Early Relief of Pruritus in Atopic Dermatitis with Crisaborole Ointment, A Non-steroidal, Phosphodiesterase 4 Inhibitor.

Pruritus occurs in all patients with atopic dermatitis and requires quick relief to reduce disease exacerbation and improve quality of life. Crisaborole ointment is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis explores crisaborole ointment for early relief of pruritus in patients with mild to moderate atopic dermatitis from 2 phase III studies. Patients received crisaborole or vehicle twice daily for 28 days. Pruritus was graded on a 4-point scale of none (0) to severe (3). Early improvement in pruritus required a score of none (0) or mild (1), with a ≥ 1-grade improvement from baseline on day 6. Significantly more patients experienced early improvement in pruritus with crisaborole than with vehicle (56.6% vs 39.5%; p< 0.001), including at earliest assessment (day 2, 34.3% vs 27.3%; p = 0.013). Crisaborole is a topical treatment option that can rapidly relieve atopic dermatitis-associated pruritus.

Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis.

BACKGROUND: Long-term topical treatment is often required for atopic dermatitis (AD), a chronic inflammatory skin disease. OBJECTIVE: To assess the long-term safety results from a multicenter, open-label, 48-week safety study (AD-303) of patients (N = 517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, a topical phosphodiesterase-4 inhibitor, after completing a 28-day phase 3 pivotal study (AD-301, AD-302). METHODS: Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28-day treatment period with crisaborole applied twice daily was initiated. Adverse events (AEs), including treatment-emergent AEs (TEAEs), and serious AEs were analyzed. RESULTS: During the pivotal studies and AD-303, 65% of patients reported ≥1 TEAE, most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment-related AEs (overall, 10.2%) were dermatitis atopic (3.1%), application-site pain (2.3%), and application-site infection (1.2%). Nine patients (1.7%) discontinued the long-term study because of TEAEs. LIMITATIONS: Long-term efficacy was not analyzed. CONCLUSION: Crisaborole ointment had a low frequency of treatment-related AEs over 48 weeks of treatment of patients with AD.

Tavaborole in Difficult-to-Treat Onychomycosis Cases: A Post-hoc Assessment of Phase III Subjects.

Toenail onychomycosis is a chronic fungal infection that often requires prolonged treatment in order to effectively manage pathogenic organisms and obtain a clear nail. Traditionally, certain clinical features of onychomycosis, including the presence of substantial lateral disease, focal fungal masses, yellow/brown streaks, and extensive nail involvement (ie, >50%), indicate a poor treatment prognosis and have proven difficult-to-treat with oral or traditional topical therapies. Owing to the novel features of topical tavaborole, we sought to understand the potential utility of tavaborole in difficult-to-treat onychomycosis. A blinded, post-hoc assessment of Phase III trials was conducted, focusing on initial presentation, midpoint assessment (24 weeks), and final outcomes (52 weeks) in subjects identified as having difficult-to-treat onychomycosis and treated for 48 weeks with once-daily application of either tavaborole 5% solution or vehicle. Our post-hoc analysis identified 84 difficult-to-treat cases (tavaborole 5%; n=60; vehicle, n=24) in subjects with toenail onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes. No subjects identified as difficult-to-treat and treated with vehicle achieved a complete cure, while 6 subjects treated with tavaborole 5% attained a completely clear nail and negative mycology. Similarly, 7 subjects treated with tavaborole 5% solution achieved an almost complete cure (≤10% involvement and negative mycology) while 1 subject on vehicle achieved an almost complete cure. We present a case series of 4 patients, of varying age and difficult-to-treat clinical features, which responded positively to tavaborole 5% solution. Three of the subjects achieved complete cure after being treated with tavaborole 5%, with one additional subject (an 88-year-old female) achieving an almost complete clear nail by treatment end. The outcomes presented here may not be reflective of patients that may present with these clinical characteristics. Additional investigations would be useful in order to assess the value of topical tavaborole 5% solution in difficult-to-treat clinical presentations of onychomycosis.

J Drugs Dermatol. 2017;16(10):1016-1021.

Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults.

BACKGROUND: Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. OBJECTIVE: We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792). METHODS: Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. RESULTS: More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = .005; 48.5% vs 29.7%, P < .001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P ≤ .001). Treatment-related adverse events were infrequent and mild to moderate in severity. LIMITATIONS: Short study duration was a limitation. CONCLUSIONS: Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD.

