Taylor Evart Woo, MSc1 and Paul Kuzel, MD, FRCPC2
1Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
2Division of Dermatology, University of Alberta, Edmonton, AB, Canada
Conflict of interest:
The authors have no conflicts to declare for this work.
Atopic dermatitis is a common cutaneous disease with significant morbidity affecting children and adults. The mainstay of atopic dermatitis therapy has typically included emollients, topical corticosteroids, and topical calcineurin inhibitors. Among the newer advances recently introduced is crisaborole (Eucrisa™), a phosphodiesterase type-4 inhibitor (PDE-4) for the treatment of mild moderate atopic dermatitis. Evidence from phase 3 trials demonstrates crisaborole as an efficacious topical agent with a favorable safety profile and limited systemic exposure. While the efficacy of crisaborole compared to existing therapies remains unknown, crisaborole is a promising candidate in the treatment of atopic dermatitis.
atopic dermatitis, crisaborole, eczema, Eucrisa, phosphodiesterase-4 inhibitor, topical treatment
Atopic dermatitis (AD) is a chronic inflammatory cutaneous condition associated with significant morbidity and stigma in affected patients.1 AD is characterized by the sudden onset of a recurrent, pruritic, erythematous and fissured dermatoses. It is estimated to affect up to 15-30% of children and up to 10% of adults living in industrialized countries.2 In the United States alone, AD imposes a considerable economic burden, with an estimated cost of up to $3.8 billion annually.1,3 Clinical features differ with age. The flexural surfaces of upper and lower extremities and face are most often affected during childhood, whereas hands and feet are more commonly involved in adult patients.4 AD can be associated with serious comorbidities including allergic rhinitis, asthma, hay fever, urticaria and asthma.3,5 Patients with genodermatoses, such as Wiskott-Aldrich syndrome, may show an AD like skin condition.6 Individuals with AD are more prone to cutaneous secondary infections by pathogens including Staphylococcus aureus, which is also a leading cause of soft-tissue infections. Moreover, secondary skin infection can lead to exacerbation of AD disease severity.7
As the frequency of AD continues to rise, renewed focused on treatment and management is increasingly important.1 As no curative options exist, therapy centers on controlling disease progression, reducing flares and providing relief from symptoms, including pain and pruritus.8,9 The mainstays of such therapies include the use of emollients, cosmeceuticals, topical and systemic corticosteroids, as well as topical calcineurin inhibitors (TCIs).2 Treatment options are predicated on age and AD severity. For instance, mild to moderate AD may be treated with TCIs or corticosteroids such as desonide 0.05% or fluocinolone 0.01%.8 In patients with moderate to severe AD who are recalcitrant to topical therapy, systemic treatment may include dupilumab administered at 300 mg subcutaneously once weekly or every other week for adults.10,11 Proactive therapy with tacrolimus 0.1% ointment or pimecrolimus 2% twice daily9 may be employed to prevent relapses and extend periods without recurrence in patients who experience frequent exacerbations. TCIs have been issued a black box warning based on theoretical concerns that their use may be linked to lymphoma,12 however, long-term surveillance has not substantiated this risk. Moreover, prolonged use of topical corticosteroids has been associated with cutaneous atrophy, telangiectasia, and striae formation.8 This has led to the development of new therapies, particularly aimed at the pediatric population. Crisaborole (formerly known as AN2728) is a novel, boron-based phosphodiesterase-4 (PDE-4) inhibitor developed to treat this populace.8,13
A Novel Treatment for Mild-Moderate AD
Crisaborole (Eucrisa™) 2% ointment is indicated as a topical treatment for patients aged ≥2 years with mild to moderate AD. Early phase 1 and 2 studies provided evidence that showed the potential for crisaborole to be an efficacious and noncarcinogenic treatment option with a positive safety profile.14-16 Approved in December of 2016 by the US FDA and June 2018 by Health Canada, it is the first topical PDE-4 inhibitor to be indicated for AD.
