Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218870 on 3 December 2020. Downloaded from Psoriatic arthritis CLINICAL SCIENCE Upadacitinib for psoriatic arthritis refractory to biologics: SELECT- PsA 2 Philip J Mease ,1,2 Apinya Lertratanakul,3 Jaclyn K Anderson ,3 Kim Papp,4 Filip Van den Bosch,5 Shigeyoshi Tsuji,6 Eva Dokoupilova,7,8 Mauro Keiserman,9 Xin Wang,3 Sheng Zhong,3 Reva M McCaskill,3 Patrick Zueger,3 Aileen L Pangan,3 William Tillett10,11 Handling editor Josef S ABSTRACT Key messages Smolen Background Upadacitinib is a Janus kinase inhibitor under evaluation for the treatment of psoriatic arthritis ► Additional material is What is already known about this subject? published online only. To view (PsA). We evaluated upadacitinib in patients with PsA ► Despite the availability of biologic disease- please visit the journal online and prior inadequate response or intolerance to at least modifying antirheumatic drugs (DMARDs) in (http:// dx. doi. org/ 10. 1136/ one biologic disease- modifying antirheumatic drug psoriatic arthritis, only a small proportion of annrheumdis- 2020- 218870). (DMARD). patients achieve the recommended target of Methods In this 24-week randomised, placebo- For numbered affiliations see minimal disease activity; therefore, additional controlled, double-blind, phase 3 trial, 642 patients were end of article. treatment options are needed. randomised (2:2:1:1) to once per day upadacitinib 15 Correspondence to mg or 30 mg, placebo followed by upadacitinib 15 mg What does this study add? Dr Philip J Mease, or placebo followed by upadacitinib 30 mg at week 24. In this phase 3 trial of patients with psoriatic Rheumatology, Swedish Medical The primary endpoint was the proportion of patients ► Center, Seattle WA 98122, USA; arthritis refractory or intolerant to biologic achieving American College of Rheumatology (ACR) 20 pmease@ philipmease. com DMARDs, greater efficacy was demonstrated response at week 12. Achievement of minimal disease for once per day upadacitinib 15 mg and 30 Received 13 August 2020 activity (MDA) was assessed at week 24. Treatment- mg versus placebo for clinical manifestations Revised 22 September 2020 emergent adverse events are reported for all patients Accepted 12 October 2020 of psoriatic arthritis including musculoskeletal who received at least one dose of trial drug. symptoms (peripheral arthritis, enthesitis, Results At week 12, significantly more patients dactylitis and spondylitis), psoriasis, physical receiving upadacitinib 15 mg and 30 mg versus placebo function, pain, fatigue and quality of life. achieved ACR20 (56.9% and 63.8% vs 24.1%; p<0.001 for both comparisons). At week 24, MDA was achieved How might this impact on clinical practice or by more upadacitinib 15 mg-treated (25.1%) and 30 future developments? mg- treated patients (28.9%) versus placebo (2.8%; Once per day upadacitinib 15 mg and 30 mg p<0.001 for both comparisons). Generally, the rates ► demonstrated significant efficacy in patients http://ard.bmj.com/ of treatment-emergent adverse events were similar with psoriatic arthritis refractory or intolerant to with placebo and upadacitinib 15 mg and higher prior biologic DMARD therapy in the 24-week with upadacitinib 30 mg at week 24. Rates of serious placebo- controlled period of this study. infections were 0.5%, 0.5% and 2.8% with placebo, Efficacy was observed as early as week 2. upadacitinib 15 mg and upadacitinib 30 mg, respectively. ► Efficacy was demonstrated in all measures of Conclusion In this trial of patients with active PsA who the various core clinical domains of psoriatic had inadequate response or intolerance to at least one on September 30, 2021 by guest. Protected copyright. arthritis. More upadacitinib-treated patients biologic DMARD, upadacitinib 15 mg and 30 mg was achieved a state of minimal disease activity. more effective than placebo over 24 weeks in improving The safety findings are consistent with the signs and symptoms of PsA. ► known safety profile of upadacitinib observed Clinical trial registration number NCT03104374 in rheumatoid arthritis; no new safety risks have been identified. © Author(s) (or their INTRODUCTION employer(s)) 2020. Re- use Psoriatic arthritis (PsA) is a systemic inflammatory by other approved therapies.1–3 While multiple permitted under CC BY- NC. No disease with heterogeneous clinical manifesta- therapeutic choices are now available, additional commercial re- use. See rights tions such as plaque psoriasis, arthritis, dactylitis options are needed as under one- third achieving and permissions. Published by BMJ. and enthesitis. Current treatment guidelines for minimal disease activity (MDA) in most placebo- PsA vary, recommending conventional synthetic controlled trials.4–9 To cite: Mease PJ, disease- modifying antirheumatic drugs (DMARDs) Upadacitinib is an oral, reversible Janus kinase Lertratanakul A, such as methotrexate as initial therapy, followed by inhibitor (JAKi) with selectivity for JAK1 over Anderson JK, et al. 10 Ann Rheum Dis Epub ahead biologic DMARDs (tumour necrosis factor inhibi- JAK2, JAK3 and tyrosine kinase 2, approved for of print: [please include Day tors (TNFi), interleukin-12/23 or interleukin-17 the treatment of rheumatoid arthritis based on five Month Year]. doi:10.1136/ inhibitors) or targeted synthetic DMARDs, such as phase 3 studies.11–15 Improvements in multiple annrheumdis-2020-218870 apremilast or tofacitinib, or TNFi initially, followed composite measures, including stringent measures Mease PJ, et al. Ann Rheum Dis 2020;0:1–9. doi:10.1136/annrheumdis-2020-218870 1 Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218870 on 3 December 2020. Downloaded from Psoriatic arthritis of low disease activity and remission, as well as patient-reported 12. Multiplicity-controlled secondary endpoints for each dose outcomes such as morning stiffness and pain, after treatment of upadacitinib versus placebo included: at week 12, change with upadacitinib 15 mg once per day, in patients with rheuma- from baseline in Health Assessment Questionnaire-Disability toid arthritis who failed biologic DMARDs were similar to those Index (HAQ- DI)17; Functional Assessment of Chronic Illness in patients who had failed conventional synthetic DMARDs or Therapy- Fatigue (FACIT- F) score18 and Short Form Health methotrexate.11–15 We report the results of the SELECT- PsA 2 Survey questionnaire (SF-36) Physical Component Summary trial, a randomised phase 3 trial of upadacitinib in patients with (PCS) score19; at week 16, proportion of patients achieving a active PsA who have had an inadequate response or intolerance Static Investigator Global Assessment (sIGA) of Psoriasis of 0 or to at least one biologic DMARD. 1 and at least a 2 point improvement from baseline (sIGA 0/1) for patients with baseline sIGA ≥220; Psoriasis Area Severity PATIENTS AND METHODS Index (PASI)75 response for patients with ≥3% BSA- psoriasis at baseline21; and change from baseline in Self- Assessment Patients 22 Eligible patients were 18 years of age or older with active PsA, had of Psoriasis Symptoms (SAPS) Questionnaire ; and at week 23 a diagnosis of PsA with symptom onset for ≥6 months, fulfilled 24, proportion of patients achieving MDA. Additional key the Classification Criteria for Psoriatic Arthritis (CASPAR),16 secondary efficacy endpoints included ACR50/70 response had historical or current plaque psoriasis, ≥3 swollen joints (of at week 12 and ACR20 response at week 2. Exploratory 66) and ≥3 tender joints (of 68) at screening and at baseline, and endpoints were proportion of patients achieving PASI90/100 an inadequate response or intolerance to at least one biologic response, resolution of enthesitis (defined by Leeds Enthesitis 24 DMARD. Patients were excluded if they had previous exposure Index (LEI)=0) for patients with baseline LEI >0 and Spon- to a JAKi, had a history of fibromyalgia, had arthritis with onset dyloarthritis Research Consortium of Canada Enthesitis Index prior to age 17 years or had diagnosis of inflammatory joint ((SPARCC)=0) for patients with baseline SPARCC Enthesitis 25 disease other than PsA. Online supplemental section 2 provides Index>0 and resolution of dactylitis (defined by Leeds 26 a complete list of eligibility criteria. Dactylitis Index (LDI)=0) for patients with baseline LDI>0, and change from baseline in individual components of ACR response, Disease Activity in Psoriatic Arthritis (DAPSA) Trial design score,27 and morning stiffness (mean of Bath Ankylosing Spon- A multicentre, randomised, double- blind, phase 3 placebo- dylitis Disease Activity Index (BASDAI) questions 5 and 6). All controlled trial at 123 sites in 17 countries has been ongoing outcomes are defined in online supplemental table S1. since April 2017, conducted per the International Conference on Adverse events (AEs) and clinical laboratory testing are Harmonization guidelines, applicable regulations and guidelines reported through week 24. An independent, external Cardio- governing clinical trial conduct, and the Declaration of Helsinki. vascular Adjudication Committee blindly adjudicated deaths All patients provided written informed consent. and cardiovascular events per predefined event definitions. An internal Gastrointestinal (GI) Perforation Adjudication Randomisation and treatments Committee blindly adjudicated reported GI perforation An Interactive Response Technology system was used to assign events as stated in the GI perforation charter. patients, in a 2:2:1:1 ratio, to one of the following