Evaluation of the Appearance of Nail Polish Following Daily Treatment of Ex Vivo Human Fingernails With Topical Solutions of Tavaborole or Efinaconazole.

INTRODUCTION: Patients with onychomycosis may mask infected nails with polish. Tavaborole topical solution, 5% is a boron-based, small-molecule pharmaceutical approved for the treatment of toenail onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes; efinaconazole topical solution, 10% is approved for the same indication. Nail polish appearance after application of tavaborole (dropper) or efinaconazole (brush); respective applicator appearance; presence of color transfer from respective applicators; and color transfer to remaining solutions after dosing of polished nails were evaluated. METHODS: Twelve ex vivo human cadaver fingernails were cleaned, polished with two coats of L'Oréal® Nail Color, Devil Wears Red #420, and mounted on floral foam. Nails were treated with tavaborole or efinaconazole solutions once daily for 7 days. Dropper and brush applicators were applied to white watercolor paper immediately after dosing to evaluate color transfer from polished nails. On day 7, remaining solutions were transferred to clear glass vials to evaluate color transfer from applicators to solutions. Nails, applicators, and papers were photographed daily following application; remaining solutions were photographed after 7 days of dosing. RESULTS: Tavaborole-treated polished nails showed no polish discoloration, and tavaborole applicators did not change in appearance during treatment. No color transfer from polished nails was evident to applicator, paper, or remaining solution. Efinaconazole-treated polished nails showed substantial polish changes after the first day of treatment, with polish appearance and discoloration progressively worsening over 7 days of treatment. Color transfer from nails was evident to applicator, paper, and remaining solution. CONCLUSIONS: Daily dropper application of tavaborole to ex vivo polished nails did not alter polish appearance. Brush application of efinaconazole produced visible changes in polish appearance and color transfer to applicators, paper, and remaining solution. Tavaborole topical solution, 5% may not alter nail polish appearance; the impact of nail polish on tavaborole clinical efficacy has not been evaluated.

Crisaborole Topical Ointment, 2%: A Nonsteroidal, Topical, Anti-Inflammatory Phosphodiesterase 4 Inhibitor in Clinical Development for the Treatment of Atopic Dermatitis.

Crisaborole topical ointment, 2% (formerly known as AN2728) is a benzoxaborole, nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor investigational compound that recently completed phase 3 studies for the treatment of mild to moderate atopic dermatitis (AD). The unique configuration of boron within the crisaborole molecule enables selective targeting and inhibition of PDE4, an enzyme that converts the intracellular second messenger 3'5'-cyclic adenosine monophosphate (cAMP) into the active metabolite adenosine monophosphate (AMP). By inhibiting PDE4 and thus increasing levels of cAMP, crisaborole controls inflammation. The use of boron chemistry enabled synthesis of a low-molecular-weight compound (251 daltons), thereby facilitating effective penetration of crisaborole through human skin. In vitro experiments showed that crisaborole inhibits cytokine production from peripheral blood mononuclear cells in a pattern similar to other PDE4 inhibitors and distinct from corticosteroids. Crisaborole also displayed topical anti-inflammatory activity in a skin inflammation model. Once crisaborole reaches systemic circulation after topical application, it is metabolized to inactive metabolites. This limits systemic exposure to crisaborole and systemic PDE4 inhibition. In phase 1 and 2 clinical studies, crisaborole ointment, 2% was generally well tolerated and improved AD disease severity scores, pruritus, and all other AD signs and symptoms. Two large, randomized, controlled, phase 3, pivotal clinical trials assessing the efficacy and safety of crisaborole topical ointment, 2% in children, adolescents, and adults with mild to moderate AD were recently completed with positive results.

Post Hoc Analyses of the Effect of Crisaborole Topical Ointment, 2% on Atopic Dermatitis: Associated Pruritus from Phase 1 and 2 Clinical Studies.

