Treatment with upadacitinib in patients with moderate-to-severe atopic dermatitis (AD) was safe, effective, and well tolerated in doses of 15- and 30-mg, and effective when used as monotherapy as well as in combination with topical corticosteroids, according to results from two replicate 16-week monotherapy studies (Measure Up 1 and Measure Up 2) and a combination trial (AD Up) published in The Lancet.
Treatment with both doses of upadacitinib brought about significant improvements in skin clearance and significant reductions in itch in adults and adolescents with moderate-to-severe atopic dermatitis compared with placebo. Results were similar when upadacitinib was used concomitantly with topical corticosteroids.
Upadacitinib is an oral Janus kinase (JAK) inhibitor approved for the treatment of rheumatoid arthritis. Based on earlier results from the Measure Up 1, Measure Up 2, and AD Up studies, AbbVie—the manufacturer of upadacitinib—submitted regulatory applications to the FDA in October 2020 for upadacitinib as a potential treatment for AD.
In the replicate, multicenter, randomized, double-blind, placebo-controlled, phase III Measure Up 1 and Measure Up 2 studies, researchers randomized adolescents aged 12 to 17 years and adults with moderate-to-severe atopic dermatitis to treatment with upadacitinib (15 mg), upadacitinib (30 mg), or placebo once daily for 16 weeks.
The Measure Up 1 study included 847 patients, while the Measure Up 2 study, 836 patients. At week 16, the coprimary endpoints—patients who achieved at least 75% improvement in Eczema Area Severity Index (EASI-75) scores from baseline and patients who achieved a validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-AD) response of 0/1 (clear/almost clear) with two or more decreases in grade from baseline—were met in both studies (all P˂0.0001).
In Measure Up 1, the number of patients achieving EASI-75 was significantly higher among those treated with 15-mg upadacitinib (70% of 281 patients) and 30-mg upadacitinib (80% of 285 patients) compared with placebo (16% of 281 patients), for adjusted differences in EASI-75 response rates compared with placebo of 53.3% and 63.4%, respectively. In addition, the proportion of patients achieving a vIGA-AD response was significantly higher in both the 15- and 30-mg upadacitinib groups compared with placebo (48% and 62%, respectively, versus 8%), for an adjusted difference of 39.8% and 53.6%, respectively.
Similarly, in Measure Up 2, 60% of 276 patients treated with 15-mg upadacitinib and 73% of 282 patients treated with the 30-mg dose achieved an EASI-75 response rate, compared with only 13% of 278 patients in the placebo group, for adjusted differences in EASI-75 response rate versus placebo of 46.9% and 59.6%, respectively. vIGA-AD response at week 16 was also seen in significantly more patients treated with the 15- and 30-mg doses of upadacitinib compared with placebo (39% and 52% versus 5%, respectively; adjusted difference vs placebo: 234.0% and 47.4%).
The rate of adverse events and serious adverse events leading to treatment discontinuation were similar in the groups. The most common treatment-emergent adverse events included acne, upper respiratory tract infection, nasopharyngitis, headache, creatine phosphokinase level elevations, and atopic dermatitis.
In the AD Up trial, researchers led by Kristian Reich, MD, of University Medical Center Hamburg-Eppendorf, Germany, studied the efficacy and safety of upadacitinib combined with topical corticosteroids compared with placebo in patients with moderate-to-severe AD.
They randomized 901 patients to upadacitinib (15 mg), upadacitinib (30 mg), or placebo once daily, all given in combination with topical corticosteroids for 16 weeks.
At week 16, significantly more patients treated with both doses of upadacitinib (15 and 30 mg) plus topical corticosteroids achieved EASI-75 compared with placebo plus topical corticosteroids (65% and 77% versus 26%, respectively; adjusted difference versus placebo: 38.1% and 50.6%; P˂0.0001 for both).
The same was true for patients treated with both the 15- and the 30-mg doses of upadacitinib who achieved a vIGA-AD at week 16 compared with placebo (40% and 59%, respectively, versus 11% in the placebo group; adjusted difference versus placebo: 28.5% and 47.6%; P˂0.0001 for both).
