Upadacitinib in active non-radiographic axial spondyloarthritis: 2-year data from the phase 3 SELECT-AXIS 2 study

Abstract

Background: In SELECT-AXIS 2, upadacitinib improved the signs and symptoms of active non-radiographic axial spondyloarthritis (nr-axSpA) through 52 weeks versus placebo and was well tolerated. Here, we evaluated the efficacy and safety of upadacitinib through 2 years.

Methods: The study enrolled eligible adult patients with a clinical diagnosis of nr-axSpA who met the 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria and had objective signs of active inflammation on magnetic resonance imaging (MRI) of sacroiliac joints and/or high-sensitivity C-reactive protein. Patients were randomized 1:1 to receive double-blinded treatment with upadacitinib 15 mg once daily (QD) or placebo for 52 weeks, after which all patients received open-label treatment with upadacitinib 15 mg QD. Efficacy results over 104 weeks were reported as observed (AO) and either AO with non-responder imputation (AO-NRI; binary endpoints) or AO with mixed-effect model for repeated measures (continuous endpoints). Treatment-emergent adverse events (TEAEs) were summarized through week 104.

Results: Of 313 patients randomized and treated, 224 (continuous upadacitinib n = 117; placebo/upadacitinib n = 107) completed 104 weeks of treatment. In patients who received continuous upadacitinib, sustained improvement was observed through 2 years of treatment across efficacy endpoints including disease activity, pain, function, enthesitis, quality of life, and MRI measures of inflammation. At week 104, 57.1%, 59.0%, and 31.4% of patients achieved ASAS40 response, and low disease activity and inactive disease (as defined by Axial Spondyloarthritis Disease Activity Score), respectively (AO-NRI); week 104 outcomes were generally similar in patients who initially received placebo and were switched to upadacitinib at week 52. In total, 286 patients were exposed to ≥ 1 dose of upadacitinib, comprising 378.3 patient-years (PY) of exposure. Upadacitinib was generally well tolerated, with exposure-adjusted event rates (EAERs) for TEAEs, serious adverse events (AEs), and AEs leading to study drug discontinuation of 207.5, 8.7, and 5.3 events/100 PY, respectively. EAERs of TEAEs of special interest were broadly consistent with those reported through week 52.

Conclusions: Treatment with upadacitinib demonstrated consistent improvement and maintenance of treatment effect across efficacy endpoints through 2 years; no new safety signals were identified with additional exposure.

Trial registration: NCT04169373.

Keywords: Axial spondyloarthritis; Disease activity; Inflammation; Janus kinase inhibitor; Safety; Upadacitinib.

Fig. 1

Patient disposition through week 104 Primary reason for discontinuation presented. ^aOne patient decided not to participate after randomization and discontinued the study before receiving study drug. ^bOne patient discontinued study treatment due to not meeting the inclusion criteria. ^cOne patient discontinued study treatment due to relocating geographically. ^dOther primary reasons for discontinuation were candida supplement use (n = 1), antibiotic medication use (n = 1), early rescue with a bDMARD (n = 1), and patient decision (n = 1). ^eOther primary reasons for discontinuation were site closure (n = 1), patient decision (n = 3), not meeting the inclusion criteria (n = 1), inability to follow study procedures (n = 1), and tuberculosis medication use (n = 1). ^fOther primary reasons for discontinuation were due to moving out of the country (n = 2), withdrew consent (n = 1), and patient decision (n = 1). nr-axSpA non-radiographic axial spondyloarthritis, QD once daily

Fig. 2

Proportion of patients achieving ASAS40, ASDAS LDA, and ASDAS inactive disease through week 104 AO as observed, ASAS40 ≥ 40% improvement in three out of the four of the Assessment of SpondyloArthritis International Society domains without worsening in the remaining domain, ASDAS Axial Spondyloarthritis Disease Activity Score, CI confidence interval, LDA low disease activity, MI multiple imputation, nr-axSpA non-radiographic axial spondyloarthritis, NRI non-responder imputation, PBO placebo, QD once daily, UPA upadacitinib, W week

Fig. 3

Change from baseline in total and nocturnal back pain, BASFI, and hsCRP through week 104 ^aN is the number of patients with observed data at each visit AO as observed, BASFI Bath Ankylosing Spondylitis Functional Index, CI confidence interval, hsCRP high-sensitivity C-reactive protein, MMRM mixed-effect model for repeated measures, PBO placebo, QD once daily, UPA upadacitinib, W week

Fig. 4

Exposure-adjusted event rates of AESIs and key EMMs through week 104 ^aExcluding TB and herpes zoster. ^bAdverse event of atypical lymphocytes (transient laboratory phenomenon; not true lymphoma). ^cNo serious events of herpes zoster were reported. ^dDefined as cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. There was one event of non-fatal stroke and one event of non-fatal myocardial infarction. ^eIncludes DVT and PE. There was one event of DVT and two events of PE. ^fIncludes uveitis, iritis, and iridocyclitis. AESI adverse event of special interest, Adj adjudicated, CI confidence interval, DVT deep vein thrombosis, E event, EMM Extra-musculoskeletal manifestation, IBD inflammatory bowel disease, NMSC non-melanoma skin cancer, PE pulmonary embolism, PY patient-years, QD once daily, TB tuberculosis, UPA upadacitinib, VTE venous thromboembolism