BACKGROUND: Two post hoc analyses assessed the antipruritic activity of crisaborole topical ointment, 2% (crisaborole; Anacor Pharmaceuticals, Inc., Palo Alto, CA), a first-in-class boron-based phosphodiesterase-4 inhibitor in development for treatment of mild to moderate atopic dermatitis (AD). METHODS: Two pooled analyses included data from 4 studies evaluating crisaborole in AD (study 1, phase 1b, systemic exposure, safety, and pharmacokinetics [PK] under maximal-use conditions in children and adolescents; study 2, phase 2a, safety and PK in adolescents; study 3, phase 2a, efficacy and safety in adults; study 4, phase 2, efficacy and safety in adolescents). Pooled data from studies 1 and 2 included whole body assessments; studies 3 and 4 included target lesion assessments. Pruritus severity was evaluated using a 4-point rating scale (0=none to 3=severe). Efficacy assessments included percent change from baseline in pruritus severity scores at days 8 (first pooled assessment), 15, 22, and 29 (whole body assessments) or days 15 (first pooled assessment), 22, and 29 (target lesions). Paired t-tests comparing change from baseline against zero were used to calculate P values. Categorical shifts in pruritus severity were also assessed (no to mild pruritus, 0-1.5; moderate to severe pruritus, 2-3). RESULTS: In the pooled analysis of studies 1 and 2 (N=57), the percent change from baseline in pruritus severity scores were 63.0% and 64.9% at days 8 and 29, respectively (P<0.001 for each). Similar results were observed in the pooled analysis of studies 3 and 4 (N=67). In both analyses, most patients had mild to no pruritus from the first time point assessed through the remainder of treatment. CONCLUSIONS: Treatment with crisaborole topical ointment, 2% resulted in statistically significant reductions in pruritus severity at the first time point evaluated in both analyses. These findings provide preliminary evidence of the antipruritic activity of crisaborole topical ointment, 2%.

Pharmacokinetic Profile, Safety, and Tolerability of Crisaborole Topical Ointment, 2% in Adolescents with Atopic Dermatitis: An Open-Label Phase 2a Study.

BACKGROUND: Phosphodiesterase-4 (PDE4) is an emerging target in treating inflammatory skin diseases. Crisaborole topical ointment, 2% is a novel, boron-based, topical PDE4 inhibitor under investigation for treatment of mild to moderate atopic dermatitis (AD). METHODS: Adolescent patients aged 12 to 17 years with treatable AD lesions involving ≥ 10% to ≤ 35% body surface area (BSA) were enrolled into a phase 2a, open-label study comprising pharmacokinetic (PK), safety, tolerability, and efficacy assessments. Crisaborole topical ointment, 2% was applied twice daily to affected areas for 28 days, with dosage based on baseline treatable BSA. PK blood samples were collected on days 1, 2, 4, 6, 8, and 9. Safety assessments included adverse events (AEs), laboratory parameters, and vital signs. Efficacy assessments included the Investigator's Static Global Assessment (ISGA) score and severity of AD signs and symptoms. RESULTS: Twenty-three patients were enrolled; 22 completed the study (1 patient discontinued due to an AE [application site dermatitis]). PK analysis demonstrated limited exposure to crisaborole topical ointment, 2% after 8 days of dosing. Ten patients reported a total of 19 AEs, most commonly application site pain and nasopharyngitis (3 patients each). There were no clinically meaningful changes in laboratory or vital sign parameters. Efficacy was demonstrated by reductions in mean ISGA and AD sign and symptom severity scores. At day 29, eight patients (35%) had achieved an ISGA score ≤ 1 with ≥ 2-grade improvement. Mean treatable BSA declined from 17.6% to 8.2%. CONCLUSION: These results provide preliminary evidence for the limited systemic exposure, safety, and effectiveness of crisaborole topical ointment, 2% in adolescents with mild to moderate AD.

Crisaborole Topical Ointment, 2% in Patients Ages 2 to 17 Years with Atopic Dermatitis: A Phase 1b, Open-Label, Maximal-Use Systemic Exposure Study.

