Safety and Efficacy of Upadacitinib in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic Dermatitis: Results From a Pivotal Phase 3, Randomised, Double-Blind, Placebo-Controlled Study (AD Up) (preprint)

ABSTRACT

Background: Systemic therapies are typically combined with topical corticosteroids (TCS) in the management of moderate-to-severe atopic dermatitis (AD). Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 being developed for AD. AD Up was designed to assess the efficacy and safety of UPA+TCS versus placebo (PBO)+TCS in adolescents and adults with moderate-to-severe AD.Methods: AD Up (ClinicalTrials.gov, NCT03568318) is an ongoing pivotal, phase 3, randomised, double-blinded, placebo-controlled, multicentre study that enrolled patients from 171 clinical centres across the Asia-Pacific region, Europe, Middle East, North America, and Oceania. Adolescents (aged 12–17 years) and adults (aged 18–75 years) with chronic AD (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] ≥16, validated Investigator’s Global Assessment for AD [vIGA-AD™] ≥3, and Worst Pruritus Numerical Rating Scale [NRS] score ≥4) were eligible to participate. Patients were randomised (111) to receive UPA 15 mg, UPA 30 mg, or PBO once daily, all in combination with TCS (medium-potency TCS [or lowpotency TCS or topical calcineurin inhibitor for sensitive skin areas] until skin was clear or almost clear or for up to 3 consecutive weeks, followed by low-potency TCS for 7 days; if lesions returned or persisted, step-down approach was repeated), stratified by baseline disease severity, geographic region, and age using interactive response technology. Study investigators, study site personnel, and patients remained blinded throughout the study. Efficacy was analysed in the intention-to-treat population, defined as all patients who were randomised in the main study. The coprimary endpoints were proportion of patients achieving ≥75% reduction from baseline in EASI (EASI 75) at week 16 and proportion of patients achieving vIGA-AD of clear or almost clear with ≥2 grades of improvement (vIGA-AD 0/1) at week 16. Selected key secondary endpoints included proportions of patients achieving EASI 90 at weeks 4 and 16, EASI 75 at weeks 2 and 4, and percent Worst Pruritus NRS improvement ≥4 at weeks 1, 4, and 16. Safety was assessed via adverse event (AE) monitoring. Missing responses were handled based on nonresponder imputation incorporating multiple imputation to handle missing data due to coronavirus disease 2019 (COVID-19; NRI-C). Safety was analysed in all patients in the main study who received ≥1 dose of study drug.Findings: Between Aug 30, 2018, and Dec 20, 2019, 901 patients were randomised. At week 16, significantly greater proportions of patients treated with UPA 15 mg+TCS or UPA 30 mg+TCS than PBO+TCS achieved the coprimary endpoints—EASI 75 (64·6% [194 of 300 patients] and 77·1% [229 of 297] vs 26·4% [80 of 304]; adjusted difference vs PBO+TCS 38·1% [95% CI 30·8–45·4] and 50·6% [43·8–57·4]; p<0·001 for both doses) and vIGA-AD 0/1 (39·6% [119 of 300] and 58·6% [174 of 297] vs 10·9% [33 of 304]; adjusted difference vs PBO+TCS 28·5% [22·1–34·9]; 47·6% [41·1–54·0]; p<0·001 for both doses). The superiority of both UPA doses vs PBO was also demonstrated for all key secondary endpoints (p<0·001). During the double-blind period, UPA 15 and 30 mg were well tolerated in combination with TCS, and no new important safety signals beyond the events in the current label. Higher rates of acne were reported in this AD study. Incidences of AEs leading to discontinuation of study drug and serious AEs were similar among treatment groups. No deaths or opportunistic infections (excluding herpes zoster), active tuberculosis, lymphoma, adjudicated gastrointestinal perforations, adjudicated major adverse cardiovascular events, or adjudicated venous thromboembolic events were reported. Efficacy and safety results for adolescents were consistent with those for the overall population.Interpretation: In this phase 3 study, UPA+TCS was well tolerated and superior to PBO+TCS across coprimary and all key secondary endpoints. UPA as combination therapy demonstrated a positive benefit-risk profile in adults and adolescents with moderate-to-severe AD.Trial Registration ClinicalTrials.gov number NCT03568318Funding: AbbVie Inc. Declaration of Interest KR has served as advisor and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Affibody, Almirall, Amgen, Avillion, Biogen, Bausch Health (Valeant), Biogen, 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. HDT, JZ, XHuang, XHu, BH, BL, ADC are full-time employees of AbbVie Inc., and may hold AbbVie stock or stock options. MdB-W has been a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Galderma, Janssen, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi Genzyme, and UCB. TB is an advisor, speaker, and researcher for AbbVie, Allmiral, AnaptysBio, Arena, Asana Biosciences, Astellas, Bayer, BioVersys, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Dermavant/Roivant, Dermtreat, Domain Therapeutics, DS Biopharma, RAPT Therapeutics (FLX Bio), Galapagos/MorphoSys, Galderma, Glenmark, GlaxoSmithKline, Incyte, Kymab, LEO Pharma, Lilly, L´Oréal, Menlo Therapeutics, Novartis, Pfizer, Pierre Fabre, Sanofi/Regeneron, and UCB. WS is a consultant for AbbVie, Pfizer, Regeneron, and Sanofi. He is a speaker for Regeneron and Sanofi, and has received research grants from AbbVie, AB Biosciences, Genentech, Glenmark, LEO Pharma, Regeneron, Sanofi, and Vanda. KK has received consulting fees, honoraria, or grant support or lecturing fees from AbbVie, Japan Tobacco, LEO Pharma, 24 Maruho, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Procter & Gamble, Sanofi, Taiho Pharmaceutical, and Torii Pharmaceutical. TW has received lecture or consultancy fees from AbbVie, Almirall, Astellas, Galderma, Janssen/Johnson & Johnson, LEO Pharma, Lilly, Novartis, Pfizer, and Regeneron/Sanofi. JIS is an advisor, speaker, or consultant for AbbVie, Asana Biosciences, Dermavant, Galderma, GlaxoSmithKline, Glenmark, Kiniksa, LEO Pharma, Lilly, Menlo Therapeutics, Novartis, Pfizer, Realm Pharma, and Regeneron-Sanofi. He is also a researcher for GlaxoSmithKline.Ethical Approval Independent ethics committees or institutional review boards at each study site approved the study protocol, informed consent form(s), and recruitment materials prior to patient enrolment. The study was conducted in accord with the International Conference for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. Adult patients and parents/legal guardians of adolescent patients provided written informed consent prior to any screening or study-related procedures. An adolescent substudy was added after the protocol was initiated to allow enrolment of additional adolescents to fulfil a regulatory commitment.