Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis refractory to biologic therapy: 2-year clinical and radiographic results from the open-label extension of the SELECT-AXIS 2 study

Abstract

Background: The efficacy and safety of upadacitinib in patients with ankylosing spondylitis (AS) and inadequate response/intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR) were evaluated through 1 year in the SELECT-AXIS 2 study. Here, we assess 2-year efficacy, safety, and imaging outcomes in SELECT-AXIS 2.

Methods: Patients who received continuous upadacitinib, and those who switched from placebo to upadacitinib at week 14, could enter the open-label extension (OLE). Efficacy endpoints included Assessment of SpondyloArthritis international Society (ASAS) and Axial Spondyloarthritis Disease Activity Score (ASDAS) responses, and changes from baseline in measures of disease activity, back pain, function, and quality of life. Radiographic progression was evaluated using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). As observed (AO) and AO with non-responder imputation (AO-NRI) analyses were used for binary endpoints; AO with mixed-effects model for repeated measures (AO-MMRM) for continuous endpoints; and AO-analysis of covariance for mSASSS. Treatment-emergent adverse events (TEAEs) in patients receiving ≥ 1 upadacitinib dose through week 104 are presented as events (E)/100 patient-years (PY). Subgroup analyses were performed by prior tumor necrosis factor/interleukin-17 inhibitor exposure and bDMARD lack of efficacy/intolerance.

Results: Of 420 patients who entered the bDMARD-IR AS study, 409 entered the OLE, and 331 (continuous upadacitinib, n = 163; placebo to upadacitinib, n = 168) completed week 104. Improvements in efficacy measures were sustained through the OLE, with similar response rates between the continuous upadacitinib and placebo to upadacitinib groups at week 104. At week 104, 64.9% and 61.7% of patients, respectively, had achieved ASAS 40% response (AO-NRI). Mean changes from baseline were similar between the two groups at week 104 across measures (ASDAS: -2.1 and -2.0; total back pain: -4.9 and -4.6, respectively; AO-MMRM). Over 93.0% of patients showed no radiographic progression (mSASSS mean change from baseline < 2) at week 104. The overall TEAE rate was 165.2 E/100 PY, with low rates of major adverse cardiovascular and venous thromboembolic events (0.3 E/100 PY each).

Conclusions: Upadacitinib efficacy, including very low rates of radiographic progression, was demonstrated through 104 weeks in treatment-refractory patients with active AS. Treatment was well tolerated, with no newly identified safety signals.

Trial registration: NCT04169373.

Keywords: Ankylosing spondylitis; Biologic DMARD; Inadequate response; Open-label extension; Radiographic axial spondyloarthritis; Refractory; Upadacitinib.

Fig. 1

Patient disposition through week 104 AE adverse event, AS ankylosing spondylitis, bDMARD biologic disease-modifying antirheumatic drug, D/C discontinuation, f/u follow-up, IR inadequate response, nr-axSpA non-radiographic axial spondyloarthritis, QD once daily

Fig. 2

Proportions of patients achieving ASAS40 (A), ASAS20 (B), ASDAS LDA (C), and ASDAS ID (D) responses through week 104 (AO-NRI and AO) Patients who were initially randomized to placebo were switched to open-label upadacitinib at week 14 AO as observed, ASAS Assessment of SpondyloArthritis international Society, ASAS40 ≥ 40% improvement in three out of the four ASAS domains without worsening in the remaining domain, ASAS20 ≥ 20% improvement in three out of the four ASAS domains without worsening in the remaining domain, ASDAS Axial Spondyloarthritis Disease Activity Score, CI confidence interval, ID inactive disease, LDA low disease activity, NRI non-responder imputation, PBO placebo, QD once daily, UPA upadacitinib, W week

Fig. 3

Mean change from baseline in total back pain (A), nocturnal back pain (B), BASFI (C), and hsCRP (D) through week 104 (AO-MMRM and AO) Patients who were initially randomized to placebo were switched to open-label upadacitinib at week 14. Δ change, AO as observed, BASFI Bath Ankylosing Spondylitis Functional Index, CI confidence interval, hsCRP high-sensitivity C-reactive protein, MMRM mixed-effects model for repeated measures, NRS numeric rating scale, PBO placebo, QD once daily, SD standard deviation, UPA upadacitinib, W week

Fig. 4

Mean change from baseline in imaging scores through week 104 (AO-MMRM and AO-ANCOVA) ^aAO-MMRM. ^bAO-ANCOVA. SPARCC scores were based on magnetic resonance imaging from baseline, week 14, and week 104 (2-year reading), and from premature discontinuation visits or unscheduled visits that occurred after week 76 and prior to week 104. mSASSS was assessed in patients with available X-rays of the spine from baseline and week 104, and from premature discontinuation visits that occurred after week 76 and prior to week 104 Δ change, ANCOVA analysis of covariance, AO as observed, BL baseline, LS least-squares, MMRM mixed-effects model for repeated measures, mSASSS modified Stoke Ankylosing Spondylitis Spinal Score, PBO placebo, SIJ sacroiliac joint, SPARCC SpondyloArthritis Research Consortium of Canada, UPA upadacitinib

Fig. 5

TEAEs through week 104 ^aAll patients who received ≥ 1 dose of upadacitinib 15 mg once daily. ^bThe most commonly reported SAEs were COVID-19 pneumonia (10 E; 1.5 E/100 PY) and COVID-19 (4 E; 0.6 E/100 PY). ^cOne patient died due to polytrauma before week 52. ^dFourteen of the 25 reported serious infections were COVID-19 events. ^eExcluding tuberculosis and herpes zoster. ^fDefined as cardiovascular death (includes acute myocardial infarction, sudden cardiac death, heart failure, cardiovascular procedure-related death, death due to cardiovascular hemorrhage, fatal stroke, pulmonary embolism, and other cardiovascular causes), non-fatal myocardial infarction, and non-fatal stroke. ^gIncludes deep vein thrombosis and pulmonary embolism (fatal and non-fatal). ^hIncludes uveitis, iritis, and iridocyclitis AE adverse event, CI confidence interval, D/C discontinuation, E event, EAER exposure-adjusted event rate, GI gastrointestinal, MACE major adverse cardiovascular events, NMSC non-melanoma skin cancer, PY patient-years, QD once daily, SAE serious AE, TEAE treatment-emergent AE, VTE venous thromboembolic events