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Atopic Dermatitis

Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic DermatitisA Randomized Clinical Trial

Educational Objective
To describe the relative efficacy of upadacitinib and dupilumab for adults with moderate-to-severe atopic dermatitis.

1 Credit CME

JAMA Dermatology

Published Online: August 4, 2021

Original Investigation

Article Information and Disclosures

Andrew Blauvelt, MD, MBA¹;

Henrique D. Teixeira, PhD, MBA²;

Eric L. Simpson, MD, MCR³;

Antonio Costanzo, MD^4,5;

Marjolein De Bruin-Weller, MD⁶;

Sebastien Barbarot, MD, PhD⁷;

Vimal H. Prajapati, MD^{8,9,10,11,12,13};

Peter Lio, MD^14,15;

Xiaofei Hu, PhD²;

Tianshuang Wu, PhD²;

John Liu, MD, MS²;

Barry Ladizinski, MD, MPH, MBA²;

Alvina D. Chu, MD²;

Kilian Eyerich, MD^16,17

Author Affiliations

¹Oregon Medical Research Center, Portland
²AbbVie Inc, North Chicago, Illinois
³Department of Dermatology, Oregon Health & Science University, Portland
⁴Dermatology Unit, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
⁵Humanitas Clinical and Research Center, Scientific Institute for Research, Hospitalization and Healthcare, Rozzano, Italy
⁶Department of Dermatology and Allergology, University Medical Center Utrecht, Utrecht, the Netherlands
⁷Department of Dermatology, Nantes Université, Centre Hospitalier Universitaire de Nantes, Nantes, France
⁸Division of Dermatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
⁹Division of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
¹⁰Division of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
¹¹Skin Health & Wellness Centre, Calgary, Alberta, Canada
¹²Dermatology Research Institute, Calgary, Alberta, Canada
¹³Probity Medical Research, Calgary, Alberta, Canada
¹⁴Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
¹⁵Medical Dermatology Associates of Chicago, Chicago, Illinois
¹⁶Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
¹⁷Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany

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Key Points

Question Are the efficacy and safety of oral upadacitinib superior to subcutaneous dupilumab in adults with moderate-to-severe atopic dermatitis (AD)?

Findings This randomized, blinded, head-to-head comparator clinical trial of 692 patients with moderate-to-severe AD demonstrated clinically meaningful skin clearance and itch relief, with statistically significant superiority for upadacitinib compared with dupilumab. There were no new safety signals reported for either upadacitinib or dupilumab.

Meaning Upadacitinib provides superior and more rapid skin clearance and itch relief with tolerable safety compared with dupilumab in patients with moderate-to-severe AD.

Abstract

Importance Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease with an unmet need for treatments that provide rapid and high levels of skin clearance and itch improvement.

Objective To assess the safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe AD.

Design, Setting, and Participants Heads Up was a 24-week, head-to-head, phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib with dupilumab among 692 adults with moderate-to-severe AD who were candidates for systemic therapy. The study was conducted from February 21, 2019, to December 9, 2020, at 129 centers located in 22 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. Efficacy analyses were conducted in the intent-to-treat population.

Interventions Patients were randomized 1:1 and treated with oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every other week.

Main Outcomes and Measures The primary end point was achievement of 75% improvement in the Eczema Area and Severity Index (EASI75) at week 16. Secondary end points were percentage change from baseline in the Worst Pruritus Numerical Rating Scale (NRS) (weekly average), proportion of patients achieving EASI100 and EASI90 at week 16, percentage change from baseline in Worst Pruritus NRS at week 4, proportion of patients achieving EASI75 at week 2, percentage change from baseline in Worst Pruritus NRS (weekly average) at week 1, and Worst Pruritus NRS (weekly average) improvement of 4 points or more at week 16. End points at week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in Worst Pruritus NRS from baseline (weekly average). Safety was assessed as treatment-emergent adverse events in all patients receiving 1 or more dose of either drug.

Results Of 924 patients screened, 348 (183 men [52.6%]; mean [SD] age, 36.6 [14.6] years) were randomized to receive upadacitinib and 344 were randomized to receive dupilumab (194 men [56.4%]; mean [SD] age, 36.9 [14.1] years); demographic and disease characteristics were balanced among treatment groups. At week 16, 247 patients receiving upadacitinib (71.0%) and 210 patients receiving dupilumab (61.1%) achieved EASI75 (P = .006). All ranked secondary end points also demonstrated the superiority of upadacitinib vs dupilumab, including improvement in Worst Pruritus NRS as early as week 1 (mean [SE], 31.4% [1.7%] vs 8.8% [1.8%]; P < .001), achievement of EASI75 as early as week 2 (152 [43.7%] vs 60 [17.4%]; P < .001), and achievement of EASI100 at week 16 (97 [27.9%] vs 26 [7.6%]; P < .001). Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related adverse events were higher for patients who received upadacitinib, whereas rates of conjunctivitis and injection-site reactions were higher for patients who received dupilumab.

Conclusions and Relevance During 16 weeks of treatment, upadacitinib demonstrated superior efficacy vs dupilumab in patients with moderate-to-severe AD, with no new safety signals.

