A Phase 2, Randomized, Controlled, Dose-Ranging Study Evaluating Crisaborole Topical Ointment, 0.5% and 2% in Adolescents With Mild to Moderate Atopic Dermatitis
December 2015 | Volume 14 | Issue 12 | Original Article | 1394 | Copyright © December 2015
Linda F. Stein Gold MD,a Lynda Spelman MBBS FACD,b Mary C. Spellman MD,c Matilda H. Hughes CCRA,d and Lee T. Zane MDd
aHenry Ford Medical Center, Detroit, MI
bVeracity Clinical Research, Woolloongabba, Queensland, Australia
cPrivate Practice, San Francisco, CA
dAnacor Pharmaceuticals, Palo Alto, CA, USA
Abstract
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.
J Drugs Dermatol. 2015;14(12):1394-1399.
INTRODUCTION
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that affects 15% to 30% of children in industrialized countries.1 Most patients with AD have mild to moderate disease and are often treated with topical therapies; systemic modalities are recommended only for patients with moderate to severe disease.2 The recent American Academy of Dermatology guidelines recommend topical moisturizers, corticosteroids, and calcineurin inhibitors for patients with mild to moderate AD.3 However, the currently available topical therapies for AD are limited either by efficacy or safety concerns.3-5 Importantly, there are currently no topical treatments with favorable efficacy and safety profiles indicated for long-term treatment of mild to moderate AD.
A novel approach to the treatment of AD involves the intracellular targeting and inhibition of phosphodiesterase-4 (PDE4), the main enzyme responsible for degrading the intracellular second-messenger cyclic AMP.6-8 Crisaborole is a novel, boron-based, small-molecule, topical PDE4 inhibitor in development for the treatment of mild to moderate AD in children, adolescents, and adults.9 By inhibiting PDE4, crisaborole suppresses the release of multiple cytokines involved in skin inflammation and has shown anti-inflammatory properties and inhibition of cytokine release in biochemical, cell-based, and animal studies.9-11 In peripheral blood mononuclear cells, crisaborole inhibits cytokine production in a pattern similar to other PDE4 inhibitors but different from corticosteroids and calcineurin inhibitors.11 The incorporation of boron into the chemical structure of crisaborole facilitates binding to its PDE4 target and is essential for PDE4 inhibition; substitution of boron with carbon eliminates its PDE4 inhibitory activity.11 Following application, any crisaborole that reaches the circulation is metabolized to inactive compounds that have no effect on PDE4 activity or cytokine release, thereby limiting systemic exposure to active PDE inhibition.
