Efficacy of Guselkumab on Axial-Related Symptoms Through up to 2 Years in Adults with Active Psoriatic Arthritis in the Phase 3, Randomized, Placebo-Controlled DISCOVER-2 Study.

Guselkumab previously showed greater improvements versus placebo in axial symptoms in patients with psoriatic arthritis (PsA) (assessed by Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] and Ankylosing Spondylitis Disease Activity Score [ASDAS]), in post hoc analyses of the phase 3, placebo-controlled, randomized DISCOVER-1 and DISCOVER-2 studies. We now evaluate durability of response in axial-related outcomes through 2 years of DISCOVER-2. DISCOVER-2 biologic-naive adults with active PsA (≥ 5 tender/ ≥ 5 swollen joints, C-reactive protein ≥ 0.6 mg/dl) were randomized to guselkumab 100 mg every 4 weeks (Q4W) or at week 0, week 4, then Q8W, or placebo → guselkumab Q4W at week 24. Among patients with imaging-confirmed sacroiliitis (investigator-identified), axial symptoms were assessed through 2 years utilizing BASDAI, BASDAI Question #2 (spinal pain), modified BASDAI (mBASDAI; excludes Question #3 [peripheral joint pain]), and ASDAS. Mean changes in scores and proportions of patients achieving ≥ 50% improvement in BASDAI (BASDAI 50) and ASDAS responses, including major improvement (decrease ≥ 2.0), were determined through week 100. Treatment failure rules (through week 24) and nonresponder imputation of missing data (post-week 24) were utilized. Mean BASDAI component scores were assessed through week 100 (observed data). Exploratory analyses evaluated efficacy by sex and HLA-B*27 status. Among 246 patients with PsA and imaging-confirmed sacroiliitis, guselkumab-treated patients had greater mean improvements in BASDAI, mBASDAI, spinal pain, and ASDAS scores, lower mean BASDAI component scores, and greater response rates in achieving BASDAI 50 and ASDAS major improvement vs. placebo at week 24. Differences from placebo were observed for guselkumab-treated patients in selected endpoints regardless of sex or HLA-B*27 status. At week 100, mean improvements were ~ 3 points for all BASDAI scores and 1.6-1.7 for ASDAS; 49-54% achieved BASDAI 50 and 39% achieved ASDAS major improvement at week 100. Guselkumab treatment provided durable and meaningful improvements in axial symptoms and disease activity in substantial proportions of patients with active PsA and imaging-confirmed sacroiliitis. Clinicaltrials.gov NCT03158285.

Mease PJ ，Gladman DD ，Poddubnyy D ，Chakravarty SD ，Shawi M ，Kollmeier AP ，Xu XL ，Xu S ，Deodhar A ，Baraliakos X ... -  《-》

Efficacy of guselkumab on axial involvement in patients with active psoriatic arthritis and sacroiliitis: a post-hoc analysis of the phase 3 DISCOVER-1 and DISCOVER-2 studies.

