Guselkumab induces robust reduction in acute phase proteins and type 17 effector cytokines in active psoriatic arthritis: results from phase 3 trials.

To investigate serum protein expression in participants with psoriatic arthritis (PsA) and changes after guselkumab treatment. Participants with PsA were treated with guselkumab or placebo in the DISCOVER-1 and DISCOVER-2 studies. Serum levels of acute phase reactants C reactive protein (CRP) and serum amyloid A (SAA) and inflammatory cytokines/chemokines were measured at weeks 0, 4 and 24 in 300 study participants and 34 healthy controls (HCs). The PSUMMIT studies measured serum interleukin (IL)-17A, IL-17F and CRP after ustekinumab treatment and levels with ustekinumab versus guselkumab treatment were compared. Baseline serum levels of CRP, SAA, IL-6, IL-17A and IL-17F were elevated in participants with active PsA vs HCs (p<0.05, geometric mean (GM) ≥40% higher). Baseline T-helper cell 17 (Th17) effector cytokines were significantly associated with baseline psoriasis but not joint disease activity. Compared with placebo, guselkumab treatment resulted in decreases in serum CRP, SAA, IL-6, IL-17A, IL-17F and IL-22 as early as week 4 and continued to decrease through week 24 (p<0.05, GM decrease from baseline ≥33%). At week 24, IL-17A and IL-17F levels were not significantly different from HCs, suggesting normalisation of peripheral IL-23/Th17 axis effector cytokines postguselkumab treatment. Reductions in IL-17A/IL-17F levels were greater in guselkumab-treated versus ustekinumab-treated participants, whereas effects on CRP levels were similar. Guselkumab treatment reduced serum protein levels of acute phase and Th17 effector cytokines and achieved comparable levels to those in HCs. In participants with PsA, reductions of IL-17A and IL-17F were of greater magnitude after treatment with guselkumab than with ustekinumab.

Sweet K ，Song Q ，Loza MJ ，McInnes IB ，Ma K ，Leander K ，Lakshminarayanan V ，Franks C ，Cooper P ，Siebert S ... -  《-》

Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study.

Guselkumab is a selective interleukin (IL)-23 inhibitor targeting the IL-23p19 subunit. In the phase 3b COSMOS trial, guselkumab demonstrated efficacy in treating participants with active psoriatic arthritis (PsA) and inadequate response (IR; lack of efficacy or intolerance) to tumor necrosis factor inhibitors (TNFi). Adults with active PsA (≥ 3 swollen joints,  ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo➔guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon ɣ (IFNɣ), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed. Associations between baseline biomarker levels and 1) baseline disease activity (28-joint disease activity score using CRP [DAS28-CRP], psoriasis area and severity index [PASI], and % body surface area [BSA] affected by psoriasis) and 2) clinical response (including  ≥ 20% improvement in American College of Rheumatology criteria [ACR20] response) at Week 24 were assessed. Baseline serum levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNɣ were significantly higher in COSMOS TNFi-IR participants than in matched healthy controls. Baseline IL-6, CRP, and SAA levels were associated with baseline DAS28-CRP. IL-17A and IL-17F levels were associated with baseline PASI score and psoriasis BSA. Baseline swollen or tender joint counts did not associate with baseline biomarker levels. At Week 24, significant decreases from baseline in CRP, SAA, IL-17A, IL-17F, and IL-22 levels were seen in guselkumab, but not placebo-, treated participants. IL-17F and IL-22 levels at Week 24 in guselkumab-treated participants did not significantly differ from those of matched healthy controls. Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNɣ levels versus nonresponders. Results from COSMOS participants with active, TNFi-IR PsA suggest guselkumab reduces levels of effector cytokines associated with the IL-23/IL-17 pathway, including those associated with baseline arthritis and skin disease activity. ClinicalTrials.gov: NCT03796858.

Schett G ，Chen W ，Gao S ，Chakravarty SD ，Shawi M ，Lavie F ，Zimmermann M ，Sharaf M ，Coates LC ，Siebert S ... -  《-》

Responsiveness of Serum C-Reactive Protein, Interleukin-17A, and Interleukin-17F Levels to Ustekinumab in Psoriatic Arthritis: Lessons From Two Phase III, Multicenter, Double-Blind, Placebo-Controlled Trials.