Mechanism of Action
In patients with AD, elevation of PDE-4 is associated with increased inflammatory mediators leading to a chronic inflammatory state.17 PDE-4 facilitates this inflammatory process through the degradation of 3’5’-cyclic adenosine monophosphate (cAMP). Crisaborole works through the selective inhibition of PDE-4, preventing the breakdown of cAMP, leading to an accumulation of cellular cAMP, suppression of pro-inflammatory cytokines, and reduction in inflammatory pathways.8,17,18 Specifically, elevated levels of cAMP result in further activation of protein kinase A and inhibition of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) signaling pathways. Crisaborole targets the underlying mechanism of the disease through suppression of pro-inflammatory cytokines, including interleukin (IL)-2, IL-5, interferon-γ, and tumor necrosis factor-α.17-19 Of note, this mechanism of cytokine-production inhibition by crisaborole is distinct from that of corticosteroids.17
Phase 3 Clinical Trials
The efficacy and safety of crisaborole was evaluated through two randomized, double-blind controlled phase 3 clinical trials, which included a total of 1522 patients ≥2 years of age with mild to moderate AD.20 Although both pediatric and adult patients were represented in the study population, the mean age of the crisaborole ointment treatment groups was 12 and 12.6 in both studies. Adult patients (≥18 years of age) constituted 12.9% and 15% of the crisaborole treatment groups. The efficacy of crisaborole within these studies was determined by the clearance or almost clearance of AD with a 2-grade or more improvement from baseline using the Investigator’s Static Global Assessment (ISGA). In both studies, more crisaborole-treated patients showed improvement in the ISGA score at day 29 (32.8%, 31.4%) as compared against vehicle-treated patients (25.4%, 18%), respectively. Furthermore, patients in the crisaboroletreated group achieved success in the ISGA score earlier than the control. Pooled data between the two studies demonstrated an improvement in disease severity, as measured by the reduction in signs and symptoms, including erythema, exudation, excoriations, induration/papulation and lichenification. Improvement and sustained relief of pruritus was achieved earlier in crisaboroletreated patients (1.37 vs. 1.7 days, p=0.001).20 A secondary analysis of the phase 3 trials performed by Yosipovitch et al.21 confirmed the early improvement in pruritus for the treatment cohort compared to control (56.6% vs. 39.5%; p<0.001).
Safety and Long-term Complications
Unlike topical corticosteroids and calcineurin inhibitors, which have potential adverse side effects with continued use, crisaborole demonstrates a promising safety profile. Crisaborole effectively penetrates through the skin due to its low molecular weight (251 Da) and lipophilic properties,17 with only trace amounts reaching the systemic circulation.22 Steady-state levels of crisaborole and its metabolites were reached in a pharmacokinetic 8-day trial under maximal-use conditions.22 In this study, the mean maximum plasma concentration of crisaborole remained stable with a mean maximum concentration of 127 ng/mL seen on day 8. Once in the bloodstream, the drug is quickly metabolized into inactive metabolites, limiting the systemic impact of crisaborole to the site of application.17,22 Whereas nausea, emesis, and/or diarrhea are side effects associated with oral PDE-4 inhibitors, similar symptoms are uncommonly observed with topical use.20,23,24 The majority of adverse events include burning or stinging at the site of application.20 Of these adverse events, 77.6% of patients experienced resolution within 1 day of onset. No serious adverse events were recorded. Lastly, the low discontinuation rates (1.2%, pooled data) that were observed in phase 3 trials may indicate the potential for higher treatment compliance.
After completion of a 28-day phase 3 pivotal study, a longitudinal multicenter, open-label trial was conducted that followed 517 patients over 48 weeks to assess the long-term safety of crisaborole.24 Only 10.3% of patients experienced treatmentrelated adverse events. Of these, the vast majority of adverse events were considered mild (51.2%) or moderate (44.6%). The most common events reported were atopic dermatitis (3.1%), application-site pain (2.3%) and application-site infection (1.2%). No change in the frequency of adverse events was observed throughout the study. Rescue therapy with a topical corticosteroid or TCI was required in 22.2% of patients, with the majority (79%) resuming crisaborole after the end of rescue therapy.
Crisaborole represents a novel and efficacious therapeutic approach for the treatment of mild to moderate AD. Through the inhibition of PDE-4 and reduction of local inflammation, crisaborole has been shown to provide a significant improvement in the management of AD.14-16,20,22 Furthermore, crisaborole demonstrates early and continued decrease in pruritus, which improves quality of life and reduces the potential risk of infection and scarring.24,25 The small size of the crisaborole molecule allows for effective skin penetration, while its quick metabolism in the bloodstream limits systemic exposure, which is associated with the long-term use of topical corticosteroids and TCIs.22 Further studies comparing crisaborole against topical corticosteroids or TCIs are warranted to establish it role in the treatment paradigm for mild to moderate AD, as well as its utility in children <2 years of age.
