Elsevier

The Lancet

Volume 400, Issue 10349, 30 July–5 August 2022, Pages 369-379
The Lancet

Articles
Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(22)01212-0Get rights and content

Summary

Background

Upadacitinib, a Janus kinase inhibitor, has been shown to be effective in patients with ankylosing spondylitis. We aimed to assess the efficacy and safety of upadacitinib in non-radiographic axial spondyloarthritis.

Methods

The SELECT-AXIS 2 non-radiographic axial spondyloarthritis study was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 113 sites across 23 countries (Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, France, Germany, Hungary, Israel, Japan, Mexico, Poland, Russia, Slovakia, South Korea, Spain, Taiwan, Turkey, Ukraine, and the USA). Eligible adults had active non-radiographic axial spondyloarthritis, with objective signs of inflammation based on MRI or elevated C-reactive protein and an inadequate response to non-steroidal anti-inflammatory drugs. Patients were randomly assigned (1:1) to receive oral upadacitinib 15 mg once daily or placebo using interactive response technology. Random treatment assignment was stratified by MRI inflammation in the sacroiliac joints and screening high-sensitivity C-reactive protein status (MRI-positive and C-reactive protein-positive, MRI-positive and C-reactive protein-negative, and MRI-negative and C-reactive protein-positive) and previous exposure to biologic disease-modifying antirheumatic drugs (yes vs no). Treatment assignment was masked from patients, investigators, study site personnel, and the study sponsor. The primary endpoint was the proportion of patients with an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Analyses were performed on the full analysis set of patients, who underwent random allocation and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04169373.

Findings

Between Nov 26, 2019, and May 20, 2021, 314 patients with active non-radiographic axial spondyloarthritis were enrolled into the study, and 313 received study drug (156 in the upadacitinib group and 157 in the placebo group); 295 (94%) patients (145 in the upadacitinib group and 150 in the placebo group) received treatment for the full 14 weeks. A significantly higher ASAS40 response rate was achieved with upadacitinib compared with placebo at week 14 (70 [45%] of 156 patients vs 35 [23%] of 157 patients; p<0·0001; treatment difference 22%, 95% CI 12–32). The rate of adverse events up to week 14 was similar in the upadacitinib group (75 [48%] of 156 patients) and placebo group (72 [46%] of 157 patients). Serious adverse events and adverse events leading to discontinuation of study drug occurred in four (3%) of 156 patients in the upadacitinib group and two (1%) of 157 patients in the placebo group. Few patients had serious infections or herpes zoster in either treatment group (each event occurred in two [1%] of 156 patients in the upadacitinib group and one [1%] of 157 patients in the placebo group). Five (3%) of 156 patients in the upadacitinib group had neutropenia; no events of neutropenia occurred in the placebo group. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, or deaths were reported with upadacitinib treatment.

Interpretation

Upadacitinib significantly improved the signs and symptoms of non-radiographic axial spondyloarthritis compared with placebo at week 14. These findings support the potential of upadacitinib as a new therapeutic option in patients with active non-radiographic axial spondyloarthritis.

Funding

AbbVie.

Introduction

Axial spondyloarthritis is a chronic inflammatory rheumatic disease of the spine and sacroiliac joints, with an estimated prevalence of up to 1·4%,1 encompassing non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis, also known as ankylosing spondylitis.1, 2 Patients with non-radiographic axial spondyloarthritis and ankylosing spondylitis share common epidemiological, genetic, and clinical features, such as inflammatory back pain, functional impairment, and extra-musculoskeletal manifestations, as well as similar disease burden,3, 4, 5 response to therapy,6, 7, 8, 9, 10 and treatment recommendations.11, 12 However, radiographic findings serve as an important differentiating characteristic, as patients with non-radiographic axial spondyloarthritis do not fulfil the criteria for radiographic sacroiliitis.1 Additionally, patients with non-radiographic axial spondyloarthritis are more frequently female, have lower C-reactive protein levels, and are less likely to be HLA-B27-positive compared with patients with ankylosing spondylitis.1, 4 Non-radiographic axial spondyloarthritis is considered an earlier form of axial spondyloarthritis that can progress to ankylosing spondylitis, particularly in patients with certain predictors for radiographic progression, including elevated C-reactive protein levels, active inflammation on MRI of the sacroiliac joints, and positive HLA-B27 status.1

Research in context

Evidence before this study

We searched PubMed for articles published in English between Jan 1, 2012, and April 7, 2022, using the search terms “non-radiographic axial spondyloarthritis” and “Janus kinase inhibitors”. Ten articles were retrieved describing the disease, treatment landscape, and the 2019 American College of Rheumatology treatment recommendations. Axial spondyloarthritis is a rheumatic disease that manifests as inflammation of the spine and sacroiliac joints and is classified into two subtypes: radiographic axial spondyloarthritis (also termed ankylosing spondylitis) and non-radiographic axial spondyloarthritis. Only treatments with two different modes of action, tumour necrosis factor inhibitors and interleukin-17 inhibitors, are approved for non-radiographic axial spondyloarthritis. Janus kinase (JAK) inhibitors have been shown to be effective in ankylosing spondylitis but, to our knowledge, no randomised trials have investigated JAK inhibitors in non-radiographic axial spondyloarthritis.

