AB0894 Efficacy and Safety of Guselkumab in Biologic-Naïve Patients With Active Axial Psoriatic Arthritis: Study Design of a Phase 4, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

BackgroundEstablished criteria for classifying axial psoriatic arthritis (PsA) are lacking, and assessments of disease activity often rely on measures developed for ankylosing spondylitis (AS). There is an unmet need to systematically identify and measure efficacy of treatments for axial PsA patients (pts). Guselkumab (GUS), a selective interleukin (IL)-23p19 inhibitor, was efficacious in improving signs and symptoms of active PsA in 2 phase 3, randomized, placebo (PBO)-controlled studies: DISCOVER-1 and DISCOVER-2. In a post-hoc pooled analysis of DISCOVER-1&2 pts with investigator-confirmed sacroiliitis, GUS-treated pts had greater improvements in axial symptoms compared with PBO.1 Imaging in DISCOVER-1&2 was restricted to the sacroiliac (SI) joints, occurring prior to/at screening as confirmed by the investigator, and locally read.ObjectivesTo design a new, dedicated study to evaluate the effects of GUS on axial PsA prospectively.MethodsCumulative evidence from DISCOVER-1&2, including exposure–response relationship, covariate adjustment for modest baseline imbalances across treatment groups, subgroup analyses, and comparisons within and across these studies, was considered in designing a new trial. Data from the pivotal registrational studies suggest similar efficacy with GUS every-4-weeks (Q4W) and Q8W regimens in treating PsA signs and symptoms, including symptoms of axial involvement. Power calculations were based on mean changes in Bath AS Disease Activity Index (BASDAI) scores in DISCOVER-1&2.ResultsThe phase 4, randomized, PBO-controlled STAR study is specifically designed to prospectively assess efficacy outcomes in PsA pts with magnetic resonance imaging (MRI)-confirmed axial inflammation. Based on observed mean (SD) changes from baseline in BASDAI score from DISCOVER-1&2 (Table 1), 405 pts, randomized (1:1:1) to GUS Q4W, GUS at W0, W4, then Q8W, or PBO →GUS Q8W at W24, are planned for enrollment (Figure 1). STAR eligibility criteria include PsA ≥6 months and active disease (≥3 swollen & ≥3 tender joints, C-reactive protein [CRP] ≥0.3 mg/dL) despite prior non-biologic disease-modifying antirheumatic drugs, apremilast, and/or non-steroidal anti-inflammatory drugs. Pts will be naïve to biologics and Janus kinase inhibitors and have BASDAI ≥4, spinal pain score (visual analog scale [VAS]) ≥4, and screening MRI-confirmed axial disease (positive spine and/or SI joints defined as centrally read Spondyloarthritis Research Consortium of Canada [SPARCC] score ≥3). Follow-up MRIs of spine and SI joints will be obtained at W0, W24, and W52 and also centrally read, with readers blinded to treatment group and timepoint. Spinal/SI joint inflammation will be scored using the SPARCC method, with the former also assessed using the CAN-DEN method. The primary endpoint is mean change in BASDAI at W24; controlled (hierarchical) secondary endpoints, all at W24, include AS Disease Activity Score (ASDAS-CRP), Disease Activity Index for PsA (DAPSA), ≥40% improvement in Assessment in AS criteria (ASAS40), and mean changes in spine/SI joint SPARCC scores.Table 1.Power calculations for the primary endpoint in the Phase 4 STAR study.Historical trial data*Observed mean (SD) change in BASDAI from W0-24Effect sizePower(N=135; α=0.05)**PBO-1.28 (2.24)GUS 100 mg Q4W-2.51 (2.00)1.23>99%GUS 100 mg Q8W-2.61 (2.47)1.33>99%* From the pooled DISCOVER-1&2 trials**Power calculations based on N=135 per study group (1:1:1 randomization) and 2-sided significance of 0.05 using a 2-sample T-test assuming equal variancesBASDAI, Bath Ankylosing Spondylitis Disease Activity Index; GUS, guselkumab; PBO, placebo; Q4W, every 4 weeks; Q8W, every 8 weeks; SD, standard deviation; W, weekConclusionThe phase 4 STAR study will allow for an in-depth, prospective evaluation of the effects of selectively inhibiting the IL-23p19 subunit with GUS in pts with MRI-confirmed axial PsA.