Upadacitinib: First-and-only oral JAK inhibitor approved for both AS and nr-axSpA

12 Dec 2022

On October 21, 2022, the United States (US) Food and Drug Administration (FDA) approved upadacitinib for the treatment of patients with non-radiographic axial spondyloarthritis (nr-axSpA).1 The approval was based on the positive results of the SELECT-AXIS 2 phase 3 clinical trial which assessed the safety and efficacy of upadacitinib in adults with active nr-axSpA.1

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease with an average symptom onset age of 28 years.2 It is estimated that the prevalence of axSpA in adults in the US ranges from 0.9 % to 1.4 %, with half of them having nr-axSpA.2 These patients usually present with predominantly axial involvement, characterized by inflammation of sacroiliac (SI) joints or the spine, or both.2 Other associated manifestations include inflammatory back pain (IBP), peripheral joint and entheseal manifestations, and extra-articular manifestations (e.g., inflammation of the uvea).2 In general, axSpA patients are treated with non-pharmaceutical therapy in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs).3,4 Some patients with active disease who do not respond to NSAIDs should be escalated to biologic disease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosis factor inhibitors (TNFis).3,4 It is now known that the Janus kinase (JAK) pathway plays an important role in the pathogenesis of axSpA.4 Clinical trials in 2019 showed that upadacitinib, an oral selective JAK inhibitor, was safe and effective in improving the signs and symptoms of bDMARDs-naïve patients with ankylosing spondylitis (AS), and was subsequently approved by the FDA.4

More recently, the SELECT-AXIS 2 study, a randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial, had been conducted to evaluate the safety and efficacy of upadacitinib in patients with nr-axSpA, another subtype of axSpA, and an inadequate response to NSAIDs .4 From November 26, 2019 to May 20, 2021, a total of 314 eligible patients were enrolled and randomized 1:1 to receive either upadacitinib 15mg daily or placebo using interactive response technology.4 The primary study endpoint was the proportion of patients achieving the Assessment in SpondyloArthritis international Society 40% (ASAS40) response at week 14.4

Results showed that upadacitinib demonstrated a significantly higher ASAS40 response rate when compared with placebo as early as week 2 (nominal p=0.043).4 At week 14, upadacitinib achieved a statistically higher ASAS40 response rate of 45% vs. 23% in the placebo group, with a treatment difference of 22% (95% CI: 12-32, p<0.0001).4 In the additional measure of disease activities, including the Bath Ankylosing Spondylitis Disease Activity Index 50% (BASDAI50), Ankylosing Spondylitis Disease Activity Score (ASDAS), ASAS partial remission, and ASAS 20%, upadacitinib also showed significantly higher response rates vs. placebo at week 14 (p<0.005).4 Moreover, patients’ quality of life was significantly improved with the upadacitinib treatment vs. placebo (p<0.0001).4

Regarding safety, similar rates of treatment-emergent adverse events (TEAEs) were observed with upadacitinib and placebo (48% vs. 46%).4 Serious TEAEs and adverse events leading to treatment discontinuation were reported in 3% of patients treated with upadacitinib and 1% in the placebo group.4 Throughout the study, no new safety signals with upadacitinib were identified, and no malignancies, major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), or deaths associated with upadacitinib were observed.4  

In conclusion, the SELECT-AXIS 2 trial revealed the rapid and significant improvement in the signs and symptoms of nr-axSpA patients with an inadequate response to NSAIDs. The favorable safety profile of upadacitinib in nr-axSpA patients was demonstrated and was consistent with the safety findings reported in the previous clinical studies of upadacitinib. The results of SELECT-AXIS 2 supported the potential role of upadacitinib as a novel treatment option for active nr-axSpA patients.4

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