Can JAK inhibitors close the current therapeutic gap in AD?

Immune dysfunction and epidermal barrier dysfunction are two key factors in the atopic dermatitis (AD) pathogenesis. “In my belief, the most promising approach is not improving the barrier function, but primarily using anti-inflammatory agents,” said Prof. Eric Simpson (Oregon Health & Science University, USA) [1].

At present, there are two important therapeutic gaps: “We need a more efficacious topical therapy than non-steroidals without significant burning or safety concern, and we would love to have pills in moderate-to-severe disease,” said Prof. Simpson. JAK inhibitors have the potential to fill these gaps. At present, there are two phase 2 trials with JAK inhibitors in AD.

A Japanese phase 2 study was performed with the topical JAK inhibitor delgocitinib in adult patients with moderate-to-severe AD [2]. In this trial, the JAK inhibitor ointment, applied twice daily, led to a significant dose dependent change in the EASI (each dose P<0.01 compared with vehicle). In the highest concentration (3%), EASI was reduced by -72.9% after 4 weeks. In addition, there was a significant reduction of itch, noticed as early as day 1 night time. The agent was well tolerated with only 1 case of burning.

Another phase 2 trial was performed with the JAK1/2 inhibitor ruxolitinib in 307 adult patients with moderate-to-severe AD [3]. Twice daily treatment with a cream containing 1.5% ruxolitinib led to 71.6% improvement in the EASI at 4 weeks compared with a 15.5% improvement in baseline EASI score in a vehicle control group. In addition, rapid and sustained reductions in pruritus, assessed in an NRS, were observed with changes as early as within a day from the initiation of therapy. Taken together, topical JAK inhibitors show equal potency to topical steroids with possibly less burning.

Phase 2 trials with oral JAK inhibitors like baricitinib, abrocitinib, and upadacitinib showed rapid itch reduction and reduced inflammation by 1-4 weeks due to targeting several key cytokines in AD. Oral JAKs are now in phase 3 trials. “The dosing of the JAKs will be most critical: low doses show less efficacy but are very safe; high doses might have a better efficacy than dupilumab but come with off-target effects on platelets, blood counts, or the risk of infection,” concluded Prof. Simpson.

1. Simpson E. Session S016, AAD Annual Meeting, 1-5 March 2019, Washington DC, USA.
2. Nakagawa H et al. Br J Dermatol 2018;178:424-32.
3. Kim B et al. Abstract FC03.01, EADV Annual Meeting, September 2018, Paris, France.



Posted on 19 April, 201916 March, 2021