Advertisement

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

Open AccessPublished:July 11, 2016DOI:https://doi.org/10.1016/j.jaad.2016.05.046

      Background

      Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks.

      Objective

      We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792).

      Methods

      Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus.

      Results

      More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = .005; 48.5% vs 29.7%, P < .001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P ≤ .001). Treatment-related adverse events were infrequent and mild to moderate in severity.

      Limitations

      Short study duration was a limitation.

      Conclusions

      Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD.

      Key words

      Abbreviations used:

      AD (atopic dermatitis), AE (adverse event), ISGA (Investigator's Static Global Assessment), MedDRA (Medical Dictionary for Regulatory Activities), PDE4 (phosphodiesterase 4), TCI (topical calcineurin inhibitor), TCS (topical corticosteroid), TEAE (treatment-emergent adverse event)
      • Phosphodiesterase 4 regulates inflammation and is overactive in atopic dermatitis.
      • In two phase III studies, crisaborole ointment, a novel phosphodiesterase 4 inhibitor, improved disease severity and pruritus with a favorable safety profile in patients with mild to moderate atopic dermatitis.
      • Crisaborole represents a promising, nonsteroidal topical treatment to improve management of atopic dermatitis.
      Atopic dermatitis (AD), a complex chronic inflammatory skin disease characterized by erythematous, eczematous lesions and often intense pruritus,
      • Bieber T.
      Atopic dermatitis.
      • Bieber T.
      Atopic dermatitis.
      • Eichenfield L.F.
      • Tom W.L.
      • Berger T.G.
      • et al.
      Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies.
      is prevalent worldwide and affects both children and adults, with up to 90% of patients presenting with mild to moderate disease.
      • Odhiambo J.A.
      • Williams H.C.
      • Clayton T.O.
      • Robertson C.F.
      • Asher M.I.
      Global variations in prevalence of eczema symptoms in children from ISAAC phase three.
      • Arkwright P.D.
      • Motala C.
      • Subramanian H.
      • Spergel J.
      • Schneider L.C.
      • Wollenberg A.
      Management of difficult-to-treat atopic dermatitis.
      AD-associated pruritus results in frequent scratching and contributes significant psychological, social, and quality-of-life burdens to patients and their families.
      • Blume-Peytavi U.
      • Metz M.
      Atopic dermatitis in children: management of pruritus.
      • Mollanazar N.K.
      • Smith P.K.
      • Yosipovitch G.
      Mediators of chronic pruritus in atopic dermatitis: getting the itch out?.
      • Schneider L.
      • Tilles S.
      • Lio P.
      • et al.
      Atopic dermatitis: a practice parameter update 2012.
      It also generates a substantial financial burden, with cost estimates of up to $3.8 billion annually in the United States alone.
      • Ellis C.N.
      • Drake L.A.
      • Prendergast M.M.
      • et al.
      Cost of atopic dermatitis and eczema in the United States.
      More than 80% of children with AD have persistence of symptoms into their adult years, a percentage much higher than previously appreciated.
      • Margolis J.S.
      • Abuabara K.
      • Bilker W.
      • Hoffstad O.
      • Margolis D.J.
      Persistence of mild to moderate atopic dermatitis.
      In addition, AD is often associated with significant comorbidities, including asthma and allergic rhinitis.
      • Bieber T.
      Atopic dermatitis.
      • Bieber T.
      Atopic dermatitis.
      • Schneider L.
      • Tilles S.
      • Lio P.
      • et al.
      Atopic dermatitis: a practice parameter update 2012.
      Topical treatments are commonly prescribed to alleviate AD symptoms, reduce inflammation, and prevent flares,
      • Carr W.W.
      Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations.
      but no new molecules have been approved for the treatment of AD in the past 15 years, and treatment guidelines recommend the use of topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), or both.
      • Eichenfield L.F.
      • Tom W.L.
      • Berger T.G.
      • et al.
      Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies.
      • Schneider L.
      • Tilles S.
      • Lio P.
      • et al.
      Atopic dermatitis: a practice parameter update 2012.
      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. Long-term TCS use is restricted to avoid local cutaneous atrophy (especially in sensitive and thin-skinned areas such as face and groin), striae formation, and systemic side effects,
      • Eichenfield L.F.
      • Tom W.L.
      • Berger T.G.
      • et al.
      Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies.
      • Schneider L.
      • Tilles S.
      • Lio P.
      • et al.
      Atopic dermatitis: a practice parameter update 2012.
      TCIs are associated with burning/stinging upon application and require enhanced patient education because of a boxed warning for increased risk of lymphoma.
      • Eichenfield L.F.
      • Tom W.L.
      • Berger T.G.
      • et al.
      Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies.
      • Schneider L.
      • Tilles S.
      • Lio P.
      • et al.
      Atopic dermatitis: a practice parameter update 2012.
      • Siegfried E.C.
      • Jaworski J.C.
      • Hebert A.A.
      Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice.
      • Walling H.W.
      • Swick B.L.
      Update on the management of chronic eczema: new approaches and emerging treatment options.
      Hence, novel topical therapies that may potentially improve upon the risk-benefit profile of current therapies are needed.
      Phosphodiesterase 4 (PDE4) is a key regulator of inflammatory cytokine production in AD through the degradation of cyclic adenosine monophosphate.
      • Jimenez J.L.
      • Punzon C.
      • Navarro J.
      • Munoz-Fernandez M.A.
      • Fresno M.
      Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation.
      • Baumer W.
      • Hoppmann J.
      • Rundfeldt C.
      • Kietzmann M.
      Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis.
      PDE4 activity is increased in circulating inflammatory cells of patients with AD,
      • Grewe S.R.
      • Chan S.C.
      • Hanifin J.M.
      Elevated leukocyte cyclic AMP-phosphodiesterase in atopic disease: a possible mechanism for cyclic AMP-agonist hyporesponsiveness.
      • Heskel N.S.
      • Chan S.C.
      • Thiel M.L.
      • Stevens S.R.
      • Casperson L.S.
      • Hanifin J.M.
      Elevated umbilical cord blood leukocyte cyclic adenosine monophosphate-phosphodiesterase activity in children with atopic parents.
      • Butler J.M.
      • Chan S.C.
      • Stevens S.
      • Hanifin J.M.
      Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis.
      • Hanifin J.M.
      Phosphodiesterase and immune dysfunction in atopic dermatitis.
      and the inhibition of PDE4 in monocytes in vitro has demonstrated reduction in the release of proinflammatory cytokines.
      • Hanifin J.M.
      • Chan S.C.
      • Cheng J.B.
      • et al.
      Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis.
      The oral PDE4 inhibitor apremilast was recently 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 nontarget tissues.
      • Moustafa F.
      • Feldman S.R.
      A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology.
      • Wittmann M.
      • Helliwell P.S.
      Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases.
      A topical PDE4 inhibitor formulation could address the need for targeted inhibition of inflammation in skin diseases while avoiding unwanted side effects.
      The novel boron chemistry of crisaborole enables synthesis of a low-molecular-weight compound (251 d) that facilitates effective penetration through human skin.
      • 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.
      Crisaborole enhances cellular control of inflammation by inhibiting PDE4 and its ability to degrade intracellular cyclic adenosine monophosphate,
      • Baumer W.
      • Hoppmann J.
      • Rundfeldt C.
      • Kietzmann M.
      Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis.
      • Akama T.
      • Baker S.J.
      • Zhang Y.K.
      • 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.
      • Dastidar S.G.
      • Rajagopal D.
      • Ray A.
      Therapeutic benefit of PDE4 inhibitors in inflammatory diseases.
      • Freund Y.R.
      • Akama T.
      • Alley M.R.
      • et al.
      Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center.
      • Nazarian R.
      • Weinberg J.M.
      AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis.
      thereby suppressing the release of cytokines by affecting downstream regulation of the nuclear factor-κB and nuclear factor of activated T-cell signaling pathways.
      • Jimenez J.L.
      • Punzon C.
      • Navarro J.
      • Munoz-Fernandez M.A.
      • Fresno M.
      Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation.
      • 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.
      • Jimenez J.L.
      • Iniguez M.A.
      • Munoz-Fernandez M.A.
      • Fresno M.
      Effect of phosphodiesterase 4 inhibitors on NFAT-dependent cyclooxygenase-2 expression in human T lymphocytes.
      • Zane L.T.
      • Chanda S.
      • Jarnagin K.
      • Nelson D.B.
      • Spelman L.
      • Stein Gold L.F.
      Crisaborole and its potential role in treating atopic dermatitis: overview of early clinical studies.
      Although systemic exposure to crisaborole may vary with the percentage of body surface area involved, it is rapidly and substantially metabolized to inactive metabolites that have no effect on PDE4 activity or cytokine release, thus limiting systemic exposure and reducing the risk of adverse effects.
      • Zane L.T.
      • Kircik L.
      • Call R.
      • et al.
      AN2728 Topical ointment, 2% in patients 2 to 17 years of age with atopic dermatitis: a phase 1b, open-label, maximal-use systemic exposure (MUSE) study.
      Preclinical analysis in rats and mice revealed that crisaborole is noncarcinogenic, and early clinical data
      • Murrell D.
      • Gebauer K.
      • Spelman L.
      • Zane L.T.
      Crisaborole topical ointment, 2% in adults with atopic dermatitis: a phase 2A, vehicle-controlled, proof-of-concept study.
      • Stein Gold L.F.
      • Spelman L.
      • Spellman M.C.
      • Hughes M.H.
      • Zane L.T.
      A phase 2, randomized, controlled, dose-ranging study evaluating crisaborole topical ointment, 0.5% and 2% in adolescents with mild to moderate atopic dermatitis.
      • Tom W.L.
      • Van S.M.
      • Chanda S.
      • Zane L.T.
      Pharmacokinetic profile, safety, and tolerability of crisaborole topical ointment, 2% in adolescents with atopic dermatitis: an open-label phase 2a study.
      demonstrated a favorable safety profile for crisaborole in children as young as 2 years of age. Two pivotal phase III studies were performed to evaluate the efficacy and safety of crisaborole 2% ointment in patients aged 2 years of age or older with mild to moderate AD.

