Investigator's Global Assessment of Chronic Prurigo: A New Instrument for Use in Clinical Trials.

Chronic prurigo is a pruritic disease characterized by the development of pruriginous lesions due to scratching. The number of lesions is representative of the stage of the disease, while the presence of excoriations reflects the scratching activity. Aim of this study was to validate a new developed tool for the objective assessment of chronic prurigo. Investigator's Global Assessment scales for stage and activity were completed for 187 patients with chronic prurigo, who also reported patient-reported outcomes for itch intensity and quality of life. To assess the reliability and objectivity of the Investigator's Global Assessment, 5 independent raters completed the Investigator's Global Assessment scales for 8 patients twice. The scores increased with increased intensity of pruritus. The Investigator's Global Assessment stage scales correlated strongly with each other (Kendall's-tau-b 0.62) and moderately with the Investigator's Global Assessment activity scale (Kendall's-tau-b 0.47). Intra-rater test-retest reliability was excellent for all items, while the congruence among raters was very good for Investigator's Global Assessment - chronic prurigo activity (Kendall's W 0.84) and good for Investigator's Global Assessment stage scales (Kendall's W 0.747). Investigator's Global Assessment - chronic prurigo stage and activity are thus the best Investigator's Global Assessment instruments for use in assessing chronic prurigo.

Diagnostic and treatment algorithm for chronic nodular prurigo.

Chronic nodular prurigo (CNPG) is a subtype of chronic prurigo, also called prurigo nodularis, and a chronic skin condition characterized by intensely pruritic nodular lesions. Although the exact cause of CNPG is unknown, it appears to result from a repetitive itch-scratch cycle induced by neuronal sensitization to chronic pruritus. CNPG is associated with an underlying dermatologic condition in about half of patients, and it can also be attributed to systemic, neurologic, psychogenic, or unknown causes. For most patients, multiple underlying causes are identified. Patients with CNPG often experience impaired quality of life, sleep disturbance, anxiety, and depression. To encourage consistent and accurate diagnosis and treatment of CNPG across regions, we are proposing a diagnostic and treatment algorithm that includes initial assessment of core symptoms, detailed dermatologic history and clinical examination, patient-reported outcomes, diagnostic workup, and recommended therapies. This information is supplemented with photographs to illustrate clinical appearance and disease severity. Because CNPG is often multifactorial and it can take months to years for lesions to heal, interdisciplinary cooperation and long-term management are important.

Serlopitant for psoriatic pruritus: A phase 2 randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Pruritus, a common symptom of psoriasis, negatively affects quality of life; however, treatment of lesional skin does not consistently alleviate psoriatic itch. OBJECTIVE: To examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639). METHODS: Patients (n = 204) were randomized to receive serlopitant, 5 mg, or placebo daily for 8 weeks. Eligible adult patients had plaque psoriasis for ≥6 months, plaques covering ≤10% of body surface area, pruritus for ≥4 weeks, and Worst Itch Numeric Rating Scale (WI-NRS) score ≥7 at the initial screening. RESULTS: Participants (54.2% women) had a mean age of 47.5 years and 85.2% were white. Mean baseline WI-NRS scores were 8.3 for serlopitant and 8.1 for placebo. The WI-NRS 4-point response rate at 8 weeks (primary end point) was 33.3% for serlopitant vs 21.1% for placebo (P = .028); at 4 weeks the rates were 20.8% for serlopitant vs 11.5% for placebo (P = .039). Treatment-related adverse events were reported for 4.9% of serlopitant-treated and 4.0% of placebo-treated patients. LIMITATIONS: This was a phase 2 study with a small study population. Patients with severe psoriasis were excluded. CONCLUSION: Serlopitant significantly reduced pruritus associated with mild to moderate psoriasis, supporting continued development of serlopitant for this patient population.

Tavaborole 5% Topical Solution for the Treatment of Toenail Onychomycosis in Pediatric Patients: Results from a Phase 4 Open-Label Study

Background: This study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of tavaborole in pediatric patients. Study Design: In this open-label, single-arm study, pediatric patients (aged 6 to <17 years) with distal subungual onychomycosis affecting ≥20% of the target great toenail applied tavaborole once daily to all affected toenails (2 drops/great toenail, 1 drop/other toenail) for 48 weeks. In addition, a maximal-use subgroup (aged 12 to <17 years) applied tavaborole to all 10 toenails and ≤2 mm of surrounding skin for the first 28 days. Results: Treatment-emergent adverse events (TEAEs) were reported by 55.6% of patients; the most frequently reported (≥5% of patients) were nasopharyngitis, contusion, sinusitis, and vomiting. Most TEAEs and local treatment reactions (LTRs) were mild or moderate and considered unrelated to treatment. There was 1 serious AE (severe appendicitis, considered unrelated to treatment) and there were no deaths, discontinuations because of AEs, or dose adjustments because of AEs. The most frequently reported LTRs were erythema and scaling. The incidence of LTRs diminished over time. Tavaborole was absorbed systemically, and plasma concentrations were measurable. The PK parameters determined in this study under maximal-use conditions indicate that steady state was achieved within the study period. For efficacy, 8.5% of patients achieved complete cure (clear nail and negative mycology [negative fungal culture and negative potassium hydroxide wet mount]) at week 52, and 14.9% achieved complete/almost complete cure at week 52 (clear or almost clear nail [≤5% dystrophic or discolored distal toenail plate] and negative mycology). Conclusion: Tavaborole was well tolerated in this pediatric population, and safety, PK, and efficacy profiles were comparable with those in adults. Trial registration: ClinicalTrials.gov identifier: NCT03405818 J Drugs Dermatol. 2019;18(2):190-195.

