Novel PDE-4 Inhibitor Safe, Effective in Mild-to-Moderate Atopic Dermatitis
A novel, nonsteroidal, topical, anti-inflammatory, phosphodiesterase (PDE)-4 inhibitor (crisaborole topical ointment, 2%) was associated with early improvement in pruritus and dermatitis scores in children and adults with mild-to-moderate atopic dermatitis (AD) in two identically designed phase 3 studies. The data were reported at AAD 2016 by Adelaide A. Hebert, MD, University of Texas Health Science Center, Houston, Texas, USA.
Crisaborole is a boron-based ointment that inhibits 3’-5’-cyclic adenosine monophosphate (cAMP)-dependent PDE-4, thereby decreasing the inflammation associated with AD.
The double-blind, multicenter AD-301 study with 759 patients [NCT02118766] and AD-302 study with 763 patients [NCT02118792]included patients 2 years of age or older, with a clinical diagnosis of mild (Investigator’s Static Global Assessment [ISGA] 2) or moderate (ISGA 3) AD, involving ≥5% of the body surface area (BSA). The use of topical calcineurin inhibitors or topical corticoid steroids during the 14 days prior to screening, the presence of significant active infection, or use of any previous biologic therapy were key exclusion criteria. Study patients were randomized 2:1 to crisaborole or vehicle twice daily and followed for 28 days. Patients had weekly evaluations.
The mean age of the patients was 12 years (range, 2-65 in AD-301; 2-79 in AD-302). About 32% of the study patients were in the 2-6 years age group and about 30% were in the 7-11 years age group. About 60% of patients were female, 60% were white, and 25% were black or African American. At baseline, about 40% had mild AD (ISGA 2) and 60% had moderate AD (ISGA 3). The mean BSA was about 19%.
The primary endpoint of the proportion of patients who achieved ISGA success, defined as clear (0) or almost clear (1) with a ≥2-grade improvement from baseline at Day 29, was significantly greater with crisaborole versus vehicle in AD-301 (32.8% vs. 25.4%, respectively; p=0.038) and in AD-302 (31.4% vs. 18.0%, respectively; p<0.001).
The improvement in ISGA was achieved as early as Day 7, with about 10% of patients exhibiting improvement, and continued in a linear fashion to Day 28. The difference between crisaborole and vehicle was statistically significant for this secondary endpoint of improvement in ISGA.
Of note, significantly more patients in the crisaborole group, compared with vehicle, achieved an ISGA score of 0 or 1 at Day 29 in AD-301 (51.7% vs. 40.6%; p=0.005) and in AD-302 (48.5% vs. 29.7%; p<0.001).
A predefined pooled analysis of the change from baseline in the signs of the severity of AD were improved at Day 29 with crisaborole compared with vehicle (Table 1).
The median time to improvement in pruritus was 1.37 days with crisaborole and 1.73 days with vehicle (p=0.001) in the pooled analysis. Further, there was a significant improvement in the proportion of patients who achieved early improvement in pruritus, based on self-reports, in the pooled analysis (Table 2).
The safety profile of the investigational drug was good, without any treatment-related serious adverse events (AEs), and most AEs were mild. In the pooled analysis, the rate of discontinuation of the study drug because of AEs was similar in the crisaborole and vehicle groups at 1.2% in each group. Application-site pain was reported by 4.4% of the crisaborole-treated patients and 1.2% of vehicle-treated patients, and upper respiratory respiratory infection was reported by 3% of each group in the pooled analysis. According to Dr. Hebert, there were no clinically meaningful differences between the patient groups, including vital signs, electrocardiograms, and laboratory parameters.
Noting the lack of new topical treatments in 15 years for AD, the most common inflammatory disorder in dermatology, Dr. Hebert stated that crisaborole is a promising, safe, and effective treatment that reduces the severity of AD in patients as young as 2 years. The early relief in pruritus was associated with statistically significant improvements in the severity of AD.