BACKGROUND: Phosphodiesterase-4 (PDE4) is a promising target in atopic dermatitis (AD) treatment. The pharmacokinetics (PK), safety, and efficacy of crisaborole topical ointment, 2% (formerly AN2728) (Anacor Pharmaceuticals, Palo Alto, CA), a boron-based benzoxaborole PDE4 inhibitor, were evaluated in children with mild to moderate AD. METHODS: This phase 1b, open-label, maximal-use study of crisaborole topical ointment, 2% applied twice daily (dose 3 mg/cm(2) ) for 28 days enrolled patients ages 2 to 17 years with extensive AD involving 25% or more or 35% or more treatable body surface area, depending on age. Primary PK and safety assessments included systemic exposure to crisaborole and its metabolites after 7 days of treatment and the incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy assessments included change from baseline in Investigator Static Global Assessment (ISGA), treatment success (ISGA score ≤1 with a two-grade or greater improvement from baseline), and improvement in five AD signs and symptoms. RESULTS: Of 34 patients enrolled, 31 completed the study. Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8. Twenty-three of 34 patients reported one or more TEAEs; 95% were mild or moderate and one patient discontinued because of a TEAE. Mean ISGA scores declined from 2.65 at baseline to 1.15 at day 29, 47.1% of patients achieved treatment success, and 64.7% of patients achieved ISGA scores of clear (0) or almost clear . Mean severity scores for AD signs and symptoms declined throughout the study. CONCLUSIONS: This open-label study provides evidence that crisaborole topical ointment, 2% was well tolerated, with limited systemic exposure under maximal-use conditions in patients ages 2 years and older.

Antifungal agents for onychomycosis: new treatment strategies to improve safety.

Onychomycosis is a common and difficult-to-treat fungal infection of the nail unit that gradually leads to dystrophic changes of the nail plate and nail bed. If untreated, infection progresses and may lead to discomfort, reduced quality of life, and risk of complications in patients with comorbid conditions (eg, diabetes, human immunodeficiency virus, peripheral vascular disease). Onychomycosis treatments are designed to eradicate causative pathogens (most commonly Trichophyton rubrum and Trichophyton mentagrophytes), restore healthy nails, and prevent recurrence or spread of infection. Given the deep-seated nature of most cases of onychomycosis, an effective antifungal agent needs to achieve and maintain sufficient drug concentrations throughout the nail unit for the duration of healthy nail in-growth. Oral antifungal drugs are the most effective available therapy and are generally well tolerated, but may be limited by safety concerns and the potential for drug-drug interactions (DDIs). Thus, treating physicians and pharmacists must be cognizant of a patient's current medications; indeed, it may not be feasible to treat onychomycosis in patients with diabetes, heart disease, or depression because of the risk for DDIs. Current topical therapy is not associated with risk of DDIs. Tavaborole and efinaconazole, two recently approved topical agents, have demonstrated good nail penetration and high negative culture rates in clinical trials of patients with onychomycosis. This article provides the treating physician and pharmacist with information on the safety and effectiveness of current oral (allylamine, azole) and topical (ciclopirox, efinaconazole, tavaborole) treatment to aid in making informed treatment decisions based on the unique characteristics (medication history, comorbidities, nature of onychomycosis) of each patient.

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.

BACKGROUND: Onychomycosis, a fungal nail infection, can impact quality of life. OBJECTIVE: We sought to evaluate the efficacy and safety of tavaborole topical solution, 5% for treatment of toenail onychomycosis. METHODS: In 2 phase-III trials, adults with distal subungual onychomycosis affecting 20% to 60% of a target great toenail were randomized 2:1 to tavaborole or vehicle once daily for 48 weeks. The primary end point was complete cure of the target great toenail (completely clear nail with negative mycology) at week 52. Secondary end points included completely or almost clear nail, negative mycology, completely or almost clear nail plus negative mycology, and safety. RESULTS: Rates of negative mycology (31.1%-35.9% vs 7.2%-12.2%) and complete cure (6.5% and 9.1% vs 0.5% and 1.5%) significantly favored tavaborole versus vehicle (P ≤ .001). Completely or almost clear nail rates also significantly favored tavaborole versus vehicle (26.1%-27.5% vs 9.3%-14.6%; P < .001). Rates of completely or almost clear nail plus negative mycology (15.3%-17.9% vs 1.5%-3.9%) were significantly greater for tavaborole versus vehicle (P < .001). Application-site reactions with tavaborole included exfoliation (2.7%), erythema (1.6%), and dermatitis (1.3%). LIMITATIONS: Duration of follow-up is a limitation. CONCLUSION: Tavaborole demonstrates a favorable benefit-risk profile in treatment of toenail onychomycosis.