      Methods

       Study design and oversight

      Two identically designed multicenter, randomized, double-blind, vehicle-controlled phase III clinical studies conducted in the United States (ClinicalTrials.gov AD-301: NCT02118766; AD-302: NCT02118792) assessed the efficacy and safety of crisaborole in patients with mild to moderate AD. Study protocols were developed and conducted, and data were recorded and reported by the study sponsor (Anacor Pharmaceuticals, Inc) in accordance with the principles of Good Clinical Practice and relevant country-specific regulatory requirements. At each participating investigational center (47 and 42 investigational centers for AD-301 and AD-302, respectively), the institutional review board approved all study protocols, informed consent/assent forms, and relevant supporting data. No participants (principal investigator, study staff, participants, nor parents/guardians) knew the treatment assignment, and blinding was maintained throughout clinical management, data management, and statistical evaluation until a database lock memo was issued.

       Patients

      Patients were randomized via the interactive World Wide Web response system 2:1 to receive crisaborole:vehicle treatment (Fig 1 and Supplementary Fig 1). Key inclusion criteria required patients to be aged 2 years or older and have a clinical diagnosis of AD according to Hanifin and Rajka
      • Hanifin J.M.
      • Rajka G.
      Diagnostic features of atopic dermatitis.
      criteria, 5% or more treatable body surface area involvement, and a baseline Investigator's Static Global Assessment (ISGA) score of mild (2) or moderate (3) (Supplementary Fig 1). Key exclusion criteria prohibited previous use of biologic therapy or systemic corticosteroids within 28 days or TCS or TCI use within 14 days. Patients with active skin infections were excluded (Supplementary Fig 1). Patients on stable regimens (consistent use ≥14 days before day 1) of inhaled corticosteroids, antihistamines, and topical retinoids for non-AD lesion treatment were allowed to continue their medications. Patients were also allowed to use acceptable bland emollients to manage dry skin areas around, but not overlapping, the treatable AD-involved areas.
      Figure thumbnail gr1
      Fig 1Atopic dermatitis. Enrollment, randomization, treatment, and follow-up. BSA, Body surface area; ISGA, Investigator's Static Global Assessment.

       Crisaborole ointment treatment

      Patients were instructed to apply a layer of study drug to cover each lesion twice daily throughout the 28-day study to all areas affected by AD at baseline. The scalp was excluded from treatment to avoid potential patient dissatisfaction with ointment application to scalp hair. Patients and caregivers were provided with documentation for designated treatment areas at each visit and instructed to apply additional study drug as needed to newly identified AD lesions that appeared after day 1. Application instructions were reviewed at scheduled weekly in-clinic visits (days 8, 15, and 22).