Both doses of upadacitinib were well tolerated when used in combination with topical corticosteroids, and the most frequent treatment-emergent adverse events included acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevations of blood creatine phosphokinase levels, headache, and atopic dermatitis. Adverse events leading to treatment discontinuation and serious adverse events were similar between all three groups, at 2% in the 15-mg upadacitinib group, 3% in the 30-mg upadacitinib group, and 3% of placebo patients.
No deaths occurred, and no new safety issues were raised. Among the newer options for the treatment of AD, the JAK inhibitors have several advantages, wrote Jacob P. Thyssen, MD, PhD, DMSci, and Simon F. Thomsen, MD, PhD, of Bispebjerg Hospital, University of Copenhagen, Denmark, in an accompanying editorial. Their rapid onset of action and strong itch reducing properties make them particularly attractive, especially for patients in acute crisis. Disadvantages include the increased risk of serious infection, non-melanoma skin cancer, and thromboembolism, as well as the need for continuous blood monitoring.
“The efficacy of upadacitinib suggests that clinicians might soon be able to offer patients with atopic dermatitis an oral treatment solution with little or no need for concomitant administration of topical corticosteroids. However, more information is needed about how to best use upadacitinib and other new systemic drugs in AD,” concluded Thyssen and Thomsen.
Limitations of the Measure Up 1 and Measure Up 2 studies—the largest studies of upadacitinib monotherapy for AD—include its short-term results, the predominance of white patients, and that it assessed upadacitinib as monotherapy.
Limitations of the AD Up study include the lack of specific data on topical corticosteroid use, the short 16-week duration of the double-blind treatment period, and the underrepresentation of Black and Asian patients.
The Measure Up 1 and Measure Up 2 studies demonstrated the efficacy of upadacitinib—in both the 15- and 30-mg doses—as well as its safety and superiority to placebo when used as monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis (AD).
The AD Up study demonstrated that combination therapy with upadacitinib and topical corticosteroids was well tolerated and superior to placebo, with a positive benefit-risk profile in adolescents and adults with moderate-to-severe AD.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
The Measure Up 1, Measure Up 2, and AD Up studies were funded by AbbVie.
Guttman-Yassky is employed by Mount Sinai and is a researcher or consultant for AbbVie, Anacor, AnaptysBio, Asana Biosciences, Botanix, Celgene, DBV Dermira, Dr Reddy’s Laboratory (Promius), DS Biopharma, Escalier Biosciences, Galderma, Glenmark, Innovaderm, Janssen, Kyowa Kirin, LEO Pharma, Lilly, AstraZeneca, Mitsubishi Tanabe Pharma, Novan, Novartis, Pfizer, Ralexar, Regeneron, Sanofi, GlaxoSmithKline, UCB, and Vitae Pharmaceuticals.
Reich has served as an adviser, paid speaker, or has participated in clinical trials sponsored by AbbVie, Affibody, Almirall, Amgen, Avillion, Biogen, Bausch Health (Valeant), Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Covagen, Dermira, Forward Pharma, Fresenius, Galapagos, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, Lilly, Medac, Merck, Novartis, Miltenyi Biotec, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Sun Pharma, Takeda, UCB, and XenoPort.
Thyssen is supported by an unrestricted grant from the Lundbeck Foundation and has attended an advisory boards meeting and been a speaker for Sanofi-Genzyme (manufacturer of dupilumab), Regeneron (manufacturer of dupilumab), AbbVie (manufacturer of upadacitinib), LEO Pharma (manufacturer of tralokinumab), Pfizer (manufacturer of abrocitinib), and Eli Lilly and Company (manufacturer of baricitinib); and has been an investigator for AbbVie, LEO Pharma, and Eli Lilly and Company.
Thomsen has been a speaker or has served on advisory boards for Sanofi-Genzyme, AbbVie, LEO Pharma, Pfizer, and Eli Lilly and Company, and for Novartis, UCB Pharma, Almirall, and Janssen Pharmaceuticals, unrelated to the topic of this Comment; has received research support from Sanofi-Genzyme, AbbVie, LEO Pharma, Novartis, UCB Pharma, and Janssen Pharmaceuticals unrelated to the topic of this Comment; and has been an investigator for Sanofi-Genzyme, Regeneron, AbbVie, LEO Pharma, and Pfizer.
Cat ID: 449
Topic ID: 75,449,730,449,192,923,925