Crisaborole

Phosphodiesterase 4 (PDE4) inhibitors are expected to exhibit efficacy against inflammatory diseases due to their broad pharmacological activity. The launched PDE4 inhibitors apremilast, crisaborole, and roflumilast have not exhibited sufficient inhibitory potential due to poor margins of effectiveness and tolerability. In this report, we describe the non-clinical efficacy, brain translocation, and vomit-inducing effects of ME3183 compared with apremilast. ME3183 showed extensive cytokine suppression in vitro studies using human peripheral blood mononuclear cells and T cells. ME3183 also significantly suppressed skin inflammation in a chronic oxazolone-induced dermatitis model and showed antipruritic effects in a substance P-induced mouse pruritus model. In these in vitro and in vivo studies, ME3183 also significantly suppressed cytokines, and focusing on tumor necrosis factor-α as a psoriasis-related cytokine and interleukin-4 as an atopic dermatitis-related cytokine, ME3183 potently inhibited both cytokines. ME3183 showed in vivo efficacy at lower doses than apremilast. The brain distribution of ME3183 was sufficiently low in mice and rats. The effective dose of ME3183 for emesis was similar to that of apremilast in ferrets. Given its high-potency inhibitory effects, ME3183 would have a wide margin of efficacy and tolerability. These wide margins demonstrate the effectiveness of ME3183 in treating many inflammatory diseases, such as psoriasis and atopic dermatitis. An on-going phase 2 trial is expected to further demonstrate the efficacy and safety of ME3183.

Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects.

We sought to systematically synthesize the benefits and harms of AD prescription topical treatments.

For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT databases to September 5, 2022, for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using 7 groups-group 1 being most potent. This review is registered in the Open Science Framework (https://osf.io/q5m6s).

The 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty evidence, pimecrolimus improved 6 of 7 outcomes-among the best for 2; high-dose tacrolimus (0.1%) improved 5-among the best for 2; low-dose tacrolimus (0.03%) improved 5-among the best for 1. With moderate- to high-certainty evidence, group 5 TCS improved 6-among the best for 3; group 4 TCS and delgocitinib improved 4-among the best for 2; ruxolitinib improved 4-among the best for 1; group 1 TCS improved 3-among the best for 2. These interventions did not increase harm. Crisaborole and difamilast were intermediately effective, but with uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus.

For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.