       Evaluation

      The primary efficacy end point of success in ISGA score at day 29 was defined as clear (0) or almost clear (1) with a 2-grade or more improvement from baseline (Supplementary Table I). Analysis of the secondary efficacy end points included the proportion of patients with an ISGA score of clear (0) or almost clear (1) at day 29, and time to success in ISGA score. Additional predefined end points assessed pruritus severity and signs of AD (erythema, exudation, excoriation, induration/papulation, and lichenification). Pruritus severity was recorded twice daily by the patient or parent/caregiver via electronic diary. Signs of AD were measured throughout the treatment period on investigator visit days 1, 8, 15, 22, and 29. Pruritus and signs of AD were measured on a 4-point scale of none (0), mild (1), moderate (2), and severe (3) (Supplementary Tables II and III). Improvement in these measures was defined as achieving none (0) or mild (1) with a 1-grade or more improvement from baseline. Change in the severity of each sign of AD was calculated as percentage change from baseline. Primary safety assessments included adverse events (AEs), vital signs, and clinical laboratory parameters. All AEs, including serious AEs, were recorded and classified by the Medical Dictionary for Regulatory Activities (MedDRA) at baseline, investigator visit days, unscheduled doctor visits, and at the end of the study. Cardiac safety was assessed in a subset of participants with electrocardiography as a safety parameter required by the US Food and Drug Administration.

       Statistical analysis

      The sample size was selected for efficacy to yield at least 90% power to achieve a statistically significant difference (2-sided test at α = .05), assuming success rates of 20% (crisaborole-treated group) and 10% (vehicle-treated group). Efficacy analyses were performed using the intent-to-treat population, which included all patients randomized and dispensed study drug, regardless of discontinuation. The odds ratio of success in ISGA score at day 29 and secondary end points were tested between treatment groups using logistic regression with factors for treatment group and analysis center. Time to success in ISGA score and time to improvement in pruritus were analyzed by Kaplan-Meier methods and the log-rank test. Severity of signs of AD and pruritus were evaluated using descriptive statistics. The analyzed safety population included all patients who were randomized, were confirmed to have received 1 or more doses of the study drug, and who received 1 or more postbaseline assessments. For treatment-emergent AEs (TEAEs), the frequency of patients with 1 or more TEAEs was tabulated and a Fisher exact test was performed on any TEAE that occurred at a frequency of 1% or greater. In addition, a Fisher exact test was performed for any treatment-related event that occurred at a frequency of 1% or greater within any treatment group.

      Results

       Patients and enrollment

      The intent-to-treat population consisted of 503:256 and 513:250 patients randomly assigned to receive crisaborole:vehicle, for AD-301 and AD-302, respectively (Supplementary Fig 1). There were no significant differences across treatment groups or across studies in baseline demographics and disease severity (Table I).
      Table IBaseline patient and disease characteristics
      CharacteristicAD-301AD-302
      Crisaborole ointment, n = 503Vehicle, n = 256Crisaborole ointment, n = 513Vehicle, n = 250
      Age, y
       Mean12.012.412.611.8
       Range2-652-632-792-79
      Age groups, %
       2-6 y32.230.533.737.2
       7-11 y30.828.526.728.4
       12-17 y24.126.224.622.8
       ≥18 y12.914.815.011.6
      Sex, %
       Male43.544.145.044.8
       Female56.555.955.055.2
      Ethnicity, %
       Hispanic or Latino25.025.814.414.0
       Not Hispanic or Latino75.074.285.686.0
      Race, %
       American Indian or Alaska Native1.61.20.60.8
       Asian5.26.65.14.0
       Black or African American27.423.828.731.2
       Native Hawaiian or other Pacific Islander0.01.61.41.6
       White61.263.360.257.6
       Other4.63.54.14.8
      Baseline ISGA, %
       Mild (2)39.036.338.440.0
       Moderate (3)61.063.761.660.0
      % BSA
       Mean18.818.617.917.7
       Range5-955-905-955-90
      AD, Atopic dermatitis; BSA, body surface area; ISGA, Investigator's Static Global Assessment score.

       Efficacy end points

      More crisaborole-treated patients achieved success in ISGA score at day 29 than vehicle-treated patients (AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001) (Fig 2, A). In addition, Kaplan-Meier analysis demonstrated that patients treated with crisaborole achieved success in ISGA score earlier than those treated with vehicle ointment (P < .001) (Fig 2, B). More patients achieved ISGA scores of clear (0) or almost clear (1) with crisaborole at day 29 (AD-301: 51.7% vs 40.6%, P = .005; AD-302: 48.5% vs 29.7%, P < .001) (Fig 2, C).
      Figure thumbnail gr2
      Fig 2Atopic dermatitis (AD). Efficacy analysis. In studies AD-301 and AD-302, a greater proportion of crisaborole-treated patients achieved success in Investigator's Static Global Assessment (ISGA) score by day 29 (A). In addition, crisaborole-treated patients achieved success in ISGA score earlier than vehicle-treated patients as analyzed by Kaplan-Meier analysis (pooled) (B). A greater proportion of crisaborole-treated patients achieved an ISGA score of clear (0) or almost clear (1) by day 29 (C). D and E, Photographs demonstrate success in ISGA score at day 29.
      Crisaborole improved disease severity as evidenced by reduction in signs and symptoms of AD (Fig 2, D and E), including pruritus. Crisaborole-treated patients achieved improvement in pruritus earlier than vehicle-treated patients (pooled data, 1.37 vs 1.70 days, P = .001). Across all visits, a greater proportion of crisaborole-treated patients achieved improvement in pruritus (pooled data, days 8, 15, 22: P < .001; day 29: P = .002) (Fig 3). For all clinical signs of AD, a greater proportion of crisaborole-treated patients than vehicle-treated patients demonstrated improvement at day 29 (Fig 4, A), along with a greater reduction in mean severity (pooled data, erythema: P < .001; exudation: P = .001; excoriation: P < .001; induration/papulation: P = .002; lichenification: P < .001) (Fig 4, B).
      Figure thumbnail gr3
      Fig 3Atopic dermatitis (AD). Improvements in pruritus. In a pooled analysis of studies AD-301 and AD-302, a greater percentage of crisaborole-treated patients achieved improvement in pruritus at the earliest evaluation and throughout treatment compared with vehicle-treated patients.
      Figure thumbnail gr4
      Fig 4Atopic dermatitis (AD). Improvement in signs of AD. In pooled analysis of AD-301 and AD-302, comparison of crisaborole-treated with vehicle-treated patients at day 29 revealed a greater proportion of crisaborole-treated patients achieved improvement in signs of AD (A), with greater mean reductions in severity from baseline (B).

