
(P = 0.048) and Hurley Stage III (P = 0.027) compared to placebo.
However, secondary efficacy measures were not significant
between EW and placebo groups, as less than one-third of all
participants experienced a reduction in their AN count to 0, 1,
or 2 (P = 0.961; chi-squared method) and NRS30 (P = 0.628;
Cochran-Mantel-Haenszel method) by week 12. Finally, there was
a reduction in Modified Sartorius Score of -15.7 and -24.4 in the
placebo and EW treatment groups (P = 0.124; ANCOVA method).

PIONEER II Trial (NCT01468233)

Three hundred and twenty-six participants (221 female and
105 male) were measured at baseline. As in PIONEER I, the
participants were randomized between the placebo and EW
treatment groups for weeks 0-12, where efficacy measures were
completed at the end of week 12. Both groups had a similar mean
participant age of 36.1 and 34.9 years for placebo and EW groups,
respectively. Primary efficacy results are summarized in Figure 2,
which show a significant increase in clinical response in all
adalimumab treatment groups compared to the placebo group
(P < 0.001). In contrast to PIONEER I secondary efficacy studies,
a decrease in AN count of 0, 1, or 2 (P = 0.01) and decrease in
NRS30 (P < 0.001) was found in a significant proportion of
adalimumab EW group participants compared to the placebo
group (Figure 3). Finally, the Modified Sartorius Score for the EW
group (-28.9) was notably improved compared to placebo (-9.5;
P < 0.001; ANCOVA method).

Figure 1.
PIONEER I primary efficacy measure of HiSCR for patients in the placebo and adalimumab every week treatment groups at week 12.

HiSCR = ≥50% abscess and inflammatory nodule count reduction

EW group = patients receiving treatment every week with adalimumab SC 160 mg at week 0, 80 mg at week 2, and 40 mg weeks for 4-12

* P = 0.003 compared to placebo; Cochran-Mantel-Haenszel method

** P = 0.048 compared to placebo; chi-squared method

*** P = 0.027 compared to placebo; chi-squared method

Figure 2.
PIONEER II primary efficacy measure of HiSCR for patients in the placebo and adalimumab every week treatment groups at week 12.

* P < 0.001 compared to placebo; Cochran-Mantel-Haenszel method

Figure 3.
PIONEER II secondary efficacy measures of AN count and NRS30 reduction for patients in the placebo or adalimumab every week treatment groups at week 12.

AN = abscess and inflammatory nodule count reduction to 0, 1, or 2

NRS30 = ≥30% and 1 unit reduction in the patient’s global assessment of skin pain numeric rating scale

* P = 0.01 compared to placebo; Cochran-Mantel-Haenszel method

** P < 0.001 compared to placebo; Cochran-Mantel-Haenszel method

Safety and Adverse Events

In the Phase II study, a low percentage of participants from each
treatment arm reported serious adverse events (SAEs), whereas
less serious adverse events (AEs) were reported in 70.59%,
63.46%, and 58.82% of EW, EOW, and placebo treatment groups,
respectively. The most common AEs were nasopharyngitis
(N = 19), headache (N = 17), and hidradenitis (N = 16).

TPIONEER I SAE rates were low in every treatment arm, seen in
only 3.29% of placebo, 1.96% of EW, 3.45% of placebo/EW (SC
placebo weeks 0-12, and SC 40 mg adalimumab weeks 12-35),
4.08% of EW/placebo (adalimumab SC 160 mg week 0, 80 mg
week 2, and 40 mg weeks 4-12, and SC placebo weeks 12-35),
6.25% of EW/EOW (adalimumab SC 160 mg week 0, 80 mg week 2,
and 40 mg for weeks 4-12, and 40 mg adalimumab every other
week for weeks 12-35), and 2.08% of EW/EW (adalimumab SC
160 mg week 0, 80 mg week 2, and 40 mg weeks 4-35) patients.
The most common SAE was hidradenitis, which was experienced
in 5 of the 6 treatment arms (N = 9). Other less serious AEs were
seen in 53.29% for placebo, 41.83% for EW, 46.90% for placebo/
EW, 61.22% for EW/placebo, 50% for EW/EOW, and 58.33%
for EW/EW groups. Common side effects were hidradenitis
(N = 61), headache (N = 47), urinary tract infection (N = 17),
upper respiratory tract infection (N = 23), and nasopharyngitis
(N = 49).

PIONEER II SAEs were also low in each treatment arm, with
occurrences of 3.68% for placebo, 1.84% for EW, 4.64% for
placebo/placebo (placebo for weeks 0-35), 0% for EW/placebo,
3.77% for EW/EOW, and 3.92% for EW/EW groups. The most
common SAE was hidradenitis seen in three treatment arms
(N = 4). Other AEs were reported in 47.24% of placebo, 40.49% of
EW, 37.19% of placebo/placebo, 52.94% of EW/placebo, 47.17%
of EW/EOW, and 41.18% of EW/EW groups. Common side effects
were nasopharyngitis (N = 31), upper respiratory tract infection
(N = 40), headache (N = 58), and hidradenitis (N = 60).

Conclusion

The data reported from two Phase III clinical trials on the
efficacy of adalimumab for the treatment of moderate to
severe HS has been promising. In both trials, patients receiving
adalimumab every week had a significant reduction in abscess
and inflammatory nodule count at week 12 compared to placebo.
Furthermore, adverse events in each treatment arm were
comparable to placebo, with no new adverse events recorded. This
indicates that adalimumab is a safe and effective therapy for the
treatment of HS by demonstrating the potential to achieve disease
control within the first 12 weeks of treatment.

References

1. von Laffert M, Helmbold P, Wohlrab J, et al. Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal follicles and at interfollicular epidermis. Exp Dermatol. 2010 Jun;19(6):533-7.
2. von Laffert M, Stadie V, Wohlrab J, et al. Hidradenitis suppurativa/acne inversa: bilocated epithelial hyperplasia with very different sequelae. Br J Dermatol. 2011 Feb;164(2):367-71.
3. Scheinfeld N. Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients. Dermatol Online J. 2013 19(4):1.
4. Cosmatos I, Matcho A, Weinstein R, et al. Analysis of patient claims data to determine the prevalence of hidradenitis suppurativa in the United States. J Am Acad Dermatol. 2013 Mar;68(3):412-9.
5. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies. J Am Acad Dermatol. 2008 Oct;59(4):596-601.
6. Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol. 2009 Apr;60(4):539-61; quiz 62-3.
7. Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med. 2012 Jan 12;366(2):158-64.
8. Mehdizadeh A, Hazen PG, Bechara FG, et al. Recurrence of hidradenitis suppurativa after surgical management: A systematic review and meta-analysis. J Am Acad Dermatol. 2015 Nov;73(5 Suppl 1):S70-7.
9. Alavi A. Hidradenitis suppurativa: Demystifying a chronic and debilitating disease. J Am Acad Dermatol. 2015 Nov;73(5 Suppl 1):S1-2.
10. Scheinfeld N. Adalimumab (HUMIRA): a review. J Drugs Dermatol. 2003 Aug;2(4):375-7.
11. Pitarch G, Sanchez-Carazo JL, Mahiques L, et al. Treatment of psoriasis with adalimumab. Clin Exp Dermatol. 2007 Jan;32(1):18-22.
12. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003 Jan;48(1):35-45.
13. van Rappard DC, Limpens J, Mekkes JR. The off-label treatment of severe hidradenitis suppurativa with TNF-alpha inhibitors: a systematic review. J Dermatolog Treat. 2013 Oct;24(5):392-404.
14. Lee RA, Eisen DB. Treatment of hidradenitis suppurativa with biologic medications. J Am Acad Dermatol. 2015 Nov;73(5 Suppl 1):S82-8.
15. Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med. 2012 Dec 18;157(12):846-55.
16. AbbVie. A phase 3 multicenter study of the safety and efficacy of adalimumab in subjects with moderate to severe hidradenitis suppurativa – PIONEER I. In: ClinicalTials.gov, Identifier: NCT01468207. Last updated October 15, 2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01468207?term=NCT0146 8207&rank=1. Accessed: May 23, 2016.
17. AbbVie. A phase 3 multicenter study of the safety and efficacy of adalimumab in subjects with moderate to severe hidradenitis suppurativa – PIONEER II. In: ClinicalTials.gov, Identifier: NCT01468233. Last updated October 15, 2015, Available at: https://clinicaltrials.gov/ct2/show/NCT01468233?term=NCT0146 8233&rank=1. Accessed: May 23, 2016.
18. Sartorius K, Lapins J, Emtestam L, et al. Suggestions for uniform outcome variables when reporting treatment effects in hidradenitis suppurativa. Br J Dermatol. 2003 Jul;149(1):211-3.

¹Department of Medicine, University of Toronto School of Medicine, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Conflict of interest: None Reported.

ABSTRACT
Melanoma is an aggressive skin cancer with a generally poor prognosis at Stage III-IV disease. Traditionally, metastatic melanoma was treated by surgical resection, when possible, and with systemic chemotherapy. New developments in molecular biology have led to the identification of immune checkpoints which are exploited by malignant cells, allowing them to go undetected by the immune system. Nivolumab (Opdivo®) is a human monoclonal antibody which prevents immune inhibition by interacting with PD-1 on tumor cells; thus, increasing tumor-specific T cell proliferation. Nivolumab has demonstrated efficacy superior to that of standard chemotherapy and relative safety in clinical trials. Indeed, the outcomes for patients with advanced melanoma are being improved by novel biologic agents such as nivolumab.

Key Words:
antineoplastic agent, melanoma, Opdivo®, PD-1 inhibitor, programmed cell death 1 receptor, signal transduction, skin neoplasms

Introduction

A melanoma is an aggressive tumor often occurring on the skin that is caused by the transformation of melanocytes into malignant cells.¹ Many cases are classified as melanoma in situ, with tumors localized only to the epidermis (Stage 0); however, some melanomas are invasive and infiltrated the dermis (Stage I-II), and still others spread to nearby lymph node(s) (Stage III), or to distant lymph nodes and/or organ systems (Stage IV).² Stage III- IV disease is termed ‘metastatic melanoma’ and occurs in roughly 30% of patients after excision of the primary tumor.^2,3 The 5-year survival rate is 23% when metastatic melanoma presents in the skin.⁴ In order to evade immune recognition, certain tumors may exploit immune-regulatory checkpoints which suppress excessive T lymphocyte function in normal physiologic conditions; thereby permitting unregulated proliferation of malignant cells.⁵

Preclinical cancer studies suggest that interrupting co-receptor interactions responsible for inhibitory signaling on tumor- specific T cells would activate the anti-tumor immune response.⁵ One such co-receptor is programmed death receptor-1 (PD-1). PD-1 inhibits T cell activation, leading to reduced proliferation, cytokine production, and cytolysis via interactions with its ligands PD-L1 and PD-L2.⁶ On December 22, 2014, nivolumab (Opdivo®), a human monoclonal antibody against PD-1 receptor, was approved by the US FDA for the treatment of unresectable or metastatic melanoma that is unresponsive to other drugs.⁷ Nivolumab binds PD-1 with high affinity and impedes both PD-L1 and PD-L2 interaction; thus, increasing tumor-specific T cell proliferation.

