Evaluation of the Efficacy and Safety of Tavaborole Topical Solution, 5%, In

Journal of Dermatological Treatment

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Evaluation of the efficacy and safety of tavaborole topical solution, 5%, in the treatment of onychomycosis of the toenail in adults: a pooled analysis of an 8-week, post-study follow-up from two randomized phase 3 studies

Aditya K. Gupta, Steve Hall, Lee T. Zane, Shari R. Lipner & Phoebe Rich

To cite this article: Aditya K. Gupta, Steve Hall, Lee T. Zane, Shari R. Lipner & Phoebe Rich (2017): Evaluation of the efficacy and safety of tavaborole topical solution, 5%, in the treatment of onychomycosis of the toenail in adults: a pooled analysis of an 8-week, post-study follow-up from two randomized phase 3 studies, Journal of Dermatological Treatment, DOI: 10.1080/09546634.2017.1329510 To link to this article: http://dx.doi.org/10.1080/09546634.2017.1329510

Accepted author version posted online: 18 May 2017. Published online: 30 May 2017.

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Download by: [Oregon Health & Science University Library] Date: 27 September 2017, At: 13:42 JOURNAL OF DERMATOLOGICAL TREATMENT, 2017 https://doi.org/10.1080/09546634.2017.1329510

ORIGINAL ARTICLE Evaluation of the efficacy and safety of tavaborole topical solution, 5%, in the treatment of onychomycosis of the toenail in adults: a pooled analysis of an 8-week, post-study follow-up from two randomized phase 3 studies

Aditya K. Guptaa,b, Steve Hallc, Lee T. Zaned, Shari R. Lipnere and Phoebe Richf aDepartment of Medicine, University of Toronto, Toronto, Canada; bMediprobe Research Inc., London, Canada; cMedical Affairs, Sandoz Pharmaceuticals Inc., Princeton, NJ, USA; dAnacor Pharmaceuticals Inc., Palo Alto, CA, USA; eDepartment of Dermatology, Weill Cornell Medicine, New York, NY, USA; fOregon Dermatology and Research, Portland, OR, USA

ABSTRACT ARTICLE HISTORY Purpose: The role of topical antifungal agents in the long-term management of toenail onychomycosis is Received 13 March 2017 not well established. The current study evaluated durability of clinical benefit of tavaborole topical solu- Accepted 17 March 2017 tion, 5%, for the treatment of toenail onychomycosis. Methods: We conducted a pooled analysis of 8-week, post-study follow-up (PSFU) data from two phase 3, KEYWORDS randomized controlled trials in a subset of patients who experienced complete or almost clear nail (CN) at Antifungal agents; AN-2690; the end of treatment (week 52); 48 weeks of treatment with once-daily tavaborole compared with placebo long-term follow-up; in adults with distal subungual onychomycosis was evaluated at week 60. Complete cure (completely CN tavaborole; tinea unguium plus negative mycology) of the target great toenail and treatment success (<10% nail involvement plus negative mycology) were evaluated at week 52 versus week 60. Results: Of the 62 patients who completed the PSFU, complete cure was higher in the tavaborole-treated group versus the vehicle control group (28.6% vs. 7.7%). Additionally, treatment success was 53.1% for the tavaborole group versus 23.1% in the vehicle group. Small sample size entering the PSFU limited robust statistical analysis. Conclusion: Tavaborole topical solution, 5%, appears to provide durable clinical benefit, making it an attractive long-term treatment option for dermatophyte-associated onychomycosis of the toenail.

