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

April 2016 | Volume 15 | Issue 4 | Original Article | 390 | Copyright © April 2016

Kurt Jarnagin PhD,a Sanjay Chanda PhD,b Dina Coronado BS,a Vic Ciaravino PhD,a Lee T. Zane MD,a Emma Guttman-Yassky MD PhD,b and Mark G. Lebwohl MDb

aAnacor Pharmaceuticals, Inc., Palo Alto, CA
bIcahn School of Medicine at Mount Sinai, New York, NY

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.

J Drugs Dermatol. 2016;15(4):390-396.


Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by intense pruritus and eczematous lesions.1-4 In addition to the physical discomfort, patients with AD often report impaired health-related quality of life and psychological distress due to the stigma of the visible skin lesions.1 AD is the most common chronic inflammatory skin disease,5 affecting approximately 15% to 30% of children and 2% to 10% of adults in developed countries; most cases present early in life, although AD can also start in adulthood. 2 Most patients with AD have mild to moderate disease, and can achieve clinical improvement and disease control with topical treatment.6,7 Current practice guidelines from the American Academy of Dermatology recommend topical treatment with nonpharmacologic moisturizers for patients with AD, and if symptoms persist, introduction of a topical corticosteroid or calcineurin inhibitor.8 Although available topical agents are generally well tolerated when used as directed, topical corticosteroids may cause cutaneous and systemic side effects when used inappropriately and topical calcineurin inhibitors carry a boxed warning for malignancy risk.8 There is a need for new effective topical treatment options without such safety concerns.
A novel approach to the topical treatment of AD is the development of boron-based topical agents. Boron chemistry allows synthesis of compounds of low molecular weight, which facilitates penetration through the skin. Crisaborole, a boron-based benzoxaborole compound, has demonstrated selective targeting of phosphodiesterase 4 (PDE4),9 the principal enzyme responsible for degrading 3’5’-cyclic adenosine monophosphate (cyclic AMP; cAMP) in inflammatory cells.10 PDE4 inhibitors act through inhibition of PDE4, increasing intracellular concentrations of cAMP, which is a regulator of NF-κB and NFAT signaling pathways.11-13 Crisaborole suppresses the release of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL), IL-2, IL-5, and interferon-γ (IFN-γ).9,14 Crisaborole topical ointment, 2% (Anacor Pharmaceuticals, Inc., Palo Alto, CA, USA) is a new class of nonsteroidal topical anti-inflammatory PDE4 inhibitor that has completed phase 3 clinical development for treatment of children, adolescents, and adults with mild to moderate AD.9,15 This review discusses the discovery and development of crisaborole, focusing on the unique characteristics of the molecule and its potential role in the treatment of AD.