Guselkumab was efficacious in reducing signs and symptoms of psoriatic arthritis in the phase 3 DISCOVER-1 and DISCOVER-2 studies. We aimed to evaluate the efficacy of guselkumab in post-hoc analyses of patients with psoriatic arthritis with imaging-confirmed sacroiliitis consistent with axial involvement. In DISCOVER-1, 381 patients with active psoriatic arthritis (defined as ≥3 swollen joints, ≥3 tender joints, and C-reactive protein [CRP] ≥0·3 mg/dL) and in DISCOVER-2, 739 patients with active psoriatic arthritis (defined as ≥5 swollen joints, ≥5 tender joints, and CRP ≥0·6 mg/dL) were randomly allocated to receive guselkumab 100 mg every 4 weeks, guselkumab 100 mg every 8 weeks (week 0, week 4, then every 8 weeks), or placebo. These pooled, post-hoc analyses included patients with axial disease documented by previous imaging or pelvic radiography at screening consistent with sacroiliitis (confirmed by investigator). Efficacy assessments included least squares mean changes, with 95% CIs, in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, modified BASDAI (mBASDAI; excluding peripheral joint pain), spinal pain, and Ankylosing Spondylitis Disease Activity Score (ASDAS), and proportions of patients achieving at least a 50% improvement in BASDAI score (BASDAI50) and achieving ASDAS responses of inactive disease (score <1·3), major improvement (change of ≥2·0), and clinically important improvement (change of ≥1·1). Of the 1120 patients in the two DISCOVER studies, 312 (28%) were included in this analysis, of whom 118 were in the placebo group, 103 were in the guselkumab every 4 weeks group, and 91 were in the guselkumab every 8 weeks group. 191 (61%) were male, and 121 (39%) were female, and the mean age was 45·1 (SD 11·2). HLA-B27 status was assessed in 190 patients; 57 (30%) were HLA-B27-positive and 133 (70%) were HLA-B27-negative. At week 24, least squares mean changes from baseline in BASDAI were -2·7 (95% CI -3·2 to -2·2) in both guselkumab groups versus -1·3 (-1·8 to -0·9) in the placebo group; similar results were observed for mBASDAI and spinal pain. Least squares mean changes in ASDAS scores at week 24 were -1·4 (95% CI -1·7 to -1·2) in both guselkumab groups and -0·7 (-0·9 to -0·5) for placebo. At week 24, 36 (38%) patients in the guselkumab every 4 weeks group and 34 (40%) of those in the guselkumab every 8 weeks group achieved BASDAI50 versus 21 (19%) of placebo patients; greater proportions of guselkumab-treated patients achieved ASDAS responses versus placebo. Across outcomes, separation from placebo was observed at week 8. Improvements with guselkumab were seen at week 24 independent of HLA-B27 status. These improvements were maintained at week 52 in the guselkumab groups. Patients with active psoriatic arthritis and imaging-confirmed sacroiliitis who were treated with guselkumab every 4 weeks or every 8 weeks had greater mean improvements in BASDAI and ASDAS (as early as week 8) than did placebo-treated participants, with sustained improvements at week 52. Janssen Research & Development LLC.

Mease PJ ，Helliwell PS ，Gladman DD ，Poddubnyy D ，Baraliakos X ，Chakravarty SD ，Kollmeier AP ，Hsia EC ，Xu XL ，Sheng S ，Agarwal P ，Zhou B ，Sweet K ，Shawi M ，Karyekar CS ，Deodhar A ，van der Heijde D ... -  《Lancet Rheumatology》

Efficacy and safety of guselkumab in biologic-naïve patients with active axial psoriatic arthritis: study protocol for STAR, a phase 4, randomized, double-blinded, placebo-controlled trial.

Axial involvement constitutes a specific domain of psoriatic arthritis (PsA). Interleukin (IL)-23 inhibitors have demonstrated improvement in axial PsA (axPsA) symptoms, but have not shown efficacy in treating ankylosing spondylitis (AS), suggesting differences in axPsA processes and treatments. In a post hoc, pooled analysis of patients with investigator- and imaging-confirmed sacroiliitis in two phase 3, randomized, placebo-controlled studies (DISCOVER-1 and DISCOVER-2), patients treated with guselkumab, an IL-23p19 inhibitor, had greater axial symptom improvements compared with placebo. Confirmatory imaging at baseline was restricted to the sacroiliac (SI) joints, occurred prior to/at screening, and was locally read. The STAR study will prospectively assess efficacy outcomes in PsA patients with magnetic resonance imaging (MRI)-confirmed axial inflammation. Eligible, biologic-naïve patients with PsA (N =  405) for ≥ 6 months and active disease (≥ 3 swollen and ≥ 3 tender joints, C-reactive protein [CRP] ≥ 0.3 mg/dL) despite prior non-biologic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs will be randomized (1:1:1) to guselkumab every 4 weeks (Q4W); guselkumab at week (W) 0, W4, then every 8 weeks (Q8W); or placebo with crossover to guselkumab at W24, W28, then Q8W. Patients will have Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4, spinal pain component score (0-10 visual analog scale) ≥ 4, and screening MRI-confirmed axial involvement (positive spine and/or SI joints according to centrally read Spondyloarthritis Research Consortium of Canada [SPARCC] score ≥ 3 in ≥ 1 region). The primary endpoint is mean change from baseline in BASDAI at W24; multiplicity controlled secondary endpoints at W24 include AS Disease Activity Score employing CRP (ASDAS), Disease Activity Index for PsA (DAPSA), Health Assessment Questionnaire - Disability Index (HAQ-DI), Investigator's Global Assessment of skin disease (IGA), and mean changes from baseline in MRI SI joint SPARCC scores. Centrally read MRIs of spine and SI joints (scored using SPARCC) will be obtained at W0, W24, and W52, with readers blinded to treatment group and timepoint. Treatment group comparisons will be performed using a Cochran-Mantel-Haenszel or chi-square test for binary endpoints and analysis of covariance, mixed model for repeated measures, or constrained longitudinal data analysis for continuous endpoints. This study will evaluate the ability of guselkumab to reduce both axial symptoms and inflammation in patients with active PsA. This trial was registered at ClinicalTrials.gov, NCT04929210 , on 18 June 2021. Version 1.0 dated 14 April 2021.

