Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis

Eichenfield, Lawrence F.; Call, Robert S.; Forsha, Douglass W.; Fowler, Joseph F.; Hebert, Adelaide A.; Spellman, Mary; Gold, Linda F Stein; Syoc, Merrie Van; Zane, Lee T.; Tschen, Eduardo

doi:10.1016/j.jaad.2017.06.010

Cited by 114 publications

(82 citation statements)

References 34 publications

(38 reference statements)

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“…The overall safety profile of crisaborole was similar to previous reports, 18,36 with no new safety findings. TEAEs were reported for 27 (67.5%) patients during the double-blind period and 16 (41.0%) patients during the open-label period (see Table E5 in this article's Online Repository at www.jacionline.org).…”

Section: Safety and Tolerabilitysupporting

confidence: 84%

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Bissonnette

Pavel

Diaz

et al. 2019

Journal of Allergy and Clinical Immunology

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Downregulated Skin Biomarkers Upregulated Crisaborole Vehicle Crisaborole Day 15 Day 8 Day 1 Day 15 Day 8 Day 1 Vehicle Day 1 NL CRISABOROLE AND ATOPIC DERMATITIS SKIN BIOMARKERS: AN INTRAPATIENT RANDOMIZED TRIAL 2 AD lesions of identical severity were randomized intrapatient to crisaborole or vehicle and biopsied at days 1, 8, and 15 (including Th2 and Th17/Th22 axes) and improved barrier function NL skin biopsied at day 1 AD, atopic dermatitis; NL, nonlesional; Th, helper T cellBackground: Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-tomoderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. Objective: This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n 5 40) with mild-to-moderate AD. Methods: Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15.

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Section: Safety and Tolerabilitysupporting

confidence: 84%

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Bissonnette

Pavel

Diaz

et al. 2019

Journal of Allergy and Clinical Immunology

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“…Finally, CMap analysis of the USS also revealed several negatively linked drugs with phosphodiesterase IV (PDE‐IV) inhibitory activity, including the A1 adenosine receptor antagonist sulmazole. Notably, the novel non‐steroidal PDE‐4 inhibitor crisaborole (EUCRISA ™ ; Pfizer) was recently approved as a topical therapeutic for AD . Although the efficacies of many of these negatively linked materials in treating dermatological disorders requires further investigation, the linkage of multiple drugs within the same chemical classes (eg anti‐infectives) that target established signalling pathways involved in cutaneous inflammation (eg PI3K, PDE‐4) highlights the utility of the USS and in silico gene expression‐based approaches such as CMap in identifying potential new dermatological therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Analysis of gene expression profiles of multiple skin diseases identifies a conserved signature of disrupted homeostasis

Mills

Robinson

Sherrill

et al. 2018

Experimental Dermatology

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Triggers of skin disease pathogenesis vary, but events associated with the elicitation of a lesion share many features in common. Our objective was to examine gene expression patterns in skin disease to develop a molecular signature of disruption of cutaneous homeostasis. Gene expression data from common inflammatory skin diseases (eg psoriasis, atopic dermatitis, seborrhoeic dermatitis and acne) and a novel statistical algorithm were used to define a unifying molecular signature referred to as the "unhealthy skin signature" (USS). Using a pattern-matching algorithm, analysis of public data repositories revealed that the USS is found in diverse epithelial diseases. Studies of milder disruptions of epidermal homeostasis have also shown that these conditions converge, to varying degrees, on the USS and that the degree of convergence is related directly to the severity of homeostatic disruption. The USS contains genes that had no prior published association with skin, but that play important roles in many different disease processes, supporting the importance of the USS to homeostasis. Finally, we show through pattern matching that the USS can be used to discover new potential dermatologic therapeutics. The USS provides a new means to further interrogate epithelial homeostasis and potentially develop novel therapeutics with efficacy across a spectrum of skin conditions.

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“…In addition, the incorporation of boron into crisaborole's structure allows for a low molecular weight (251 Daltons) and thus easier penetration into the skin . In available maximal‐use and long‐term studies with crisaborole, AEs were primarily mild to moderate application site reactions …”

Section: Pde4 Inhibitors Currently Available and In Development For Admentioning

confidence: 99%

“…Most treatment‐emergent AEs were mild or moderate, and the most common treatment‐related AE was application site pain (crisaborole: 4.4% and vehicle: 1.2%) . Because AD often necessitates prolonged treatment, longer term safety of crisaborole was explored in an open‐label extension study of patients (N = 517) who completed these two phase 3 studies, revealing a similar safety profile after being treated for an additional 48‐week period, with no serious treatment‐related AEs . Clinical testing of crisaborole in patients aged ≥2 years under maximal‐use conditions demonstrated a mean maximum plasma concentration (C max ) of 127 ng/mL after 8 days of treatment .…”

Section: Pde4 Inhibitors Currently Available and In Development For Admentioning

confidence: 99%

The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition

Guttman‐Yassky

Hanifin

Boguniewicz

et al. 2018

Experimental Dermatology

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Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that affects children and adults. The pathophysiology of AD is complex and involves skin barrier and immune dysfunction. Many immune cytokine pathways are amplified in AD, including T helper (Th) 2, Th22, Th17 and Th1. Current treatment guidelines recommend topical medications as initial therapy; however, until recently, only two drug classes were available: topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Several limitations are associated with these agents. TCSs can cause a wide range of adverse effects, including skin atrophy, telangiectasia, rosacea and acne. TCIs can cause burning and stinging, and the prescribing information lists a boxed warning for a theoretical risk of malignancy. Novel medications with new mechanisms of action are necessary to provide better long‐term control of AD. Phosphodiesterase 4 (PDE4) regulates cyclic adenosine monophosphate in cells and has been shown to be involved in the pathophysiology of AD, making it an attractive therapeutic target. Several PDE4 inhibitors are in clinical development for use in the treatment of AD, including crisaborole, which recently became the first topical PDE4 inhibitor approved for treatment of mild to moderate AD. This review will further describe the pathophysiology of AD, explain the possible role of PDE4 in AD and review PDE4 inhibitors currently approved or being investigated for use in AD.

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Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis

Abstract: Crisaborole ointment had a low frequency of treatment-related AEs over 48 weeks of treatment of patients with AD.

Cited by 114 publications

References 34 publications

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Analysis of gene expression profiles of multiple skin diseases identifies a conserved signature of disrupted homeostasis

The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition

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