Phase I and II

Two phase I dose-escalation trials were performed to assess the preliminary efficacy, safety and pharmacokinetics of nivolumab.^6,8 Both trials enrolled participants with advanced metastatic non- small cell lung cancer (NSCLC), melanoma, castrate-resistant prostate cancer, renal cell carcinoma, and colorectal cancer. Doses ranging from 0.1-10 mg/kg of nivolumab were administered by intravenous (IV) infusion every 2 weeks. Pharmacokinetic data from these studies showed that the median time to peak serum concentration of nivolumab is 1 to 4 hours after dosing.⁸ Nivolumab yields an approximate serum half-life (t1/2) of 12 days for 0.3, 1, and 3 mg/kg doses and up to 20 days for the 10 mg/kg dose.⁶ Maximum concentration (C_max) and area under the curve (AUC) are directly related to dose.^6,8 PD-1-receptor occupancy on the surface of circulating CD3+ cells was also assessed.^6,8 After one infusion at a dose of 0.1 to 10 mg/kg, surface occupancy was dose-independent with a mean peak occupancy of 85% (70% to 97%) observed at 4 to 24 hours and a mean plateau occupancy of 72% observed at ≥57 days;⁶ however, another study of cell surface occupancy in participants with melanoma showed that the median occupancy was 64% to 70% and varied according to dose.⁸ Tumor biopsies from phase I suggested a potentially significant association between PD-L1 cell surface expression and clinical response to nivolumab (P=0.048)⁶ which was further investigated in subsequent studies.

One-hundred and seven advanced melanoma participants from the phase I trial were followed for up to 4 years after treatment initiation to monitor survival, tumor remission and the long-term safety of nivolumab.⁸ Sixty-two percent of these participants had received at least two prior systemic treatments.⁹ The objective response rate (ORR), defined as the proportion of participants who had a complete or partial response was 25%, 18/26 participants were treated for a year or more.⁸ The ORR increased to 33% at 4 years’ follow-up, with a median response duration of 2 years.^8,9 Stable disease lasting ≥24 weeks was originally observed in 6% of participants and increased by another 1% at 4 years’ follow-up.^8,9 Median overall survival was 16.8 months (95% confidence interval [CI] = 12.5-31.6), and 1 and 2 year survival rates were 62% (95% CI = 53%-72%) and 44% (95% CI = 32%-53%), respectively.⁹

The most common treatment emergent adverse events (TEAEs) in participants treated with nivolumab were fatigue (32%), rash (23%), and diarrhea (18%).⁹ TEAEs of immunologic significance included skin disorders (35%), gastrointestinal disorders (18%), and endocrinopathies (13%). Five participants experienced Grade 3 or 4 TEAEs.⁹ The majority of AEs occurred within the first 6 months of treatment and the frequency of AEs did not increase with prolonged use.⁹

Yamazaki and colleagues reported preliminary results from their phase II study of 35 participants with advanced melanoma.¹⁰ Nivolumab was administered at a dose of 2 mg/kg every 3 weeks until unacceptable toxicity, disease progression, or complete response. The ORR was 23% (8/35) with median progression- free survival of 6.14 months. TEAEs occurred in 45.7% of participants and consisted mainly of elevated gamma-glutamyl transpeptidase, anemia, decreased hematocrit, hemoglobin and red blood cell counts, and loss of appetite. No drug-related deaths were reported.

Phase III

A randomized, double-blind, phase III trial assessed the efficacy and safety of nivolumab versus standard chemotherapy (dacarbazine) in melanoma without BRAF mutation.¹¹ Four- hundred and eighteen participants were randomized to nivolumab 3 mg/kg every 2 weeks (N=210) or dacarbazine 1000 mg/m² every 3 weeks (N=208). ORRs and median progression-free survival are presented in Table 1. The ORR was significantly higher in the nivolumab group compared to the dacarbazine group and the proportion of participants with a complete response was higher with nivolumab than with dacarbazine (7.6% vs. 1.0%). The duration of progression-free survival was also longer in participants treated with nivolumab compared to those treated with dacarbazine.

The trial was stopped early due to nivolumab’s clear benefit over standard chemotherapy in improving overall survival.¹² The median overall survival was not reached in the nivolumab group and was 10.8 months (95% CI = 9.3%-12.1%) in the dacarbazine group.¹¹ Overall survival rates at 1 year were 72.9% (95% CI = 65.5%-78.9%) and 42.1% (95% CI = 33%-50.9%) in the nivolumab and dacarbazine groups, respectively. Nivolumab significantly increased overall survival compared to dacarbazine (hazard ratio for death = 0.42; 99.79% CI = 0.25-0.73; P<0.001).

The incidence of AEs was similar between treatments (74.3% vs. 75.6% in the nivolumab and dacarbazine groups, respectively); yet the frequency of AEs of grade 3 or 4 was lower for participants treated with nivolumab than with dacarbazine (11.7% vs. 17.6%).¹¹ The most common TEAEs with nivolumab were fatigue (19.9%), pruritus (17.0%), and nausea (16.5%). The proportion of participants who discontinued the study due to TEAEs was 6.8% and 11.7% in the nivolumab and dacarbazine groups, respectively. No drug-related deaths occurred in either group.

Nivolumab’s efficacy in treating ipilimumab- or ipilimumab/ BRAF inhibitor-refractory melanoma was investigated in 405 participants.¹³ Participants were randomized to receive an IV infusion of nivolumab at a dose of 3 mg/kg, or investigator’s choice of chemotherapy (ICC), either dacarbazine 1000 mg/m² every 3 weeks or carboplatin AUC 6 plus paclitaxel 175 mg/m² every 3 weeks by IV infusion, until disease progression or unacceptable toxicity. Tumors were assessed at baseline, 9 weeks, and every 6 weeks for the first year, then every 12 weeks until disease progression, death or study withdrawal. Safety was assessed in all participants who received at least one dose of study drug. The primary endpoint was the proportion of participants who had an OR. Secondary endpoints included progression-free survival rates, and PD-L1 tumor expression.

ORRs and median progression-free survival are displayed in Table 1. ORRs were higher with nivolumab than with ICC, although no statistical comparison was made. Median time to response was 2.1 months and 3.5 months in the nivolumab and ICC groups, respectively. Median progression-free survival was not significantly different between nivolumab and ICC. The ORR with nivolumab was higher for PD-L1 positive tumors (43.6%) than PD-L1 negative tumors (20.3%), while ORRs were similar with ICC in both types of tumors (9.0% vs. 13.0%).

Rates of TEAEs were 68% in the nivolumab group and 79% in the ICC group. Fatigue, pruritus and diarrhea were the most common AEs with nivolumab, while nausea, alopecia and fatigue were the most common AEs with ICC. Grade 3 to 4 AEs occurred in 9% of participants treated with nivolumab and in 31% of participants treated with ICC. Drug toxicity led to the discontinuation of treatment in 3% and 7% of the participants in the nivolumab and ICC groups, respectively.

Clinical trials have also assessed the safety and efficacy of nivolumab in combination with ipilimumab for the treatment of advanced melanoma.^14,15 Eighty-six participants in a phase I trial were treated either concurrently with escalating doses of nivolumab (cohort 1: 0.3 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 2: 1 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 3: 3 mg/kg nivolumab + 1 mg/kg ipilimumab, cohort 4: 3 mg/kg nivolumab + 3 mg/kg ipilimumab, cohort 5: 10 mg/kg nivolumab + 3 mg/kg ipilimumab, 10 mg/kg nivolumab + 10 mg/kg ipilimumab), or sequentially with nivolumab 1 mg/kg and 3 mg/kg every 2 weeks for up to 48 doses.¹⁴ Participants were followed for 2.5 years after the start of treatment. Clinical activity was assessed at weeks 12, 18, 24, 30 and 36, and every 12 weeks thereafter in the concurrent therapy cohorts, while the sequentially treated cohorts were assessed at week 8 and every 8 weeks thereafter. PD-L1 tumor-cell expression was also characterized.

The ORR in the concurrent regimen cohorts was 40% (95% CI = 27-55) across all doses.¹⁴ Sixteen participants experienced a ≥80% reduction in tumor size. Five complete responses were included among those with a ≥80% reduction. Nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg were the maximum doses associated with an acceptable safety profile in the sequential treatment cohort. The ORR in participants who received the sequential regimen was 53% (95% CI = 28%-77%), including three complete responses; all participants who attained OR had a ≥80% tumor reduction at the rst scheduled assessment. Twenty percent of participants (95% CI = 8%-39%) in the sequenced regimen cohorts had an OR, including one complete response. Four participants in the sequenced regimen cohorts had a tumor reduction of ≥80%. ORs were noted in 6/13 and 9/22 participants with PD-L1 positive and PD-L1 negative tumors, respectively. Ninety-three percent of participants experienced TEAEs, the most common being rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%). Eleven participants (11%) in the concurrent regimen group and three (9%) in the sequenced regimen discontinued treatment due to TEAEs.

In a double-blind, phase III study, 945 participants were randomized to receive either: 1) nivolumab 3 mg/kg every 2 weeks (plus ipilimumab matched placebo) for 4 doses; 2) nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks for cycle 3 and thereafter; or 3) ipilimumab 3 mg/kg every 3 weeks (plus nivolumab-matched placebo) for 4 doses by IV infusion.¹⁵ Treatment continued until disease progression, unacceptable toxicity or study withdrawal.

Median progression-free survival was significantly longer with nivolumab plus ipilimumab than with ipilimumab alone and with nivolumab than with ipilimumab (Table 1).¹⁵ No significant difference in the hazard of death or disease progression between the combination treatment and nivolumab only groups was found. The ORRs were highest among participants treated with nivolumab plus ipilimumab, followed by those treated with nivolumab only, and ipilimumab only (Table 1). Median time to OR was similar in the three groups (2.76, 2.78, and 2.79 months in the nivolumab plus ipilimumab, nivolumab, and ipilimumab groups, respectively). Complete response rates were also highest with nivolumab plus ipilimumab (11.5%), than with nivolumab (8.9%) or ipilimumab (2.2%) alone. The highest ORRs were observed in participants with PD-L1-positive tumors treated with nivolumab plus ipilimumab (72.1%; 95% CI = 59.9%-82.3%) or nivolumab only (57.5%; 95% CI = 45.9%-68.5%).

TEAEs occurred in 95.5% of the nivolumab plus ipilimumab group, in 86.2% of the ipilimumab group, and in 82.1% of the nivolumab group.¹⁵ The most common TEAEs in all groups were diarrhea, fatigue, pruritus and rash. The incidence of grade 3 or 4 AEs was highest in the combination group (55.0%), compared to the ipilimumab (27.3%) and nivolumab-only (16.3%) groups. TEAEs led to study discontinuation in 36.4%, 14.8% and 7.7% of the nivolumab plus ipilimumab, ipilimumab only and nivolumab only groups, respectively. One participant in the nivolumab group died of neutropenia and one participant in the ipilimumab group died of cardiac arrest. No deaths were reported with the combination treatment.

Discussion

Nivolumab has demonstrated greater efficacy when compared to standard chemotherapy in clinical trials.^11,13 Nivolumab produced higher objective response rates, longer median progression-free survival, and increased overall survival compared to standard chemotherapy.^11,13 Participants with ipilimumab- or ipilimumab/ BRAF inhibitor-refractory melanoma treated with nivolumab also had higher response rates and a faster time to response than those treated with investigator’s choice of chemotherapy.¹³ Participants treated with nivolumab had significantly longer progression-free survival and higher OR and complete response rates compared to participants treated with ipilimumab monotherapy.¹⁴ Furthermore, patients who did not respond to previous ipilimumab therapy did have a response to treatment with nivolumab.¹⁴ Nivolumab/ipilimumab combination therapy is also encouraging.¹⁵ Nivolumab treatment is associated with a risk of immune-mediated pneumonitis, colitis, hepatitis, renal dysfunction and endocrinopathy.¹⁶ The most common TEAEs with nivolumab were fatigue, pruritus, rash, diarrhea and nausea; however, AE rates were similar or lower with nivolumab than with dacarbazine or carboplatin plus paclitaxel.^11,13 Furthermore, the incidence of grade 3 or 4 AEs was lower with nivolumab compared to standard chemotherapy or with ipilimumab monotherapy.^11,13,15

Until recently, surgical resection, when possible, coupled with standard chemotherapy was the rst-line treatment for Stage III melanoma and for palliation of Stage IV disease. However, the rates of recurrence and metastasis remained high, as the disease is often refractory to surgery and/or systemic treatment. Advances in genetics and tumor biomarker recognition have led to the synthesis of novel biological agents for the treatment of metastatic melanoma. Nivolumab is one such agent and with an improved safety and efficacy profile over traditional therapy, it proves a promising development in the treatment of advanced melanoma.

