Background: The interleukin-23/Th17 pathway is implicated in psoriatic arthritis pathogenesis. Guselkumab, a an interleukin-23-inhibitor that specifically binds the IL23p19-subunit, human anti-interleukin-23p19-subunit monoclonal antibody, significantly and safely improved psoriatic arthritis in a Phase-2 study. Methods: This Phase-3, double-blind, placebo-controlled study (118 sites in 13 countries) enrolled biologic-naïve patients with active psoriatic arthritis (≥5 swollen, ≥5 tender joints, C-reactive-protein ≥0•6mg/dL) despite standard therapies. Patients were randomised (1:1:1; computer-generated permuted blocks; stratified by baseline disease-modifying antirheumatic drug use and C-reactive-protein) to subcutaneous guselkumab 100mg every-4-weeks (q4w); guselkumab 100mg at Weeks 0, 4, every-8-weeks (q8w); or placebo. The primary endpoint was ACR20 response at Week24 among randomized and treated patients. Clinicaltrials.gov identifier-NCT03158285 (active-not recruiting). Findings: From 07/13/2017-03/06/2019, 739 randomised patients received guselkumab q4w (N=245), q8w (N=248), or placebo (N=246); 716 patients continued treatment through Week24. Significantly greater proportions of guselkumab q4w-(156 [63•74%] of 245; 95% confidence interval: 57%, 70%) and q8w-(159 [64•1%] of 248; 95% confidence interval: 58%, 70%) than placebo-(81 [32•93%] of 246; 95% confidence interval: 27%, 39%) treated patients achieved Week24 ACR20 response (% differences [95% confidence intervals]: 30•81 (22•4, 39•1) and 31•2 (22•93, 39•540), respectively; both p<0•0001). Both guselkumab regimens significantly improved psoriasis, enthesitis, dactylitis, physical function, and quality-of-life vs. placebo at Week24. Mean changes in total modified van der Heijde-Sharp scores at Week24 were 4 significantly (0•29) and numerically (0•52) lower with guselkumab q4w and q8w, respectively, than placebo (0•95; p=0.011 and p=0.07). Through Week24, serious adverse events, and specifically serious infections, occurred in eight (3•3%) and three (1•2%) of 245 patients receiving guselkumab q4w, three (1•2%) and one (0•4<1%) of 248 receiving guselkumab q8w, and seven (2•83%) and one (0•4<1%) of 246 receiving placebo, respectively. No deaths occurred. Interpretation: Guselkumab, a human anti-interleukin-23p19-subunit monoclonal antibody that specifically inhibits interleukin-23 by binding the cytokine's p19-subunit, was efficacious and well tolerated in patients with active psoriatic arthritis who were biologic naive. These data support the further development of guselkumab for treating psoriatic arthritis.

This is a repository copy of Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial.

Objective. Guselkumab, a human monoclonal antibody specific to interleukin-23p19, demonstrated efficacy and safety versus placebo through week 24 of the phase III DISCOVER-2 trial in biologic-naive patients with psoriatic arthritis (PsA). Here we report 1-year DISCOVER-2 findings. Methods. Adults with active PsA (≥5 swollen and ≥5 tender joints; C-reactive protein level ≥0.6 mg/dl) despite standard nonbiologic treatment were randomized to receive subcutaneous injections of guselkumab 100 mg every 4 weeks, guselkumab 100 mg at week 0, week 4 and every 8 weeks thereafter, or placebo with crossover to guselkumab 100 mg every 4 weeks at week 24. We primarily evaluated clinical efficacy through week 52 by imputing missing data (nonresponse for categorical end points; no change/using multiple imputation for continuous end points). Observed radiographic scores and adverse events (AEs) were summarized. Results. Of 739 randomized, treated patients, 93% completed week 52. The proportions of patients in whom a ≥20% improvement from baseline in American College of Rheumatology criteria (ACR20) was achieved were maintained after week 24, reaching 71% (173 of 245) and 75% (185 of 248) for patients randomized to receive treatment every 4 weeks or every 8 weeks, respectively, by week 52. The proportions of patients in whom ACR50/ACR70 and skin responses, minimal or very low disease activity, and dactylitis or enthesitis resolution were achieved at week 24 were also maintained through week 52. Further, low levels of radiographic progression, along with improvements in physical function and health-related quality of life, were sustained through week 52 with continued guselkumab treatment. Few patients experienced serious infections through week 52, with no evidence of a dosing regimen response or increase from weeks 0-24 (4 of 493 [0.8%]) to weeks 24-52 (3 of 493 [0.6%]) among guselkumabrandomized patients. No patient developed an opportunistic infection or died. Conclusion. In biologic-naive PsA patients, guselkumab provided sustained improvements across diverse manifestations and maintained a favorable risk-benefit profile through week 52.

