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

October 2015 | Volume 14 | Issue 10 | Original Article | 1108 | Copyright © October 2015

Dedee F. Murrell MD FRCP,a Kurt Gebauer MD,b Lynda Spelman MBBS FACD,c and Lee T. Zane MDd

aSt. George Hospital, University of New South Wales, Sydney, Australia
bFremantle Dermatology, Fremantle, Western Australia
cVeracity Clinical Research, Brisbane, Australia
dAnacor Pharmaceuticals, Inc., Palo Alto, CA

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 (identifier NCT01301508).

J Drugs Dermatol. 2015;14(10):1108-1112.


Atopic dermatitis (AD) is a chronic inflammatory skin disorder that is estimated to affect 15% to 30% of children and 2% to 10% of adults in developed countries.1 Disease manifestations vary with patient age and include red, eczematous lesions, intense pruritus, crusted erosions, and lichenification of lesions, particularly in adulthood. The etiology of AD involves a complex interplay between immune system dysfunction and skin barrier breakdown.1 The majority of 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 or refractory disease.2 However, no topical pharmacologic treatment is available for patients with mild to moderate AD that is efficacious, safe, and permits long-term use.3
A novel approach to the treatment of AD involves inhibition of phosphodiesterase 4 (PDE4), an enzyme that degrades the intracellular messenger cyclic adenosine monophosphate (cAMP) to 5’-AMP.4,5 Through the breakdown of cAMP, PDE4 enzymes initiate proinflammatory responses; inhibiting the degradation of cAMP modulates this inflammatory response and has long served as a target for therapeutic drug development in inflammatory skin disease.4 PDE4 inhibitors have been shown to inhibit proinflammatory responses involved in AD pathogenesis, including cytokine release.5 Treatment with PDE4 inhibitors is best suited to topical therapy to limit systemic exposure and systemic adverse effects, including nausea and emesis.5,6
In recent years, a family of boron-based compounds known as phenoxybenzoxaboroles has been shown to effectively inhibit PDE4 at micromolar concentrations.7,8 Crisaborole topical ointment, 2% (previously known as AN2728 topical ointment, 2%; Anacor Pharmaceuticals, Inc., Palo Alto, CA) is a novel, boron-based, topically administered PDE4 inhibitor that has demonstrated anti-inflammatory properties in biochemical, cell-based, and animal studies.7-9 The presence of boron in the chemical structure of crisaborole is essential for the inhibition of PDE4 activity; substitution of boron with carbon eliminates