Upadacitinib (Rinvoq, AbbVie) in combination with topical corticosteroids is safe and effective for the treatment of moderate to severe atopic dermatitis in adolescents and adults out to 52 weeks, and it is superior to the biologic drug dupilumab (Dupixent), according to the results of two new studies.
"The 52-week results from AD Up reported here provide the first evidence of long-term efficacy and acceptable safety profile of upadacitinib in atopic dermatitis," the authors of the first study, published this month in the Journal of Allergy and Clinical Immunology, report.
Building on previous findings, "most patients who did well at week 16 maintained their response through week 52," coauthor David Rosmarin, MD, from the Department of Dermatology, Tufts University School of Medicine, in Boston, told Medscape Medical News.
Upadacitinib, an oral Janus kinase (JAK) inhibitor, is currently approved for the treatment of moderately or severely active rheumatoid arthritis (RA), and was shown in the Measure Up 1 and Measure Up 2 phase 3 clinical trials to have efficacy as monotherapy in doses of 15 mg and 30 mg in the treatment of atopic dermatitis, compared with placebo, after 16 weeks.
In the subsequent phase 3 AD Up trial, the combination of upadacitinib with topical corticosteroids was evaluated and showed safety and superiority in comparison with placebo plus topical corticosteroids in adolescents and adult patients with moderate to severe atopic dermatitis after 16 weeks.
The current study updates the ongoing blinded extension of AD Up, describing outcomes of 901 randomized patients, 300 who received upadacitinib 15 mg plus topical steroids, 297 who received upadacitinib 30 mg plus topical corticosteroids, and 304 who received placebo plus the topical corticosteroids.
All patients had chronic atopic dermatitis, affecting at least 10% of their body surface area, with an Eczema Area and Severity Index (EASI) score of at least 16, an Investigator's Global Assessment for Atopic Dermatitis (vIGA-AD) score of at least 3, and a Worst Pruritus-Numerical Rating Scale (WP-NRS) score of at least 4.
At week 16, 283 of those in the placebo group were rerandomized to either the upadacitinib 15 mg group (n = 144) or 30 mg (n = 139), plus corticosteroids.
At 52 weeks, 50.8% of those in the upadacitinib 15 mg plus topical corticosteroids group achieved the endpoint — an improvement in EASI score of at least 75% — as did 69.0% of the 30 mg plus topical corticosteroid group.
The proportions of patients achieving an improvement in EASI score of at least a 90% at 52 weeks were 37.3% and 55.0% in the upadacitinib 15 mg and 30 mg groups, respectively.
"Even the stringent endpoint of EASI-90, 37.7% and 55.4% achieved that high bar," Rosmarin said.
In the other measures, 33.5% in the 15 mg plus steroids group achieved a Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of clear or almost clear, with an improvement of at least 2 grades, as did 45.2% in the 30 mg group.
And 45.3% in the 15 mg group achieved a WP-NRS improvement of at least 4, as did 57.5% in the 30 mg plus topical steroids group.
This is "consistent with our understanding of upadacitinib being highly effective for treating itch," Rosmarin added.
There were no new safety risks reported at 52 weeks, compared with those seen in the drug's treatment for RA; however, safety concerns linger, as the US Food and Drug Administration approval of the drug for RA in 2019 included a black-box warning regarding an increased risk for infection malignancy and thrombosis, as is observed with other approved JAK inhibitors, including tofacitinib.
Acne was the most common treatment-emergent adverse event, occurring in 14% in the 15 mg upadacitinib group and 18.6% in the 30 mg group, which is higher than the rate observed in the treatment of RA; however, the events were not serious and rarely led to treatment discontinuation, the authors note.
Major adverse cardiac events or venous thromboembolisms occurred in 0.2 per 100 person-years or less, and no deaths occurred.
In terms of lab-related adverse events, creatine phosphokinase (CPK) elevations were observed that were generally not serious, related to vigorous physical activity, and did not lead to treatment discontinuation.
Regarding the safety concerns of upadacitinib, Rosmarin suggested upfront conversations with patients to clarify what's known about the risks.