Trial Registration ClinicalTrials.gov Identifier: NCT03738397

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Article Information

Accepted for Publication: June 26, 2021.

Published Online: August 4, 2021. doi:10.1001/jamadermatol.2021.3023

Correction: This article was corrected on December 15, 2021, to fix a percentage and include P values at week 24 in the Results section and to add more data to eTable 5 in Supplement 2.

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Blauvelt A et al. JAMA Dermatology.

Corresponding Author: Andrew Blauvelt, MD, MBA, Oregon Medical Research Center, 9495 SW Locust St, Ste G, Portland, OR 97223 (ablauvelt@oregonmedicalresearch.com).

Author Contributions: Drs Ladizinski and Chu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Teixeira, Hu, Ladizinski, Chu.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Teixeira, Prajapati, Hu, Liu, Ladizinski, Chu.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Teixeira, Hu, Wu.

Obtained funding: Teixeira, Chu.

Administrative, technical, or material support: Teixeira, Simpson, Liu, Eyerich.

Supervision: Blauvelt, Teixeira, de Bruin-Weller, Barbarot, Prajapati, Chu, Eyerich.

Conflict of Interest Disclosures: Dr Blauvelt reported receiving personal fees and reimbursement for performing clinical studies from AbbVie and Regeneron; and personal fees from Sanofi during the conduct of the study; and served as a scientific adviser and/or clinical study investigator for Abcentra, Aligos, Almirall, Amgen, Arcutis, Arena, ASLAN, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly and Company, Evommune, Forte, Galderma, Incyte, Janssen, Landos, Leo, Novartis, Pfizer, Rapt, Sun Pharma, and UCB Pharma. Drs Teixeira, Hu, Wu, Liu, Ladizinski, and Chu are full-time employees of AbbVie Inc, and may hold AbbVie stock and/or stock options. Dr Simpson reported receiving grants from AbbVie, Amgen, Eli Lilly, Incyte, Kyowa Hakko Kirin, Leo Pharmaceuticals, Merck, Novartis, Pfizer, Regeneron, Sanofi, Tioga, and Vanda; personal fees from AbbVie, Amgen, Arena, BenevolentAI Bio Limited, BiomX Ltd, Bluefin Biomedicine Inc, Boehringer Ingelheim, Boston Consulting Group, Collective Acumen LLC (CA), Coronado, Dermira, Eli Lilly, Evidera, ExcerptaMedica, Forte Bio RX, Incyte, Janssen, Kyowa Kirin Pharmaceutical Development, Leo Pharm, Medscape LLC, Novartis, Ortho Dermatologics, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron, Roivant, Sanofi Genzyme, SPARC India, and Valeant outside the submitted work. Dr Costanzo reported receiving grants from AbbVie during the conduct of the study; grants from Novartis and Galderma; and personal fees from Janssen, UCB, Lilly, and Sanofi outside the submitted work. Dr de Bruin-Weller reported receiving grants from and serving as a speaker, advisory board member, and consultant for AbbVie; serving as a speaker and consultant for Almirall; serving as an advisory board member for Arena; serving as an advisory board member for ASLAN; serving as a speaker and advisory board member for Galderma; serving as an advisory board member for Janssen; serving as a speaker, advisory board member, and consultant for Pfizer; grants from Eli Lilly, Leo Pharma, Regeneron, and Sanofi Genzyme outside the submitted work. Dr Barbarot reported receiving grants from Novartis; and personal fees from Sanofi, Leo Pharma, AbbVie, Janssen, Lilly, Pfizer, UCB, and Almirall during the conduct of the study. Dr Prajapati reported receiving personal fees from AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Homeocan, Incyte, Janssen, Leo Pharma, Medexus, Novartis, Pediapharm, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant outside the submitted work. Dr Lio reported receiving grants from AOBiome, Regeneron/Sanofi Genzyme, and AbbVie; personal fees from Regeneron/Sanofi Genzyme, Leo, Eli Lilly, Pfizer, Galderma, L’Oreal, Almirall, ASLAN Pharma Advisory board, Dermavant, Pierre Fabre, Menlo Therapeutics, IntraDerm, Exeltis, AOBiome, Arbonne, and Amyris; stock options from Micreos and; other royalties from patented product from Theraplex; in addition, Dr Lio had a patent for Theraplex AIM moisturizer pending Theraplex company. Dr Chu reported receiving personal fees from AbbVie during the conduct of the study; and personal fees from AbbVie outside the submitted work. Dr Eyerich reported receiving grants and personal fees from AbbVie during the conduct of the study; personal fees from Almirall, BMS, Lilly, Leo, Janssen, Novartis, UCB, and Sanofi; and grants from Lilly, Leo, Janssen, Novartis, and UCB outside the submitted work. No other disclosures were reported.

Funding/Support: AbbVie funded the research for these studies and provided writing support for this manuscript.

Role of the Funder/Sponsor: AbbVie Inc participated in the study design; study research; collection, analysis, and interpretation of data; and writing, reviewing, and approving this manuscript for submission.

Additional Information: AbbVie and the authors thank all study investigators for their contributions and the patients who participated in this study. Priya S. Mathur, PhD, AbbVie, provided medical writing support in production of this publication; she was compensated as a full-time employee of AbbVie Inc.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.