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.

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.

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 NK1 receptor antagonist serlopitant for treatment of chronic pruritus.

Introduction: Pruritus is a common symptom associated with several potential underlying causes, including both dermatologic and systemic diseases; it can also occur without an identifiable cause. Current treatment options are limited and most patients experience impaired quality of life. Serlopitant is a neurokinin 1 (NK1) receptor antagonist under development for the treatment of pruritus associated with various dermatologic conditions and chronic pruritus of unknown origin. Areas covered: This review describes the epidemiology and unmet needs of patients with chronic pruritus, focusing specifically on patients with prurigo nodularis, psoriatic itch, and chronic pruritus of unknown origin; the rationale for targeting the NK1 receptor for treatment of chronic pruritus; and the clinical development of serlopitant, including efficacy and safety data from completed phase II studies. Expert opinion: There is an unmet need for novel, safe, and effective therapies to treat chronic pruritus. Serlopitant has shown promising efficacy, safety, and tolerability across different patient populations, including adolescents and elderly patients. In contrast to less convenient administration options, serlopitant is a once-daily oral tablet, which is expected to facilitate compliance.

Anti-CD23 monoclonal antibody, lumiliximab, inhibited allergen-induced responses in antigen-presenting cells and T cells from atopic subjects.

BACKGROUND: CD23 plays a role in the regulation of IgE production and allergy-induced immune and inflammatory responses. A novel anti-CD23 monoclonal antibody, lumiliximab, is a potential therapeutic antibody recently demonstrated to be safe in human beings. OBJECTIVE: This study investigated the effects of lumiliximab on allergen-induced immune responses from atopic subjects compared with blocking HLA-DR and costimulatory molecules, CD80 and CD86. METHODS: Allergen-stimulated PBMCs from atopic subjects were pretreated with lumiliximab or antibodies to CD80, CD86, and HLA-DR. Cultures were analyzed for cell proliferation and IL-1beta, TNF-alpha, and IL-5 cytokine secretion. An allergen-specific T-cell line was developed and analyzed for lymphocyte proliferation in response to allergen with or without lumiliximab. Lumiliximab's effect on CD86 expression was evaluated by flow cytometry in the U937 monocytic cell line. RESULTS: Lumiliximab reduced allergen-induced PBMC proliferation by 50% (n = 6; P = .006). In addition, cultures pretreated with lumiliximab had a reduction in the proinflammatory cytokines IL-1beta (P < .003) and TNF-alpha (P = .05) and the T(H)2 cytokine IL-5 (P = .002). Blocking CD86 resulted in greater reduction in proliferation than lumiliximab (P = .003) but similar effects in cytokine secretion. The anti-CD80 blocking antibody had no effect on cytokine production but did reduce proliferation. Furthermore, the addition of lumiliximab to cytokine stimulated U937 cells reduced surface expression of CD86 (P = .012). CONCLUSION: These results indicate that the anti-CD23 mAb, lumiliximab, may be involved in modulating antigen presenting cells and reducing TH2-type immune responses. The use of this antibody may provide clinical benefit for treating allergic diseases.

The efficacy and tolerability of clobetasol propionate foam 0.05% in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions.

BACKGROUND: Clobetasol propionate foam 0.05% (Connetics Corporation, Palo Alto, CA) is approved by the United States Food and Drug Administration for the treatment of corticosteroid-responsive scalp dermatoses, but there is only limited data available for its efficacy and tolerability in treating dermatoses which affect nonscalp sites. OBJECTIVE: The efficacy and tolerability of clobetasol propionate foam (clobetasol foam) in treating psoriatic lesions at nonscalp sites was evaluated in a multicenter, randomized, double-blinded, placebo-controlled study of 279 patients with mild to moderate plaque-type psoriasis. METHODS: The patients applied clobetasol foam or placebo to the psoriatic lesions twice daily for two weeks. In addition to receiving clinical evaluations, the study patients completed a questionnaire evaluating various characteristics of the foam formulation, including their preference for its use and their projected likelihood to comply with similar therapy in a nonstudy environment. RESULTS: At Week 2 (or end of treatment), 68% (94/139) of patients who received clobetasol foam had a Physician's Static Global Assessment score of 0 (clear, except for minor residual discoloration) or 1 (majority of lesions have individual scores for plaque thickness, erythema, and scaling that averages 1). This was significantly more than the 21% (30/140) observed in the placebo group (P < 0.0001). Similar results were obtained for the Patient's Global Assessment score at Week 2 and in changes (from Baseline to Week 2) in the scores for the signs of psoriasis at a target lesion and for pruritus. Adverse effects were generally limited to mild and transient burning or other application site reactions in only a few patients in each treatment group. In the patient's poststudy questionnaire (completed at Week 2, or end of treatment) a majority of patients rated the characteristics of the foam formulation very highly. The patients ranked the foam formulation as superior to other topical formulations based on factors impacting their quality of life and indicated they would be more likely to comply with a recommended course of therapy with the foam formulation than with other topical formulations. CONCLUSION: Clobetasol propionate foam 0.05% is safe and effective for the treatment of plaque-type psoriasis on scalp and nonscalp areas, when applied twice daily for two weeks. As it is understood that patient dissatisfaction with select topical formulations affects their compliance with therapy, which necessarily affects the effectiveness of the therapy, the results of the patient's poststudy questionnaire suggest that there are multiple and integrated benefits for the use of clobetasol foam in the treatment of psoriasis of nonscalp sites.