"When discussing treatment with patients, we always decide together, weighing benefits and risks," he said. "Upon reviewing the goals of the patient, it is important we go over chances of success and potential side effects."
The authors note that the combination of upadacitinib and topical corticosteroids shows similar efficacy in skin improvement and itch reduction to monotherapy in the short term, and a report comparing the two regimens is in the works.
Head-to-Head With Dupilumab
In a separate study comparing how upadacitinib performs against other atopic dermatitis treatments, a multicenter, head-to-head study — Heads Up — published this month in JAMA Dermatology, compared the drug with subcutaneous dupilumab in 692 adults with moderate to severe dermatitis.
At 24 weeks, 71.0% of patients treated with upadacitinib 30 mg once daily achieved the primary endpoint of EASI-75, as did 61.1% of those treated with subcutaneous dupilumab 300 mg every other week (P = .006), with upadacitinib showing superiority in all secondary endpoints.
In terms of safety issues, rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-test-related adverse events were numerically higher with upadacitinib, whereas rates of conjunctivitis and injection-site reaction were numerically higher with dupilumab, however all were infrequent the authors note.
There were no venous thromboembolic events, major adverse cardiovascular events, or gastrointestinal perforations reported with either treatment.
The rate of acne in the upadacitinib group at 16 weeks was 15.8%, consistent with the AD Up trial, compared with just 2.6% with dupilumab.
In commenting on the research, Jacob P. Thyssen, MD, PhD, from the Department of Dermatology and Venereology, Bispebjerg Hospital, at the University of Copenhagen, noted that upadacitinib shows promise as an important addition to the armamentarium of atopic dermatitis treatment, with key caveats.
"Atopic dermatitis can be very difficult to treat; inflammation can be severe and persistent and patients very depressed about their situation," he told Medscape Medical News.
"Upadacitinib seems to be the hitherto most potent medication to treat atopic dermatitis with very fast onset of action and strong itch reducing capacity," he said. "It is therefore reassuring to see 52-week data that emphasize sustained efficacy and no new safety signals."
"The efficacy is very impressive, slightly better than abrocitinib, and markedly better than barictinib, but the risk of acne seems also to be higher," he noted.
Consistent with concerns raised in the black-box warning for RA, he added that "there was a notable percentage of infections and there is a need for real-world data where patients with comorbidities and previous or existing conditions, such as mild hepatic disease, kidney disease, cancers, etc., are also treated with upadacitinib, as we may here see additional safety signals not picked up in the trials."
"Remember, this patient group is older and they have more risk factors and are often treated with methotrexate at the same time, so for me, it is premature to make any conclusions," he said.
Peck Y. Ong, MD, associate professor of clinical pediatrics at the University of Southern California Keck School of Medicine, Los Angeles, added that the head-to-head study offers further important insights.
"I commend the authors for taking on this study to directly compare with dupilumab," he told Medscape Medical News. "This will certainly open up another treatment option for patients with moderate to severe atopic dermatitis."
He noted that "the study also offered sufficient length up to 24 weeks but a follow-up on or off these medications would be very useful data for clinicians."
Notable benefits of the drug include "complete clearance in a larger percentage of subjects, more rapid onset of decreased severity, and anti-itch effect even at 1 week," Ong said.
However, Ong agreed with Rosmarin on the importance of having discussions with patients over the drug's safety concerns.
"These advantages versus potential side effects including acne, herpes zoster infections or other serious infections will need to be discussed with patients."
The studies were funded by AbbVie. Rosmarin has received honoraria as a consultant for AbbVie. Ong has served on the AbbVie advisory board. Thyssen is a speaker, advisory board member, and/or investigator for AbbVie, Almirall, Regeneron, Sanofi-Genzyme, Eli Lilly & Co, Pfizer, and LEO Pharma. He has no patents, ownership, or financial gain from any atopic dermatitis drug.
J Allergy Clin Immunol. Published online August 14, 2021. Full text
JAMA Dermatology. Published August 4, 2021. Full text
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Cite this: Upadacitinib Effective and Safe in Atopic Dermatitis at 52 Weeks - Medscape - Aug 19, 2021.