Introduction epidermal necrolysis, Stevens–Johnson syndrome) that warrant monitoring, particularly in children, the elderly, patients with liver The overall incidence of onychomycosis in North America is disease and immunocompromised individuals (6,13,14). In 2014, approximately 14% (1), increasing in prevalence with advancing the US Food and Drug Administration (FDA) approved two topical age; it affects 28–40% of individuals aged >60 years (2). antifungal solutions, efinaconazole and tavaborole, for the treat- Onychomycosis is primarily caused by dermatophytes in temper- ate climates, with Trichophyton rubrum and Trichophyton menta- ment of toenail onychomycosis caused by T. rubrum and T. menta- grophytes being the predominant causative pathogens (3,4). grophytes (16,17). However, their role in the long-term Although onychomycosis may be asymptomatic, progressive management of toenail onychomycosis has not been well destruction and deformity of the toenails and fingernails may established. occur if the condition is left untreated (5). This can result in dis- Tavaborole topical solution, 5% (developed by Anacor comfort and/or pain (6), impairment or loss of tactile function (7), Pharmaceuticals Inc., Palo Alto, CA; marketed by PharmaDerm a impaired foot mobility (8) and reduced quality of life (7–10). Division of Fougera Pharmaceuticals Inc., Princeton, NJ), is a novel, Downloaded by [Oregon Health & Science University Library] at 13:42 27 September 2017 Furthermore, treatment failure and recurrences are common boron-based medication that inhibits fungal protein synthesis (17). (11,12). Risk factors such as age, gender, lifestyle and comorbid- Two phase 3 clinical trials evaluated the efficacy and safety of ities (e.g. diabetes, psoriasis, immunodeficiency) increase the likeli- tavaborole for the treatment of distal subungual onychomycosis hood of disease recurrence. The burden of onychomycosis (18). Tavaborole demonstrated a favorable benefit-risk profile after highlights the importance of effective long-term management 52 weeks, with significantly higher complete cure rates (6–9%) and strategies to prevent and treat infection or recurrence of infection. higher rates of completely clear nail (CN) or almost CN (<10% nail Current treatment options for onychomycosis include oral and involvement) plus negative mycology (15–18%) compared with topical antifungals, adjunctive treatments (i.e. nail filing, trimming, vehicle control (18). Both studies were amended to include add- curettage or debridement), mechanical interventions (e.g. chemical itional 8-week, post-study follow-up (PSFU) assessments in a sub- or surgical nail avulsion), and laser and light therapies (6). Oral set of patients. The objective of this week-60 extension phase was antifungal therapies, such as terbinafine and itraconazole, provide to assess the durability of clinical benefit after 48 weeks of treat- higher complete cure rates (38–14%) than topical treatments ment with tavaborole in patients with distal subungual toenail (5–18%) (13–17), but are associated with several safety concerns onychomycosis. The durability of clinical benefit was summarized (e.g. hepatotoxicity, clinically significant drug interactions, toxic for the subset of patients who participated in the PSFU, and was

CONTACT Aditya K. Gupta [email protected] Mediprobe Research Inc., 645 Windermere Road, London, ON, N5X 2P1, Canada ß 2017 Informa UK Limited, trading as Taylor & Francis Group 2 A. K. GUPTA ET AL.

defined as the complete cure rate at week 52 versus week 60, and Efficacy outcomes the treatment success outcome at week 52 versus week 60. The efficacy outcomes at 52 weeks of both studies have been described in detail (18). Patients eligible for PSFU were assessed at Methods week 60 for durability of clinical benefit, which included evaluation of the primary endpoint: complete cure of the TGT at week Patients and study treatments 52 versus week 60. Treatment success at week 52 versus week 60 Patient eligibility criteria have been described in detail (18). was also evaluated. Negative mycology (defined as negative KOH Briefly, adult patients (aged 18 years) with distal subungual toe- wet mount and negative fungal culture) was also evaluated at nail onychomycosis involving 20–60% of one or more target great week 60. The clinical characteristics of the nail from the end of toenails (TGTs) were eligible for inclusion if they had a positive treatment (week 48) through week 60 were also assessed. potassium hydroxide (KOH) wet mount and positive fungal culture Complete cure was defined as completely CN and negative for dermatophytes. Major exclusion criteria included conditions mycology of the TGT. Treatment success was defined as com- affecting the TGT (e.g. proximal subungual onychomycosis, super- pletely or almost (<10%) CN and negative mycology of the TGT. ficially white onychomycosis, infection/coinfection with a nonder- matophyte fungus), anatomic abnormalities of the toe(s) or toenail(s) to be treated, chronic moccasin-type tinea pedis, active Safety interdigital tinea pedis or exclusively plantar tinea pedis, and the Safety assessments were conducted at each visit, as was a physical concurrent use of topical/systemic antifungals, anti-inflammatory, examination evaluating the frequency and severity of application- corticosteroid, or immunomodulatory agents applied to the toes, site reactions (ASRs): burning/stinging, induration/edema, oozing/ toenails or feet. crusting, pruritus, erythema and scaling. Adverse events (AEs), Study treatments included tavaborole topical solution, 5%, or treatment-emergent AEs, serious AEs and vital signs were moni- vehicle control, which was self-administered by patients once daily tored throughout the study, including the PSFU period. Disease- for 48 weeks. Patients were instructed to apply the study treat- focused physical examination and assessment of ASRs were con- ment on, under and around infected TGTs and infected nontarget ducted during the PSFU period. Digital photographs were also toenails in a thin, even layer after bathing and preferably just taken of local areas affected by ASRs. AEs were classified using prior to sleep. the Medical Dictionary for Regulatory Activities version 13.1.

