Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Bissonnette, Robert; Pavel, Ana B.; Diaz, Aisleen; Werth, John; Zang, Chuanbo; Vranić, Ivana; Purohit, Vivek S.; Zielinski, Michael A.; Vlahos, Bonnie; Estrada, Yeriel; Proulx, Étienne Saint‐Cyr; Ports, William C.; Guttman‐Yassky, Emma

doi:10.1016/j.jaci.2019.06.047

Cited by 95 publications

(92 citation statements)

References 91 publications

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“…It should be noted that effectiveness was an exploratory endpoint in this study and there was no comparator group. However, these results are consistent with a recently published vehicle-controlled phase IIa study, which demonstrated improvements in crisaborole-treated target lesion EASI score by day 15 in adults with mild-tomoderate AD [20].…”

Section: Discussionsupporting

confidence: 91%

Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1)

Schlessinger¹,

Shepard

Gower³

et al. 2020

Am J Clin Dermatol

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Background Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD).Objectives The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study. Methods Infants (3 to < 24 months) with Investigator's Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory). Results Included were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was − 57.5%, and mean change in Patient-Oriented Eczema Measure total score was − 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years.Conclusions In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mildto-moderate AD with systemic exposures similar to patients aged ≥ 2 years. Clinical Trial Registration NCT03356977.William C. Ports: Affiliation at the time of this study. Electronic supplementary materialThe online version of this article (https ://doi.org/10.1007/s4025 7-020-00510 -6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1)

Schlessinger¹,

Shepard

Gower³

et al. 2020

Am J Clin Dermatol

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“…However, the use of ustekinumab in AD showed a rather weak response, although drawing explicit implications is difficult due to bias in the patient treatment status as topical steroid were applied concurrently [243]. Following another treatment regime, the effectiveness of topical application of the phosphodiesterase type 4 inhibitor crisaborol was recently verified in the transcriptomic profile of AD lesions (e.g., upregulation of IL37) [244].The investigation of a rather unconventional therapeutic approach by utilizing umbilical cord mesenchymal stem cells showed their immunoregulatory effects after subcutaneous injections in an Aspergillus fulmigatus mouse model [218].…”

Section: Prognostics and Treatmentmentioning

confidence: 99%

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

Schwingen

Kaplan

Kurschus

2020

IJMS

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During the last decades, high-throughput assessment of gene expression in patient tissues using microarray technology or RNA-Seq took center stage in clinical research. Insights into the diversity and frequency of transcripts in healthy and diseased conditions provide valuable information on the cellular status in the respective tissues. Growing with the technique, the bioinformatic analysis toolkit reveals biologically relevant pathways which assist in understanding basic pathophysiological mechanisms. Conventional classification systems of inflammatory skin diseases rely on descriptive assessments by pathologists. In contrast to this, molecular profiling may uncover previously unknown disease classifying features. Thereby, treatments and prognostics of patients may be improved. Furthermore, disease models in basic research in comparison to the human disease can be directly validated. The aim of this article is not only to provide the reader with information on the opportunities of these techniques, but to outline potential pitfalls and technical limitations as well. Major published findings are briefly discussed to provide a broad overview on the current findings in transcriptomics in inflammatory skin diseases.

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“…Systemic exposure to topical calcineurin inhibitors decreases over time as skin inflammation resolves and barrier function improves 22 . A similar change in systemic exposure would be expected with crisaborole treatment, as it also reduces skin inflammation and improves skin barrier function as measured by transepidermal water loss 11 . However, studies with longer‐term treatment and multiple PK sample collections over time with crisaborole are not available to evaluate this potential effect.…”

Section: Discussionmentioning

confidence: 97%

“…PDE4 inhibition by crisaborole leads to increased intracellular cAMP levels and modulation of pathways, such as nuclear factor‐κB‐mediated inflammatory cytokine synthesis, resulting in suppression of the production of proinflammatory cytokines (eg, interferon‐γ, tumor necrosis factor‐α, interleukin [IL]‐2, IL‐5, IL‐10) 10 . Additionally, crisaborole significantly modulates key molecular pathways, including type 1 helper T cell (Th1), Th2, and Th17/Th22 axes 11 …”

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confidence: 99%

Predictors of Systemic Exposure to Topical Crisaborole: A Nonlinear Regression Analysis

Purohit

Riley

Tan

et al. 2020

The Journal of Clinical Pharma

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Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Results from 2 randomized, double‐blind, vehicle‐controlled phase 3 studies showed that twice‐daily crisaborole in children and adults with mild to moderate atopic dermatitis was efficacious and well tolerated. Initial pharmacokinetics (PK) studies of crisaborole indicated absorption with measurable systemic levels of crisaborole. The current analysis was conducted to correlate steady‐state systemic exposure parameters with ointment dose and identify covariates impacting PK parameters in healthy participants and patients with atopic dermatitis or psoriasis. A nonlinear regression analysis was conducted using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUCss] and maximum concentration [Cmax,ss]). PK data were available from 244 participants across 6 clinical studies (AUCss, N = 239; Cmax,ss, N = 241). Disease condition had the greatest impact on slope in both models, corresponding to 2.5‐fold higher AUCss and Cmax,ss values at a given ointment dose in patients with atopic dermatitis or psoriasis relative to healthy participants. Disease severity, race/ethnicity, and sex had marginal effects on AUCss and Cmax,ss. Systemic exposures were similar across age groups ≥2 years of age when the same percentage of body surface area (%BSA) was treated. Predictive performance plots for AUCss and Cmax,ss for different age groups demonstrated that the models adequately describe the observed data. Model predictions indicated that systemic exposure to crisaborole in pediatric patients (2‐17 years) is unlikely to exceed systemic exposure in adults (≥18 years), even at the highest possible ointment dose corresponding to a %BSA of 90.

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Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Cited by 95 publications

References 91 publications

Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1)

Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: A Phase IV Open-Label Study (CrisADe CARE 1)

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

Predictors of Systemic Exposure to Topical Crisaborole: A Nonlinear Regression Analysis

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