Crisaborole for Atopic Dermatitis

Atopic Dermatitis (AD) is a chronic, pruritic, relapsing inflammatory skin disease.¹ AD onset is most common between 3 months and 6 months of age, with approximately 60% of patients developing the eruption in the first year of life and 90% by 5 years of age. The majority of affected individuals (70% to 90%) have resolution of disease by adulthood.¹

AD has a complex pathogenesis involving genetic, immunologic, and environmental factors that lead to a dysfunctional skin barrier and dysregulation of the immune system.¹ The diagnosis of AD is made based on historical features, morphology and distribution of skin lesions, and associated clinical signs. Notable clinical findings include erythema, edema, xerosis, erosions/excoriations, oozing and crusting, and lichenification, but these vary by patient age and chronicity of lesions. Pruritus is a hallmark of the condition that’s responsible for much of the disease burden borne by patients and their families.¹

Sleep disturbance is common and is mostly due to the significant itch associated with AD.¹ Sleep is disrupted in up to 60% of children, increasing to 83% during exacerbation. Greater skin disease severity also appears to have an effect on mood. Depression has been noted in both teens and adults affected with AD. It’s associated with a number of other disorders including Attention Deficit Hyperactivity Disorders (ADHD), cancer, and obesity.¹

According to the American Academy of Dermatology (AAD) guidelines, topical agents are the mainstay of AD therapy.² The AAD guidelines state that moisturizers, topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) are the most impactful therapies. The choice of a moisturizer should be based on individual preference. The ideal agent should be safe, effective, inexpensive, and free of additives, fragrances, perfumes, and other potentially sensitizing agents.²

TCS are used in the management of AD in both adults and children and are the mainstay of anti-inflammatory therapy.² Topical corticosteroids have been used for treatment of atopic dermatitis for more than 60 years. Topical corticosteroids are grouped into 7 classes, from very low/lowest potency (eg, hydrocortisone 0.5% cream or ointment) to very high potency (eg, augmented betamethasone dipropionate 0.05% ointment). A variety of factors should be considered when choosing a particular topical corticosteroid for the treatment of AD, including patient age; areas of the body to which the medication will be applied; and other patient factors such as degree of xerosis, patient preference, and cost of medication. The potential for both topical and systemic adverse effects should be considered, particularly in children with AD in whom corticosteroids are used. Some of the possible adverse effects of topical corticosteroids include skin atrophy, hypothalamic-pituitary-adrenal axis suppression, changes to skin appearance and acne-like or rosacea-like eruptions. Monitoring by physical examination for cutaneous adverse effects during long-term, potent steroid use is recommended. Patient fears of adverse effects associated with the use of topical corticosteroids for AD should be recognized and addressed to improve adherence and to avoid undertreatment.²

TCI (topical tacrolimus ointment [Protopic] and pimecrolimus cream [Elidel]) are recommended and effective for acute and chronic treatment, along with maintenance, for AD.² Elidel is indicated as second-line therapy for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis.^2,3 Protopic ointment is indicated as second-line therapy for the short-term and noncontinuous chronic treatment of moderate to severe atopic.^2,4 TCIs may be preferred to TCS when treating sensitive areas and in cases of steroid-induced atrophy.² Proactive, intermittent use of TCIs as maintenance therapy (2-3 times per week) on areas that commonly flare is recommended to help prevent relapses while reducing the need for topical corticosteroids, and is more effective than the use of emollients alone. The most common adverse effects of TCIs are stinging and burning; however, the greatest concern may be the black boxed warning about risk of malignancy (eg, skin and lymphoma).²

Despite their efficacy, both TCS and TCI are associated with limitations in their use as a result of application reactions and safety concerns with long-term use.⁵ As a result, researchers have been searching for novel topical therapies that may potentially improve upon the risk-benefit profile of current therapies. One such therapy is crisaborole, an investigational nonsteroidal topical anti-inflammatory phosphodiesterase 4 inhibitor (PDE-4) in development for the potential treatment of mild to moderate atopic dermatitis.^5,6 PDE-4 is a key regulator of inflammatory cytokine production in AD through the degradation of cyclic adenosine monophosphate.⁵ PDE-4 regulates inflammation and is overactive in patients with AD.⁵ The oral PDE4 inhibitor apremilast (Otezla) is approved for treatment of moderate to severe plaque psoriasis and psoriatic arthritis, but requires dose titration to avoid gastrointestinal side effects (nausea and diarrhea) because of PDE4 inhibition in non-target tissues.⁵ A topical PDE4 inhibitor formulation could address the need for targeted inhibition of inflammation in skin diseases while avoiding unwanted adverse effects.⁵

According to ClinicalTrials.gov, the efficacy and safety of crisaborole ointment in the treatment of AD has been assessed in multiple phase 2 and phase 3 clinical trials.⁷ Paller et al published the results from two identically designed multicenter, randomized, double-blind, vehicle-controlled phase III trials that evaluated the efficacy and safety of crisaborole 2% ointment in patients aged 2 years of age or older with mild to moderate AD.⁵ Patients were instructed to apply crisaborole or the placebo vehicle twice daily to all affected areas (excluding the scalp) for the duration of the 28-day studies.⁵ The primary end point was Investigator’s Static Global Assessment (ISGA) score at day 29 of clear (0) or almost clear (1) with 2-grade or greater improvement from baseline.⁵ The ISGA is a 5-point scale ranging from 0 (clear skin) to 4 (severe; deep or bright red erythema with severe induration/papulation and with oozing/crusting).⁵

In both studies, more crisaborole-treated patients achieved success in ISGA score at day 29 than placebo-treated patients.⁵ Crisaborole improved disease severity as evidenced by reduction in signs and symptoms of AD, including pruritus.⁵ Treatment with crisaborole was well tolerated, with similar rates of treatment-emergent adverse events as placebo. The majority of treatment-related adverse events were application site pain, primarily reported as burning or stinging. Application site pain was the only treatment-related adverse events that occurred in 1% or more of patients.⁵

Anacor Pharmaceuticals, the manufacturer of crisaborole, expects the FDA to complete its review of crisaborole by January 7, 2017.⁸ Currently the proposed brand name for crisaborole is Eucrisa.⁹

References

• Eichenfield LF, Wynnis LT, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. doi: 10.1016/j.jaad.2013.
• 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;71(1):116-132. doi: 10.1016/j.jaad.2014.03.023.
• Elidel [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; August 2014.
• Protopic [package insert]. Deerfield, IL: Astellas Pharma US, Inc.; May 2012.
• 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;75(3):494-503. doi: 10.1016/j.jaad.2016.05.046.
• Anacor Pharmaceuticals announces FDA acceptance of NDA for crisaborole topical ointment, 2% for the treatment of mild-to-moderate atopic dermatitis. Anacor Pharmaceuticals website. March 22, 2016. investor.anacor.com/releasedetail.cfm?releaseid=961687. Accessed October 15, 2016.
• Clinical trials for AN2728. ClinicalTrials.gov website. clinicaltrials.gov/ct2/results?term=an2728. Accessed October 20, 2016.
• Crisaborole topical ointment, 2%, a novel non-steroidal topical anti-inflammatory PDE-4 inhibitor, is our lead product development candidate for the potential treatment of mild-to-moderate atopic dermatitis and psoriasis. Anacor Pharmaceuticals website. anacor.com/R-and-D/crisaborole. Accessed October 25, 2016.
• Pfizer adds eczema drug with $5.2bn Anacor acquisition. PMLiVE website. pmlive.com/pharma_news/pfizer_adds_eczema_drug_with_$5.2bn_anacor_acquisition_1023628. Accessed October 25, 2016.