In January 2022, the FDA approved two oral JAK-1 inhibitors for treatment of patients with moderate-to-severe atopic dermatitis (AD): upadacitinib and abrocitinib. The approvals mark the entry of oral JAK-1 inhibitors into the treatment algorithm of this chronic inflammatory skin disease.   

Why is this important? 

Although patients with mild-to-moderate AD are able to control their disease with topical corticosteroids or topical calcineurin inhibitors, these treatments are often inadequate in patients with moderate-to-severe AD, where systemic immunosuppression (eg, cyclosporine, oral corticosteroids) is often needed for sustained improvement and disease control. However, systemic immunosuppression may be associated with significant well-established side effects. There is a need for safer, more effective, and better-tolerated treatment options to reduce the burden of disease associated with moderate-to-severe AD.   

Advances in our understanding of AD pathophysiology have led to the development of targeted therapeutic options. The JAK/STAT signaling pathway modulates several immune pathways thought to involve AD pathogenesis. As a result, oral JAK inhibitors represent a promising alternative treatment in patients with moderate-to-severe AD with a history of inadequate response or intolerance to treatment.

Upadacitinib (oral selective JAK-1 inhibitor)

Upadacitinib is indicated for the treatment of refractory, moderate-to-severe AD in patients 12 years and older whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable. The recommended dosage is 15 mg once daily, increasing to 30 mg once daily for those patients not achieving adequate response.

The recommended dosage in patients older than 65 years of age and in patients with severe renal impairment is 15 mg once daily. Upadacitinib may be associated with acne, upper respiratory tract infections, headache, increased blood creatine phosphokinase, fatigue, myalgia, and influenza-like illness. Please check its prescribing information for a complete list of side effects and warnings.  

Safety and efficacy outcomes for upadacitinib

The safety and efficacy of upadacitinib in the treatment of moderate-to-severe AD were established in the Measure Up 1 and Measure Up 2 trials and the AD UP trial. Upadacitinib 15 mg and 30 mg once daily significantly improved EASI-75 and vIGA-AD at 16 weeks compared with placebo in patients with moderate-to-severe AD both as monotherapy and in combination with topical corticosteroids. Long-term efficacy of the combination therapy has been established to 52 weeks. All three trials concluded upadacitinib had a positive benefit-risk ratio and was well-tolerated.   

Abrocitinib (oral selective JAK-1 inhibitor)

Abrocitinib is indicated for the treatment of adults with refractory, moderate-to-severe AD whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable. The recommended dosage is 100 mg once daily, which may be increased to 200 mg if the patient does not respond to the lower dose. Antiplatelet therapies, with the exception of low-dose aspirin (≤81 mg daily), are contraindicated during the first 3 months of abrocitinib therapy. 

Safety and efficacy outcomes for abrocitinib

A multicenter, double-blind, randomized, placebo-controlled study published in 2020 found that abrocitinib monotherapy (either 100 mg or 200 mg) resulted in significantly higher EASI-75 and IGA responses at 12 weeks in patients with moderate-to-severe AD. Similar results were observed in a 2021 study which found both doses of abrocitinib superior to placebo for EASI-75 and IGA. However, in that study, 200 mg abrocitinib, but not 100 mg, was superior to dupilumab for itch response at 2 weeks in patients with moderate-to-severe AD. Importantly, neither dose of abrocitinib differed significantly from dupilumab in most key secondary endpoints at 16 weeks.   

An integrated safety analysis found that with proper patient and dose selection, abrocitinib has a manageable tolerability and safety profile appropriate for long-term treatment of moderate-to-severe AD. That said, abrocitinib may be associated with nasopharyngitis, nausea, headache, fatigue, increases in blood creatinine phosphokinase—please check its prescribing information for a complete list of side effects and warnings.  

Similar limitations

The prescribing information for both upadacitinib and abrocitinib contain “black box warnings,” which cite the risk of serious infections, mortality, malignancy, major cardiovascular events and thrombosis. Similarly, neither agent should be used in combination with other JAK inhibitors, biologic immunomodulators or with other immunosuppressants.    

Sources

1. Bieber T, Simpson EL, Silverberg JI, et al. Abrocitinib versus placebo or dupilumab for atopic dermatitis. N Engl J Med. 2021;384(12:1101-1012.

2. Boguniewicz M, Alexis AF, Beck LA, et al. Expert perspectives on management of moderate-to-severe atopic dermatitis: a multidisciplinary consensus addressing current and emerging therapies. J Allergy Clin Immunol Pract. 2017;5(6):1519-1531.

3. Cibinqo™ (abrocitinib) tablets, prescribing information, revised January 2022. Pfizer Labs, New York, NY 10017. 

4. Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure UP 1 and Measure Up 2): results from two replicate double-blind, randomized controlled phase 3 trials. Lancet. 2021;397(10290):2151-2168.

5. Reich K, Teixeira HD, de Bruin-Weller M, et al. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397(10290):2169-2181.

6. Rinvoq ® (upadacitinib) extended-release tablets, prescribing information, revised January 2022. AbbVie Inc., North Chicago, IL 60064.

7. Silverberg JI, de Bruin-Weller M, Bieber T, et al. Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results. J Allergy Clin Immunol. 2021 Aug 14.

8. Simpson EL, Silverberg JI, Nosbaum A, et al. Integrated safety analysis of abrocitinib for the treatment of moderate-to-severe atopic dermatitis from the phase II and phase III clinical trial program. Am J Clin Dermatol. 2021;22(5):693-707.

9. Simpson EL, Sinclair R, Forman S, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomized, placebo-controlled, phase 3 trial. Lancet. 2020;396(10246):255-266.