JAK inhibitors for Atopic Dermatitis – STAT!

Efficacy and Safety

The first clinical evidence of effectiveness of JAK inhibitors in AD emerged in 2015, with the report of 6 patients with moderate to severe AD successfully treated with tofacitinib.15 All 6 patients had previously failed common treatments, including systemic agents. Treatment with tofacitinib led to a 54.8% reduction in the Scoring of AD (SCORAD) Index and 69.9% and 71.2% reductions in pruritus and sleep loss scores, respectively, over 8 to 14 weeks, with stable or further improvement with continued treatment.15 Since then, we have treated several more patients with moderate to severe AD with tofacitinib with good effect (Figure 2). 

treatment with Jak inhibitor before and after clinical photos

Figure 2. Atopic dermatitis. Fifteen-year-old girl with atopic dermatitis. Before and after 12 weeks of tofacitinib 5 mg twice daily.

Subsequently, in 2016, the results of a randomized, double-blind, vehicle-controlled study using tofacitinib 2% ointment showed an 81.7% reduction in Eczema Area and Severity Index (EASI) scores compared with only 29.9% in the control group over the 4-week study period.16 In the treatment group, approximately 80%, 60%, and 40% of patients achieved EASI 50, EASI 75, and EASI 90 (≥ 50%, 75% and 90% reduction in EASI score relative to baseline), respectively. A rapid decrease in pruritus with topical tofacitinib was also observed.

Presently, there are several large clinical trials evaluating both oral and topical JAK inhibitors in the treatment of AD (Table). Baricitinib, PF-04965842, and upadacitinib are currently in phase 3 trials. The latter 2, PF-0496584217 and upadacitinib,18 have been granted Breakthrough Therapy designation by the FDA for AD. 

In a phase 2 trial of oral baricitinib, a JAK1/2 inhibitor,19 124 patients with moderate to severe AD were treated with baricitinib 2 mg, 4 mg, or placebo once daily for 16 weeks, topical corticosteroids were permitted during the study. More patients in the baricitinib 4-mg group  achieved ≥50% reduction in the EASI score compared with placebo (61% vs 37%) at 16 weeks; significant separation between the baricitinib 2 mg and 4 mg groups and the placebo group was evident at week 4. Improvement in pruritus was evident at 1 week. 

JAK Table

The results of a phase 2 study of PF-04965842, a selective JAK1 inhibitor, in moderate to severe AD have not yet been published but data presented at the 2017 European Academy of Dermatology and Venereology meeting seem promising.20 Similarly, results of a phase 2b study of upadacitinib, another selective JAK1 inhibitor, have not yet been published but data presented at the 2018 American Academy of Dermatology Annual Meeting suggest benefit of upadacitinib.21 

The results of a phase 2 trial evaluating topical JTE-052 ointment (0.25%, 0.5%, 1%, and 3%), a JAK 1/2 inhibitor, with mild activity in JAK3 and Tyk2, in 327 adults with moderate to severe AD demonstrated change from baseline in the modified EASI score of –72·9% for the 3% ointment compared with –12.2% for the vehicle over 4 weeks.22 Notably, the pruritus scores, measured with the numerical rating scale, showed improvement the first day of application of JTE-052. 

The results of a phase 2 trial evaluating topical ruxolitinib (cream 0.15%, 0.5%, and 1.5%), a JAK1/2 inhibitor, compared with vehicle and triamcinolone 0.1% cream in 307 adults with AD have not yet been published but data presented at the 2018 European Academy of Dermatology and Venereology meeting seem promising.23

Regarding safety, the immunomodulatory effects of JAK inhibition must be considered. Most data regarding safety comes from large clinic trials of tofacitinib or baricitinib in the treatment of rheumatoid arthritis.24-27 In these trials, patients were always taking concomitant methotrexate, with or without nonsteroidal anti-inflammatory drugs and glucocorticoids. Overall, while these medicines have a black box warning for malignancy and serious infection, the collective data suggests these medicines have a safety profile comparable to most of the biologics.28,29 

Conclusion

JAK inhibitors appear to be effective for the treatment of AD, and this class of medications is certain to influence the current paradigm of AD management. Not only do JAK inhibitors offer the promise of reliably effective oral therapy for moderate to severe AD, they also offer the possibility of reliably effective topical therapy.  The future is bright for our patients with AD, many of whom have suffered for years without effective treatment for their disease. Together with our patients, we eagerly await the future. 