References

1. Bichakjian CK, Halpern AC, Johnson TM, et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol. 2011 Nov;65(5):1032-47.
2. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009 Dec 20;27(36):6199-206.
3. Essner R, Lee JH, Wanek LA, et al. Contemporary surgical treatment of advanced- stage melanoma. Arch Surg. 2004 Sep;139(9):961-6; discussion 6-7.
4. Sandru A, Voinea S, Panaitescu E, et al. Survival rates of patients with metastatic malignant melanoma. J Med Life. 2014 Oct-Dec;7(4):572-6.
5. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015 Apr 13;27(4):450-61.
6. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti- programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-75.
7. Gohil K. Pharmaceutical approval update. P T. 2015 Mar;40(3):172-3.
8. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54.
9. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014 Apr 1;32(10):1020-30.
10. Yamazaki N, Tahara H, Uhara H, et al. Phase 2 study of nivolumab (Anti-PD-1; ONO-4538/BMS-936558) in patietns with advanced melanoma. Eur J Cancer. 2013;49(s2):s868.
11. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30.
12. Improved survival ends nivolumab trial early. Cancer Discov. 2014 Sep;4(9): 979-80.
13. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84.
14. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33.
15. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34.
16. Opdivo® (nivolumab) injection, for intravenous use [Full prescribing information]; revised January 2016. Bristol-Myers Squibb Company Princeton, NJ. Available at: http://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed February 1, 2016.

¹Wayne State University, Detroit, MI, USA
²Mediprobe Research Inc., London, ON, Canada
³Department of Medicine, University of Toronto, Toronto, ON, Canada

Conflicts of interest:
Gita Gupta has no conflicts of interest. Aditya Gupta has been a clinical trials investigator, advisory board member, consultant, and speaker for Valeant. Aditya Gupta was involved in preclinical studies of tavaborole for Anacor Pharmaceuticals Inc. and has consulted for Anacor. Kelly Foley is an employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of Aditya Gupta.

ABSTRACT
Onychomycosis is a stubborn fungal infection of the nails that can be difficult to effectively manage. One of the challenges with topical therapies is penetrating the nail plate to reach the site of infection. As the first antifungal in a boron-containing class of drugs with a novel mechanism of action, tavaborole is able to penetrate the nail plate more effectively than ciclopirox and amorolfine lacquers. In Phase II/III clinical trials, tavaborole was shown to be safe and clinically effective. Tavaborole 5% solution was approved by the US FDA for the treatment of toenail onychomycosis in July 2014 and is an important addition to the topical treatment arsenal against this stubborn infection.

Key Words:
clinical efficacy, dermatophyte, fungal infection, nail penetrance, nondermatophyte, onychomycosis, tavaborole, topical treatment

Introduction

Onychomycosis is a persistent fungal infection of the nails and nail bed, predominantly caused by the dermatophytes Trichophyton
rubrum or Trichophyton mentagrophytes.¹ The prevalence of onychomycosis in Europe and North America ranges from 3.22- 8.9%,^2,3 with recurrence and reinfection occurring in up to 25%⁴. Distal lateral subungual onychomycosis (DLSO) is the most common clinical presentation, invading the nail plate, nail bed, and hyponychium from the distal edge and lateral nail folds.¹

Treatment for onychomycosis consists of systemic (oral) and topical medications, with or without mechanical/chemical debridement. Systemic therapy is generally more successful
than topical therapy with clinical cure rates ranging from 40-80%.⁵ The advantage to systemic therapy is that medication can directly reach the site of infection in the nail bed.⁶ However, systemic therapy may not be feasible for those who are immunocompromised or at risk for drug-drug interactions (e.g., the elderly and/or diabetics).⁷ Alternatively, other patients are uncomfortable with long-term use of oral medications. Oral antifungal medications have been associated with asymptomatic increases in liver enzymes and there is a small risk of hepatotoxic injury.^8,9 Thus, topical therapies have an important role in onychomycosis management.

The efficacy of topical therapy for onychomycosis ranges from 5.5-17.8% for complete cure and 29-55% for mycological cure.¹⁰ The lower efficacy of topical treatments as compared to systemic therapy can be attributed to their limited ability to reach the site of infection.¹¹ In order for topical treatments to be effective, they need to penetrate the nail plate and down into the nail bed, and mechanical or chemical nail debridement of nails may facilitate this. The major advantage to topical therapy is that long-term use is safe, with minimal side effects.¹¹ Additionally, topical treatments used in combination with systemic treatment may increase clinical efficacy. Furthermore, fungal resistance to azole medications has become a concern in recent years.¹² Therefore, there is a need for new topical therapies for onychomycosis.

Tavaborole: A Novel Topical Antifungal

Tavaborole 5% solution (Kerydin^®) was approved by the US FDA for treatment of onychomycosis in July 2014. Tavaborole is the first in a new class of boron atom-containing drugs, the oxaboroles. Tavaborole’s mechanism of action is unique from current antifungals. Other antifungal agents act by blocking ergosterol synthesis (triazoles and terbinafine),⁶ or interfering with microbial metabolism (ciclopirox).¹³ Tavaborole inhibits protein synthesis, and thus fungal cell growth, by binding to leucyl-tRNA synthetase (LeuRS), an aminoacyl-tRNA synthetase (AARS).¹⁴ AARSs are critical for correct DNA translation and contain proofreading editing sites. Tavaborole binds to the editing site of LeuRS, trapping tRNA and preventing further DNA translation and protein synthesis.¹⁴ In vitro studies have shown that tavaborole can inhibit a wide range of fungal species, with minimum inhibitory concentrations (MIC) against dermatophytes, nondermatophyte molds, and yeasts (Table 1)¹⁵ allowing for potential treatment of mixed dermatophyte-nondermatophyte/mold infections. Of note is the potential for tavaborole to act against Fusarium and Malassezia species.¹⁵ Additionally, tavaborole’s low molecular weight compared to other available topical antifungal agents appears to allow for increased nail penetrance, with increased penetrance demonstrated compared to both amorolfine and ciclopirox.^16,17 Tavaborole’s broad spectrum of antifungal activity, coupled with its ability to penetrate the nail plate, suggested that it may be an effective topical treatment for toenail onychomycosis and led to its investigation in Phase I-III clinical trials.

Clinical Efficacy

Phase I
A Phase I study assessed the efficacy of once daily tavaborole 7.5% solution for 28 days in 15 otherwise healthy patients with severe onychomycosis of both great toenails (at least 80% involvement).¹⁸ Additionally, at least one great toenail was potassium hydroxide (KOH) positive, each great toenail had a combined thickness of the nail plate and nail bed of >3 mm, and at least six other toenails were diagnosed with onychomycosis. After 14 and 28 days of treatment, negative culture was reported for 88% (21/24) and 100% (24/24) of toenails, respectively. Clinical improvement was also observed 2-4 months following treatment, with an average clear nail growth of 1.2 mm.¹⁸

Phase II
Three Phase II studies have been conducted to evaluate the efficacy of a range of doses for tavaborole.¹⁹ All of these studies enrolled adult patients (18-65 years of age) with mild to moderate onychomycosis of at least one great toenail (20-60% nail involvement) and did not allow debridement of the nails during treatment. Study 200/200A (N=187) was a double-blind, randomized, vehicle-controlled trial evaluating 2.5%, 5%, and 7.5% tavaborole solution applied to affected toenails once daily for 3 months, followed by three times weekly for 3 months.¹⁹ The primary efficacy endpoint at 6 months was treatment success of the target toenail, defined as an Investigator Static Global Assessment (ISGA) of clear or almost clear plus negative culture or ≥2 mm of new clear nail growth plus negative culture. The rates of treatment success for all tavaborole treatments were significantly greater than vehicle control (P=0.030). While the number of patients that achieved negative culture was higher in tavaborole groups than vehicle, the differences were not statistically significant (Table 2).¹⁹

Studies 201 (N=89) and 203 (N=60) were open-label trials with the same primary efficacy endpoint as Study 200/200A, treatment success.¹⁹ Patients in Study 201 applied tavaborole 5% solution (Cohort 1) or tavaborole 7.5% solution (Cohort 2) to all affected toenails once daily for 6 months. Cohort 3 applied tavaborole 5% solution once daily for 12 months. Patients in Study 203 applied tavaborole 1% once daily for 6 months or tavaborole 5% once daily for 30 days, followed by three times weekly for 5 months. Efficacy outcomes are listed in Table 2.¹⁹ Overall, treatment with tavaborole was very promising and well tolerated, prompting larger-scale Phase III trials to be conducted. The 5% concentration of tavaborole was selected for Phase III testing.

Phase III

Two identical multi-center, randomized, double-blind, vehiclecontrolled clinical trials were conducted (Study 301, N=593 and Study 302, N=601).^20,21 Patients aged 18 years and older with mycologically confirmed (positive KOH and culture) onychomycosis involving 20-60% of the great toenail applied either tavaborole 5% solution or vehicle solution once daily for 48 weeks. At Week 52, complete cure (completely clear nail and mycological cure) and mycological cure (negative KOH and negative culture) were assessed (Table 3). ^20,21 Treatment with tavaborole 5% solution led to a significantly greater complete cure and mycological cure rates than vehicle treatment in both clinical trials (Ps≤0.001). Additionally, the outcome of completely or almost completely clear nail (≤10% nail involvement) plus negative mycology was significantly greater with tavaborole 5% solution compared to vehicle (Study 301: 15.3% vs. 1.5%; Study 302: 17.9% vs. 3.9%, P≤0.001).^20,21

Adverse Events

For all three Phase II studies combined, treatment-emergent adverse events (TEAEs) occurred in 177 of 366 patients.¹⁹ There were 13 reports of serious adverse events (AEs), unrelated to treatment. A reduction in dosing frequency and/or treatment discontinuation resolved any mild to moderate application site reactions. Specifically, in Study 200/200A, four patients in the tavaborole 7.5% solution group required ‘drug holidays’ (discontinued treatment until persistent grade 2 stinging/burning, pruritus, or grade ≥3 irritation was resolved, then treatment resumed with reduced frequency), while no patients in the tavaborole 5% solution group required a break from treatment. Other TEAEs reported included influenza (9.0%), pharyngitis (3.8%), upper respiratory tract infection (3.6%), tinea pedis (3.8%), headache (3.6%), contact dermatitis (2.5%), onychomadesis (1.4%), and tooth extraction (0.8%).¹⁹

Safety data was available for 1186 participants in the Phase III clinical trials.²⁰ No serious AEs were considered treatment related. In both trials, discontinuation due to treatment was comparable for tavaborole 5% solution and vehicle groups. TEAEs in ≥1% of participants treated with tavaborole were limited to application site reactions (exfoliation 2.7%, erythema 1.6%, and dermatitis 1.3%), and there were few reports of TEAE’s due to vehicle (exfoliation 0.3%, erythema and dermatitis 0%).20,21 Taken together, these results demonstrate that tavaborole 5% solution is both safe and more effective than vehicle in treating toenail onychomycosis.

Discussion

Tavaborole 5% solution was approved by the US FDA in July 2014 for use as a topical treatment for onychomycosis. Phase III clinical trials demonstrated that once daily use of tavaborole 5% solution for 48 weeks produced significantly higher rates of mycological and complete cure than vehicle.^20,21 Adverse events reported from Phase II and III trials indicate that the 5% formulation of tavaborole provides optimum efficacy and safety, producing mild application site reactions in a small number of patients.^19-21 As with all topical treatments for toenail onychomycosis, treatment outcomes are, in part, reliant on patient compliance and commitment to therapy, as toenails generally require at least 10-12 months to regrow.