Crisaborole Topical Ointment, 2% in Adults With Atopic Dermatitis: A Phase 2a, Vehicle-Controlled, Proof-of-Concept Study.

BACKGROUND: A novel approach for treating atopic dermatitis (AD) is the inhibition of phosphodiesterase 4 (PDE4), an enzyme involved in the proinflammatory cascade. Crisaborole topical ointment, 2% is a novel, boron-based small-molecule PDE4 inhibitor with anti-inflammatory properties. The objective of this proof-of-concept study was to assess the efficacy and safety of crisaborole topical ointment, 2% in adults with mild to moderate AD. METHODS: This phase 2a, randomized, double-blind, bilateral, 6-week study of crisaborole topical ointment, 2% was conducted in adult patients with mild to moderate AD with 2 comparable target AD lesions. Patients were randomly assigned to twice-daily application of crisaborole topical ointment, 2% or vehicle, each to 1 of the 2 target lesions. The primary efficacy endpoint was change from baseline in Atopic Dermatitis Severity Index (ADSI) score at day 28. Safety assessments included local tolerability and incidence of adverse events (AEs). RESULTS: A total of 25 enrolled patients received study medication. At day 28, 17 patients (68%) experienced a greater decrease in ADSI score in the active-treated lesion than in the vehicle-treated lesion; 5 patients (20%) had a greater decrease in ADSI score in the vehicle-treated lesion than in the active-treated lesion. Local application-site reactions were reported in 3 patients (12%). A total of 29 AEs were reported in 11 patients; most (90%) were mild in intensity and unrelated to study medication. No serious or severe AEs were reported, and no patient discontinued due to an AE. CONCLUSIONS: These findings provide preliminary evidence of the efficacy and safety of treatment with crisaborole topical ointment, 2% in adults with mild to moderate AD. The study is registered on ClinicalTrials.gov (identifier NCT01301508).

In Vitro Nail Penetration and Antifungal Activity of Tavaborole, a Boron-Based Pharmaceutical.

An effective topical antifungal medication must penetrate through the nail plate at sufficient concentrations to eradicate the fungal infection. Tavaborole topical solution, 5% is a novel boron-based pharmaceutical approved for the treatment of toenail onychomycosis due to Trichophyton rubrum or T mentagrophytes. Four in vitro studies assessed the antifungal activity and nail penetration of tavaborole. In Study 1, tavaborole demonstrated minimum inhibitory concentration (MIC) values ranging from 0.25-2 µg/mL against all fungi tested; addition of 5% keratin powder did not affect the MIC against T rubrum. The minimum fungicidal concentration (MFC) values for tavaborole against T rubrum and T mentagrophytes were 8 and 16 µg/mL, respectively. In Study 2, tavaborole effectively penetrated through the nail plate; mean concentrations in the ventral/intermediate nail layer were significantly higher than ciclopirox at day 15. In Study 3, mean cumulative tavaborole penetration through ex vivo human nails was significantly higher than ciclopirox at day 15. In Study 4, tavaborole demonstrated superior nail penetration and fungicidal activity, as measured by zones of inhibition. These studies demonstrated the superior penetration of tavaborole through the nail plate vs ciclopirox. Tavaborole demonstrated robust antifungal activity, with low MIC and MFC values, even in the presence of keratin.

In Vitro Nail Penetration of Tavaborole Topical Solution, 5%, Through Nail Polish on Ex Vivo Human Fingernails.