- Carroll CL, Balkrishnan R, Feldman SR, et al. The burden of atopic dermatitis: impact on the patient, family, and society. Pediatr Dermatol. 2005 May-Jun;22(3):192-9.
- Bieber T. Atopic dermatitis. Ann Dermatol. 2010 May;22(2):125-37.
- Ellis CN, Drake LA, Prendergast MM, et al. Cost of atopic dermatitis and eczema in the United States. J Am Acad Dermatol. 2002 Mar;46(3):361-70.
- Garmhausen D, Hagemann T, Bieber T, et al. Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy. 2013 Apr;68(4):498-506.
- Elias PM, Steinhoff M. “Outside-to-inside” (and now back to “outside”) pathogenic mechanisms in atopic dermatitis. J Invest Dermatol. 2008 May;128(5):1067-70.
- Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016 Mar 12;387(10023):1109-
- Kong HH, Oh J, Deming C, et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012 May;22(5):850-9.
- Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014 Jul;71(1):116-32.
- Carr WW. Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations. Paediatr Drugs. 2013 Aug;15(4):303-10.
- Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014 Aug;71(2):327-49.
- Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management
of moderate-to-severe atopic dermatitis with dupilumab and concomitant
topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, doubleblinded,
placebo-controlled, phase 3 trial. Lancet. 2017 Jun 10;389(10086):2287-303.
- Castellsague J, Kuiper JG, Pottegard A, et al. A cohort study on the risk of lymphoma and skin cancer in users of topical tacrolimus, pimecrolimus, and corticosteroids (Joint European Longitudinal Lymphoma and Skin Cancer Evaluation – JOELLE study). Clin Epidemiol. 2018 10:299-310.
- Akama T, Baker SJ, Zhang YK, et al. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2129-32.
- Murrell DF, Gebauer K, Spelman L, et al. Crisaborole topical ointment, 2% in adults with atopic dermatitis: a phase 2a, vehicle-controlled, proof-of-concept study. J Drugs Dermatol. 2015 Oct;14(10):1108-12.
- Stein Gold LF, Spelman L, Spellman MC, et al. A phase 2, randomized, controlled, dose-ranging study evaluating crisaborole topical ointment, 0.5% and 2% in adolescents with mild to moderate atopic dermatitis. J Drugs Dermatol. 2015 Dec;14(12):1394-9.
- Tom WL, Van Syoc M, Chanda S, et al. Pharmacokinetic profile, safety, and tolerability of crisaborole topical ointment, 2% in adolescents with atopic dermatitis: an open-label phase 2a study. Pediatr Dermatol. 2016 Mar-Apr;33(2):150-9.
- Jarnagin K, Chanda S, Coronado D, et al. Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis. J Drugs Dermatol. 2016 Apr;15(4):390-6.
- Freund YR, Akama T, Alley MR, et al. Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. FEBS Lett. 2012 Sep 21;586(19):3410-4.
- Jimenez JL, Punzon C, Navarro J, et al. Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. J Pharmacol Exp Ther. 2001 Nov;299(2):753-9.
- Paller AS, Tom WL, Lebwohl MG, et al. 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. J Am Acad Dermatol. 2016 Sep;75(3):494-503 e6.
- Yosipovitch G, Gold LF, Lebwohl MG, et al. Early relief of pruritus in atopic dermatitis with crisaborole ointment, a non-steroidal, phosphodiesterase 4 inhibitor. Acta Derm Venereol. 2018 Apr 27;98(5):484-9.
- Zane LT, Kircik L, Call R, et al. Crisaborole topical ointment, 2% in patients ages 2 to 17 years with atopic dermatitis: a phase 1b, open-label, maximal-use systemic exposure study. Pediatr Dermatol. 2016 Jul;33(4):380-7.
- Wittmann M, Helliwell PS. Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. Dermatol Ther (Heidelb). 2013 Jun;3(1):1-15.
- Eichenfield LF, Call RS, Forsha DW, et al. Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am Acad Dermatol. 2017 Oct;77(4):641-9 e5.
- Blume-Peytavi U, Metz M. Atopic dermatitis in children: management of pruritus. J Eur Acad Dermatol Venereol. 2012 Nov;26(Suppl 6):2-8.