Small molecules: interesting novel treatment options in AD

There is a high need for oral treatments for atopic dermatitis (AD) that cannot be controlled with local therapy. Both phosphodiesterase (PDE) inhibitors and Janus kinase (JAK) inhibitors are interesting approaches [1].

PDE4 is involved in the regulation of pro-inflammatory cytokines via the degradation of cyclic adenosine monophosphate. Targeting PDE4 reduces the production of pro-inflammatory mediators in AD and may be an interesting treatment target with a favourable safety profile [2]. Apremilast, an orally available PDE4 inhibitor, is approved for the treatment of adults with moderate-to-severe psoriasis and active psoriatic arthritis. This immune modulator regulates a number of the pro-inflammatory signals involved in AD, including IL-17, IL-22, IL-13, and IL-31 [3].

A phase 2 study published earlier this year evaluated the treatment effect of 30 mg and 40 mg of apremilast on skin clearance, assessed in EASI percentage change from baseline in patients with moderate-to-severe AD [4]. After 12 weeks, the 40 mg dose led to a modest but statistically significant improvement of -31.6% compared with -11% in the placebo group (P<0.04). A biopsy substudy showed that apremilast reduced the mRNA expression of inflammatory markers associated with the Th17/Th22 pathways. More adverse events were observed within the 40 mg group. Due to 6 cases of cellulitis, an independent safety monitoring committee discontinued the study. “These results are disappointing; however, AD is a heterogeneous disease and we have to stratify patients that may have a benefit,” said Prof. Tilo Biedermann (Helmholtz Center Munich, Germany).

A topical PDE4 inhibitor that has been FDA approved for AD is crisaborole ointment. Evidence from phase 3 trials demonstrating that crisaborole is an efficacious topical agent for mild-to-moderate AD with a favourable safety profile and limited systemic exposure [5].

JAK inhibitors enter the therapeutic arena

“The JAK inhibitors are really the most important novel oral drug class in AD,” said Prof. Biedermann. There are several differences between the JAK inhibitors depending on the cytokine pathway they influence [6]. An in vitro study showed that the different JAK inhibitors modulate distinct cytokine pathways to varying degrees. JAK inhibitors can be used topically and systemically. Tofacitinib ointment was shown to be effective in patients with mild-to-moderate AD [7]. Patients treated with the tofacitinib ointment showed significant improvements versus vehicle across all efficacy endpoints and for pruritus [7]. “However, the main theme is systemic treatment with JAK inhibitors,” said Prof. Biedermann. A phase 2 study published this year showed that 61% of patients treated with oral baricitinib plus TCS achieved an EASI 50 response compared to 37% with placebo plus TCS. Baricitinib also improved pruritus and sleep loss [8]. “Their efficacy may not reach dupilumab but it is not bad,” said Prof. Biedermann. “With the new drugs we understand that TH2 cytokines are really in the centre of AD pathogenesis; this is even more important,” concluded Prof. Biedermann.

1 Biedermann T. D1T01.1B, EADV 2019, 9-13 Oct, Madrid, Spain.

2 Zebda R, Paller AS. J Am Acad Dermatol 2018;78 (3 Suppl 1):S43-52.

3 Schafer PH, et al. Cell Sign 2014;26;2016-9.

4 Simpson EL, et al. J Investig Dermatol 2019;139:1063-72.

5 Woo TE, et al. Skin Therapy Lett 2019;24:4-6.

6 McInnes IB, et al Arthritis Research & Therapy 2019;21:183.

7 Bissonnette R, et al. Br J Dermatol 2016;175:902-11.

8 Guttman-Yassky E, et al. J Am Acad Dermatol 2019;80:913-21.

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