BACKGROUND: Onychomycosis is a common infection of the toenails that causes nail thickening and discoloration. The physical appearance of the infected nail can diminish self-image and negatively impact quality of life. Patients may use nail polish to mask the appearance of infected nails. OBJECTIVE: To evaluate the in vitro nail penetration properties of tavaborole topical solution, 5%, through nail polish using ex vivo, non-diseased human fingernails. METHODS: In study 1, tavaborole penetration was evaluated over 20 days of dosing using the Franz finite dose technique and modified Franz diffusion cells. Nails received either 1 coat of over-the-counter (OTC) typical polish or were left unpolished (controls). In study 2, tavaborole penetration was measured over 14 days of dosing using the finite dose technique and vertical diffusion cells. Nails were polished with either 4 coats or 1 coat of salon typical polish or with 2 coats or 1 coat of OTC typical polish, or they were left unpolished. RESULTS: In study 1, the mean ± standard deviation (SD) cumulative tavaborole penetration at day 21 was numerically higher, though not statistically significant, through polished nails (3,526 ± 1,433 µg/cm(2))vs unpolished nails (2,661 ± 1,319 µg/cm(2)).In study 2, the mean cumulative tavaborole penetration was also numerically higher (statistical significance not assessed) through all nails that received polish vs unpolished nails. At day 15, mean ± SD cumulative tavaborole nail penetration was 1,179 ± 554 µg/cm(2) through 4 coats of salon typical polish, 1,227 ± 974 µg/cm(2) through 1 coat of salon typical polish, 1,493 ± 1,322 µg/cm(2) through 2 coats of OTC typical polish, 1,428 ± 841 µg/cm(2) through 1 coat of OTC typical polish, and 566 ± 318 µg/cm(2) through unpolished nails. CONCLUSION: Results from these in vitro studies demonstrated that tavaborole penetrated through human nails with up to 4 layers of nail polish.

A Phase 2, Randomized, Controlled, Dose-Ranging Study Evaluating Crisaborole Topical Ointment, 0.5% and 2% in Adolescents With Mild to Moderate Atopic Dermatitis.

BACKGROUND: Crisaborole is a novel, boron-based, small-molecule, topical phosphodiesterase-4 inhibitor in development for the treatment of patients with mild to moderate atopic dermatitis (AD). METHODS: In this multicenter, randomized, double-blind, dose-ranging, phase 2 study, adolescent patients 12 to 17 years of age with mild to moderate AD and 2 distinct target AD lesions were randomized to once-daily (QD) or twice-daily (BID) treatment with crisaborole topical ointment. For each patient, 2 target lesions were randomized to receive 29 days of treatment with 0.5% or 2% crisaborole topical ointment. The primary endpoint was change from baseline in AD severity index (ADSI) score for each lesion. Exploratory efficacy endpoints and safety were also assessed. RESULTS: A total of 86 patients were enrolled and received crisaborole topical ointment 0.5% or 2% QD (n=44) or BID (n=42). All dosing regimens produced dose-related improvements in ADSI as well as in all 5 component signs and symptoms of AD (erythema, excoriation, exudation, lichenification, and pruritus). The greatest improvements were consistently observed with crisaborole topical ointment, 2% applied BID. With this regimen, ADSI improved from baseline by 71%, and total or partial clearance of target lesions (ADSI ≤ 2) was achieved by 62% of patients after 29 days of treatment. Both doses of crisaborole topical ointment were well tolerated; mild application site reactions were the only treatment-related adverse events (QD, n=3; BID, n=1). CONCLUSION: These results provide preliminary evidence of the efficacy and safety of crisaborole topical ointment, 2% applied topically BID in adolescents with mild to moderate AD.

The efficacy and safety of tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the topical treatment of toenail onychomycosis.

OBJECTIVE: To assess the potential efficacy, safety, and optimal dosing concentration of tavaborole, a novel, boron-based pharmaceutical agent with broad-spectrum antifungal activity, for the treatment of onychomycosis of the toenail due to dermatophytes. METHODS: One double-blind, randomized, vehicle-controlled study (study 1) and two open-label studies (studies 2 and 3) examined the efficacy, safety, and optimal dosing concentration of tavaborole topical solution applied once daily or three times weekly for 180 days at concentrations of 1.0%, 2.5%, 5.0%, or 7.5%. Patient cohort 3 of study 2 received open-label tavaborole 5.0% once daily for 360 days. All three studies assessed day 180 treatment success, defined as complete or partial clinical evidence of clear nail growth plus negative fungal culture. RESULTS: A total of 336 patients were included in the intent-to-treat (ITT) or modified ITT populations and efficacy analyses across the 3 studies. In study 1, treatment success rates at day 180 were higher with tavaborole 2.5%, 5.0%, and 7.5% vs vehicle (27%, 26%, and 32% vs 14%, respectively; slope P=0.030). In cohort 3 of study 2, 7% of patients achieved treatment success with tavaborole 5.0% at day 360. Negative culture rates at day 180 in study 1 were numerically higher for tavaborole 2.5%, 5.0%, and 7.5% vs vehicle (slope P=0.046). Application-site reactions of general irritation, erythema, scaling, and stinging/burning were most common with tavaborole 7.5%, were generally mild to moderate, and resolved with treatment discontinuation and/or a reduction in dosing frequency. No systemic safety concerns were observed. CONCLUSION: Tavaborole solution demonstrated favorable efficacy and safety in phase 2 clinical studies. Based on these findings, tavaborole topical solution, 5% was further investigated in larger, more definitive phase 3 studies. Results from these completed phase 3 studies will provide additional evidence regarding the safety and efficacy of tavaborole in the treatment of toenail onychomycosis.

