Crisaborole Ointment 2% Skin Biomarker Biopsy Study in Atopic Dermatitis

The lesion TSS is an assessment of target lesion severity based on the severity of the following 4 clinical signs: (1) erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification, each of which was rated on a scale of 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe). These 4 ratings were then added to create the TSS, which ranges from 0 (none) to 12 (most severe), with higher score representing greater severity.

CCL17 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by Taqman low density array (TLDA) reverse-transcriptase (RT) polymerase chain reaction (PCR) were normalized to the housekeeping gene ribosomal protein lateral stalk subunit P0 (RPLP0) and log2-transformed prior to analysis.

CCL18 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis.

CCL22 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis.

IL-13 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis.

KRT16 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis.

Elafin/PI3 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis.

S100A12 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis.

Epidermal thickness was one of the other skin biomarkers of atopic dermatitis and was studied using immunohistochemistry (IHC). Expression data were log2-transformed.

CD11c+ dendritic cells (DCs), CD3+ T cells, FcEpsilon + DCs, Ki 67+ cells, and langerin+ cells (for langerhans cells) were studied using IHC. These parameters were referred to as CD11c, CD3, FceR1, Ki67, langerin, respectively, in the outcome measure title above and data table below. Expression data were log2-transformed.

TLDA RT PCR was used to analyze the following other skin biomarkers: CCL13, CCL20, CCL26, CRLF2, CXCL1, CXCL2, CXCL9, CXCL10, DEFB4A, filaggrin (FLG), FOXP3, IFNG, IL-1B, IL-2, IL-2RA, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12A, IL-15, IL-15RA, IL-17A, IL-17F, IL-19, IL-22, IL-23A, IL-31, IL-32, LOR, MMP-12, PDE4A, PDE4B, PDE4D, PPL, RNA18SP5, S100A7, S100A8, and S100A9. Expression levels were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis.

FLG expression was studied using IHC and categorized as no change, partial normalization, full normalization, or worsening by a blinded expert pathologist based on visual scoring.

Histological response was studied using IHC and categorized as non-responder or responder by a blinded expert pathologist based on a global assessment of all thickness, KRT16 and FLG stains.

KRT16 expression was studied using IHC and categorized as no change, slight improvement, good improvement, excellent improvement, or worsening by a blinded expert pathologist based on visual scoring.

The lesion TSS is an assessment of target lesion severity based on the severity of the following 4 clinical signs: (1) erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification, each of which was rated on a scale of 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe). These 4 ratings were then added to create the TSS, which ranges from 0 (none) to 12 (most severe), with higher score representing greater severity.

The lesion ISGA is an assessment of target lesion severity of atopic dermatitis. The lesion ISGA score ranges from 0 to 4 (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe), with higher score representing greater severity.

The intensity of pruritus was assessed by an NRS, which was a numeric rating scale ranging from 0 (no itching) to 10 (worst imaginable itching), with higher score indicating greater severity.

AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. AEs included both SAEs and non-serious AEs. Treatment-emergent AEs were those with initial onset or increasing in severity on or after the first dose of study treatment. Each participant received both crisaborole (for one target lesion) and vehicle (for the other target lesion) on the same days during double-blind period, and only crisaborole during open-label period; therefore AEs were reported for each treatment group for participants to capture all AEs, instead of each treatment for treated area as it only captures AEs occurred at treated areas (see next Outcome Measure).

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Treatment-emergent AEs were those with initial onset or increasing in severity on or after the first dose of study treatment. During double-blind period, there were a total of 2 treatment areas (for target lesions) for each participant. For this outcome measure, treatment-emergent AEs occurred at each treated area during double-blind period were summarized. MedDRA version 21.0 coding dictionary was used.