To evaluate the associations of C-reactive protein (CRP) and circulating Th17-associated cytokine levels with psoriatic arthritis (PsA) disease activity and therapeutic response to ustekinumab. Interleukin-17A (IL-17A), IL-17F, IL-23, and CRP concentrations were measured in serum samples collected as part of the 2 PSUMMIT phase III studies of ustekinumab in PsA (n = 927). In post hoc analyses, relationships of IL-17A, IL-17F, and CRP levels at baseline, week 4, and week 24 with baseline skin and joint disease activity and response to therapy were evaluated using generalized linear models and Pearson's product-moment correlation tests. Baseline serum levels of IL-17A and IL-17F were positively correlated with baseline skin disease scores (r = 0.39-0.62). IL-23 levels were correlated with skin disease scores to a lesser extent (r = 0.26-0.31). No significant correlations were observed between these cytokine or CRP levels and baseline joint disease activity. There was no significant association of baseline levels of IL-17A, IL-17F, IL-23, or CRP with therapeutic response to ustekinumab in either the skin or joints. Significant reductions from baseline in levels of IL-17A, IL-17F, and CRP were seen in patients treated with ustekinumab compared to those treated with placebo. Ustekinumab-treated patients in whom 75% improvement in the Psoriasis Area and Severity Index score or 20% improvement according to the American College of Rheumatology criteria was achieved after 24 weeks of treatment had greater reductions in CRP level (geometric mean decreases of 51-58% versus 32-33%; P < 0.05), but not IL-17A or IL-17F levels, than nonresponders. Baseline serum IL-23/IL-17 levels correlated with skin, but not joint, disease activity, suggesting tissue-specific variation. However, neither baseline Th17-associated cytokine levels nor CRP level were predictive of therapeutic response to ustekinumab in the skin or joints, despite rapid reductions in their levels following ustekinumab therapy.

Siebert S ，Sweet K ，Dasgupta B ，Campbell K ，McInnes IB ，Loza MJ ... -  《-》

Modulation of Interleukin-23 Signaling With Guselkumab in Biologic-Naive Patients Versus Tumor Necrosis Factor Inhibitor-Inadequate Responders With Active Psoriatic Arthritis.

Siebert S ，Coates LC ，Schett G ，Raychaudhuri SP ，Chen W ，Gao S ，Seridi L ，Chakravarty SD ，Shawi M ，Lavie F ，Sharaf M ，Zimmermann M ，Kollmeier AP ，Xu XL ，Rahman P ，Mease PJ ，Deodhar A ... -  《-》

Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial.

The interleukin-23 (IL-23)/T-helper 17 cell pathway is implicated in psoriatic arthritis pathogenesis. Guselkumab, an IL-23 inhibitor that specifically binds the IL-23 p19 subunit, significantly and safely improved psoriatic arthritis in a phase 2 study. DISCOVER-2 was a phase 3 trial to assess guselkumab in biologic-naive patients with psoriatic arthritis. This phase 3, double-blind, placebo-controlled study was done at 118 sites in 13 countries across Asia, Europe, and North America. We enrolled biologic-naive patients with active psoriatic arthritis (at least five swollen joints, at least five tender joints, and C-reactive protein ≥0·6 mg/dL) despite standard therapies. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline disease-modifying antirheumatic drug use and C-reactive protein concentration) to subcutaneous injections of guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) response at week 24 in all patients per assigned treatment group. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03158285 (active, not recruiting). From July 13, 2017, to Aug 3, 2018, 1153 patients were screened, of whom 741 were randomly assigned to receive guselkumab every 4 weeks (n=246), every 8 weeks (n=248), or placebo (n=247). One patient in the every 4 weeks group and one in the placebo group did not start treatment, and the remaining 739 patients started treatment; 716 patients continued treatment up to week 24. Significantly greater proportions of patients in the guselkumab every 4 weeks group (156 [64%] of 245 [95% CI 57-70]) and every 8 weeks group (159 [64%] of 248 [58-70]) than in the placebo group (81 [33%] of 246 [27-39]) achieved an ACR20 response at week 24 (percentage differences vs placebo 31% [95% CI 22-39] for the every 4 weeks group and 31% [23-40] for the every 8 weeks group; both p<0·0001). Up to week 24, serious adverse events occurred in eight (3%) of 245 patients receiving guselkumab every 4 weeks (three serious infections), three (1%) of 248 receiving guselkumab every 8 weeks (one serious infection), and seven (3%) of 246 receiving placebo (one serious infection). No deaths occurred. Guselkumab, a human monoclonal antibody that specifically inhibits IL-23 by binding the cytokine's p19 subunit, was efficacious and demonstrated an acceptable benefit-risk profile in patients with active psoriatic arthritis who were naive to treatment with biologics. These data support the use of selective inhibition of IL-23 to treat psoriatic arthritis. Janssen Research and Development.

Mease PJ ，Rahman P ，Gottlieb AB ，Kollmeier AP ，Hsia EC ，Xu XL ，Sheng S ，Agarwal P ，Zhou B ，Zhuang Y ，van der Heijde D ，McInnes IB ，DISCOVER-2 Study Group ... -  《-》