The Show Must Go On

An Update on Clinical Experiences and Clinical Studies on Novel Pharmaceutical Developments for the Treatment of Atopic Dermatitis

Tatjana Honstein; Thomas Werfel

Disclosures

Curr Opin Allergy Clin Immunol. 2020;20(4):386-394. 

In This Article

Targeting Janus Kinases for the Treatment of Atopic Dermatitis With Baricitinib, Upadacitinib, Abrocitinib, or Gusacitinib

In addition to receptor or cytokine blockade on the extracellular portions via antibodies, it is possible to inhibit signal transmission of cytokine receptors with Janus kinase inhibitors acting in the intracellular part of receptors. JAK inhibitors are small molecules, which can be applied orally or topically, which is a theoretical advantage over the application modi of therapeutical antibodies particularly in children.

Baricitinib is a selective and reversible inhibitor of Janus kinases 1 and 2, which was already approved for the treatment of rheumatoid arthritis by the FDA and EMA. A first 'full publication' was published for a phase II study in atopic dermatitis with baricitinib in 2018.[41] Here 124 patients with moderate-to-severe atopic dermatitis were treated orally in two doses or with placebo in combination with topical corticosteroids. A 50% reduction in eczema score ('EASI50') was achieved in 61% of patients under the higher dose of 4 mg after 16 weeks of baricitinib compared with 37% in the placebo group; the therapeutic effect was significant only after 4 weeks. Itching and sleeping disturbances were also significantly reduced in the treatment group. The drug significantly improved eczema severity measured by EASI75 score by 16% of the highest dose subjects compared with 4.8% of the placebo group.

The results of two phase III studies with a total of more than 1200 subjects treated with baricitinib daily for 16 weeks were recently reported: at week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of atopic dermatitis (0, 1) on baricitinib compared with placebo in baricitinib 4 mg 16.8% and 2 mg 11.4% compared with placebo 4.8% on the first study and in baricitinib 4 mg 13.8% and 2 mg 10.6% compared with placebo 4.5%. Improvement in itch was achieved as week 1 for 4 mg and week 2 for 2 mg. Improvements in health-related life quality were also reported. Nasopharyngitis, upper respiratory tract inflammation, elevated blood creatine phosphokinase levels and headache were the most common adverse events reported in all treatment groups.[42]

Upadacitinib is a selective, reversible JAK1 inhibitor that blocks Th2 typical IL-4, IL- 13, IL- 31 cytokine-signaling pathways and was already approved by FDA and EMA for the treatment of rheumatoid arthritis. A randomized, blinded, placebo-controlled phase IIb clinical trial was conducted in 167 atopic dermatitis patients who received orally varying doses of the inhibitor or placebo for 16 weeks. A significant dose-dependent change in EASI of 50, 75% compared with control and positive development of SCORAD, BSA, and POEM was reported. Here were the most adverse effects described as for Baricitinib except for acne. A saturation plateau was not observed in this study but a steady increase in symptom improvement was observed during the 16 weeks of treatment. Therefore a long-term study was recommended and the testing of higher doses to increase potential efficacy.[43]

The selective JAK1 inhibitor abrocitinib was tested in a blinded, randomized, placebo-controlled phase IIb clinical trial with 267 subjects, who were orally administered different doses of the study drug for 12 weeks daily. EASI75 was achieved by 64.6% in the subgroup getting 200 mg of the drug versus 15.4% participants in the placebo group. A decrease in involved body surface area, the pruritus Numerical Rating Scale (NRS) score and the eczema score SCORAD was observed in all groups. 16.5% of the subjects stopped their participation in this study because of adverse reactions, such as worsening of atopic dermatitis or abdominal pain. One patient had to discontinue treatment because of thrombocytopenia.[44]

Gusacitinib is a potent dual inhibitor of spleen tyrosine kinase (SYK) and Janus kinases (JAK), also known as ASN002. In addition to the Janus kinases, SYK is involved in the modulation of the immune response by controlling the release of cytokines, regulation of dendritic cells and differentiation of keratinocytes.[45,46] A double-blind, randomized, placebo-controlled clinical trial tested different oral doses of the inhibitor in 36 subjects. The 40 mg dose showed the best improvement of sign shown by EASI75 in 71% treated versus 22% untreated patients after 4 weeks. Hundred percent of the subjects in the 40 mg, 83% in the 80 mg, and 22% in the placebo-controlled group achieved EASI50. Additional skin biopsies of volunteers allowed an investigation of RNA expression patterns and showed a shift of the transcriptome towards a healthy phenotype. Serum samples showed a reduction of the inflammatory markers of the Th1, Th2, Th17/22 immune responses and a reduction of E selectin.[47,48]

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