Study design Statistical analysis The two phase 3, multicenter, randomized, double-blind, vehicle- Details on the statistical analysis of the main 52-week portions of controlled, parallel-group trials were identical in design. Study 1 both studies have been previously described (18). The current (NCT01270971) was conducted between December 2010 and analysis was based on both studies’ PSFU data, which were November 2012 at 27 sites across the USA and Mexico. Study 2 pooled into a single dataset. The PSFU population was defined as (NCT01302119) was conducted at 32 sites across the USA and all patients in the intention-to-treat population who had not Canada from February 2011 to January 2013. In both studies, eli- already completed the week-52 visit at the time of the amend- gible patients participated for a minimum of 52 weeks, which ment, who had almost CN or completely CN at week 48, and who comprised a 4- to 10-week screening period, a 48-week treatment completed the week-60 visit. Descriptive statistics were presented period and a 4-week post-treatment follow-up period (week 52). for each pooled treatment group for the PSFU population; cat- Eligible patients were randomly assigned 2:1 in blocks of six to egorical variables were tabulated with frequencies and percen- receive either tavaborole or vehicle control and were stratified by tages, and continuous variables were tabulated with mean, investigational site. Treatment assignment was accomplished by median, standard deviation, minimum and maximum. No imputa- an interactive web-randomization system in a double-blind fash- tions were made for missing data. No statistical tests were con- ion. Nail debridement was not permitted. ducted due to a lack of power. In September 2012, a protocol amendment was implemented for both studies to assess durability of clinical benefit, which allowed patients with completely CN and negative mycology (i.e. Results no clinical evidence of onychomycosis based on a normal toenail Patients Downloaded by [Oregon Health & Science University Library] at 13:42 27 September 2017 plate, no onycholysis and no subungual hyperkeratosis) or almost CN and negative mycology (i.e. no more than minimal evidence of The disposition of patients (Study 1, N ¼ 20; Study 2, N ¼ 42) who onychomycosis based on a toenail plate that was dystrophic or entered the PSFU phase and completed the week-60 visit is discolored on 10% of the distal aspect, with minimally evident depicted in Figure 1. Demographic and clinical characteristics of onycholysis and subungual hyperkeratosis) at week 48 to be fol- the pooled PSFU populations from both studies were comparable lowed for an additional 8-week PSFU period (weeks 52–60). between the two treatment groups (Table 1). The majority of Determination of durability of clinical benefit was not adequately patients were male (80.6%), were white (85.5%) and lived in the powered to show statistical significance, and only descriptive USA (85.5%). The average patient age was 55.6 years. results are presented. Both studies were conducted in accordance with the ethical Efficacy principles originating in the Declaration of Helsinki, and they com- plied with the principles of Good Clinical Practice and all applic- The pooled results of durability of clinical benefit during the PFSU able regulatory requirements. Study protocols (AN2690-ONYC-301 period are presented in Figure 2. Of the 49 patients who were ran- and AN2690-ONYC-302) were approved by an institutional review domly assigned to tavaborole and entered the PSFU period, 13 board/independent ethics committee at each site, and all patients (26.5%) presented with complete cure at week 52. Additionally, provided written informed consent. 28.6% presented with complete cure at week 60 (16.3% presented JOURNAL OF DERMATOLOGICAL TREATMENT 3

Figure 1. Patient dispositions of two phase 3 studies comparing tavaborole topical solution, 5%, and vehicle control in patients with toenail onychomycosis. PSFU: post-study follow-up.