       Safety end points

      Crisaborole demonstrated a favorable safety profile in which the majority of TEAEs reported were mild to moderate in severity (pooled data, crisaborole: 94.3% of TEAEs; vehicle: 96.9% of TEAEs), and most were considered unrelated or unlikely to be related to treatment (pooled data, crisaborole: 78.6%; vehicle: 84.2%). Treatment with crisaborole was well tolerated, with similar rates of TEAEs as vehicle (Table II). The majority of treatment-related AEs were application site pain, primarily reported as burning or stinging (Table II). Application site pain was the only treatment-related AE that occurred in 1% or more of patients. Of the patients with application site pain, 76.7% reported it on the first day of treatment, and 77.6% had resolution within 1 day of onset. No reports of treatment-related serious AEs were reported. The rates of study discontinuation because of AEs were the same in the crisaborole (1.2%) and vehicle (1.2%) treatment groups. In addition, no clinically meaningful differences were observed in patients' vital signs, electrocardiograms, and clinical laboratory parameters between treatment groups.
      Table IIAll treatment-related adverse events and treatment-emergent adverse events (≥1% of patients)
      Crisaborole ointment, n = 1012Vehicle, n = 499
      Treatment-related adverse event, n (%)
       Application site pain
      Refers to skin burning or stinging.
      45 (4.4)
      P value for the difference between treatment groups from Fisher exact test (P = .001).
      6 (1.2)
      Treatment-emergent adverse event, n (%)
       Gastrointestinal disorders27 (2.7)12 (2.4)
      Vomiting15 (1.5)5 (1.0)
       General disorders and administration site conditions75 (7.4)25 (5.0)
      Application site pain
      Refers to skin burning or stinging.
      45 (4.4)
      P value for the difference between treatment groups from Fisher exact test (P = .001).
      6 (1.2)
      Application site pruritus5 (0.5)6 (1.2)
      Pyrexia19 (1.9)7 (1.4)
       Infections and infestations118 (11.7)59 (11.8)
      Nasopharyngitis18 (1.8)6 (1.2)
      Staphylococcal skin infection1 (0.1)
      P value for the difference between treatment groups from Fisher exact test (P = .017).
      5 (1.0)
      Upper respiratory tract infection30 (3.0)15 (3.0)
       Injury, poisoning, and procedural complications20 (2.0)9 (1.8)
       Investigations
      Included clinical laboratory tests, radiologic tests, physical examination parameters, and physiologic tests.
      10 (1.0)6 (1.2)
       Nervous system disorders14 (1.4)2 (0.4)
      Headache11 (1.1)1 (0.2)
       Respiratory, thoracic, and mediastinal disorders47 (4.6)15 (3.0)
      Cough12 (1.2)8 (1.6)
      Oropharyngeal pain11 (1.1)2 (0.4)
       Skin and subcutaneous tissue disorders37 (3.7)21 (4.2)
      Dermatitis atopic7 (0.7)8 (1.6)
      Refers to skin burning or stinging.
      P value for the difference between treatment groups from Fisher exact test (P = .001).
      P value for the difference between treatment groups from Fisher exact test (P = .017).
      § Included clinical laboratory tests, radiologic tests, physical examination parameters, and physiologic tests.

