Prof. Iain McInnes, the lead author of DISCOVER-2, discusses the latest findings of the phase-3 global trial to assess guselkumab in biologic-naïve patients with psoriatic arthritis. Peter Doyle reports
Sustained improvements over 52 weeks were noted in biologic-naïve patients with psoriatic arthritis (PsA) who were given a monoclonal antibody against interleukin-23 normally used for the treatment of plaque psoriasis, a recent study is reporting.
In 2017, guselkumab, a human monoclonal antibody specific to interleukin-23p19, was approved to treat adults with moderate-to-severe plaque psoriasis and who were candidates for systemic therapy or phototherapy.
Three years later, in July 2020, the biologic drug – which is administered by subcutaneous injection – became the first selective IL-23 inhibitor approved in several countries including the United States (US), Canada, Ecuador, and Brazil to treat active PsA.
During DISCOVER-2, adults with active PsA (≥5 swollen+≥5 tender joints; C-reactive protein ≥0.6mg/dL), and who had been treated with standard nonbiologic drugs, were randomised to receive 100mg doses of guselkumab every four weeks (Q4W); guselkumab 100mg at Week 0, Week 4, Q8W; or placebo with crossover to guselkumab 100mg Q4W at Week 24.
In a paper published in the October 2020 edition of Arthritis & Rheumatology, the official journal of the American College of Rheumatology, researchers explained that they had “primarily evaluated clinical efficacy through Week 52 by imputing missing data (nonresponse for categorical endpoints; no change/using multiple imputation for continuous endpoints)”.
Observed radiographic scores and adverse events (AEs) were also summarised, they added (‘Efficacy and Safety of Guselkumab, an Interleukin‐23p19‐Specific Monoclonal Antibody, Through 1 Year in Biologic‐naïve Psoriatic Arthritis Patients’; McInnes et al; https://doi.org/10.1002/art.41553).
Explaining the background to their study, investigators said PsA was a heterogeneous, chronic inflammatory disorder which could encompass peripheral arthritis, psoriasis, enthesitis, dactylitis, and axial involvement.
“Current therapies vary in their ability to address the protean manifestations of PsA,” they wrote.
“Not all patients respond to each treatment, and some with initial response lose the effect over time.”
Citing data from the 51,640-plus patient Corona Registry, which describes itself as “the largest rheumatoid arthritis real world prospective cohort study in the world”, McInnes et al said that approximately 30 per cent of tumour necrosis factor-inhibitors (TNFi) started by PsA patients were discontinued within one year.
They also said that biologic-experienced patients demonstrated lower TNFi drug persistence than biologic-naïve patients, and the high proportion (80%) of these patients discontinuing the index TNFi because of inadequate efficacy had highlighted “the need to consider other modes of action to treat these PsA patients”.
Guselkumab, they said, had previously “demonstrated robust benefit in patients with moderate-to-severe psoriasis”, with recent reports of the 24-week placebo-controlled portions of two pivotal trials of guselkumab in PsA (DISCOVER-1 [NCT03162796]; DISCOVER-2 [NCT03158285]) indicating that guselkumab 100 mg every 4 (Q4W) or 8 (Q8W) weeks significantly improved signs and symptoms of joint and skin disease and guselkumab 100 mg Q4W significantly inhibited progression of structural damage.
Participants in their trial had previously been treated with either non-biologic, disease-modifying antirheumatic drugs (DMARDs), apremilast, or nonsteroidal anti-inflammatory drugs (NSAIDs) and were naïve to biologic agents and Janus kinase inhibitors.
During the phase-3, randomised, double-blind, placebo-controlled, three-arm study, which was conducted at 118 sites (Bulgaria, Czech Republic, Estonia, Latvia, Lithuania, Malaysia, Poland, Russia, Spain, Taiwan, Turkey, Ukraine, and the United States), there was a six-week screening period, a 100-week treatment phase (placebo-controlled Week 0–Week24, active treatment Week 24–Week 100), and 12 weeks of safety follow-up.
Participants were randomised 1:1:1 to receive subcutaneous injections of guselkumab 100 mg Q4W; guselkumab 100 mg at Week 0, Week 4, and then Q8W; or placebo Q4W until starting guselkumab 100 mg Q4W at Week 24.
Patients could continue baseline use of stable doses of selected non-biologic DMARDs (limited to either methotrexate ≤25 mg/week, sulfasalazine ≤3 g/day, hydroxychloroquine ≤400 mg/day, or leflunomide ≤20 mg/day), oral corticosteroids ≤10 mg/day of prednisone or equivalent dose, and NSAIDs or other analgesics up to regionally approved doses.
Using the five-point Investigator’s Global Assessment of psoriasis (IGA), where 0 is cleared and 4 severe, the extent of participants’ skin disease during the study was assessed.
The Psoriatic Arthritis Severity Index (PASI, total score 0–72) was used to assess the extent (percentage of body surface area [BSA] affected) and degree of associated redness, thickness, and scaling (each graded from none to maximum of 4).
The results showed that out of 739 randomised, treated patients, 93 per cent had completed Week 52 of the study.
Proportions of patients achieving ≥20 per cent improvement from baseline in American College of Rheumatology (ACR) criteria (ACR20) were maintained post-Week 24, reaching 71 per cent (173/245) and 75 per cent (185/248) for Q4W – and Q8W – randomised patients, respectively, by Week 52.
The proportions of patients achieving ACR50/ACR70 and skin responses, minimal or very low disease activity, and dactylitis or enthesitis resolution were also maintained through Week 52.
It was also observed that 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.
Few patients experienced serious infections through Week 52, with no evidence of a dosing regimen response or increase from Week 0-24 (4/493 [0.8%]) to Week 24-52 (3/493 [0.6%]) among guselkumab-randomised patients, while no patient developed an opportunistic infection or died.
Discussing the study with Irish Medical Times (IMT), lead author Prof. Iain McInnes, Vice-Principal and Head of College of Medical, Veterinary and Life Sciences, University of Glasgow, said that the findings showed guselkumab was associated with sustained benefits up to one year in the joints, enthesis, and skin of people with PsA.
“These improvements were associated with improvements in quality of life and function as reported by patients themselves,” he said, adding that the safety profile “appeared acceptable”.
Noting that PsA was a lifelong condition, for which there was no cure, Prof. McInnes said there was a need to have a range of options to treat people with this condition over time.
“Until recently we had very few options – now we have a range of options including methotrexate, biologic medicines like TNF inhibitors, IL-17A inhibitors IL-23 inhibitors, and also oral bioavailable JAK inhibitors,” he said.
“These are now included, or will in future be included, in international recommendations.”
Asked why a treatment for plaque psoriasis (guselkumab) was identified as a possible therapy for PsA, he said that numerous studies in the last decade have identified common immune pathways that lead to inflammation in the skin and also in the joints and entheses.
“Amongst these are tissue cytokine pathways that are driven by IL-23, in turn the target of guselkumab,” Prof. McInnes told IMT.
“We have also a precedent in the benefits accrued by treating people with PsA with other cytokine inhibitors, for example targeting TNF or IL-17A, and we know that both skin and joints can benefit in that context. It was therefore a plausible and logical step to test guselkumab in people with PsA.”
Prof. McInness also recommended that follow-up studies of people with PsA treated with guselkumab in the longer term “to confirm safety and durable responses” should be carried out.
“In the wider field, we need to better understand which patients will benefit most from each of the modes of action now available to us,” he explained.
“How do we choose early and choose wisely to maximise benefits, with minimal toxicity risk?” he added.