To assess long-term efficacy and safety of guselkumab, an interleukin-23 p19 subunit (IL-23p19) inhibitor, in patients with active psoriatic arthritis (PsA) from the phase III DISCOVER-2 trial.Methods. In the DISCOVER-2 trial, patients with active PsA (≥5 swollen joints and ≥5 tender joints; C-reactive protein level ≥0.6 mg/dl) despite prior nonbiologic therapy were randomized to receive the following: guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks; or placebo with crossover to guselkumab 100 mg every 4 weeks, beginning at week 24. Efficacy assessments included American College of Rheumatology ≥20%/50%/70% improvement criteria (ACR20/50/70), Investigator's Global Assessment (IGA) of psoriasis score of 0 (indicating complete skin clearance), resolution of enthesitis (Leeds Enthesitis Index) and dactylitis (Dactylitis Severity Score), and changes in the Sharp/van der Heijde modified radiographic scores for PsA. Clinical data (imputed as no response/no change from baseline if missing) and observed radiographic data were summarized through week 100; safety assessments continued through week 112.Results. Of the 739 randomized and treated patients, 652 (88%) completed treatment through week 100. Across groups of guselkumab-treated patients (including those in the placebo-guselkumab crossover group), the following findings at week 100 indicated that amelioration of arthritis signs/symptoms and extraarticular manifestations was durable through 2 years: ACR20 response (68-76%), ACR50 response (48-56%), ACR70 response (30-36%), IGA score of 0 (55-67%), enthesitis resolution (62-70%), and dactylitis resolution (72-83%). Mean changes in the Sharp/ van der Heijde modified score for PsA from weeks 52 to week 100 (range 0.13-0.75) indicated that the low rates of radiographic progression observed among guselkumab-treated patients at earlier time points extended through week 100. Through week 112, 8% (5.8 per 100 patient-years) and 3% (1.9 per 100 patient-years) of the 731 guselkumabtreated patients had a serious adverse event or serious infection, respectively; 1 death occurred (road traffic accident).Conclusion. In biologic-naive PsA patients, guselkumab provided durable improvements in multiple disease domains with no unexpected safety findings through 2 years.

ObjectiveEvaluation of the efficacy and safety of guselkumab, a human monoclonal antibody targeting the interleukin-23p19 subunit, in patients with psoriatic arthritis (PsA) through 1 year.MethodsAdults who met ClASsification criteria for Psoriatic ARthritis, with active disease (≥3 swollen and ≥3 tender joints; C reactive protein ≥0.3 mg/dL) despite standard treatment (31% previously received ≤2 tumour necrosis factor inhibitors (TNFi)), were randomised (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at Week0, Week4, then Q8W; or placebo with cross-over to guselkumab 100 mg Q4W at Week24 (PBO→Q4W) through Week48. Clinical efficacy through Week52 (employing non-responder imputation) and adverse events (AEs) through Week60 were evaluated.ResultsOf 381 treated patients, 90% completed the study. Numerical increases in the proportions of patients achieving ≥20% improvement in ACR criteria (ACR20) were observed post-Week24, reaching 73% (94/128) and 60% (76/127) for Q4W-randomised and Q8W-randomised patients, respectively, by Week52. Proportions of patients achieving ACR50/ACR70/skin responses and minimal/very low disease activity were maintained, as were improvements in physical function and health-related quality of life, through Week52 in guselkumab-randomised patients. Response to guselkumab was maintained in both TNFi-naïve and TNFi-experienced patients. Serious AEs and serious infections occurred in similar proportions of guselkumab Q4W-randomised (3% and 0%) and Q8W-randomised (6% and 2%) patients through Week60, with no new safety concerns versus observations through Week24. No guselkumab-treated patient and two patients receiving placebo died; no study participant developed opportunistic infection or inflammatory bowel disease.ConclusionGuselkumab provided sustained improvement across multiple clinical manifestations of PsA, maintaining a favourable benefit-risk profile, through 1 year regardless of prior TNFi exposure.