Elsevier

The Lancet

Volume 395, Issue 10230, 4–10 April 2020, Pages 1115-1125
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(20)30265-8Get rights and content

Summary

Background

Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial.

Methods

This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting).

Findings

From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50–68]) and every 8 weeks group (66 [52%] of 127 [43–61]) than in the placebo group (28 [22%] of 126 [15–30]), with percentage differences versus placebo of 37% (95% CI 26–48) for the every 4 weeks group and 30% (19–41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections.

Interpretation

Guselkumab demonstrated a favourable benefit–risk profile and might be an effective treatment option for patients with active psoriatic arthritis.

Funding

Janssen Research and Development.

Introduction

As a heterogeneous inflammatory disorder, psoriatic arthritis demands individualised and targeted treatment based on specific clinical manifestations, symptom severity, and comorbidities. For patients with moderate-to-severe disease activity, aggressive treatment with non-biologic or biologic disease-modifying antirheumatic drugs (DMARDs) can substantially improve joint and skin symptoms and prevent permanent structural damage.1, 2 When a patient has an inadequate response to, or is intolerant of, one biologic treatment, switching to another with a different mechanism of action can be a useful strategy.3, 4 Furthermore, patients often lose response over time, so new mechanisms to catalyse development of alternative treatments are needed.5, 6

Biologic treatment options for psoriatic arthritis include tumor necrosis factor (TNF) inhibitors, an interleukin-12/23 (IL-12/23) inhibitor, and IL-17 inhibitors. These biologics have been shown to significantly improve skin and joint responses in patients when used alone or with conventional DMARDs. Other biologics and targeted synthetic DMARDs are available to treat psoriatic arthritis but have not demonstrated inhibition of joint damage and appear to be less effective in resolving symptoms of skin disease.7, 8, 9

Research in context

Evidence before this study

We searched PubMed on Oct 14–16, 2019, with various combinations of the following search terms: “psoriatic arthritis”, “biologic”, “interleukin”, “DMARD”, “TNF inhibitor”, “treatment”, “mechanism of action”, “guidelines”, and “psoriasis”, for original research and review articles published in English since Jan 1, 2010, to document outcomes associated with existing psoriatic arthritis treatments and treatment guidelines. Psoriatic arthritis is a heterogeneous inflammatory disorder that often requires targeted treatment. Psoriatic arthritis patients with either inadequate response to or inability to tolerate one biologic might benefit from switching to another biologic with a different mechanism of action. Guselkumab, a high-affinity, human, anti-IL-23 monoclonal antibody specific to the IL-23 p19 subunit that is approved to treat moderate-to-severe psoriasis, showed efficacy in patients with active psoriatic arthritis in a phase 2 study.

Added value of this study

These results from one of two trials comprising the first phase 3 development programme for specifically inhibiting IL-23 by binding the IL-23 p19 subunit in psoriatic arthritis provide pivotal evidence of guselkumab efficacy in this indication. Across patients with active disease, guselkumab 100 mg significantly improved joint symptoms, physical function, skin symptoms of psoriasis, and health-related quality of life when administered every 4 or 8 weeks. Improvements in disease activity were equally robust in patients who had received or had inadequate response to one or two TNF inhibitors. For both guselkumab dose regimens, the safety profile up to week 24 in patients with psoriatic arthritis was consistent with that in patients treated for psoriasis.

Implications of all the available evidence

Results of this confirmative phase 3 trial provide strong evidence that guselkumab offers a novel mechanism of action, via targeting the p19 subunit of IL-23, to treat the diverse peripheral clinical manifestations of psoriatic arthritis. Guselkumab might provide an additional treatment option for patients with psoriatic arthritis with active disease despite previous receipt of standard therapies, including TNF inhibitors.

Although TNF inhibitors are frequently chosen as the first biologic therapy for patients with psoriatic arthritis, a substantial proportion of patients assessed in clinical trials do not achieve meaningful American College of Rheumatology (ACR)-defined responses. TNF inhibitors have a complicated safety profile, particularly with regard to infection risk,10 and anti-IL-17 therapies have warnings about new-onset or exacerbation of inflammatory bowel disease in addition to infection risk.11, 12, 13

Evidence from preclinical models and clinical trial data indicate that the IL-23/T-helper 17 (Th17) cell pathway is pivotal in the development of both the skin and joint manifestations of psoriatic arthritis.14, 15 IL-23 is a heterodimer composed of both p19 and p40 subunits. Guselkumab (Janssen Biotech, Horsham, PA, USA) is a novel human monoclonal antibody that binds to the p19 subunit of IL-23 with high specificity and affinity. In a phase 2 proof-of-concept study, guselkumab 100 mg at week 0, week 4, and then every 8 weeks showed efficacy across all endpoints related to joint signs and symptoms, physical function, skin disease, enthesitis, dactylitis, and health-related quality of life.16 In biomarker assessments from that study, guselkumab-treated patients demonstrated decreased serum concentrations of IL-17A, IL-17F, and C-reactive protein (CRP), with IL-17A and IL-17F levels similar to those of healthy controls by week 16. These changes were associated with 20% or greater improvement in ACR response criteria (ACR20) and psoriasis area and severity index (PASI) 75% improvement responses.17 Such associations confirm the relevance of the IL-23/Th17 pathway in psoriatic arthritis and that of guselkumab treatment in suppressing the pathway common to both skin and joint pathologies.

Here, we report results from one of two pivotal phase 3 trials (DISCOVER-1), conducted to assess guselkumab in patients with active psoriatic arthritis, including those who were previously treated with one or two TNF inhibitors. Results from the other phase 3 registrational trial of guselkumab in psoriatic arthritis (DISCOVER-2), which sought to enrol biologic-naive patients with psoriatic arthritis who had higher levels of disease activity, are reported separately.18

Section snippets

Study design

DISCOVER-1 is a randomised, double-blind, placebo-controlled, multicentre (appendix p 10), international, three-arm phase 3 trial of guselkumab in patients with active psoriatic arthritis despite standard therapies (non-biologic DMARDs, apremilast, and non-steroidal anti-inflammatory drugs [NSAIDs]). The trial was done at 86 sites in 13 countries (Australia, Canada, Czech Republic, Germany, Hungary, Malaysia, Poland, South Korea, Russia, Spain, Taiwan, Ukraine, and the USA). This trial

Results

We screened patients from Aug 28, 2017, to Aug 17, 2018; the final week 24 visit was on March 14, 2019. Among the 624 patients screened, 241 did not meet the study entrance criteria, most commonly because CRP was less than 0·3 mg/dL (figure 1). 382 patients were randomly assigned to either the every 4 weeks group (n=128), the every 8 weeks group (n=128), or the placebo group (n=126). All patients received treatment except one in the every 8 weeks group, who was therefore not included in

Discussion

The phase 3 DISCOVER-1 study met its primary endpoint, with both guselkumab 100 mg regimens eliciting significantly higher ACR20 response rates at week 24 than placebo. Robust treatment effects were also attained using the more stringent ACR50 response criteria.

Given the complex and variable disease presentation of psoriatic arthritis, discontinuation or switching of biologics because of inadequate efficacy or intolerance is common, as is loss of efficacy over time.3, 21 As a human monoclonal

Data sharing

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available online. Requests for access to the study data can be submitted through the Yale Open Data Access Project site.

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