Formulating an agent capable of penetrating the nail plate is one of the major challenges in developing topical treatments for onychomycosis. Tavaborole’s low molecular weight and high solubility allow for greater nail penetration and subsequent delivery of medication to the nail bed. The ability of tavaborole to effectively penetrate the nail plate prevents the need for mechanical debridement that may be required with other topical treatments. Additionally, tavaborole 5% solution’s broad-spectrum antifungal activity against dermatophytes, nondermatophytes, and yeasts make it a potential treatment for mixed infections. This is a relevant concern as little is known about the efficacy of current treatments for mixed infections, which may also contribute to the high recurrence rates observed in onychomycosis.

The availability of tavaborole 5% solution for the topical management of toenail onychomycosis may represent the promising start of a new line of treatments with increased nail penetrance and a novel mechanism of action against pathogenic fungi.

References

1. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
2. Gupta AK, Daigle D, Foley KA. The prevalence of culture-confirmed toenail onychomycosis in at-risk patient populations. J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1039-44.
3. Sigurgeirsson B, Baran R. The prevalence of onychomycosis in the global population: a literature study. J Eur Acad Dermatol Venereol. 2014 Nov;28(11):1480-91.
4. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol. 2003 Sep;149 Suppl 65:5-9.
5. de Sa DC, Lamas AP, Tosti A. Oral therapy for onychomycosis: an evidencebased review. Am J Clin Dermatol. 2014 Feb;15(1):17-36.
6. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol. 1993 May;28(5 Pt 1):S28-S34.
7. Baran R, Hay RJ, Garduno JI. Review of antifungal therapy, part II: treatment rationale, including specific patient populations. J Dermatolog Treat. 2008 19(3):168-75.
8. Garcia Rodriguez LA, Duque A, Castellsague J, et al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharmacol. 1999 Dec;48(6):847-52.
9. Kao WY, Su CW, Huang YS, et al. Risk of oral antifungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol. 2014 Jan;77(1):180-9.
10. Gupta AK, Daigle D, Foley KA. Topical therapy for toenail onychomycosis: an evidence-based review. Am J Clin Dermatol. 2014 Dec;15(6):489-502.
11. Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv. 2008 Nov;5(11):1267-82.
12. . Parker JE, Warrilow AG, Price CL, et al. Resistance to antifungals that target CYP51. J Chem Biol. 2014 Oct;7(4):143-61.
13. Gupta AK, Ryder JE, Baran R. The use of topical therapies to treat onychomycosis. Dermatol Clin. 2003 Jul;21(3):481-9
14. Rock FL, Mao W, Yaremchuk A, et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science. 2007 Jun 22;316(5832):1759-61.
15. Sanders V, Baker SJ, Alley MRK, et al. Microbiological activity of AN2690, a new antifungal agent in development for the topical treatment of onychomycosis. [Poster P1608]. Presented at the 64th Annual Meeting of the American Academy of Dermatology; March 3-7, 2006; San Francisco, CA.
16. Elewski BE, Tosti A. Tavaborole for the treatment of onychomycosis. Expert Opin Pharmacother. 2014 Jul;15(10):1439-48.
17. Hui X, Baker SJ, Wester RC, et al. In vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci. 2007 Oct;96(10):2622-31.
18. Beutner KR, Sanders V, Hold K, et al. An open-label, multi-dose study of the absorption and systemic pharmacokinetics of AN2690 applied as a 7.5% solution to all toenails of adult patients with moderate to severe onychomycosis. [Poster 1823]. Presented at the 65th Annual Meeting of the American Academy of Dermatology; February 2-6, 2007; Washington, DC.
19. Toledo-Bahena ME, Bucko A, Ocampo-Candiani J, et al. The efficacy and safety of tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the topical treatment of toenail onychomycosis. J Drugs Dermatol. 2014 Sep;13(9):1124-32.
20. 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 Jul;73(1):62-9.
21. Kerydin^™ (tavaborole) topical solution, 5% [Full prescribing information]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.; revised July 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204427s000lbl.pdf. Accessed September 20, 2015.
22. Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.

¹Wayne State University, Detroit, MI, USA
²Mediprobe Research Inc., London, ON, Canada
³Department of Medicine, University of Toronto School of Medicine, Toronto, ON, Canada
⁴Henry Ford Medical Center, Department of Dermatology, Detroit, MI, USA

ABSTRACT
The etiology of papulopustular rosacea (PPR) is not well understood yet appears to involve both the innate and adaptive immune response in addition to possible infestation with Demodex mites. Current treatments for PPR consist mainly of antibiotics. Ivermectin cream 1%, a new topical treatment for PPR, possesses both anti-inflammatory and anti-parasitic properties. After 12 weeks of treatment, subjects treated with ivermectin cream 1% had significantly greater reductions in PPR symptoms and enhanced diseaserelated quality of life improvements compared to subjects who received vehicle. Furthermore, PPR symptoms continued to improve with prolonged treatment (40 weeks). Ivermectin cream 1% offers a multi-pronged approach to combat the complex pathophysiology of rosacea.

Key Words:
anti-parasitic, avermectin, Demodex, erythema, inflammation, insecticide, papulopustular rosacea, Rosiver®, Soolantra®,
topical ivermectin

Introduction

Rosacea is a chronic inflammatory condition affecting the central facial skin of the cheeks, nose, chin and forehead. Rosacea typically affects females approximately 30 years of age and increases in severity throughout the lifespan.¹ The exact cause of rosacea is unknown and its pathogenesis is not well understood.^2,3 Innate and adaptive immune responses, vascular abnormalities, dermal microorganism imbalances, and environmental factors may interact to produce chronic inflammation and the development of fibrosis.² Four subtypes of rosacea have been identified: 1) erythematotelangiectatic rosacea, 2) papulopustular rosacea (PPR), 3) phymatous rosacea, and 4) ocular rosacea²; yet, whether these represent a distinct variation or a continuum of disease severity remains a matter of debate.² PPR, previously known as acne rosacea, is characterized by erythema, telangiectasia, papules, pustules, edema, and sometimes pain, stinging or burning.⁴ Patients report that symptoms are a cause of low self-esteem, as they are a source of shame, embarrassment, and physical discomfort.⁵ Treatment is strongly encouraged to moderate the detrimental effect on patient quality of life (QoL) and to prevent the condition from worsening. Few therapeutic alternatives exist for the treatment of PPR. There is some evidence supporting the efficacy of azelaic acid, topical metronidazole and sub-antimicrobial dose doxycycline in the treatment of moderate to severe rosacea, although it remains unclear which agent is most effective.⁶

Ivermectin is derived from avermectin, a class of broadspectrum anti-parasitic agents isolated from the fermentation of Streptomyces avermitilis.⁷ Ivermectin possesses both antiparasitic and anti-inflammatory properties and has been shown to reduce the number of Demodex mites in demodicidosis and blepharitis and to inhibit the production of lipopolysaccharide inflammatory cytokines, such as tumor necrosis factor-alpha and interlukin (IL)-1b, while upregulating the production of the anti-inflammatory cytokine IL-10.⁸ Because PPR is recognized as an inflammatory condition whose pathogenesis may involve parasitic infestation with Demodex mites, vehicle-controlled and active comparator trials were undertaken to evaluate the efficacy and safety of topical ivermectin 1% cream in the treatment of PPR.

Pivotal Phase 3 Studies

Two pivotal phase 3 trials assessed the efficacy and safety of ivermectin cream 1% for moderate to severe PPR.⁹ These trials were part of a larger study comprised of a second long-term active comparator trial10 and a 4 week follow-up safety study. The pivotal phase 3 studies were identically designed multicenter, randomized, double-blind, vehicle-controlled trials that enrolled participants aged 18 years or older with moderate to severe PPR and 15-70 inflammatory facial lesions.⁹ Subjects were randomized in a 2:1 ratio to receive either ivermectin 1% cream or vehicle cream for 12 weeks. Participants were instructed to apply their respective cream to the face once daily at bedtime while avoiding the upper and lower eyelids and lips. Participants were also asked to avoid known rosacea triggers, such as specific foods and environments, whenever possible. Evaluations occurred at baseline and at weeks 2, 4, 8 and 12. Co-primary efficacy outcomes for this study included the percentage of participants who achieved an Investigator Global Assessment (IGA) of “clear” or “almost clear” and mean change in inflammatory lesion counts between groups at week 12. Other efficacy outcomes were percent change in inflammatory lesion counts from baseline, subjective assessment of rosacea improvement, and QoL scores on the Dermatology Life Questionnaire Index (DLQI) and the Rosacea Quality of Life Index (RosaQoL™). Adverse events (AEs) and laboratory parameters (hematology and blood chemistry) were also monitored.

Study 1 enrolled 683 participants and Study 2 enrolled 688 participants, the majority of whom were female (Study 1: 68.2% and Study 2: 66.7%) and approximately 50 years of age on average. Participants in Study 1 had an average of 30.9 lesions, while subjects in Study 2 had an average 32.9 inflammatory lesions at baseline. The proportion of participants with an IGA of ‘severe’ was 18% and 24.1% in Studies 1 and 2, respectively. There were no differences in DLQI scores between treatment groups at baseline.

Efficacy results are presented in Table 1. In both studies, a significantly higher percentage of participants who received ivermectin 1% had an IGA of ‘clear’ or ‘almost clear’ at week 12 compared to vehicle (P<0.001) and the significant difference between active and control arms was noted at week 4 (10.9% and 11.8% vs. 5.6% and 5.7%, respectively; P The mean difference in inflammatory lesion counts between ivermectin 1% and vehicle from baseline to week 12 was -8.13 and -8.22 for Studies 1 and 2, respectively (ivermectin 1% vs. vehicle, both P<0.001). There was also a significant difference in the median reduction in lesion count from baseline between the ivermectin 1% and vehicle groups (both studies P<0.001) observed as early as week 2. In both studies, a significantly higher proportion of participants who received ivermectin 1% cream reported improvement of their rosacea symptoms as ‘excellent’ or ‘good’ compared to participants who received vehicle (P<0.001). QoL scores also improved in the ivermectin 1% groups compared to vehicle at the end of 12 weeks. In both studies, a significantly greater proportion of participants in the ivermectin 1% group (approximately 53%) than the vehicle group (approximately 35%) considered their rosacea had no effect on their QoL (P<0.001). Improvement in RosaQoL scores was also significantly higher for ivermectin 1% compared to vehicle (-0.64 ± 0.7 and -0.60 ± 0.6 vs. -0.35 ± 0.5 in both vehicle groups; P=0.001 for Studies 1 and 2).

For Studies 1 and 2, no serious treatment-related AEs were reported in either the ivermectin 1% cream or vehicle groups. Burning (1.8% for ivermectin 1% cream and 2.6% for vehicle) was the most commonly reported treatment-related AE in Study 1, while pruritus and dry skin were the most commonly reported treatment-related AEs in Study 2 (pruritus: 0.7% vs. 0% and dry skin: 0.7% vs. 0.9% for ivermectin 1% cream vs. vehicle). Furthermore, treatment-related AEs with active drug were less than with vehicle alone. Laboratory tests showed no clinically significant abnormalities.

Ivermectin 1% Cream vs. Azelaic Acid 15% Gel

Ivermectin 1% cream was then evaluated against azelaic acid 15% gel in a 40 week extension study.¹⁰ In this continuation of the pivotal phase 3 trials, participants with PPR originally assigned to ivermectin 1% cream once daily in the 12-week study continued to be treated as such and participants initially randomized to vehicle were switched to azelaic acid 15% gel twice daily for 40 weeks. Efficacy was assessed at 4 week intervals using the IGA. Safety assessments were comprised of documentation of AEs, tolerability signs and symptoms, and laboratory tests.