      Discussion

      Crisaborole ointment, a novel PDE4 inhibitor, significantly reduced the signs and symptoms of AD in children and adults in these two phase III studies. Its positive efficacy profile was based on: (1) improvement in disease severity, as early as day 8 of treatment; (2) reduction in AD signs and symptoms; and (3) early and sustained improvement in pruritus. This novel medication showed relief of pruritus, which is important for AD treatment, as disruption of the itch-scratch cycle can mitigate AD signs, improve quality of life,
      • Garcia P.L.
      • Ebert U.
      Frontiers of rapid itch relief: a review of methylprednisolone aceponate.
      and reduce the risk for infection and scarring.
      • Blume-Peytavi U.
      • Metz M.
      Atopic dermatitis in children: management of pruritus.
      The significant efficacy of crisaborole versus vehicle was noted, despite a strong “vehicle effect” observed in these studies, which is a common phenomenon in AD clinical studies that compare active therapeutics with their emollient bases.
      • Schachner L.A.
      • Lamerson C.
      • Sheehan M.P.
      • et al.
      Tacrolimus ointment 0.03% is safe and effective for the treatment of mild to moderate atopic dermatitis in pediatric patients: results from a randomized, double-blind, vehicle-controlled study.
      For example, vehicle-treated patients in a tacrolimus study demonstrated therapeutic success in 19.5% of vehicle-treated patients at 4 weeks.
      • Schachner L.A.
      • Lamerson C.
      • Sheehan M.P.
      • et al.
      Tacrolimus ointment 0.03% is safe and effective for the treatment of mild to moderate atopic dermatitis in pediatric patients: results from a randomized, double-blind, vehicle-controlled study.
      In treating patients with AD, a topical medication should ideally disrupt the inflammatory process and provide protective benefits often seen with an emollient, including improving the skin barrier to reduce antigen access and increasing skin hydration by preventing transepidermal water loss.
      • Arkwright P.D.
      • Motala C.
      • Subramanian H.
      • Spergel J.
      • Schneider L.C.
      • Wollenberg A.
      Management of difficult-to-treat atopic dermatitis.
      As such, topical drug vehicles have physiologic cutaneous effects, adding to the drug effect in improving outcomes for patients. The incorporation of crisaborole into the vehicle significantly improved the efficacy in treating AD on a global scale and in reducing pruritus and signs of AD.
      Because of potential adverse side effects and restricted long-term use of TCS and TCI, a safe and efficacious topical alternative is needed to treat AD. Crisaborole has low systemic absorption and is quickly metabolized to its inactive metabolites, reducing the risk of systemic side effects, making it a promising therapeutic alternative to existing topical therapies.
      • Zane L.T.
      • Kircik L.
      • Call R.
      • et al.
      AN2728 Topical ointment, 2% in patients 2 to 17 years of age with atopic dermatitis: a phase 1b, open-label, maximal-use systemic exposure (MUSE) study.
      • Tom W.L.
      • Van S.M.
      • Chanda S.
      • Zane L.T.
      Pharmacokinetic profile, safety, and tolerability of crisaborole topical ointment, 2% in adolescents with atopic dermatitis: an open-label phase 2a study.
      Twice-daily application of crisaborole ointment for 28 days demonstrated a favorable safety profile in these two phase III studies based on: (1) low incidence of treatment-related AEs, (2) lack of serious treatment-related AEs, and (3) low discontinuation rates. The low incidence and mild severity of AEs observed indicate that the novel topical formulation of crisaborole allows for targeted therapy at the site of inflammation while reducing the risk of systemic side effects observed with oral PDE4 inhibitors.
      • Wittmann M.
      • Helliwell P.S.
      Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases.
      Gastrointestinal AEs, which have been observed with oral PDE4 inhibitors, were reported by crisaborole-treated patients at a low frequency (2.7%) similar to that in vehicle-treated patients (2.4%) and were not considered treatment related. Application site burning or stinging is a commonly reported side effect with TCS or TCI treatment.
      • Callen J.
      • Chamlin S.
      • Eichenfield L.F.
      • et al.
      A systematic review of the safety of topical therapies for atopic dermatitis.
      Although a direct comparison study with TCS and TCI has yet to be performed, crisaborole ointment demonstrated a low incidence of application site pain (4.4%), defined by updated MedDRA guidelines as stinging and/or burning, compared with rates of application site burning reported by tacrolimus (20%-58%) and pimecrolimus (8%-26%).
      US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)
      Protopic NDA 50-777 pharmacology review.
      US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)
      Elidel NDA 21-302 pharmacology review.
      Crisaborole-treated patients did not report cutaneous TCS AEs such as telangiectasia or skin atrophy, but these potential risks only occur with TCS treatment for 4 weeks or longer.
      • Berth-Jones J.
      • Damstra R.J.
      • Golsch S.
      • et al.
      Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study.
      The favorable safety profile demonstrated in these 28-day studies will be investigated further with a long-term safety extension study. Overall, twice-daily application of crisaborole ointment to all areas of the body with the exception of the scalp for 28 days demonstrated a favorable safety profile.
      Crisaborole represents a first-in-class nonsteroidal topical treatment that inhibits overactive PDE4 in AD to reduce the local inflammation that drives exacerbations of the disease.
      • Baumer W.
      • Hoppmann J.
      • Rundfeldt C.
      • Kietzmann M.
      Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis.
      • Akama T.
      • Baker S.J.
      • Zhang Y.K.
      • 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.
      • Dastidar S.G.
      • Rajagopal D.
      • Ray A.
      Therapeutic benefit of PDE4 inhibitors in inflammatory diseases.
      • Freund Y.R.
      • Akama T.
      • Alley M.R.
      • et al.
      Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center.
      • Nazarian R.
      • Weinberg J.M.
      AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis.
      The anti-inflammatory effect on AD pathology is clear, and crisaborole also provided early and sustained improvement in pruritus in these two trials. This significant reduction in pruritus provides additional support to the antipruritic effect observed with other PDE4 inhibitors in inflammatory skin diseases such as psoriasis.
      • Sobell J.M.
      • Foley P.
      • Toth D.
      • et al.
      Effects of apremilast on pruritus and skin discomfort/pain correlate with improvements in quality of life in patients with moderate to severe plaque psoriasis.
      The mechanism through which PDE4 regulates pruritus is not well understood but is believed to be partially an indirect result of reducing inflammation,
      • Mollanazar N.K.
      • Smith P.K.
      • Yosipovitch G.
      Mediators of chronic pruritus in atopic dermatitis: getting the itch out?.
      • Stull C.
      • Lavery M.J.
      • Yosipovitch G.
      Advances in therapeutic strategies for the treatment of pruritus.
      similar to the antipruritic effects observed with TCS treatment.
      • Stull C.
      • Lavery M.J.
      • Yosipovitch G.
      Advances in therapeutic strategies for the treatment of pruritus.
      Preclinical studies have demonstrated that PDE4 directly regulates pruritus through reduction of cutaneous neuron
      • Andoh T.
      • Yoshida T.
      • Kuraishi Y.
      Topical E6005, a novel phosphodiesterase 4 inhibitor, attenuates spontaneous itch-related responses in mice with chronic atopy-like dermatitis.
      and dorsal root ganglion neuron activity.
      • Mollanazar N.K.
      • Smith P.K.
      • Yosipovitch G.
      Mediators of chronic pruritus in atopic dermatitis: getting the itch out?.
      • Wakita H.
      • Ohkuro M.
      • Ishii N.
      • Hishinuma I.
      • Shirato M.
      A putative antipruritic mechanism of the phosphodiesterase-4 inhibitor E6005 by attenuating capsaicin-induced depolarization of C-fiber nerves.
      Mounting evidence indicates that PDE4 inhibitors directly regulate pruritus in inflammatory skin diseases, providing early relief for the most troublesome symptom of AD.
      • Schneider L.
      • Tilles S.
      • Lio P.
      • et al.
      Atopic dermatitis: a practice parameter update 2012.
      • Yosipovitch G.
      • Papoiu A.D.
      What causes itch in atopic dermatitis?.
      Crisaborole represents a promising new option for patients with mild to moderate AD based on the favorable safety profile and improvement in AD seen in these studies. Future studies could apply alternative AD severity grading scales that may provide additional efficacy information by anatomic region to further our understanding and elaborate on the role crisaborole could play in the treatment of AD. In addition, because 45% to 60% of children develop AD in their first 6 months to 1 year of life, respectively,
      • Bieber T.
      Atopic dermatitis.
      future studies may explore the potential for crisaborole treatment in patients younger than 2 years of age. Future analysis using the Eczema Area and Severity Index will provide valuable insight into site-specific efficacy of crisaborole ointment for comparison with TCS and TCI. In addition, long-term treatment is often required because of the chronic nature of AD, and patients in these two trials were enrolled in an extension study to evaluate the long-term safety of crisaborole ointment. Overall, crisaborole ointment targets the underlying mechanism of the disease and has the potential to effectively treat AD without the limitations of current therapies.
      We thank the study patients, investigators, and investigational sites, whose participation made these studies possible. We also thank John Quiring, PhD, of QST Consultations Ltd, for performing the statistical analyses, and Diane B. Nelson, RN, MPH, of Anacor Pharmaceuticals, Inc, who provided critical review and revision of the manuscript. Sarah Utley, PhD, and Corey Mandel, PhD, of ApotheCom provided writing and editorial assistance, which was funded by Anacor Pharmaceuticals, Inc.

      Appendix.

