Elsevier

The Lancet

Volume 395, Issue 10230, 4–10 April 2020, Pages 1126-1136
The Lancet

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

https://doi.org/10.1016/S0140-6736(20)30263-4Get rights and content

Summary

Background

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.

Methods

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).

Findings

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.

Interpretation

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.

Funding

Janssen Research and Development.

Introduction

Psoriatic arthritis is a chronic inflammatory disease associated with peripheral joint inflammation, enthesitis, dactylitis, axial disease, and cutaneous and nail involvement, all of which can substantially limit physical function and impair quality of life. Although the introduction of biologics (eg, tumor necrosis factor-α [TNF] inhibitors, ustekinumab, interleukin-17A [IL-17A] inhibitors, and abatacept) and oral drugs (eg, apremilast and tofacitinib) has increased the extent and duration of achievable clinical responses, new therapies are needed to treat the diverse manifestations of psoriatic arthritis while maintaining a favourable benefit–risk profile.1

The origins of the varying clinical manifestations of psoriatic arthritis remain under study. The IL-23/T-helper cell 17 (Th17) pathway—via downstream IL-17 expression—appears crucial to skin manifestations. IL-23 can also induce IL-22, a cytokine implicated in enthesitis and bone formation,2 and, in part via IL-17A and TNF induction, elicit the joint symptoms and damage that are hallmarks of psoriatic arthritis. IL-23 is a heterodimer formed by pairing p19 and p40 subunits, the latter of which is shared with IL-12. Although IL-12 and IL-23 share the p40 subunit, they also encompass unique subunits (p35 for IL-12 and p19 for IL-23).3, 4 IL-23 has been established to be a predominant driver of autoimmune-mediated articular inflammation, whereas IL-12 is more likely to facilitate protection from autoimmune inflammation and T-cell exhaustion.4, 5, 6, 7 The divergent roles of these closely related cytokines are highlighted by differential skin effects, whereby abnormal differentiation of keratinocytes is triggered by IL-23 but not IL-12,6 and differing roles in the body's response to bacterial and viral infections, as well as tumour control via their regulation of T-cell function.5 Targeting the p19 subunit of IL-23, and thus sparing IL-12, has demonstrated robust efficacy in psoriasis,7, 8, 9, 10 suggesting a prominent upstream position of the cytokine in the inflammatory hierarchy across the psoriatic disease spectrum, and thereby meriting analysis of selective IL-23 inhibition via IL-23 p19 binding in psoriatic arthritis.

Research in context

Evidence before this study

We searched PubMed on Oct 7–8, 2019, for original research and review articles published in English since Jan 1, 2000, with the following search terms: “biologic”, “cytokine”, “dactylitis”, “enthesitis”, “interleukin”, “outcome”, “psoriasis”, “psoriatic arthritis”, “radiograph”, “structural damage”, and “treatment”. Current literature indicates that IL-23 is instrumental in driving the chronic inflammation associated with several immune-mediated diseases, including psoriasis and psoriatic arthritis. Guselkumab is a high-affinity, anti-IL-23 human monoclonal antibody that specifically binds the cytokine's p19 subunit and is approved to treat moderate-to-severe psoriasis. In a phase 2 study, selective blockade of IL-23 by guselkumab significantly improved signs and symptoms of active psoriatic arthritis and was well tolerated during 1 year of exposure.

Added value of this study

Results of DISCOVER-2, the larger of two trials comprising the first phase 3 programme investigating a novel mechanism of action to treat psoriatic arthritis, confirm that targeting the p19 subunit of IL-23 effectively treats the diverse manifestations across psoriatic arthritis domains. Specifically, in patients with active disease despite standard treatments, but no previous exposure to biologics, subcutaneous guselkumab 100 mg significantly improved joint symptoms, dactylitis, enthesitis, psoriasis, physical function, and health-related quality of life when administered every 4 or 8 weeks. Guselkumab given every 4 weeks afforded significantly less progression of structural damage up to week 24 than did placebo, providing evidence of inhibition of radiographic progression by an IL-23 inhibitor that targets the p19 subunit. The overall safety profile of guselkumab in psoriatic arthritis patients was similar to that observed in patients with psoriasis treated with guselkumab.

Implications of all the available evidence

Consistent with previous findings of a proof-of-concept study confirming that IL-23 plays a crucial role in the pathogenesis of psoriatic arthritis, data from this phase 3 trial provide pivotal evidence that guselkumab offers a novel mechanism of action to treat the diverse clinical manifestations and inhibit the structural damage progression of psoriatic arthritis.

Guselkumab (Janssen Biotech, Horsham, PA, USA), a high-affinity, human monoclonal antibody that binds specifically to the p19 subunit of IL-23, is approved to treat patients with moderate-to-severe psoriasis who are candidates for systemic or phototherapy. In a randomised, placebo-controlled, phase 2 trial in patients with psoriatic arthritis, guselkumab demonstrated efficacy across all endpoints related to joint signs and symptoms, physical function, skin disease, enthesitis, dactylitis, and health-related quality of life.11

Here, we report 24-week results from one of two phase 3 trials (DISCOVER-2), conducted to assess guselkumab in biologic-naive patients with active psoriatic arthritis. DISCOVER-2 assessed patient outcomes related to joint and skin manifestations as well as structural damage. Results from the other registrational trial of guselkumab in psoriatic arthritis (DISCOVER-1), which aimed to enrol patients with a broader range of baseline levels of disease activity, some of whom were previously treated with one or two TNF inhibitors, are reported separately.12

Section snippets

Study design

DISCOVER-2 is a randomised, double-blind, placebo-controlled, multicentre, three-arm phase 3 trial of guselkumab in patients with active psoriatic arthritis who were biologic naive and had inadequate response to standard therapies (non-biologic disease-modifying antirheumatic drugs [DMARDs], apremilast, or non-steroidal anti-inflammatory drugs [NSAIDs]). The trial was done at 118 sites in 13 countries (Bulgaria, Czech Republic, Estonia, Latvia, Lithuania, Malaysia, Poland, Russia, Spain,

Results

From July 13, 2017, to Aug 3, 2018, we screened 1153 patients, of whom 412 were not eligible, most often for having serum CRP levels lower than 0·6 mg/dL. 741 patients were enrolled and randomly assigned to receive either guselkumab every 4 weeks (n=246), guselkumab every 8 weeks (n=248), or placebo (n=247). All patients received treatment except one in the every 4 weeks group and one in the placebo group, who were therefore not included in analyses (figure 1). At week 16, 12 (5%) of 245

Discussion

Results of the DISCOVER-2 trial up to week 24 indicate that guselkumab, a selective IL-23 inhibitor that binds the cytokine's p19-subunit, effected robust improvements in signs and symptoms of joint disease in patients with psoriatic arthritis. The study met its primary endpoint for ACR20 response at week 24 in both the guselkumab 100 mg every 4 weeks and every 8 weeks groups compared with placebo-treated patients. Similarly, ACR50 and ACR70 response rates demonstrated that treatment with

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 Yale Open Data Access Project.

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