Gladman DD ，Mease PJ ，Bird P ，Soriano ER ，Chakravarty SD ，Shawi M ，Xu S ，Quinn ST ，Gong C ，Leibowitz E ，Poddubnyy D ，Tam LS ，Helliwell PS ，Kavanaugh A ，Deodhar A ，Østergaard M ，Baraliakos X ... -  《Trials》

Effects of ustekinumab on spondylitis-associated endpoints in TNFi-naïve active psoriatic arthritis patients with physician-reported spondylitis: pooled results from two phase 3, randomised, controlled trials.

The interleukin-12/23p40-subunit-inhibitor ustekinumab significantly improved spondylitis-related symptoms through Week 24 in psoriatic arthritis (PsA) patients with peripheral arthritis and physician-reported spondylitis (PA-PRS) in PSUMMIT-1&2. We further evaluated ustekinumab's effect on spondylitis-related endpoints in PSUMMIT-1&2 tumour necrosis factor-inhibitor (TNFi)-naïve patients with PA-PRS. Patients with active PsA (≥5 swollen and ≥5 tender joints, C-reactive-protein ≥ 3.0 mg/L) despite conventional (PSUMMIT-1&2) and/or prior TNFi (PSUMMIT-2) therapy received subcutaneous ustekinumab 45 mg, 90 mg or placebo (Week 0, Week 4, Week 16). Changes in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) neck/back/hip pain question (#2) and modified BASDAI (mBASDAI, excluding PA) scores and Ankylosing Spondylitis Disease Activity Score (ASDAS) responses were assessed at Weeks 12 and 24. The pooled PSUMMIT-1&2, TNFi-naïve (n=747), PA-PRS (n=223) subset (158 with human-leucocyte-antigen (HLA)-B27 results) presented with moderate-to-severe spondylitis-related symptoms (mean BASDAI-neck/back/hip pain-6.51, mBASDAI-6.54, BASDAI-6.51, ASDAS-3.81). Mean Week 24 changes were larger among ustekinumab than placebo-treated patients for both neck/back/hip pain (-1.99 vs -0.18) and mBASDAI (-2.09 vs -0.59). Improvements in neck/back/hip pain and fatigue appeared numerically greater in HLA-B27+ than HLA-B27 - patients; those for other domains were generally consistent. Greater proportions of ustekinumab versus placebo-treated patients achieved ASDAS clinically important improvement at Week 24 (decrease ≥ 1.1; 49.6% vs 12.7%; nominal p<0.05). Improvements in BASDAI neck/back/hip pain and mBASDAI among ustekinumab-treated, TNFi-naïve, PsA patients with PA-PRS were clinically meaningful and consistent across assessment tools. Numerically greater improvements in neck/back/hip pain in HLA-B27+ than HLA-B27 - patients, noted in the context of similar overall mBASDAI improvements between the subgroups, suggest ustekinumab may improve disease activity in TNFi-naïve PsA patients likely to exhibit axial disease. PSUMMIT 1, NCT01009086; PSUMMIT 2, NCT01077362.

Helliwell PS ，Gladman DD ，Chakravarty SD ，Kafka S ，Karyekar CS ，You Y ，Campbell K ，Sweet K ，Kavanaugh A ，Gensler LS ... -  《-》

Guselkumab in Biologic-Naïve Patients with Active Psoriatic Arthritis in Russia: A Post Hoc Analysis of the DISCOVER-1 and -2 Randomized Clinical Trials.

Mease P ，Korotaeva T ，Shesternya P ，Kokhan M ，Rukavitsyn A ，Vasilchenkov D ，Sharaf M ，Lavie F ，Deodhar A ... -  《Rheumatology and Therapy》