      Figure thumbnail fx1
      Supplementary Fig 1Atopic dermatitis (AD). Study design and treatment. Key screening criteria, patient enrollment, randomization, and assessments. AD, Atopic dermatitis; BID, twice daily; BSA, body surface area; ECG, electrocardiography; ISGA, Investigator's Static Global Assessment; TCI, topical calcineurin inhibitor; TCS, topical corticosteroid. *Proprietary vehicle developed by Anacor Pharmaceuticals, Inc.
      Supplementary Table IInvestigator's Static Global Assessment
      ScaleGradeDefinition
      0ClearMinor residual hypopigmentation/hyperpigmentation; no erythema or induration/papulation; no oozing/crusting
      1Almost clearTrace faint pink erythema, with barely perceptible induration/papulation and no oozing/crusting
      2MildFaint pink erythema with mild induration/papulation and no oozing/crusting
      3ModeratePink-red erythema with moderate induration/papulation with or without oozing/crusting
      4SevereDeep or bright red erythema with severe induration/papulation and with oozing/crusting
      To assess the patient's overall disease severity across all treatable atopic dermatitis lesions, Investigator's Static Global Assessment (ISGA) was assessed at screening and days 1, 8, 15, 22, and 29. ISGA was assessed on a 5-point scale from clear (0) to severe (4).
      Supplementary Table IISeverity of pruritus scale
      ScaleGradeDefinition
      0NoneNo itching
      1MildOccasional, slight itching/scratching
      2ModerateConstant or intermittent itching/scratching that is not disturbing sleep
      3SevereBothersome itching/scratching that is disturbing sleep
      Severity of pruritus was recorded twice daily via electronic diary by patients or caregivers before study drug was applied from days 1-29. Severity of pruritus was assessed on a 4-point scale from none (0) to severe (3).
      Supplementary Table IIISigns of atopic dermatitis scale
      ScoreGradeDefinition
      Erythema (redness)
       0NoneNo redness
       1MildMildly detectable erythema; pink
       2ModerateDull red; clearly distinguishable
       3SevereDeep, dark red; marked and extensive
      Exudation (oozing and crusting)
       0NoneNo oozing or crusting
       1MildMinor or faint signs of oozing
       2ModerateDefinite oozing or crusting
       3SevereMarked and extensive oozing or crusting
      Excoriation (evidence of scratching)
       0NoneNo evidence of excoriation
       1MildMild excoriation
       2ModerateDefinite excoriation
       3SevereMarked, deep, or extensive excoriation
      Induration/papulation
       0NoneNone
       1MildSlightly perceptible elevation
       2ModerateClearly perceptible elevation but not extensive
       3SevereMarked and extensive elevation
      Lichenification (epidermal thickening)
       0NoneNo epidermal thickening
       1MildMinor epidermal thickening
       2ModerateModerate epidermal thickening; accentuated skin lines
       3SevereSevere epidermal thickening; deeply accentuated skin lines
      Signs of atopic dermatitis were assessed at every scheduled in-clinic visit from baseline through day 29. Signs of atopic dermatitis were assessed on a 4-point scale from none (0) to severe (3).

      List of investigators

       Study AD-301: 4-Week Crisaborole Topical Ointment, 2%, Study (All study sites were located in the United States)

      William Berger, Allergy & Asthma Associates of Southern California, Mission Viejo, CA; Suzanne Bruce, Suzanne Bruce and Associates, PA, The Center for Skin Research, Houston, TX; Sunil Dhawan, Center for Dermatology Clinical Research, Inc, Fremont, CA; Francisco Flores, FXM Research Miramar, Miramar, FL; Steven Kempers, Minnesota Clinical Study Center, Fridley, MN; Edward Kent, Timber Lane Allergy & Asthma Research, LLC, South Burlington, VT; Leon Kircik, Derm Research, PLLC, Louisville, KY; David Pariser, Virginia Clinical Research, Inc, Norfolk, VA; Elyse Rafal, DermResearchCenter of New York, Inc, Stony Brook, NY; Nathan Segall, Clinical Research Atlanta (CRA)-Atlanta, Stockbridge, GA; Craig Spiegel, Craig A. Spiegel, MD, Bridgeton, MO; Dow Stough, Burke Pharmaceutical Research, Hot Springs, AR; Leonard Swinyer, Dermatology Research Center, Inc, Salt Lake City, UT; Wynnis Tom, Rady Children's Hospital-San Diego, San Diego, CA; Eduardo Tschen, Academic Dermatology Associates, Albuquerque, NM; Diane McConnehey, Northwest Clinical Trials, Inc, Boise, ID; David Fivenson, David Fivenson, MD, Dermatology, PLLC, Ann Arbor, MI; James Solomon, Leavitt Medical Associates of Florida dba Ameriderm Research, Ormond Beach, FL; Zoe Draelos, Dermatology Consulting Services, High Point, NC; Robert Sidbury, Seattle Children's Hospital, Seattle, WA; Leslie Baumann, Baumann Cosmetic & Research Institute, Miami, FL; Michael Simon, Michael W. Simon, MD, PSC, Nicholasville, KY; George Murakawa, Somerset Skin Centre/Dermatology Center, Troy, MI; David Goldberg, Skin Laser & Surgery Specialists of New York and New Jersey, LLC, Hackensack, NJ; Paul Ratner, Sylvana Research Associates, San Antonio, TX; Aftab Naz, Madera Family Medical Group, Madera, CA; Oral Alpan, O&O Alpan, LLC, Fairfax, VA; Colony Fugate, Oklahoma State University Center for Health Sciences, Tulsa, OK; Angela Yen Moore, Arlington Research Center, Arlington, TX; Emily Becker, Texas Dermatology and Laser Specialists, San Antonio, TX; Michael Tharp, Rush University Medical Center, Chicago, IL; Moise Levy, Seton Healthcare dba Seton Family of Hospitals, Austin, TX; Paul Qaqundah, Pediatric Care Medical Group, Inc, Huntington Beach, CA; Mark Lebwohl, Mount Sinai Health System, New York, NY; Timothy Jochen, Palmtree Clinical Research, Palm Springs, CA; Joe Williams Jr, IMMUNOe International Research Centers, Thornton, CO; Neil Sadick, Sadick Research Group, New York, NY; Sharon Glick, SUNY Downstate Medical Center, Brooklyn, NY; Benjamin Lockshin, DermAssociates, Silver Spring, MD; Michael Chapman, Dartmouth Hitchcock Medical Center, Lebanon, NH; Andrea Zaenglein, Pennsylvania State University and Milton S. Hershey Medical Center, Hershey, PA; Sarah Arron, UCSF, San Francisco, CA; Joshua Berlin, Berlin Dermatology, Boynton, FL; Shani Francis, Northshore University Health System, Skokie, IL; Mark Nestor, Center for Cosmetic Enhancement, Aventura, FL; Paul Wisman Jr, Pediatric Research of Charlottesville, LLC, Charlottesville, VA; Richard Gower, Marycliff Allergy Specialists, Spokane, WA; David Bank, The Center for Dermatology, Cosmetic and Laser Surgery, Mt. Kisco, NY.