Six hundred and twenty-two and 683 participants enrolled in the 40-week extension studies (see previous section for participant demographics). The efficacy of ivermectin 1% cream increased over time as IGA scores of ‘clear’ and ‘almost clear’ increased from 38.4% to 71.1% by the end of Study 1 and from 40.1% to 76% by the end of Study 2; 59.4% and 57.9% of participants who received azelaic acid had an IGA of ‘clear’ or ‘almost clear’ by the end of Studies 1 and 2, respectively. No statistical comparisons were made because of the differing treatments lengths between the ivermectin 1% and azelaic acid 15% groups. Furthermore, because the ivermectin group had already been treated with ivermectin for 3 months, while the azaleic acid group had previously received vehicle, baseline factors may not have been comparable between groups.

The incidence of treatment-related AEs in the ivermectin 1% cream and azelaic acid 15% gel groups was 1.9% vs. 6.7% and 2.1% vs. 5.8% in Studies 1 and 2, respectively. No severe or serious AEs were deemed related to ivermectin 1% cream in Studies 1 or 2 and no serious AEs were considered related to azelaic acid 15% gel in either study; however, 1 severe case of skin irritation was considered related to azelaic acid in Study 2. In Study 1, 4 participants in the azelaic acid group and 5 in the ivermectin group discontinued the study as a result of AEs. In Study 2, 5 participants in the azelaic acid group and 3 in the ivermectin group discontinued the study due to AEs. None of the AEs in either study were considered related to ivermectin 1% cream; however, in the azaleic acid group, 3 AEs in Study 1 and 4 AEs in Study 2 were considered related to azaleic acid (Study 1: skin irritation, eye and skin irritation, and skin pain and burning; Study 2: skin irritation, skin burning, skin discomfort, and skin burning and pruritus).

Ivermectin 1% Cream vs. Metronidazole 0.75% Cream

Another phase 3, investigator-blinded, randomized trial conducted in Europe explored the efficacy and safety of ivermectin 1% cream compared to metronidazole 0.75% cream for the treatment of moderate to severe PPR (Table 2).¹ Nine-hundred and sixty-two participants age 18 years or older with moderate or severe PPR and presenting with 15-70 facial lesions were randomized 1:1 to receive either ivermectin 1% cream (n=478) once daily or metronidazole 0.75% gel (n=484) twice daily for 16 weeks. Treatments were applied to the entire face, avoiding the upper and lower eyelids and lips. Participants were also asked to avoid known rosacea triggers. Study visits were at baseline and at weeks 3, 6, 9, 12 and 16. Efficacy endpoints included inflammatory lesion counts, the IGA, participants’ subjective evaluation of rosacea improvement, and the DLQI. The safety evaluation consisted of AE assessments over the course of the study, as well as local tolerance and laboratory parameters.

At baseline, the majority of participants had moderate rosacea (16.7% severe) with an average 32.5 inflammatory lesions. Participants had a mean age of 52 years and were primarily female (65.2%). In terms of efficacy at week 16, ivermectin was significantly more effective than metronidazole 0.75% cream in reducing the percentage of inflammatory lesions (83% vs. 73.7%; P<0.001) with a significant difference between the two treatments observed at week 3. The IGA of disease severity was also significantly better for ivermectin 1% cream compared to metronidazole 0.75%, with 84.9% of the ivermectin 1% cream and 75.4% of the metronidazole 0.75% cream groups rated as ‘clear’ or ‘almost clear’ at week 16 (P<0.001), with the greatest difference in IGA noted at week 12. Approximately 86% of the ivermectin group rated their global improvement as ‘excellent’ or ‘good’ compared to 74.8% in the metronidazole 0.75% group. Although the DLQI scores were similar between treatment groups at baseline (6.93 and 6.05 for ivermectin and metronidazole, respectively), participants treated with ivermectin 1% cream showed a greater improvement in QoL as indicated by a reduction in their DLQI scores (-5.18 vs. -3.92; P<0.01).

A similarly low proportion of participants experienced a treatment-related AE (1.9% in the ivermectin 1% cream group and 2.5% in the metronidazole 0.75% group). The most common treatment-related AE was skin irritation experienced by 3 and 4 participants in the ivermectin 1% cream and metronidazole 0.75% cream groups, respectively. Three participants in the ivermectin 1% cream group discontinued the study because of skin irritation and hypersensitivity, while 10 participants in the metronidazole 0.75% cream group discontinued the study due to skin irritation, allergic dermatitis, aggravation of rosacea, erythema, pruritus and feeling hot. Worsening of local tolerance parameters from baseline was more pronounced in
the metronidazole 0.75% group than the ivermectin 1% cream group for stinging/burning (15.5% vs. 11.1%), dryness (12.8% vs. 10%), and itching (11.4% vs. 8.8%). No clinically significant abnormalities in laboratory parameters were found.

Discussion

Ivermectin 1% cream is markedly more effective than vehicle in reducing inflammatory lesions of rosacea as it results in a significant reduction in lesion counts after only 2 weeks of treatment and produces substantially greater improvements in IGA ratings of ‘clear’ or ‘almost clear’ as early as week 4.⁹ The efficacy of ivermectin 1% cream increases with prolonged treatment as evidenced in the 40 week trials.¹⁰ Also, when compared to the standard treatment for PPR, metronidazole 0.75% cream, topical ivermectin was markedly superior to metronidazole in terms of reducing inflammatory lesions and IGA ratings.¹ Ivermectin 1% cream had a significantly greater positive impact on patient QoL compared to vehicle or metronidazole 0.75%.^1,9 Ivermectin 1% cream was well-tolerated and demonstrated a favorable safety profile across phase 3 studies, with skin irritation being the most common treatmentrelated AE.

In phase 3 trials, ivermectin 1% cream produced greater objective and subjective outcomes and improvements in disease-specific QoL over vehicle and an active comparator. Topical ivermectin represents a novel approach to the treatment of PPR that appears to confer superior efficacy and tolerability as compared to current treatment options, while offering the added convenience of once daily dosing. Since ivermectin possesses both anti-parasitic and anti-inflammatory properties, its effectiveness in treating PPR may be attributed to its ability to combat several pathogenic factors linked to the condition. Further studies are needed to elucidate the contribution of the anti-parasitic versus the antiinflammatory modes of action of ivermectin.

References

1. Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015 Apr;172(4):1103-10.
2. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004 Sep;51(3):327-41.
3. Diamantis S, Waldorf HA. Rosacea: clinical presentation and pathophysiology. J Drugs Dermatol. 2006 Jan;5(1):8-12.
4. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1): S15-26.
5. van der Linden MM, van Rappard DC, Daams JG, et al. Health-related quality of life in patients with cutaneous rosacea: a systematic review. Acta Derm Venereol. 2015 Apr 15;95(4):395-400.
6. van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011 Oct;165(4):760-81.
7. Merck & Co. Inc. Stromectal (ivermectin) tablets [Internet]. 2010 [cited 2015 Feb 20].
8. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogenactivated protein kinase activation pathway. Fundam Clin Pharmacol. 2009 Aug;23(4):449-55.
9. Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014 Mar;13(3):316-23.
10. Stein Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled,investigator-blinded trials. J Drugs Dermatol. 2014 Nov;13(11):1380-6.

¹Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Conflict of interest:None reported
ABSTRACT

External genital warts (EGWs) resulting from the human papilloma virus (HPV) are a common sexually transmitted infection and cause significant impairments in patient quality of life and sexual well-being. Therapeutic options for EGWs can be provider assisted, but many patients opt for treatment that can be applied at home. Sinecatechins 10% ointment is a new botanically based patient-administered therapy for EGWs. It is comprised of >85% catechins, green tea polyphenols that have been shown to possess antioxidant, antiproliferative, antiviral, and antitumor properties. Phase III trials of sinecatechins 10% ointment have demonstrated higher efficacy and lower recurrence rates compared to currently available patient-applied treatments. Therefore, sinecatechins 10% ointment presents an alternative self-administered topical treatment for EGWs.

Key Words:
catechins, condylomata acuminata, EGCG, epigallocatechin-3-gallate, genital warts, green tea extract, human papillomavirus, HPV, sinecatechins, Veregen, Polyphenon E

Introduction

It is estimated that 10-30% of the adult population in Canada is infected with human papilloma virus (HPV).¹ While high-risk strains of HPV cause various types of cancer, low-risk strains can cause condyloma acuminate, also known as external anogenital warts (EGWs). EGWs are highly contagious and are, therefore, one of the most common forms of sexually transmitted infections. The prevalence of EGWs in Canada is an estimated 1.8%, with an annual incidence rate of 154/100,000 for males and 120/100,000 for females.² Patients with EGWs present with one or several cauliflower-like growths on the genitals and/or anal regions and clinical appearance is often sufficient for a diagnosis. EGWs are associated with a significant burden of illness and considerable impairment of patients’ emotional and sexual well-being.³ Although up to 50% of untreated cases spontaneously regress at 6 months⁴, it is impossible to predict which lesions will regress, remain unchanged, or proliferate⁵; therefore it is recommended that treatment be offered to all patients with EGWs.

EGW treatment includes provider-assisted and patient-applied therapies or a combination of these modalities. Treatment can be categorized as ablative, antiproliferative, or immunomodulatory.⁶ CO2 laser, trichloroacetic acid, excision, cryotherapy, and electrocautery are ablative therapies that necessitate the assistance of a trained healthcare professional. Until recently, patient-applied therapies were either antiproliferative or immunomodulatory in nature. Podophyllin 10-25% and podophyllotoxin 0.5% are patient-applied antiproliferative agents, while imiquimod is an immunomodulatory agent that is available in both 5% and 3.75% formulations. Podophyllotoxin and imiquimod are considered the first choice among patient-applied treatment options;⁷ however, despite the greater ease and autonomy offered by patient-applied therapy, clearance rates with these treatments are lower than those achieved with physician-assisted options.⁸ Furthermore, lesion reappearance is common regardless of treatment choice as there is no way to eradicate the underlying viral infection.⁶

Sinecatechins ointment 10% (Veregen®), a new patient-applied treatment formulated from green tea (Camellia sinensis) extracts, has recently been licensed in Canada for the treatment of EGWs.⁹ Sinecatechins 10% ointment is comprised of >85% catechins, which are flavonoids responsible for the antioxidant effects of green tea. Sinecatechins 10% ointment contains eight different catechins, of which >55% is epigallocatechin-3-gallate (EGCG), the most abundant and potent catechins.¹⁰ Although the exact mechanisms of action of sinecatechins 10% ointment in regression of EGWs are currently unknown, they are likely multimodal, consisting of antiviral, pro-apoptotic and antiinflammatory responses.¹¹ The antiviral properties of EGCG may result from the inhibition of activator protein 1 (AP-1) transcriptional activity that effectively down-regulate expression of HPV genes. Transcription of anti-apoptotic HPV genes by the infected cell could be counteracted by EGCG directly activating pro-apoptotic proteins as well as upregulating and downregulating the expression of pro- and anti-apoptotic proteins, respectively, resulting in cell death.¹² EGCG also possesses anti-inflammatory activity by inducing anti-inflammatory interleukin (IL)-12 and reducing pro-inflammatory IL-10 activity. This would shift towards a T helper cell type 1 (Th1)-mediated immune response promoting the elimination of HPV-infected cells by the immune system. The various catechins and other molecular constituents of sinecatechins ointment likely work synergistically to modulate these complex biologic pathways to promote the regression of EGWs.¹⁰ Therefore, although the exact mechanisms of action of sinecatchins 10% ointment have not been fully elucidated, its efficacy in treating EGWs may be attributable to its antioxidant, antiproliferative, antiviral, and antitumor properties.¹¹

Clinical Efficacy

Gross et al. conducted a Phase II/III, randomized, double-blind trial to assess the efficacy and safety of two formulations of sinecatechins ointment for the treatment of EGW.¹³ Two hundred and forty-two participants (125 males, 117 females) with 2-30 warts (wart area of 12-600 mm²) were randomized to receive either sinecatechins 15% ointment, sinecatechins 10% cream, or placebo (two placebo arms pooled for analyses). Participants were instructed to apply their respective treatments three times a day for 12 weeks and those who achieved complete clearance at the end of 12 weeks were followed for an additional 12 weeks. Rates of complete clearance of baseline warts and of all warts (baseline and new) as well as recurrence rates for sinecatechins 10% cream and vehicle are displayed in Table 1. No significant differences between sinecatechins 10% cream and placebo groups were found.