Table 1. Demographics and baseline characteristics of pooled data from Study patients in the vehicle group (46.2% and 30.8%, respectively). 1 and Study 2 (PSFU population). Figure 3 depicts cases of complete cure and treatment success Tavaborole Vehicle during the PSFU period. Characteristic n ¼ 49 n ¼ 13 The occurrence of AEs during the PSFU period is summarized Age, years in Table 3. Overall, there was a low incidence of AEs after week Mean (SD) 54.6 (10.2) 59.6 (8.5) 52 (i.e. weeks 52–60), with four (8.2%) and two (15.4%) patients – – Range 34.0 73.0 41.0 75.0 reporting AEs in the tavaborole and vehicle groups, respectively. Gender, n (%) Male 38 (77.6) 12 (92.3) The only AE that occurred in more than one patient was hyper- Female 11 (22.4) 1 (7.7) tension, which was reported in two (4.1%) patients in the tavabor- Race, n (%) ole group and one (7.7%) patient in the vehicle group. There were White 42 (85.7) 11 (84.6) no serious AEs reported during this period, with all AEs being Black 3 (6.1) 1 (7.7) American Indian/Alaskan Native 0 1 (7.7) mild to moderate in severity; no AE was considered to be related Asian 2 (4.1) 0 to study treatment. Similarly, no ASRs were reported during the Native Hawaiian/Pacific Islander 1 (2.0) 0 PSFU period. No significant changes in vital signs were observed Other 1 (2.0) 0 from weeks 52 to 60 in either treatment group. Country, n (%) USA 42 (85.7) 11 (84.6) Canada 7 (14.3) 2 (15.4) Discussion Number of affecteda nontarget toenails Mean (SD) 3.0 (2.7) 3.2 (3.1) This extended follow-up of two phase 3 trials demonstrated the Range 0–9.0 0–9.0 Proportion of completely clear or almost clear toenailsb efficacy and safety of 48-week treatment with once-daily tavabor- Mean (SD) 0.67 (0.31) 0.61 (0.34) ole topical solution, 5%. In the tavaborole group, a complete cure Range 0.0–1.0 0.0–1.0 (completely CN with negative mycology) occurred in 28.6% of SD: standard deviation. patients compared with 7.7% in the vehicle group. Treatment suc- a>10% affected. cess (<10% clinical nail plate involvement plus negative mycology) Excluding TGT. was observed in 53.1% of patients treated with tavaborole compared with 23.1% in the vehicle group. In the tavaborole group, a withacompletecureatweeks52and60and12.2%improvedto complete cure or treatment success was maintained at week 60 in complete cure at week 60), while 71.4% failed to obtain complete a substantial proportion of patients (46.9%) who had a complete cure at week 60 (10.2% had a complete cure at week 52 but not cure or treatment success at week 52. Furthermore, complete cure

Downloaded by [Oregon Health & Science University Library] at 13:42 27 September 2017 week 60 and 61.2% did not have a complete cure at weeks 52 or and treatment success was observed in 12.2% and 6.1% of patients 60). In contrast, only one patient (7.7%) in the vehicle group had a in the tavaborole group at week 60 who did not have these out- complete cure at week 60, with the majority of vehicle-treated comes at week 52. From a clinician perspective, more than half of patients (84.6%) without a complete cure at either week 52 or 60. At the patients in the tavaborole group (53.1%) had a clinical out- week 60, a large proportion of patients (53.1%) in the tavaborole come that would have been acceptable to the patient. group had treatment success (46.9% had treatment success at weeks Thus far, oral antifungal therapy has been justified over topical 52 and 60, while 6.1% improved to treatment success at week 60). therapy on the basis of efficacy. Itraconazole and terbinafine have Fewer patients in the vehicle group (23.1%) had treatment success complete cure rates of 14% and 30%, respectively, at week 48; the at week 60 (7.7% had treatment success at weeks 52 and 60, while corresponding mycological cure rates are 54% and 70%. While the 15.4% improved to treatment success at week 60) (Figure 2). cure results are not directly comparable with those of other thera- Negative mycology at week 60 was numerically greater for pies, tavaborole demonstrated efficacy rates of 28.6% and 53.1% patients receiving tavaborole (Table 2). Overall, 53.1% of patients at week 60 for complete cure and mycological cure, respectively. in the tavaborole group achieved negative mycology compared An ex vivo study evaluated the ability of tavaborole to pene- with 23.1% of patients in the vehicle group. Additionally, numeric- trate the nail achieved high levels of the 7.5% solution in the nail ally more patients in the tavaborole group achieved negative KOH plate and therapeutic levels were retained for at least 12 weeks or culture results (69.4% and 65.3%, respectively) compared with (19). Previous studies also demonstrated that tavaborole, 5%, 4 A. K. GUPTA ET AL.

