ArticlesSafety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial
Introduction
Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are highly effective therapies that have greatly improved the clinical, functional, and radiographic outcomes for patients with rheumatoid arthritis.1, 2 However, some patients might not respond to, or are intolerant to bDMARD therapy; additionally, patients might lose response to treatment with a bDMARD over time.3, 4, 5, 6, 7, 8 These patients, in many of whom multiple conventional synthetic DMARDS (csDMARDs) have also previously failed, have few treatment options, particularly because those with inadequate response to one or more bDMARDs or targeted DMARDs are less likely to achieve optimal disease control.8, 9, 10 Studies have shown that patients refractory to tumor necrosis factor (TNF) inhibition might benefit from therapy with a different mechanism of action.11, 12, 13
A new class of therapies targeting Janus kinases (JAKs) has shown efficacy in rheumatoid arthritis in a range of patient populations, including those with an inadequate response to bDMARDs.11, 14, 15 These cytoplasmic tyrosine kinases are comprised of four isotypes (JAK1, JAK2, JAK3, and non-receptor tyrosine-protein kinase TYK2), which are associated with membrane cytokine receptors to mediate signalling downstream of multiple cytokines and growth factors.16 Activation of JAK pathways initiates expression of survival factors and additional molecules that facilitate leucocyte cell trafficking and proliferation, and contribute to the pathogenesis of multiple inflammatory and autoimmune disorders. Inhibitors with different selectivity profiles against JAKs have been developed—eg, tofacitinib and baricitinib. Upadacitinib (ABT-494) is an orally administered JAK inhibitor, engineered for greater selectivity for JAK1 than for other members of the JAK family. Upadacitinib improved rheumatoid arthritis signs and symptoms in patients with an inadequate response to methotrexate or TNF inhibitors in phase 2 studies.17, 18 We did this study (SELECT-BEYOND) to further assess the safety and efficacy of upadacitinib in patients with an inadequate response to bDMARDs. This Article describes the results from the first 24 weeks of the SELECT-BEYOND study.
Section snippets
Study design and participants
SELECT-BEYOND is a double-blind, randomised controlled phase 3 trial with a 12-week placebo-controlled period followed by a double-blind extension of up to 5 years. The study enrolled patients at 153 sites in 26 countries (appendix). Patients were aged 18 years or older, diagnosed with rheumatoid arthritis for at least 3 months before enrolment, and fulfilled the 2010 American College of Rheumatology (ACR) and European League Against Rheumatism classification criteria for rheumatoid arthritis.19
Results
Between March 15, 2016, and Jan 10, 2017, 778 patients were screened, of which 279 patients were excluded (figure 1). 499 patients were randomly assigned (n=165 upadacitinib 15 mg; n=165 upadacitinib 30 mg; n=85 placebo then upadacitinib 15 mg; and n=84 placebo then upadacitinib 30 mg) and one patient withdrew from the upadacitinib 15 mg group before the start of study treatment because of accidental randomisation. 498 patients received at least one dose of study drug, 451 (91%) completed 12
Discussion
The SELECT-BEYOND study recruited patients with rheumatoid arthritis who had an inadequate response or intolerance to bDMARDs, and high disease activity on a background of csDMARDs; approximately a quarter of patients had received three or more bDMARDs that had failed. In this treatment-refractory population, once-daily treatment with upadacitinib at 15 mg or 30 mg resulted in rapid and significant improvements in clinical responses and functional and patient-reported outcomes. Responses were
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