Added value of this study

SELECT-AXIS 2 is the first phase 3 clinical trial to investigate the efficacy and safety of upadacitinib, a JAK inhibitor, for the treatment of non-radiographic axial spondyloarthritis. Upadacitinib met the primary endpoint of Assessment of SpondyloArthritis international Society 40 response and 12 of 14 ranked secondary endpoints at week 14 versus placebo. Patients treated with upadacitinib had significant improvements in disease activity, pain, objective signs of inflammation, and quality of life compared with placebo. Treatment with upadacitinib was well tolerated, and the safety profile of upadacitinib was consistent with what has been observed in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. This trial showed, for the first time to our knowledge, the potential use of upadacitinib as an oral treatment option in patients with non-radiographic axial spondyloarthritis.

Implications of all the available evidence

The results from this phase 3 trial show that upadacitinib could be a safe and effective treatment option for patients with non-radiographic axial spondyloarthritis, who might prefer to use an oral therapy. The findings from this trial complement those observed in SELECT-AXIS 1 in patients with ankylosing spondylitis, showing the potential use of upadacitinib across the full spectrum of patients with axial spondyloarthritis, including those who have not received treatment or have had an inadequate response to biological therapy. The SELECT-AXIS 2 trial of patients with non-radiographic axial spondyloarthritis is ongoing to assess the long-term efficacy and safety of upadacitinib in patients with non-radiographic axial spondyloarthritis.

Because of the overall disease burden and the progressive nature of axial spondyloarthritis, treatment is recommended to manage signs and symptoms. International treatment recommendations advise using non-steroidal anti-inflammatory drugs (NSAIDs) as a first-line therapy for axial spondyloarthritis.11, 12 In patients who do not respond to NSAIDs, biologic disease-modifying antirheumatic drugs (bDMARDs), such as tumour necrosis factor (TNF) inhibitors or interleukin-17 (IL-17) inhibitors are available to treat axial spondyloarthritis.3 The Janus kinase (JAK) pathway has been found to play a part in the pathogenesis of axial spondyloarthritis,13 and JAK inhibitors have emerged as an alternative, oral treatment option in patients with ankylosing spondylitis.1, 14, 15 Upadacitinib is engineered for greater inhibitory potency for JAK1 versus other JAK isoforms; similarly, filgotinib is a JAK1 selective inhibitor.16 Other JAK inhibitor compounds have different selectivity profiles, such as baricitinib, a selective JAK1 and JAK2 inhibitor, and tofacitinib, a potent inhibitor of JAK1 and JAK3 that is less active against JAK2 and tyrosine kinase 2.16

Upadacitinib 15 mg once daily has been shown to be safe and effective in improving the signs and symptoms of ankylosing spondylitis for 2 years in a phase 2/3 clinical trial of patients naive to bDMARDs.17, 18, 19 Overall, few treatment options are available for non-radiographic axial spondyloarthritis and, to our knowledge, no clinical trials have evaluated a JAK inhibitor in patients with non-radiographic axial spondyloarthritis. Therefore, we aimed to investigate the efficacy and safety of upadacitinib 15 mg in a population with non-radiographic axial spondyloarthritis, including patients who were naïve to or had an inadequate response to bDMARDs.

Section snippets

Study design and participants

SELECT-AXIS 2 is a phase 3 programme that was conducted under a master protocol with two separate axial spondyloarthritis studies (appendix p 1). The SELECT-AXIS 2 non-radiographic axial spondyloarthritis study is a randomised, double-blind, placebo-controlled, multicentre trial that comprises a 35-day screening period; a 52-week, randomised, double-blind, parallel-group, placebo-controlled period; and a 52-week open-label extension period (figure 1). Here, we report the primary 14-week results

Results

Between Nov 26, 2019, and May 20, 2021, 1352 patients were assessed for eligibility to participate in the SELECT-AXIS 2 programme, of whom 618 (46%) were ineligible (figure 2; appendix p 3). 314 patients were enrolled into the non-radiographic axial spondyloarthritis study, 158 (50%) in the placebo group and 156 (50%) in the upadacitinib group. 295 (150 [96%] of 157 patients in the placebo group and 145 [93%] of 156 patients in the upadacitinib group) of 313 patients who received study drug

Discussion

In this trial, the first, to our knowledge, to investigate a JAK inhibitor for the treatment of patients with active non-radiographic axial spondyloarthritis, upadacitinib met the primary endpoint of ASA40 and most of the ranked secondary endpoints (change from baseline in ASDAS [C-reactive protein], SPARCC MRI sacroiliac joint, total back pain, nocturnal back pain, BASFI, ASQoL, ASAS Health Index; and the percentage of patients achieving BASDAI50, ASDAS inactive disease, ASDAS low disease

Data sharing

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymised, individual, and trial-level data (analysis datasets), as well as other information (eg, protocols, clinical study reports, or analysis plans), if the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified

Declaration of interests

AD has received grant or research support from AbbVie, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Lilly, Novartis, Pfizer, and UCB; and honoraria or consultation fees from AbbVie, Amgen, Aurinia, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Lilly, MoonLake, Novartis, Pfizer, and UCB. FVdB has received speaker or consulting fees from AbbVie, Amgen, Galapagos, Janssen, Lilly, Merck, MoonLake, Novartis, Pfizer, and UCB. DP has received consulting fees, speaking fees, or honoraria

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