The efficacy of sinecatechins 10% ointment in the treatment of EGWs was further assessed in two identically-designed, randomized, double-blind, Phase III trials,^14,15 the pooled results were also reported.¹⁶ A total of 1,005 participants (535 men and 470 women) with 2-30 EGWs and a lesion area of 12-600 mm² were allocated in a 2:2:1 ratio to receive sinecatechins 15% ointment, sinecatechins 10% ointment or vehicle. Treatment was applied at 8-hour intervals three times a day for 16 weeks or until complete resolution of all baseline warts was observed. Complete responders were followed for an additional 12 weeks. Phase III trial results are displayed in Table 1. Rates of complete clearance of all warts in both sinecatechins ointment groups were significantly superior to vehicle (Ps<0.001). Time to complete clearance was also shorter for participants treated with sinecatechins 15% and 10% ointment than those treated with vehicle (P<0.01). Median time to complete wart clearance in the two trials was 16 weeks and 10 weeks in the sinecatechins 15% and 10% ointment groups, respectively. In all studies, recurrence rates were low and complete clearance rates were higher in women than in men.

Safety and Adverse Events

No serious adverse events (AEs) were reported in the Phase II/III study.¹³ Only two participants in the sinecatechins 10% group had AEs considered possibly or probably related to the study drug and these included hyperkeratosis and skin discoloration. A number of local skin reactions were reported, but no significant differences in severe local reactions between active treatment groups and placebo were found. AE rates were also similar between treatment groups and vehicle in the Phase III trials.¹⁶ One patient in the sinecatechins 10% group developed severe pustular vulvovaginitis, which was considered related to study drug.¹⁴ Three patients in the other Phase III trial developed moderate lymphadenitis, moderate rash, and moderate phimosis, all were considered possibly related to the study medication.¹⁵ The overall incidence of any local reaction during treatment was higher in active treatment groups than vehicle (85.9% and 82.9% vs. 60.4%).¹⁶ Incidence of most common application-site reactions are presented in Table 2. In all studies, application-site reactions declined over the study period regardless of initial intensity. It has been suggested that local reactions such as erythema are associated with the release of pro-inflammatory cytokines; thus, patients should be advised that these signs may be indicative of clinical response and are correlated with higher clearance rates.¹⁵ Sinecatechins 10% ointment is contraindicated in individuals with a history of hypersensitivity to any of its components and treatment should be discontinued if hypersensitivity occurs.

Discussion

Sinecatechins 10% ointment was the first botanical drug approved by the US FDA and is now available in Canada for the treatment of EGWs. Although provider-assisted therapies have higher efficacy rates than patient-applied therapies, they are subject to the patient’s pain tolerance and aesthetic concerns, as some can cause considerable discomfort and/or result in scarring. Provider-assisted therapies are also dependent upon the doctors’ and patients’ schedules and patients may be hesitant to comply with repeat clinic visits because of the sensitive nature of this condition. Consequently, many patients opt for more convenient treatment that can be self-administered in the privacy and comfort of their home. Efficacy rates from the Phase III trials of sinecatechins 10% ointment are higher than those achieved with podophyllotoxin 0.5% or imiquimod 5% and 3.75%. However, it is recommended that sinecatechins 10% ointment be applied three times a day in comparison to thrice weekly application with imiquimod 5% and once daily application with imiquimod 3.75%. Therefore, patient adherence to the dosing regimen may need to be considered, as compliance is an important factor in achieving treatment effectiveness. Unlike other at-home treatments, it is not necessary to wash off the ointment prior to the next application. Sinecatechins 10% ointment has lower recurrence rates relative to other patient-applied therapies and is also the first EGW treatment to possess several disease-fighting mechanisms, such as anti-inflammatory, antiviral, and antiproliferative properties. Therefore, sinecatechins 10% ointment presents a botanically based alternative to currently available treatments for EGWs that offers a satisfactory balance of clearance rates, reduced frequency of lesion recurrence after successful treatment, and favorable adverse event profile.

References

1. The Society of Obstetricians and Gynaecologists of Canada (SOGC). Incidence and prevalence of HPV in Canada [Internet]. 2007.
2. Kliewer EV, Demers AA, Elliott L, et al. Twenty-year trends in the incidence and prevalence of diagnosed anogenital warts in Canada. Sex Transm Dis. 2009 Jun;36(6):380-6.
3. Qi SZ, Wang SM, Shi JF, et al. Human papillomavirus-related psychosocial impact of patients with genital warts in China: a hospital-based crosssectional study. BMC Public Health. 2014 14:739.
4. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis. 2005 Mar 1;191(5):731-8.
5. Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003 Sep;189(3 Suppl):S3-11.
6. Vender R, Bourcier M, Bhatia N, et al. Therapeutic options for external genital warts. J Cutan Med Surg. 2013 Dec;17 Suppl 2:S61-7.
7. Lopaschuk CC. New approach to managing genital warts. Can Fam Physician. 2013 Jul;59(7):731-6.
8. Yanofsky VR, Patel RV, Goldenberg G. Genital warts: a comprehensive review. J Clin Aesthet Dermatol. 2012 Jun;5(6):25-36.
9. Medigene press release. Medigene’s drug Veregen® receives market approval in Canada [Internet]. September 10, 2013. Available at: http://www.medigene.com/presse-investoren/news/pressemitteilungen/medigenes-drug-veregen-receives-market-approval-in-canada. Accessed November 24, 2014.
10. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin- 3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011 Dec 15;82(12):1807-21.
11. Veregren® (sinecatechins) ointment 10%
    • 

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    . Paladin Labs Inc., St-Laurent, QC. Revised October 28, 2014. Available at: http://www.paladin-labs.com/our_products/Veregen-PM-En.pdf. Accessed November 24, 2014.
12. Stockfleth E, Meyer T. The use of sinecatechins (polyphenon E) ointment for treatment of external genital warts. Expert Opin Biol Ther. 2012 Jun;12(6):783-93.
13. Gross G, Meyer KG, Pres H, et al. A randomized, double-blind, four-arm parallel-group, placebo-controlled Phase II/III study to investigate the clinical efficacy of two galenic formulations of Polyphenon E in the treatment of external genital warts. J Eur Acad Dermatol Venereol. 2007 Nov;21(10):1404-12.
14. Tatti S, Swinehart JM, Thielert C, et al. Sinecatechins, a defined green tea extract, in the treatment of external anogenital warts: a randomized controlled trial. Obstet Gynecol. 2008 Jun;111(6):1371-9.
15. Stockfleth E, Beti H, Orasan R, et al. Topical Polyphenon E in the treatment of external genital and perianal warts: a randomized controlled trial. Br J Dermatol. 2008 Jun;158(6):1329-38.
16. Tatti S, Stockfleth E, Beutner KR, et al. Polyphenon E: a new treatment for external anogenital warts. Br J Dermatol. 2010 Jan;162(1):176-84.

¹Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Conflict of interest:
None reported

ABSTRACT
Minoxidil is a Health Canada and US FDA-approved medication for hair loss in men and women. While 5% minoxidil foam has been approved for men since 2006, Health Canada and the FDA only approved 5% minoxidil foam for female pattern hair loss (FPHL) in 2014. Recent Phase III clinical trials demonstrated the efficacy of once daily 5% minoxidil foam for treatment of FPHL, where a significant change from baseline in the target area hair count was observed compared to placebo. Similar changes in hair count for 5% foam and twice daily 2% minoxidil solution established noninferiority of the 5% foam formulation. Five percent minoxidil foam provides an additional option for women with FPHL and will soon be available in Canada.

Key Words:
androgenetic alopecia, AGA, female pattern hair loss, FPHL, 5% minoxidil foam, hair loss, treatment, clinical efficacy

Introduction

Female pattern hair loss (FPHL), also known as androgenetic alopecia (AGA), is one of the most common forms of alopecia in women. Onset of hair loss can occur as early as one’s 20s and affect as many as 40% of Caucasian women over the age of 70 years.^1,2 FPHL can be a source of social distress and greatly impair quality of life.³ There are a variety of treatments for FPHL including antiandrogen medications, topical treatments, laser/light devices, and hair transplantation,⁴ with choice of treatment depending on the extent of hair loss, patient health, cost, and preference. The goal of treatment is to slow hair loss and potentially increase hair growth; however, treatment is not always successful.

Until recently, the only US FDA-approved medication for women was 2% minoxidil solution, while both the 2% and 5% solutions are available for men. Minoxidil may stimulate hair growth by increasing the anagen phase of the hair cycle, but the exact mechanisms are currently unknown.⁵ In 2006, the FDA approved 5% minoxidil foam for the treatment of androgenetic alopecia in men after clinical testing showed that it increased hair growth after 48 weeks of twice daily use.^6,7 Additionally, the incidence of pruritus in men was lower with the 5% foam than the 5% solution, likely due to propylene glycol in the solution formulation.^6,7 Because of its efficacy in treating male hair loss, 5% minoxidil became a viable option for women suffering from FPHL. Clinical trial results in women suggest that 5% minoxidil foam is an effective treatment for FPHL, leading to its Health Canada and FDA approvals for this indication in 2014.⁸

Past Clinical Evidence

In Phase III clinical trials, both the 5% and 2% minoxidil formulations have demonstrated similar efficacy in promoting hair growth in women with hair thinning over the frontoparietal scalp. Lucky et al. conducted a 48-week randomized, doubleblind, placebo controlled trial that assessed target area hair count (TAHC) following twice daily application of 5% minoxidil solution, 2% minoxidil solution, or 5% solution vehicle in women with frontoparietal hair loss that could be accompanied with, or without, frontal hairline recession.⁹ Patient and investigator assessments of hair growth and scalp coverage were performed in addition to TAHC. Both the 5% and 2% minoxidil solutions showed significantly higher TAHCs compared to placebo (P < 0.001, Table 1). The investigator assessments followed the same pattern as the TAHC results; however, patient-reported assessment of hair growth was significantly greater in the 5% minoxidil solution group than the 2% minoxidil solution or vehicle groups.⁹

The efficacy of once daily application of 5% minoxidil foam against 2% minoxidil solution in the treatment of frontoparietal hair loss in women was investigated in a randomized, singleblind Phase III trial.¹⁰ Change in non-vellus hair count and width, blind evaluator and patient review of photographs, and patient assessment of product aesthetics and benefits were assessed after 24 weeks of use. Five percent minoxidil foam applied once daily was shown to be noninferior to twice daily 2% minoxidil solution, as measured by change in non-vellus hair count (Table 2) and hair width. Women in the 5% foam group agreed more strongly that treatment did not interfere with grooming routines than did women in the 2% solution group (P = 0.002).¹⁰ In separate studies, both the twice daily use of 5% minoxidil solution and once daily use of 5% minoxidil foam were shown to be noninferior compared to twice daily use of 2% minoxidil solution.