Figure 2. Durability of clinical benefit during the PSFU period as assessed by the achievement of complete cure (Panel A) and treatment success (Panel B): pooled data from Study 1 and Study 2. Completely CN plus negative mycology; †Completely or almost CN plus negative mycology.

Table 2. Summary of the mycology results at week 60: pooled data from Study Table 3. Summary of adverse eventsa during the PSFU periodb: pooled data 1 and Study 2. from Study 1 and Study 2. Tavaborole Vehicle Tavaborole Vehicle n ¼ 49 n ¼ 13 n (%) n ¼ 49 n ¼ 13 n n End point (%) (%) Patients with 1 AE 4 (8.2) 2 (15.4) Negative mycologya 26 (53.1) 3 (23.1) Preferred term Negative KOH of TGT 34 (69.4) 6 (46.2) Hypertension 2 (4.1) 1 (7.7) Negative culture of TGT 32 (65.3) 4 (30.8) Headache 1 (2.0) 1 (7.7) KOH: potassium hydroxide; TGT: target great toenail. Dizziness 1 (2.0) 0 aNegative mycology was defined as negative KOH wet mount and negative fun- Dyspnea 1 (2.0) 0 gal culture. Influenza-like illness 1 (2.0) 0 Nasopharyngitis 1 (2.0) 0 Angina pectoris 1 (2.0) 0 Palpitations 1 (2.0) 0 Ecchymosis 1 (2.0) 0 AE: adverse event. aClassified using the Medical Dictionary for Regulatory Activities version 13.1. bDefined as post-week 52.

The incidence of AEs reported in both the tavaborole and vehicle groups at the week-60 visit was low, with all events being mild to moderate in severity. Furthermore, no serious AEs or ASRs were reported during the PSFU period (post-week 52). These findings suggest that tavaborole has an acceptable long- term safety and tolerability profile, with no new AEs arising after

Downloaded by [Oregon Health & Science University Library] at 13:42 27 September 2017 60 weeks of follow-up (i.e. 12 weeks after cessation of tavaborole therapy). Clinical studies of onychomycosis are usually conducted over a period of 48–52 weeks, which may not provide an accurate assessment of long-term treatment outcomes (21). Given the slow growth of toenails (average 1 mm/month), which can take from 1 to 1.5 years to grow out fully, clinical trials of 52 weeks Figure 3. Toenail onychomycosis. Illustrative cases of durability of clinical benefit or less may fail to capture residual infection, late recurrence during the PSFU period, as assessed by complete cure (completely CN plus negative mycology) of the TGT (top panels A and B) and treatment success (<10% events, long-term AEs, or treatment-related improvements associ- nail involvement plus negative mycology) of the TGT (bottom panels C and D). ated with better long-term outcomes (21,22). Although long-term follow-up studies of systemic antifungal therapies have been previously conducted (23), clinical data on topical agents beyond levels in the nail plate were substantially higher than those of 52 weeks of follow-up are lacking. Therefore, the promising effi- ciclopirox after dosing, with tavaborole levels 40 times higher cacy and safety findings of this 60-week follow-up provide clin- than that of ciclopirox 14 days after the final dose (20). The clinical evidence that suggests tavaborole may be considered as a ical significance of these findings is unknown. long-term treatment option. JOURNAL OF DERMATOLOGICAL TREATMENT 5

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