Efficacy and safety of upadacitinib dose escalation and reduction in adults with moderate-to-severe atopic dermatitis: results of a randomized blinded treat-to-target multicentre phase IIIb/IV study (Flex Up)
- PMID: 40581082
- DOI: 10.1093/bjd/ljaf236
Efficacy and safety of upadacitinib dose escalation and reduction in adults with moderate-to-severe atopic dermatitis: results of a randomized blinded treat-to-target multicentre phase IIIb/IV study (Flex Up)
Abstract
Background: Pivotal clinical trials have assessed the efficacy and safety of fixed-dose upadacitinib 15 mg (UPA15) and 30 mg (UPA30) once daily in atopic dermatitis (AD).
Objectives: To assess the efficacy and safety of dose escalation to UPA30 and dose reduction to UPA15 based on a clinical response [90% reduction in Eczema Area and Severity Index (EASI 90)] after 12 weeks of treatment in adults with moderate-to-severe AD enrolled in a randomized blinded treat-to-target multicentre phase IIIb/IV study.
Methods: A total of 461 patients were randomized in a 1 : 1 ratio to receive oral doses of UPA15 (n = 229) or UPA30 (n = 232) once daily during the 12-week double-blinded period. At week 12, patients on UPA15 not achieving EASI 90 were dose escalated to UPA30 (UPA15/30); patients achieving ≥ EASI 90 continued on UPA15 (UPA15/15). Patients on UPA30 not achieving EASI 90 at week 12 continued on UPA30 (UPA30/30); patients achieving ≥ EASI 90 received a reduced dose of UPA15 (UPA30/15) for 12 additional weeks. The primary efficacy endpoint was EASI 90 achievement at week 24. Results were reported descriptively as observed. Safety outcomes were assessed.
Results: At week 24, of patients who received dose escalation (UPA15/30), 48.1% [n = 64/133; 95% confidence interval (CI) 39.6-56.6] achieved EASI 90; of patients who received a dose reduction (UPA30/15), 68.5% (n = 89/130; 95% CI 60.5-76.4) maintained EASI 90. Of patients who continued on their initial dose, 29.3% (n = 24/82; 95% CI 19.4-39.1) on UPA30/30 achieved EASI 90 and 74.6% (n = 53/71; 95% CI 64.5-84.8) on UPA15/15 maintained EASI 90. At week 24, 32.5% (n = 27/83; 95% CI 22.5-42.6) and 38.0% (n = 38/100; 95% CI 28.5-47.5) of patients on UPA15/30 and UPA30/15, respectively, achieved a worst pruritus numerical rating scale score of 0 or 1 (WP-NRS 0/1), and 20.7% (n = 17/82; 95% CI 12.0-29.5) and 35.0% (n = 35/100; 95% CI 25.7-44.3), respectively, achieved combined EASI 90 and WP-NRS 0/1. At week 24, treatment emergent adverse events were reported in 43.1% (n = 31/72; UPA15/15), 54.2% (n = 78/144; UPA15/30), 61.5% (n = 56/91; UPA30/30) and 48.9% (n = 65/133; UPA30/15) of patients. No malignancies, adjudicated venous thromboembolic events or deaths were reported.
Conclusions: Treatment of moderate-to-severe AD with UPA15 or UPA30, with dose escalation or dose reduction based on achievement of the optimal treatment target of EASI 90 at week 12, demonstrated that both approaches support the achievement and maintenance of EASI 90 at week 24. Overall safety findings were consistent with the known UPA safety profile, with no new safety signals identified.
Plain language summary
Eczema, also known as atopic dermatitis (‘AD’), is a skin disease that causes itchiness, redness and scaling of the skin. Previous studies have tested how effective and safe a drug called upadacitinib (‘UPA’ for short) is in treating AD. The doses of UPA that have been tested are 15 mg and 30 mg. This study looked at how effective and safe adjusting the dose of UPA in adults with moderate-to-severe AD was over a period of 24 weeks. To do this, patients were divided into two groups. Patients in one group took the lower dose of UPA (15 mg). The other group took the higher dose (30 mg). All patients took their allocated dose of UPA every day for 12 weeks. If a patient’s skin did not improve by 90% when taking the initial dose, they were either given the higher dose or they stayed on the same higher dose. If a patient’s skin improved considerably, they either stayed on the lower dose or were moved from the higher dose to the lower dose. After 24 weeks, approximately half of the patients with AD who switched from the lower dose to the higher dose of UPA had 90% improvement in their skin. Most patients who switched from the higher dose to the lower dose of UPA kept their good skin. Across both dose adjustment groups, patients also experienced improvements in their quality of life. The safety findings were consistent with what is already known about UPA. No new safety concerns were found. The results support dosing strategies for the approved doses of UPA in managing moderate-to-severe AD. Dose adjustments helped to achieve and maintain treatment goals.