Recent Clinical Trials

Two randomized, double-blind, parallel, international multicenter Phase III trials of 5% minoxidil foam were recently completed. Both trials assessed the efficacy of once daily use of 5% minoxidil foam in female participants aged 18 years and older.^11,12 In the first trial, participants were assigned to once a day treatment with 5% minoxidil foam or vehicle foam for 24 weeks (minoxidil: n=203, vehicle: n=201).¹¹ Efficacy was assessed at weeks 12 and 24 and safety and adverse events were monitored every 6 weeks. At weeks 12 and 24, changes in TAHC from baseline were significantly higher in the minoxidil-treated group than the vehicle-treated group (P < 0.0001, Table 2). Also at 24 weeks, patient-reported assessment of scalp coverage was determined to be significantly higher with minoxidil treatment compared to vehicle (P < 0.0001).¹¹

Participants in the second trial were assigned to once a day treatment with 5% minoxidil foam or 2% minoxidil solution twice daily for 52 weeks (n=161 in each group).¹² TAHC was assessed at weeks 12, 24, and 52 and safety and adverse events were monitored regularly. The change in TAHC from baseline in the 5% minoxidil group was shown to be similar to that of the 2% topical minoxidil solution group at weeks 12 (P < 0.4158) and 24 (P = 0.9170, Table 2), as well as at week 52 (P = 0.5980).¹²

Adverse Events

Five percent minoxidil foam was well tolerated in each of the recent clinical trials. The number of participants reporting adverse events after using 5% minoxidil foam was similar to that of participants who used 2% minoxidil solution or vehicle. The most common adverse events reported in at least 2% of participants included weight gain, headache, pruritus, and nasal and upper respiratory tract infections.^11,12 These are similar to the adverse events reported previously by Lucky et al. and Blume- Peytavi et al., who also reported dermatitis, dandruff, erythema, and burning/stinging in both 5% and 2% minoxidil treatment groups.^9,10 Additionally, 5% foam may encourage greater compliance, as Blume-Peytavi et al. reported that pruritus and dandruff occurred significantly less with application of 5% foam than with the 2% solution.¹⁰

Hypertrichosis is a well-known concern among women using hair growth products. While hypertrichosis has been reported with the use of 5% minoxidil,^9,10,13 unwanted growth in sideburn areas was significantly less with 5% foam than with the 2% solution.¹⁰ Advice to women to further limit hypertrichosis includes application of the medication 2-4 hours prior to bedtime and hand washing immediately after application;⁸ however, the presence of hirsutism or hypersensitivity may increase susceptibility to unwanted hair growth that is beyond physician and patient control.^13,14

Six participants in the 5% minoxidil group reported serious adverse events (SAEs) in the placebo controlled trial (1 incidence each of cardiac disorder, gastritis, dehydration, osteoarthritis, ovarian neoplasm, uterine leiomyoma, renal failure, and hypertensive crisis) in comparison to 4 participants in the vehicle group (1 incidence each of fatigue, ovarian cancer, memory impairment, mental status changes, and PTSD; 2 incidences each of cardiac disorder and asthenia).¹¹ In the comparative trial, 2 participants treated with 5% minoxidil reported SAEs (wrist fracture and anxiety) in comparison to 8 participants in the 2% minoxidil group (1 incidence each of angina pectoris, abdominal pain, bile duct stone, anal abscess, influenza, metastatic neoplasm, menometrorrhagia, and asthma).¹² The SAEs are not considered to be clinically relevant to the drug.

Discussion

Recent clinical trials of 5% minoxidil foam for the treatment of FPHL have demonstrated it to be safe and effective, with hair growth outcomes similar to that of the traditional 2% minoxidil solution.^11,12 Phase III clinical trials demonstrated that hair growth with once daily use of 5% minoxidil foam is noninferior to twice daily use of 2% minoxidil solution in women with frontoparietal hair loss.^10,12 Patient-reported improvement in hair volume and coverage appears to be greater with 5% minoxidil foam and once daily application does not substantially interfere with grooming routines.¹⁰ Adverse events may occur with both 5% foam and 2% solution, but these rarely lead to discontinued use. Susceptibility to hypertrichosis may be individual-specific, and should be discussed with patients as a possible side-effect of minoxidil use.

It is suggested that 5% minoxidil be applied for 3-6 months before noticeable improvement can be observed.⁸ While the results of clinical trials demonstrate a statistically significant increase in the total hair count, sometimes these results may fall short of patient expectations; therefore, patients need to be informed that individual results may vary even after 6-12 months of therapy.^4,16 Recent evidence demonstrates that a sulfotransferase enzyme test can successfully identify non-responders to minoxidil.¹⁷ To our knowledge, this test is not commercially available. In addition, some patients may experience an increase in hair shedding, or at least continued hair loss, for the first few months and should be counselled accordingly.^4,16 When women experience improvement in hair growth, continued treatment is required or else improvement will likely be lost and hair loss will revert back to its natural course.^4,18

Five percent minoxidil foam, applied only once daily, has the potential for milder side effects, improved compliance, and greater patient satisfaction with treatment. Indeed, the use of minoxidil as a treatment for FPHL has been shown to improve women’s quality of life.³ Additionally, 5% minoxidil foam provides an alternative option for women who do not wish to use, or who are unable to use, oral anti-androgen or hormonal contraceptive medications as hair loss treatments. The recent approval and availability of 5% minoxidil foam in Canada provides a safe and effective treatment for women with FPHL.

References

1. Blumeyer A, Tosti A, Messenger A, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men. J Dtsch Dermatol Ges. 2011 Oct;9 Suppl 6:S1-57.
2. Norwood OT. Incidence of female androgenetic alopecia (female pattern alopecia). Dermatol Surg. 2001 Jan;27(1):53-4.
3. Zhuang XS, Zheng YY, Xu JJ, et al. Quality of life in women with female pattern hair loss and the impact of topical minoxidil treatment on quality of life in these patients. Exp Ther Med. 2013 Aug;6(2):542-6.
4. Herskovitz I, Tosti A. Female pattern hair loss. Int J Endocrinol Metab. 2013 Oct;11(4):e9860.
5. Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004 Feb;150(2):186-94.
6. Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2002 Sep;47(3):377-85.
7. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebocontrolled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007 Nov;57(5):767-74.
8. Drugs@FDA: FDA Approved Drug Products. Women’s rogaine 5% minoxidil topical aerosol, approval history and label. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed September 1, 2014.
9. Lucky AW, Piacquadio DJ, Ditre CM, et al. A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004 Apr;50(4):541-53.
10. Blume-Peytavi U, Hillmann K, Dietz E, et al. A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. J Am Acad Dermatol. 2011 Dec;65(6):1126-34 e2.
11. Johnson & Johnson Consumer and Personal Products Worldwide. A phase 3 multi-center parallel design clinical trial to compare the efficacy and safety of 5% minoxidil foam vs. vehicle in females for the treatment of female pattern hair loss (androgenetic alopecia). In: ClinicalTrials.gov, Identifier: NCT01226459. Last updated June 3, 2014. Available at: http://clinicaltrials.gov/ct2/show/results/NCT01226459?term=minoxidil&sect=X4301256#othr. Accessed September 1, 2014.
12. Johnson & Johnson Consumer and Personal Products Worldwide. A phase 3 multi-center parallel design clinical trial to compare the efficacy and safety of 5% minoxidil foam vs. 2% minoxidil solution in females for the treatment of female pattern hair loss – androgenetic alopecia. In: ClinicalTrials.gov, Identified: NCT01145625. Last updated May 19, 2014. Available at: http:// clinicaltrials.gov/ct2/show/study/NCT01145625?term=minoxidil&sect=X430126. Accessed September 1, 2014.
13. Dawber RP, Rundegren J. Hypertrichosis in females applying minoxidil topical solution and in normal controls. J Eur Acad Dermatol Venereol. 2003 May;17(3):271-5.
14. Peluso AM, Misciali C, Vincenzi C, et al. Diffuse hypertrichosis during treatment with 5% topical minoxidil. Br J Dermatol. 1997 Jan;136(1):118-20.
15. Hillmann K, Geburtsort K. Results of an investigator-initiated, two-armed, randomized, controlled clinical trial to proof efficacy of a 5% minoxidil topical foam once daily versus a 2% minoxidil solution twice daily on hair volume in women with mild to moderate androgenetic alopecia. Free University of Berlin; 2013. Available at: http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000095104. Accessed September 1, 2014.
16. Levy LL, Emer JJ. Female pattern alopecia: current perspectives. Int J Womens Health. 2013;5:541-56.
17. Goren A, Shapiro J, Roberts J, et al. Clinical utility and validity of minoxidil response testing in androgenetic alopecia. Dermatol Ther. 2014 Aug 12. [Epub ahead of print]
18. Rogers NE. Medical therapy for female pattern hair loss (FPHL). Hair Transpl Forum Int. 2014;24(3):81,86-8.

¹Department of Medicine, University of Toronto, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada

Introduction

Onychomycosis is a common nail disorder for which successful treatment can be clinically challenging. The prevalence of onychomycosis is estimated at 2-8% of the global population. A number of medical conditions can also increase the risk of co-morbid onychomycosis infection including diabetes, peripheral vascular disease, HIV, immunosupression, obesity, smoking, and increased age.^1-5 Onychomycosis has traditionally been treated by oral and topical antifungals that often yield low to moderate efficacy.⁶ Even when pharmacotherapy initially results in a mycological cure, the relapse and/or reinfection rate ranges between 16-25%.^7-8 Efinaconazole, a sterol 14α-demethylase inhibitor, is an emerging antifungal therapy for the topical treatment of onychomycosis, which has shown greater efficacy in vitro than terbinafine, itraconazole, ciclopirox and amorolfine against dermatophytes, yeasts and non-dermatophyte molds.⁹ Further, it may be a useful adjunct to oral and device-based therapies, during the main course of treatment, and as a subsequent maintenance therapy to prevent reinfection.

Background

• Onychomycosis is a fungal infection of the nail apparatus.¹⁰ It is primarily caused by dermatophytes, yeasts and non-dermatophyte molds.
• Keratinolytic dermatophytes infect and colonize the nail plate, bed, and matrix.¹¹ This may cause symptoms such as onycholysis, discoloration, and thickening of the nail plate.¹¹
• Onychomycosis needs to be treated for both cosmetic and medical purposes. Left untreated, the infection can spread to other nails and potentially cause further complications, especially in at-risk populations like diabetics and the immunosuppressed.^2,12
• The treatment of onychomycosis poses a number of challenges due to the nail plate’s lack of intrinsic immune function and the poor accessibility of drugs into the nail plate.
• The current gold standard therapy for onychomycosis is oral antifungals because their systemic distribution allows them to penetrate the nail apparatus and to a certain extent, the nail plate via the circulatory system.¹³
• Problematically, all of the oral drugs suffer from a potential for systemic adverse events and drug interactions.¹⁴
• This potential for negative side effects and drug interactions is often higher in the very populations who are at the greatest risk for onychomycosis, such as diabetics and the immunosuppressed; however, these individuals are the most susceptible to health complications if left untreated.
• Existing topical antifungals are not associated with adverse events to the same extent as oral therapy, as they rarely penetrate the systemic circulation and gain a significant concentration in the body.
• The topical antifungals available in the past were less widely used because their poor penetrance into the nail plate results in correspondingly poor mycological and complete cure rates.¹⁵
• The ideal topical antifungal would have a higher nail plate penetrance than existing drugs but maintain the advantage of minimal systemic uptake.^15,16

Diagnosis of Onychomycosis Caused by Dermatophytes

• • Diagnosing onychomycosis on clinical grounds alone is challenging; therefore, correlation with mycological evidence remains critical for an accurate diagnosis.¹⁷
  • Definitive laboratory criteria include positive microscopic evidence of septate hyphae and/or arthroconidia (KOH preparation, Calcofluor white, Sigma-Aldrich, St Louis, Mo), periodic acid Schiff, and/or biopsy, and positive fungal culture findings for dermatophytes (Trichophyton, Epidermophyton, or Microsporum species) or certain nondermatophyte nail pathogens (eg, Scytalidium dimidiatum and S hyalinum).¹⁷
  • The primary criteria for clinical diagnosis are:¹⁷
    • White/yellow or orange/brown patches or streaks
  • Secondary criteria are*
    • Onycholysis
    • Subungual hyperkeratosis/debris
    • Nail-plate thickening

* Tinea pedis often occurs concomitantly with pedal onychomycosis, and tinea manuum with infected fingernails.

