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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Patient Disposition Through Week 24

CONSORT diagram for patient enrollment, randomization, and discontinuation. The primary reason for discontinuation is listed. EASI indicates Eczema Area and Severity Index.

Figure 2.. Efficacy Over Time

A, Proportion of patients achieving 75% improvement in Eczema Area and Severity Index (EASI75) B, Proportion of patients achieving 90% improvement in EASI (EASI90). C Proportion of patients achieving 100% improvement in EASI (EASI100). D, Mean percentage change in Worst Pruritus Numerical Rating Scale (NRS) for patients treated with upadacitinib or dupilumab by nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19. Error bars indicate 95% CIs (synthetic result based on t test distribution from the PROC MIANALYZE procedure in SAS if there were missing data due to COVID-19 or was based on the normal approximation to the binomial distribution if there were no missing data due to COVID-19). aP ≤ .001. bP ≤ .01. cP ≤ .05.