By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved two oral, selective, reversible Janus kinase-1 (JAK-1) inhibitors to treat atopic dermatitis (AD). Abrocitinib is a new chemical entity, while upadacitinib is a currently approved agent that has been granted an additional indication. Both received breakthrough therapy designations. Abrocitinib is distributed as Cibinqo and upadacitinib as Rinvoq.
INDICATIONS
Both drugs can be prescribed to treat adults with refractory, moderate-to-severe AD that is not adequately controlled with other systemic drug products, including biologics, or when using those therapies is inadvisable.1,2 Upadacitinib also is indicated for pediatric patients age 12 years and older weighing at least 40 kg.2
DOSAGE
Abrocitinib: 100 mg orally once daily. For those who are not responding, 200 mg is recommended. The dose is reduced 50% in the presence of a strong CYP2C19 inhibitor or known or suspected CYP2C19-poor metabolizers. It is available as 50 mg, 100 mg, and 200 mg tablets.
Upadacitinib: Pediatric and adult patients younger than age 65 years, 15 mg orally once daily. If response is not adequate, increase the dose to 30 mg. The dose is 15 mg for those age 65 years and older and in the presence of a strong CYP3A4 inhibitor. It is available as 15 mg and 30 mg extended-release tablets.
POTENTIAL ADVANTAGES
Abrocitinib and upadacitinib provide orally administered options for refractory moderate-to-severe AD. Both have been shown to be more effective than dupilumab (subcutaneous injection).3-5 These small molecules have less immunogenicity than biologics such as dupilumab.3 The higher selectivity also may offer a better benefit-risk profile vs. less selective JAK inhibitors.3
POTENTIAL DISADVANTAGES
Both drugs carry a warning for an increased risk of serious infections (bacterial, fungal, viral), higher risk of all-cause mortality, possible malignancies, and a higher risk of thrombosis. Patients also should avoid live virus vaccines.1,2
COMMENTS
The efficacy of abrocitinib as monotherapy was evaluated in three randomized, double placebo-controlled trials and one that included dupilumab as an active control in subjects with moderate-to-severe AD.1,4,7,8 Similarly, upadacitinib was evaluated in three trials.2,9,10 In addition, upadacitinib was directly compared to dupilumab in one study.5 The coprimary efficacy outcomes were the Investigator’s Global Assessment (IGA), a five-point scale based on disease severity, and the Eczema Area and Severity Index (EASI). Treatment success was defined as an IGA score of clear (0) or almost clear (1), and a reduction from baseline of two or more points and ≥ 75% improvement of EASI from baseline. Subjects were randomized to abrocitinib 100 mg, 200 mg, or placebo in one set of studies, and upadacitinib 15 mg, 30 mg, or placebo in the other set. The study population and duration differed between abrocitinib and upadacitinib. Also, the study duration was 12 weeks for abrocitinib vs. 16 weeks for upadacitinib. The ratio of severe to moderate disease was 36%/64% for abrocitinib vs. 51%/49% for upadacitinib. Both drugs were significantly better than placebo, with a dose-dependent response for the coprimary endpoints. The higher dose for each drug was more effective than dupilumab.3,4 In a systematic literature review and network meta-analysis, the authors ranked relative efficacy in monotherapy as follows: udapacitinib 30 mg, abrocitinib 200 mg, upadacitinib 15 mg, dupilumab 300 mg, and abrocitinib 100 mg.5 Both drugs share some common adverse reactions, such as upper respiratory infections, nausea, nasopharyngitis, headache, and potential for hematologic abnormalities.1,2
CLINICAL IMPLICATIONS
AD is a common, multifactorial, inflammatory skin condition involving multiple cytokines.3 Before the approval of abrocitinib and upadacitinib, dupilumab (a parenteral interleukin-4 inhibitor) was the only biologic approved for this indication. The JAK and transducer and activator (JAK-STAT) transcription pathway plays a role in the pathogenesis. Both abrocatinib and upadacitinib inhibit this pathway and downstream signaling of inflammatory cytokines, thus providing an option for refractory moderate-to-severe AD. Both abrocitinib and upadacitinib have been shown to be more effective than dupilumab and can be given orally. There are some differences between these drugs that would affect prescribing decisions. Abrocitinib is metabolized by CYP2C19/2C9, which requires avoidance of moderate to strong inhibitors of both CYP2C19 and CYP2C9 and strong CYP2C19 or CYP2C9 inducers. Abrocitinib also is contraindicated concomitantly with antiplatelet therapies during the first three months. Upadacitinib, which is metabolized by CYP3A4, requires avoidance of strong CYP3A4 inducers, and contraception is recommended during treatment and four weeks after the last dose in women of childbearing potential. Abrocitinib is not approved in adolescents, although two of the clinical trials included adolescent subjects.7,8 Abrocitinib is cheaper — $4,914 for a 30-day supply vs. $5,671 for upadacitinib.
REFERENCES
- Pfizer. Cibinqo prescribing information. January 2022.
- AbbVie. Rinvoq prescribing information. January 2022.
- Ferreira S, Guttman-Yassky E, Torres T. Selective JAK1 inhibitors for the treatment of atopic dermatitis: Focus on upadacitinib and abrocitinib. Am J Clin Dermatol 2020;21:783-798.
- Bieber T, Simpson EL, Silverberg JI, et al. Abrocitinib versus placebo or dupilumab for atopic dermatitis. N Engl J Med 2021;384:1101-1112.
- Blauvelt A, Teixeira HD, Simpson EL, et al. Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: A randomized clinical trial. JAMA Dermatol 2021;157:1047-1055.
- Silverberg JI, Thyssen JP, Fahrbach K, et al. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: A systematic literature review and network meta-analysis. J Eur Acad Dermatol Venereol 2021;35:1797-1810.
- Silverberg JI, Simpson EL, Thyssen JP, et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: A randomized clinical trial. JAMA Dermatol 2020;156:863-873.
- 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, randomised, placebo-controlled, phase 3 trial. Lancet 2020;396:255-266.
- 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, randomised controlled phase 3 trials. Lancet 2021;397:2151-2168.
- 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;397:2169-2181.
Abrocitinib and upadacitinib can be prescribed to treat adults with refractory, moderate-to-severe atopic dermatitis that is not adequately controlled with other systemic drug products, including biologics, or when using those therapies is inadvisable.
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