Age-related differences in the reproductive and metabolic implications of polycystic ovarian syndrome: findings in an obese, United States population.

The objective of this study was to explore age-related differences in the reproductive and metabolic manifestations of polycystic ovarian syndrome (PCOS). Using a prospective cross-sectional design, we compared metabolic and reproductive findings in women attending a multidisciplinary clinic for PCOS, stratified across the following age groups: 18-25 (n = 71), 26-35 (n = 129), and 36-45 (n = 29). The study included primarily overweight and obese women, with a mean BMI of 31.1 in the entire study group. Older women had a decreased prevalence of biochemical hyperandrogenemia (p-trend: 0.0005). Of women meeting diagnostic criteria for PCOS, older women (n = 15) had larger median waist circumference and higher median diastolic blood pressure, total cholesterol, LDL cholesterol and fasting glucose compared to younger women (p-trend: 0.03, 0.01, 0.01, 0.01 and 0.06, respectively). The odds of metabolic syndrome for women ages 36-45 are increased four-fold relative to the younger groups (OR: 4.01; 95% CI: 1.04-15.4; p = 0.04). We conclude that there are significant age-related differences in both the clinical presentation and metabolic manifestations of PCOS.

Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea.

BACKGROUND: Erythematotelangiectatic (ET) rosacea is commonly treated with a variety of laser and light-based systems. Although many have been used successfully, there are a limited number of comparative efficacy studies. OBJECTIVE: To compare nonpurpuragenic pulsed dye laser (PDL) with intense pulsed light (IPL) treatment in the ability to reduce erythema, telangiectasia, and symptoms in patients with moderate facial ET rosacea. METHODS: Twenty-nine patients were enrolled in a randomized, controlled, single-blind, split-face trial with nonpurpuragenic treatment with PDL and IPL and untreated control. Three monthly treatment sessions were performed with initial PDL settings of 10-mm spot size, 7 J/cm(2), 6-ms pulse duration and cryogen cooling, and initial IPL settings of 560-nm filter, a pulse train of 2.4 and 6.0 ms in duration separated by a 15-ms delay, and a starting fluence of 25 J/cm(2). Evaluation measures included spectrophotometric erythema scores, blinded investigator grading, and patient assessment of severity and associated symptoms. RESULTS: PDL and IPL resulted in significant reduction in cutaneous erythema, telangiectasia, and patient-reported associated symptoms. No significant difference was noted between PDL and IPL treatment. CONCLUSION: A series of nonpurpuragenic PDL and IPL treatments in ET rosacea was performed with similar efficacy and safety, and both modalities seem to be reasonable choices for the treatment of ET rosacea.

Recent advances in acne vulgaris research: insights and clinical implications.

Understanding of acne vulgaris has taken major steps forward over the past few years. The renewed interest in the effect of dietary interventions on acne, the elucidation of the involvement of TLR and MMPs in acne pathogenesis, and a more detailed functional understanding of various treatment modalities at the molecular level are all promising indications that advances in therapeutics are sure to follow. Health utilities will serve not only as powerful outcome measures of treatment effects but also as clinical decision-making aids in everyday practice. It is hoped that future advances will further uncover additional molecular and cellular details of pathophysiology, leading to rational targeted design of medications, and advance clinical management through improved understanding of the psychosocial impact of acne on patients.

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.

PURPOSE: The role of topical antifungal agents in the long-term management of toenail onychomycosis is not well established. The current study evaluated durability of clinical benefit of tavaborole topical solution, 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, randomized controlled trials in a subset of patients who experienced complete or almost clear nail (CN) at the end of treatment (week 52); 48 weeks of treatment with once-daily tavaborole compared with placebo in adults with distal subungual onychomycosis was evaluated at week 60. Complete cure (completely CN 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.