© The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists.
Conflict of interest statement
Conflicts of interest: M.G. is an investigator, speaker and/or advisor for AbbVie, Akros, Amgen, AnaptysBio, Arcutis, Aristea, ASLAN, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen, Johnson&Johnson, Kyowa Kirin, LEO Pharma, MedImmune, Meiji, Merck, MoonLake, Nimbus, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, Tarsus, UCB, Union and Ventyx. T.T. has served as an advisor, consultant, investigator and/or speaker for AbbVie, Almirall, Amgen, Apogee Therapeutics, Arena, Biocad, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Fresenius Kabi, J&J Innovative Medicine, LEO Pharma, Lilly, MSD, Mylan, Novartis, Pfizer, Samsung-Bioepis, Sanofi Genzyme, Sandoz and UCB. S.I. has received honoraria as a speaker/consultant for AbbVie, Amgen, Celgene, Daiichi Sankyo, Eisai, Eli Lilly, Janssen Pharmaceuticals, Kyowa Kirin, LEO Pharma, Maruho, Novartis, Pfizer, Sanofi, Sun Pharma, Taihoyakuhinkogyo and Torii Pharmaceutical. M.R. is an investigator for AbbVie, Akesobio, ASLAN, AstraZeneca, Boehringer Ingelheim, Evommune, Galderma and Suzhou Connect. V.H.P. has served as an advisor, consultant and/or speaker for AbbVie, Actelion, Amgen, Apogee Therapeutics, Aralez, Arcutis, Aspen, Bausch Health, BioJAMP/JAMP Pharma, BioScript Solutions, Boehringer Ingelheim, Bristol Myers Squibb, Canadian Psoriasis Network, Celgene, Celltrion, Cipher, CorEvitas, Eczema Society of Canada, Eli Lilly, Galderma, GlaxoSmithKline, Homeocan, Incyte, J&J Innovative Medicine, Janssen, Johnson&Johnson, LEO Pharma, Medexus, Novartis, Organon, Pediapharm, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, Tribute and UCB; as an investigator for AbbVie, AnaptysBio, Apogee Therapeutics, Apollo Therapeutics, Arcutis, Arena, Asana, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, CorEvitas, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Nektar Therapeutics, Nimbus Lakshmi, Novartis, Pfizer, RAPT Therapeutics, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Takeda, UCB and Vyne Therapeutics; and has received grants from AbbVie, Bausch Health, Janssen, LEO Pharma, Novartis and Sanofi Genzyme. A.T. is an employee of Fachklinik Bad Bentheim and has been an investigator in an AbbVie clinical trial. D.F.M. is an investigator, advisor and/or speaker for AbbVie, AnaptysBio, Arcutis, Arena, ArgenX, ASLAN, Attovia, Dermavant, Incyte, LEO Pharma, Eli Lilly, Galderma, Dermira, Pfizer, Bristol Myers Squibb, Kineska, Fujisawa, Novartis, Evelo, UCB, Sanofi Regeneron, Principia, Janssen, Ono, Nektar, Nurix, Almirall, RAPT, Sun Pharma and Roche. W.O. has received honoraria for lectures and clinical research from AbbVie, Aflofarm Farmacja, Alfasigma, Almirall, Amgen, Apotex Polska Astellas Pharma, AstraZeneca, Bausch Health Poland, Berlin Chemie Menarini, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, EGIS, Eli Lilly, Galderma, Janssen Cilag, LEO Pharma, Medac, Merck, Mylan Healthcare, Novartis, Pfizer, Pierre Fabre Medicamente, TZF Polfa, Roche Diagnostics, Sandoz, Sanofi Aventis, SUN-FARM, Teva Pharmaceuticals and UCB Pharma. Y.H., W.-J.L., G.L., N.I. and A.M. are full-time salaried employees of AbbVie and may own stock/options. K.S. has been an investigator and/or consultant/advisor for AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Galderma, Celgene, Eli Lilly, Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Sandoz, Sanofi Genzyme, UCB Pharma and Unilever.
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