• Laboratory diagnostic criteria are:¹⁷
  • Positive microscopic evidence
  • Positive culture of dermatophyte
• If onychomycosis is suggested based on clinical observation, diagnostic laboratory tests should be performed. If these produce negative findings, they should be repeated.

Treatment

• The primary aim of treatment is to eradicate the organism as evidenced on microscopy and culture.¹⁸

Oral Therapies Approved in Canada

• There are two oral therapies currently approved for use in Canada:
  1. Terbinafine 250mg/day for 12 weeks
  2. Itraconazole pulse therapy: for dermatophyte onychomycosis
     • 1 pulse = 200mg twice daily for 1 week on, 3 weeks off.
     • 3 pulses are standard for toenail onychomycosis.
• Oral therapies provide access to the nail bed and matrix of all toes; both terbinafine and itraconazole may persist in nails for long periods after treatment.
• Oral therapy can also treat concomitant skin infections such as tinea pedis.
• Current prescribing information should be consulted for contraindications and monitoring requirements.
• Liver function testing should be done prior to therapy, and periodically during therapy.

Topical Therapies Approved in Canada

• Ciclopirox nail lacquer 8%, once daily for 48 weeks.¹⁰
• Adverse events are few, with mild localized reactions at the application site.
• It may not provide adequate penetration where nails are thick or severe onycholysis is present.
• Efinaconazole 10% topical triazole antifungal was approved by Health Canada in October 2013.

Efinaconazole, A New Topic Antifungal

• Efinaconazole is a topical triazole antifungal developed specifically for the topical treatment of distal and lateral subungual onychomycosis (DLSO).¹⁹
• Efinaconazole expands on the success of the existing triazole antifungals, while being intentionally formulated to more effectively penetrate the nail plate.²⁰
• Additionally, because it is a solution, there is no product build-up and removal time.

In Vitro Efficacy

• Efinaconazole is an inhibitor of sterol 14α-demethylase (14-DM).²¹
• In broth dilution tests in vitro against reference strains, efinaconazole was more potent than terbinafine, ciclopirox, itraconazole and amorolfine.⁹
• The efficacy of efinaconazole was comparable in clinical isolates of T. mentagrophytes and T. rubrum from Canada, the USA and Japan.
• The high in vitro efficacy of efinaconazole against the reference strains suggests that the agent would be effective in onychomycosis should the formulation provide sufficient nail penetrance.

Clinical Efficacy

• A randomized, parallel-group, double-blind, vehicle-controlled, Phase II clinical trial of efinaconazole was conducted at 11 sites in Mexico.²² This initial trial compared the use of 10% solution, 5% solution and 10% solution with semi-occlusion in a 2:2:2:1 ratio with placebo. The treatment period was 36 weeks with a 4 week wash-out period prior to the evaluation of the outcome measures.
• The efficacy variables reported were mycological cure, complete cure, clinical efficacy, and effective treatment (Table 1). Efinaconazole 10% solution without semi-occlusion was the most effective treatment for all outcomes measured.
• Recently, two parallel, double-blind, randomized, controlled, Phase III trials of efinaconazole 10% nail solution (ENS) were completed.¹⁹ Trial participants applied ENS daily for 48 weeks followed by a 4-week wash-out period. Trial outcome measures were evaluated at week 52. Results demonstrated that ENS was superior to vehicle for all outcome measures. The primary outcome measure, complete cure for efinaconazole, was 17.8% and 15.2% respectively in the two parallel studies.
• The mycological cure rates were 55.2% and 53.4% respectively. Table 1 shows a comparison of the mycological cure rates for efinaconazole, itraconazole, terbinafine and ciclopirox.^22-24 The mycological and complete cure rates for efinaconazole were comparable to oral itraconazole.

Safety and Adverse Events

• In Phase II, 76.9% of the ENS group experienced treatment associated adverse events (TEAEs) compared with 63.6% of vehicle.²²
• The main TEAEs associated with efinaconazole were blisters, contact dermatitis, erythema and ingrown nail, none of which resulted in study discontinuation.
• In the duplicate Phase III studies, the reporting rates for a single adverse event during treatment with efinaconazole were comparable to vehicle (S1: 66.0% vs. 61.0%; S2: 64.5% vs. 58.5%).²⁰
• The reported primary TEAEs were application site dermatitis and vesicles; however, the rates for localized skin reactions were comparable to vehicle.
• Discontinuation as a result of TEAEs was low, with 3.2% and 1.9% vs. 0.5% and 0% of participants in the efinaconazole and vehicle groups respectively.
• Overall, efinaconazole showed low rates of treatment emergent adverse events.

Other Therapies

• Mechanical or chemical debridement lessens the burden of infection and may benefit any degree of onychomycosis; it can be performed in office, or by other healthcare professionals.

Combination Therapy

• Dual therapies: oral/topical, oral/debridement, or topical/ debridement.²⁶
• Triple therapies: oral/topical/debridement: Oral therapy combined with topical therapy can provide penetration of the nail plate from inside and out, which may increase the overall amount of antifungal medication reaching the infection, particularly where the nail is thickened, shows extensive onycholysis, has lateral or matrix involvement, or is a dermatophytoma.²⁶
• Debridement may increase access to the infection by topical medications.

Clinical Variables Affecting Treatment and Outcomes

Nail Disease Variables

• Number of nails affected
• Percentage of affected nail plate area
• Is it DLSO or another presentation?
• Infection confirmed as dermatophyte? (i.e., Trichophyton sp., Microsporum sp., or Epidermophyton sp.)
• Thickness of nails
• Is matrix (proximal nail fold) area involved in infection?
• Are lateral streaks or central spikes (dermatophytoma) present?

Patient Variables

• Presence of peripheral vascular disease
• Diabetes
• Age of patient
• Obesity
• Other co-morbid conditions, e.g., liver disease
• Oral drugs patient is using
• Compliance
• Drug insurance status
• Patient preference

Criteria for Onychomycosis Mycological and Complete Cures

• Criteria for a mycological cure are eradication of the fungus as confirmed by negative fungal culture and negative KOH examination.²⁷
• Criteria for a complete cure are mycological cure plus complete clearance.²⁸

Factors Affecting Treatment Failure and Recurrence29

• Poor adherence
• Poor absorption
• Immunosuppression
• Dermatophyte resistance
• Zero nail growth
• Concomitant disease
• Age >60 years
• Trauma/faulty biomechanics
• Moisture exposure
• Poor patient hygiene/footwear

Recurrence

• Patient education on recurrence is recommended, specifically:³⁰
  • One course of treatment may not produce the optimum results.
  • May require multiple courses of antifungals.
• Recurrence of onychomycosis is very common.
• If the patient experiences any signs of onychomycosis recurrence or tinea pedis, they should be treated immediately.
• Proper foot care may minimize the chance of recurrence.
• Due to the high rate of recurrence and relapse, even in completely cured individuals, long-term topical therapy is often recommended concurrently or following oral therapy.^7,8,31

Foot Care & Maintenance³²

• Wear footwear and cotton socks that minimize humidity.
• Replace or sanitize shoes and socks as they can be contaminated with the microorganism.
• Dry feet and interdigital spaces thoroughly after washing.
• Use footwear to avoid fungal transmission from shared public spaces such as swimming pools.
• Keep nails clean and cut short.
• Avoid sharing nail clippers or footwear.
• Bring their own nail clippers, files, and emery boards to the salon.
• Prevent further trauma to toenails (nonrestrictive footwear or orthotics).
• Wear rubber gloves with cotton liners to protect the fingernails in those persons who have hands immersed in water for long periods of time.
• Apply emollients on cracked skin to reduce further entry points for fungus.
• Control chronic health conditions such as diabetes mellitus or peripheral vascular disease.

Table 2: Simple treatment algorithm for dermatophyte toenail onychomycosis

Conclusion

Efinaconazole 10% solution is a significant advancement in the efficacy of topical therapy for onychomycosis. It has demonstrated good tolerability and as such, the increase in efficacy is not met with the increase in complications observed with oral drugs. The safety profile for participants treated with efinaconazole is good, with minimal and transient TEAEs that ceased upon conclusion of treatment and minimal contact sensitization. Used either as monotherapy or in addition to device-based or oral therapy, it offers a promising addition to the clinical management of onychomycosis.

References

1. Gupta AK, Gupta MA, Summerbell RC, et al. J Eur Acad Dermatol Venereol. 2000;
   14:466-469.
2. Gupta AK, Taborda P, Taborda V, et al. Int J Dermatol. 2000;39:746-753.
3. Gulec AT, Demirbilek M, Seckin D, et al. J Am Acad Dermatol. 2003;49:187-192.
4. Baran R. Clin Dermatol. 2011;29:54-60.
5. Döner N, Yasar S, Ekmekçi TR. Turk Derm. 2011;45:146-151.
6. Gupta AK, Uro M, Cooper EA. J Drug Dermatol. 2010;9:1109-1113.
7. Scher RK, Baran R. Br. J. Dermatol. 2003;149 Suppl 65:5- 9.
8. Tosti A, Piraccini BM, Stinchi C, et al. Dermatology (Basel). 1998;197:162-166.
9. Jo Siu WJ, Tatsumi Y, Senda H, et al. Antimicrob. Agents Chemother. 2013;[Epub ahead of print].
10. Zaias N. Onychomycosis. Arch Dermatol. 1972;105:263-274.
11. Welsh O, Vera-Cabrera L, Welsh E. Clin. Dermatol. 2010;28:151-159.
12. Gupta AK, Humke S. Eur J Dermatol. 2000;10:379-384.
13. Gupta AK, Paquet M, Simpson F, et al. Journal of the European Academy of Dermatology and Venereology: JEADV. 2013;27:267-272.
14. Shear N, Drake L, Gupta AK, et al. Dermatology. 2000;201:196-203.
15. Murdan S. Expert Opin Drug Deliv. 2007;4:453-455.
16. Murdan S. Expert Opin Drug Deliv. 2008;5:1267-1282.
17. Scher RK, Tavakkol A, Sigurgeirsson B, et al. J Am Acad Dermatol 2007;56:939-944.
18. Roberts DT, Taylor WD, Boyle J. Brit J. Dermatol, 2003; 148: 402-410
19. Elewski BE, Rich P, Pollak R, et al. J Am Acad Dermatol. 2012;[Epub ahead of print].
20. Suguira K, Sugimoto N, Hosaka S, et al. Antimicrob Agents Chemother. 2014;58: 3837-3842
21. Tatsumi Y, Nagashima M, Shibanushi T, et al. Antimicrob. Agents Chemother. 2013; 57:2405.
22. Tschen EH, Bucko AD, Oizumi N, et al. J Drugs Dermatol. 2013;12:186-192.
23. Janssen Pharma. SPORANOX® (itraconazole) Capsules. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020083s048s049s050lbl.pdf.
24. Novartis. LAMISIL (terbinafine hydrochloride) Tablets, 250 mg. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020539s021lbl.pdf. Accessed March 15, 2013.
25. Valeant. Penlac® Nail Lacquer (ciclopirox) Topical Solution, 8%. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21022s004lbl.pdf. Accessed March 15, 2013.
26. Gupta AK, Lynch LE. Cutis. 2004;74(1 Suppl):5-9.
27. Gupta MA. Gupta AK. Intl J of Derm. 2003;4:833-842
28. CRC Press. Onychomycosis: The Current Approach to Diagnosis and Therapy: Baran R, Hay R, Haneke E, Tosti A. 1999. 0000415385792: 405.
29. Westerberg DP, Voyack MJ. Am Fam Physician. 2013;88:771-772.
30. Pariser D, Scher RK, Elewski B, et al. Semin Cutan Med Surg. 2013;32(2 Suppl 1):S13-14
31. Arrese JE, Piérard GE. Dermatology. 2003;207:255-260.
32. Miller P. Skin Disorders: Fungal Nail Infections. Available at: https://www.etherapeutics.ca/ Accessed June 10 2014.