       Study AD-302: 4-Week Crisaborole Topical Ointment, 2% Study (All study sites were located in the United States)

      Robert Call, Clinical Research Partners, LLC, Richmond, VA; Fran Cook-Bolden, Skin Specialty Dermatology, New York, NY; Steven Feldman, Wake Forest University Health Sciences, Winston-Salem, NC; Douglass Forsha, Jordan Valley Dermatology & Research Center, West Jordan, UT; Joseph Fowler Jr, Dermatology Specialists Research, LLC, Louisville, KY; Scott Fretzin, Dawes Fretzin Clinical Research Group, LLC, Indianapolis, IN; Sherwin Gillman, CHOC PSF, AMC, Division of Allergy, Asthma & Immunology, Orange, CA; Adelaide Hebert, University of Texas Health Science Center Houston, Houston, TX; Alfonso Henriquez, Altus Research, Inc, West Palm Beach, FL; Mark Lee, Progressive Clinical Research, PA, San Antonio, TX; William Rees, PI-Coor Clinical Research, Burke, VA; Joel Schlessinger, Skin Specialists, PC, Omaha, NE; Linda Stein Gold, Henry Ford Health System, Detroit, MI; William Werschler, Premier Clinical Research, Spokane, WA; Michael Jarratt, DermResearch Inc, Austin, TX; Johnnie Woodson, J. Woodson Dermatology and Associates, Ltd, Henderson, NV; Hector Wiltz, FXM Research Corp, Miami, FL; Eric Simpson, Oregon Heath & Science University, Portland, OR; James Hedrick, Kentucky Pediatric/Adult Research, Bardstown, KY; Loretta Gremillion, Clinical Trials of America, Inc, Monroe, LA; Lesley Loss, Skin Search of Rochester, Inc, Rochester, NY; Steven Grekin, Grekin Skin Institute, Warren, MI; Elaine Siegfried, St. Louis University School of Medicine, St. Louis, MO; Frank Calcagno, Cyn3rgy Research, Gresham, OR; Richard Fried, Yardley Dermatology Associates, PC, Morrisville, PA; Ellen Frankel, Clinical Partners, LLC, Johnston, RI; Jeffrey Leflein, Respiratory Medicine Research Institute of Michigan, PLC, Ypsilanti, MI; Cheryl Hull, Northwest Arkansas Clinical Trials Center, PLLC, Rogers, AR; David Cardona, Universal Biopharma Research Institute, Inc, Dinuba, CA; Aida Lugo Somolinos, UNC Dermatology, Chapel Hill, NC; Stacy Smith, California Dermatology & Clinical Research Institute, Encinitas, CA; Yolanda Helfrich, University of Michigan Dermatology, Ann Arbor, MI; M. Alan Menter, Menter Dermatology Research Institute, Dallas, TX; Duane Harris, Intermountain Clinical Research, Draper, UT; Jonathan Crane, DermOne of North Carolina, Wilmington, NC; Harper Price, Phoenix Children's Hospital, Phoenix, AZ; Nathan Forbush, Tanner Clinic, Layton, UT; Julie Shepard, Ohio Pediatric Research Association, Dayton, OH; Joyce Teng, Stanford University, Palo Alto, CA; Mark Boguniewicz, National Jewish Health, Denver, CO; Frank Armstrong, Florida Research Specialists, Seminole, FL; Amy Paller, Northwestern University Feinberg School of Medicine, Chicago, IL; Jeffrey Sugarman, Redwood Family Dermatology, Santa Rosa, CA; Anna Bruckner, University of Colorado Hospital (Aurora, Colorado) - Children's Hospital Colorado, Aurora, CO; Stephen Tyring, Dermatology Associates of Texas, Houston, TX.

