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

Abstract

BackgroundPhosphodiesterase‐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.MethodsThis phase 1b, open‐label, maximal‐use study of crisaborole topical ointment, 2% applied twice daily (dose 3 mg/cm2) 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.ResultsOf 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 1. Mean severity scores for AD signs and symptoms declined throughout the study.ConclusionsThis 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.

Immunologic Targets in Atopic Dermatitis and Emerging Therapies: An Update

“…In the phase IIa adult study, 68 % experienced a decrease in ADSI in the crisaborole-treated lesion compared with only 20 % in the vehicle-treated lesion [137]. The phase IIa open-label adolescent study demonstrated that [70 % of subjects achieved an Investigator's Static Global Assessment (ISGA) score of 0 or 1 (clear or almost clear) with crisaborole [138,139]. Two post hoc pooled analyses of the four studies found that [80 % of subjects experienced a categorical shift of pruritus intensity (0-1.5 = no-mild, 2-3 = moderate-severe) at the earliest post-baseline efficacy assessment (day 8 or 15, depending on the study), and this effect was maintained for the duration of the study [140].…”

“…Crisaborole (AN-2728) is a boron-containing topical PDE4 inhibitor, for which three phase II trials in adolescents and adults have been published [136][137][138][139]. Results from the largest of these, a dose-justification study that enrolled adolescents, observed that bid application of crisaborole 2 % ointment resulted in total or partial clearance of target lesions in 62 % of subjects after 29 days of treatment and a 71 % reduction in the Atopic Dermatitis Severity Index (ADSI) score [136].…”

2-Year animal carcinogenicity results for crisaborole, a novel phosphodiesterase 4 inhibitor for atopic dermatitis

“…Skin irritation scoring was based on the Draize scale [27]. Safety margins for crisaborole administered topically to mice were calculated based on area under the concentration-time curve (AUC 24 ), taking into account the systemic exposure of topically administered crisaborole in pediatric and adult patients with AD (plasma levels in a clinical study conducted by Anacor Pharmaceuticals, Inc; Maximal Use Systemic Exposure [MUSE]) [28].…”

Emerging Treatment Options in Atopic Dermatitis: Topical Therapies

“…Seven studies have been conducted on the topical formulation of the compound to date, and two of them have reached phase III (NCT02118792 and NCT02118766). Data on the previous phase I and II studies showed positive results across a accumulated cohort of 189 subjects with AD as young as 2 years of age [54,[56][57][58][59]. The first study conducted assessed the safety profile and pharmacokinetics in both children and adolescents under conditions with a supposed maximal use of topical crisaborole [56].…”