New Understanding Leads to Exciting Therapies in Atopic Dermatitis

Atopic dermatitis (AD) is a common inflammatory skin disease that has had an unmet need for treatment until recently. However, according to Emma Guttman, MD, PhD, Waldman Professor and System Chair of Dermatology and Immunology at the Icahn School of Medicine at Mount Sinai, director of the Center for Excellence in Eczema and the Occupational Dermatitis Clinic, and director of the Laboratory for Inflammatory Skin Diseases, "The therapeutic drought is finally ending in atopic dermatitis."

There have been treatments for patients with AD, but these treatments have safety concerns, because they were not specific and targeted “every cytokine under the sun.” Particularly of concern right now is the fact that these older treatments increase infections, Guttman said.

The increase in treatments has been a result of increased research and knowledge of the pathogenesis of AD, and there are many new agents being developed, as a result. Dupilumab is already approved, and it targets the main axis, the Th2 immune axis, and interleukin (IL)-4 and IL-13. Although dupilumab has some sadverseide effects of conjunctivitis and rashes, overall it is a very safe drug for long-term use, according to Guttman.

Importantly, dupilumab not only doesn’t increase skin infections, but there is actually a trend of less skin infections, “and this is, again, super important, particularly now,” she emphasized.

In the pipeline there are 3 drugs in phase 3: tralokinumab and lebrikizumab, which target IL-13 like dupilumab, and nemolizumab, which targets IL-31.

Since dupilumab targets both IL-13 and IL-4, there has been some inquiry into whether IL-13 inhibition would be enough to control AD. Studies of tralokinumab and lebrikizumab have both indicated that IL-13 is enough, with findings indicating that they have reached significance by 16 weeks in terms of achieving Investigator’s Global Assessment 0 or 1 and ≥ 75% improvement in Eczema Area and Severity Index (EASI-75).

“So far it seems that IL-13 is the most important cytokine in atopic dermatitis,” Guttman confirmed.

Other agents in development are the Janus kinase (JAK) inhibitors, which are generating excitement. There are 3 in development: abrocitinib, upadicitinib, and baricitinib, all of which are in phase 3 or finishing up phase 3 trials. AD is a heterogeneous disease, but JAK inhibitors target several key AD cytokines.

The JADE MONO-1 study is a phase 3 trial of abrocitinib, which evaluated abrocitinib 100 mg and 200 mg vs placebo.¹ The study showed the agent achieved high significance, primarily with the 200-mg dose. Most of the EASI-75 results were seen by week 4, and there was continuous improvement by week 12. At week 12, 62.7% of patients on 200 mg and 39.7% of patients on 100 mg had achieved EASI-75.

Measure Up 1 and Measure Up 2 evaluated upadacitinib 30 mg and 15 mg vs placebo and had the “best results we’ve seen so far in atopic dermatitis,” Guttman said. The data were presented at the 2020 meeting of the European Academy of Dermatology and Venereology.

In Measure Up 1, 79.7% of patients on 30-mg dose and 69.6% of patients on the 15-mg dose reached EASI-75 vs 16.3% on placebo. In Measure Up 2, 72.9% of patients on the 30-mg dose and 60.1% of patients on the 15-mg dose reached EASI-75 vs 13.3% of placebo.

In addition, 65.8% on 30 mg and 53.1% on 15 mg vs 8.1% on placebo achieved EASI-90 in Measure Up 1. In Measure Up 2, 58.5% in 30 mg dose and 42.4% in 15 mg dose vs 5.4% in placebo achieved EASI-90.

“So quite impressive results, because we are seeking clearance,” Guttman said. “We are seeking to clear our patients [and] these are the highest EASI-90 responses achieved so far in our patients with atopic dermatitis.”

The third JAK inhibitor, baricitinib has been approved in Europe. It showed a little lower efficacy compared with the other 2 JAK inhibitors, with 28.3% of patients on baricitinib 1 mg, 32.5% on 2 mg, and 36.0% on 4 mg achieving EASI-75 vs 19.7% on placebo.²

“I think we are experiencing a really exciting medical and scientific path for a new treatment paradigm for our patients with atopic dermatitis,” Guttman concluded.

References

1. Gooderham MJ, Forman SB, Bissonnette R, et al. Efficacy and safety of oral janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial. JAMA Dermatol. 2019;155(12):1371-1379. doi:10.1001/jamadermatol.2019.2855

2. Simpson EL, Lacour J-P, Spelman L, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br J Dermatol. 2020;183(2):242-255. doi:10.1111/bjd.18898