 

Dr Wambier is an associate professor of dermatology at the State University of Ponta Grossa in Ponta Grossa, Parana, Brazil, and a clinical research affiliate in the department of dermatology at the Yale University School of Medicine in New Haven, CT. 

Dr King is an associate professor of dermatology at the Yale University School of Medicine in New Haven, CT. 

Disclosure: Dr King has served on advisory boards or is a consultant for Aclaris Therapeutics Inc, Concert Pharmaceuticals Inc, Dermavant Sciences Inc, Eli Lilly and Company, and Pfizer Inc. He is on the speakers bureau for Dupixent for Regeneron Pharmaceuticals and Sanofi Genzyme. 

Dr Wambier has no financial relationships. 

References

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13. Zhang Q, Putheti P, Zhou Q, Liu Q, Gao W. Structures and biological functions of IL-31 and IL-31 receptors. Cytokine Growth Factor Rev. 19(5-6):347-356. 

14. Oetjen LK, Mack MR, Feng J, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017;171(1):217-228.e13. 

15. Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015;73(3):395-399. 

16. Bissonnette R, Papp KA, Poulin Y, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 2016;175(5):902-911.

17. Pfizer receives breakthrough therapy designation from FDA for PF-04965842, an oral JAK1 inhibitor, for the treatment of patients with moderate-to-severe atopic dermatitis [news release]. New York: Pfizer; February 14, 2-19. https://press.pfizer.com/press-release/pfizer-receives-breakthrough-therapy-designation-fda-pf-04965842-oral-jak1-inhibitor-t. Accessed October 5, 2018.

18.  AbbVie’s upadacitinib granted breakthrough therapy fesignation from the U.S. Food and Drug Administration for atopic dermatitis [news release]. North Chicago, IL; AbbVie; January 8, 2018. https://news.abbvie.com/news/abbvies-upadacitinib-granted-breakthrough-therapy-designation-from-us-food-and-drug-administration-for-atopic-dermatitis.htm.   Accessed October 5, 2018.

19. Guttman-Yassky E, Silverberg JI, Nemoto O, et al. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study [published online February 1, 2018]. J Am Acad Dermatol. doi:10.1016/j.jaad.2018.01.018

20. Gooderham M, Forman S, Bissonnette R, et al. A pf-04965842, a selective jak1 inhibitor, for treatment of moderate-severe atopic dermatitis: a 12 week, randomized, double blind, placebo controlled phase 2 clinical trial. Presented at: 26th European Academy of Dermatology and Venereology Congress;  September 13-17, 2018; Geneva, Switzerland. 

21. Guttman, E. Primary results from a phase 2b, randomized, placebo-controlled trial of upadacitinib for patients with atopic dermatitis. Presented at: 2018 American Academy of Dermatology Annual Meeting; February 16-20, 2018; San Francisco, CA. 

22. Nakagawa H, Nemoto O, Igarashi A, Nagata T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study. Br J Dermatol. 2018;178(2):424-432. doi:10.1111/bjd.16014

23. Kim B, Nasir A, Kim P, et al.  A phase 2, randomized, dose-ranging, vehicle- and active-controlled study to evaluate the safety and efficacy of topical ruxolitinib in adult patients with atopic dermatitis. Presented at: 27th European Academy of Dermatology and Venereology Congress; September 12-18, 2018; Paris, France.

24. Curtis JR, Lee EB, Kaplan I V, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann Rheum Dis. 2016;75(5):831-841. 

25. Cohen SB, Tanaka Y, Mariette X, et al. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis. 2017;76(7):1253-1262.

26. Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41(5):837-852. 

27. Keystone EC, Genovese MC, Schlichting DE, et al. Safety and efficacy of baricitinib through 128 weeks in an open-label, longterm extension study in patients with rheumatoid arthritis. J Rheumatol. 2018;45(1):14-21. 

28. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662. 

29. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508-519. 



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