      References

        • Bieber T.
        Atopic dermatitis.
        Ann Dermatol. 2010; 22: 125-137
        • Bieber T.
        Atopic dermatitis.
        N Engl J Med. 2008; 358: 1483-1494
        • Eichenfield L.F.
        • Tom W.L.
        • Berger T.G.
        • 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: 116-132
        • Odhiambo J.A.
        • Williams H.C.
        • Clayton T.O.
        • Robertson C.F.
        • Asher M.I.
        Global variations in prevalence of eczema symptoms in children from ISAAC phase three.
        J Allergy Clin Immunol. 2009; 124: 1251-1258
        • Arkwright P.D.
        • Motala C.
        • Subramanian H.
        • Spergel J.
        • Schneider L.C.
        • Wollenberg A.
        Management of difficult-to-treat atopic dermatitis.
        Journal of Allergy Clin Immunol Pract. 2013; 1: 142-151
        • Blume-Peytavi U.
        • Metz M.
        Atopic dermatitis in children: management of pruritus.
        J Eur Acad Dermatol Venereol. 2012; 26: 2-8
        • Mollanazar N.K.
        • Smith P.K.
        • Yosipovitch G.
        Mediators of chronic pruritus in atopic dermatitis: getting the itch out?.
        Clin Rev Allergy Immunol. 2015; ([Epub ahead of print])
        • Schneider L.
        • Tilles S.
        • Lio P.
        • et al.
        Atopic dermatitis: a practice parameter update 2012.
        J Allergy Clin Immunol. 2013; 131: 295-299
        • Ellis C.N.
        • Drake L.A.
        • Prendergast M.M.
        • et al.
        Cost of atopic dermatitis and eczema in the United States.
        J Am Acad Dermatol. 2002; 46: 361-370
        • Margolis J.S.
        • Abuabara K.
        • Bilker W.
        • Hoffstad O.
        • Margolis D.J.
        Persistence of mild to moderate atopic dermatitis.
        JAMA Dermatol. 2014; 150: 593-600
        • Carr W.W.
        Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations.
        Paediatr Drugs. 2013; 15: 303-310
        • Siegfried E.C.
        • Jaworski J.C.
        • Hebert A.A.
        Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice.
        Am J Clin Dermatol. 2013; 14: 163-178
        • Walling H.W.
        • Swick B.L.
        Update on the management of chronic eczema: new approaches and emerging treatment options.
        Clin Cosmet Investig Dermatol. 2010; 3: 99-117
        • Jimenez J.L.
        • Punzon C.
        • Navarro J.
        • Munoz-Fernandez M.A.
        • Fresno M.
        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; 299: 753-759
        • Baumer W.
        • Hoppmann J.
        • Rundfeldt C.
        • Kietzmann M.
        Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis.
        Inflamm Allergy Drug Targets. 2007; 6: 17-26
        • Grewe S.R.
        • Chan S.C.
        • Hanifin J.M.
        Elevated leukocyte cyclic AMP-phosphodiesterase in atopic disease: a possible mechanism for cyclic AMP-agonist hyporesponsiveness.
        J Allergy Clin Immunol. 1982; 70: 452-457
        • Heskel N.S.
        • Chan S.C.
        • Thiel M.L.
        • Stevens S.R.
        • Casperson L.S.
        • Hanifin J.M.
        Elevated umbilical cord blood leukocyte cyclic adenosine monophosphate-phosphodiesterase activity in children with atopic parents.
        J Am Acad Dermatol. 1984; 11: 422-426
        • Butler J.M.
        • Chan S.C.
        • Stevens S.
        • Hanifin J.M.
        Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis.
        J Allergy Clin Immunol. 1983; 71: 490-497
        • Hanifin J.M.
        Phosphodiesterase and immune dysfunction in atopic dermatitis.
        J Dermatol Sci. 1990; 1: 1-6
        • Hanifin J.M.
        • Chan S.C.
        • Cheng J.B.
        • et al.
        Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis.
        J Invest Dermatol. 1996; 107: 51-56
        • Moustafa F.
        • Feldman S.R.
        A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology.
        Dermatol Online J. 2014; 20: 22608
        • Wittmann M.
        • Helliwell P.S.
        Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases.
        Dermatol Ther (Heidelb). 2013; 3: 1-15
        • 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; 15: 390-396
        • Akama T.
        • Baker S.J.
        • Zhang Y.K.
        • 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; 19: 2129-2132
        • Dastidar S.G.
        • Rajagopal D.
        • Ray A.
        Therapeutic benefit of PDE4 inhibitors in inflammatory diseases.
        Curr Opin Investig Drugs. 2007; 8: 364-372
        • Freund Y.R.
        • Akama T.
        • Alley M.R.
        • et al.
        Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center.
        FEBS Lett. 2012; 586: 3410-3414
        • Nazarian R.
        • Weinberg J.M.
        AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis.
        Curr Opin Investig Drugs. 2009; 10: 1236-1242
        • Jimenez J.L.
        • Iniguez M.A.
        • Munoz-Fernandez M.A.
        • Fresno M.
        Effect of phosphodiesterase 4 inhibitors on NFAT-dependent cyclooxygenase-2 expression in human T lymphocytes.
        Cell Signal. 2004; 16: 1363-1373
        • Zane L.T.
        • Chanda S.
        • Jarnagin K.
        • Nelson D.B.
        • Spelman L.
        • Stein Gold L.F.
        Crisaborole and its potential role in treating atopic dermatitis: overview of early clinical studies.
        Future Med. 2016; 8: 853-866
        • Zane L.T.
        • Kircik L.
        • Call R.
        • et al.
        AN2728 Topical ointment, 2% in patients 2 to 17 years of age with atopic dermatitis: a phase 1b, open-label, maximal-use systemic exposure (MUSE) study.
        Pediatr Dermatol. 2016; ([In press])
        • Murrell D.
        • Gebauer K.
        • Spelman L.
        • Zane L.T.
        Crisaborole topical ointment, 2% in adults with atopic dermatitis: a phase 2A, vehicle-controlled, proof-of-concept study.
        J Drugs Dermatol. 2015; 14: 1108-1112
        • Stein Gold L.F.
        • Spelman L.
        • Spellman M.C.
        • Hughes M.H.
        • Zane L.T.
        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; 14: 1394-1399
        • Tom W.L.
        • Van S.M.
        • Chanda S.
        • Zane L.T.
        Pharmacokinetic profile, safety, and tolerability of crisaborole topical ointment, 2% in adolescents with atopic dermatitis: an open-label phase 2a study.
        Pediatr Dermatol. 2016; 33: 150-159
        • Hanifin J.M.
        • Rajka G.
        Diagnostic features of atopic dermatitis.
        Acta Dermatol Venereol. 1980; 92: 44-47
        • Garcia P.L.
        • Ebert U.
        Frontiers of rapid itch relief: a review of methylprednisolone aceponate.
        J Eur Acad Dermatol Venereol. 2012; 26: 9-13
        • Schachner L.A.
        • Lamerson C.
        • Sheehan M.P.
        • et al.
        Tacrolimus ointment 0.03% is safe and effective for the treatment of mild to moderate atopic dermatitis in pediatric patients: results from a randomized, double-blind, vehicle-controlled study.
        Pediatrics. 2005; 116: e334-e342
        • Callen J.
        • Chamlin S.
        • Eichenfield L.F.
        • et al.
        A systematic review of the safety of topical therapies for atopic dermatitis.
        Br J Dermatol. 2007; 156: 203-221
        • US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)
        Protopic NDA 50-777 pharmacology review.
        Center for Drug Evaluation and Research, Silver Spring, MD2000 (Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/50777_protopic.cfm. Accessed May 3, 2016)
        • US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)
        Elidel NDA 21-302 pharmacology review.
        Center for Drug Evaluation and Research, Rockville, MD2001 (Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-302_Elidel.cfm. Accessed May 3, 2016)
        • Berth-Jones J.
        • Damstra R.J.
        • Golsch S.
        • et al.
        Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study.
        BMJ. 2003; 326: 1367
        • Sobell J.M.
        • Foley P.
        • Toth D.
        • et al.
        Effects of apremilast on pruritus and skin discomfort/pain correlate with improvements in quality of life in patients with moderate to severe plaque psoriasis.
        Acta Derm Venereol. 2016; 96: 514-520
        • Stull C.
        • Lavery M.J.
        • Yosipovitch G.
        Advances in therapeutic strategies for the treatment of pruritus.
        Expert Opin Pharmacother. 2015; 1-17: 671-687
        • Andoh T.
        • Yoshida T.
        • Kuraishi Y.
        Topical E6005, a novel phosphodiesterase 4 inhibitor, attenuates spontaneous itch-related responses in mice with chronic atopy-like dermatitis.
        Exp Dermatol. 2014; 23: 359-361
        • Wakita H.
        • Ohkuro M.
        • Ishii N.
        • Hishinuma I.
        • Shirato M.
        A putative antipruritic mechanism of the phosphodiesterase-4 inhibitor E6005 by attenuating capsaicin-induced depolarization of C-fiber nerves.
        Exp Dermatol. 2015; 24: 215-216
        • Yosipovitch G.
        • Papoiu A.D.
        What causes itch in atopic dermatitis?.
        Curr Allergy Asthma Rep. 2008; 8: 306-311

      Linked Article

      • Correction
        Journal of the American Academy of DermatologyVol. 76Issue 4
        • Preview
          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;75:494-503.
        • Full-Text
        • PDF