Guselkumab inhibition of the IL-23 p19 subunit effective in PsA

Psoriatic arthritis

By Mardi Chapman

24 Mar 2020

The IL-23 inhibitor guselkumab has been shown to be effective in psoriatic arthritis patients including those who are biologic-naive or been previously treated with one or two anti-TNFs.

The DISCOVER trials, published in The Lancet, showed treatment with guselkumab improved the primary outcome of ACR20 and a number of secondary outcomes including skin and joint symptoms.

In DISCOVER-1, 381 patients from 86 sites across 13 countries including Australia were randomised to either 100mg guselkumab every four weeks, or every eight weeks after treatment at week 0 and week 4, or placebo.

Patients had active PsA, at least three tender and swollen joints and a CRP ≥0.3mg/dL. About a third of patients had previously been treated with up to two TNF inhibitors.

During the study, they were permitted but not required to continue stable doses of one selected nonbiologic DMARD, oral corticosteroids (≤10 mg/day of prednisone or equivalent dose), and NSAIDs or other analgesics.

The study found a higher proportion of patients in both guselkumab groups achieved ACR 20 compared to the control group (59% v 52% v 22%).

In DISCOVER-2, 716 biologic-naive patients from 118 sites across 13 countries were also randomised in a similar fashion.

They had an average of 12-13 swollen and 20-22 tender joints and a median CRP of 1·2–1·3 mg/dL.

ACR20 was achieved by 64% in the 4-weekly treatment group, 64% in the 8-weekly treatment group and 33% in the control group.

In both studies, rates of achieving ACR50 and ACR70 were also higher with guselkumab than placebo.

Other secondary outcomes such as DAS28-CRP and resolution of dactylitis, enthesitis and skin disease were also observed.

For example, in DISCOVER-1 the PASI175 response was achieved in 86% and 76% of gulsekumab -related patients compared to just 14% of the control group.

“Guselkumab also significantly improved physical function as assessed by changes in HAQ-DI scores, and most guselkumab-treated patients with impaired physical function at study outset had clinically meaningful improvement (≥0·35) in HAQ-DI scores at week 24.”

“Improvements in psoriasis and physical function are particularly important given that these disease manifestations can lead to depression and diminished quality of life.”

In both studies, the benefits of the IL-23 inhibitor were seen by 8 weeks.

Adverse events included elevations in aminotransferases, nasopharyngitis or upper respiratory tract infections. Serious adverse events were few.

“In conclusion, week 24 results of this confirmative phase 3 study provide strong evidence that guselkumab provides a novel mechanism of action, via targeting the p19 subunit of IL-23, to treat the diverse clinical manifestations of psoriatic arthritis.” DISCOVER-1 said.

“Guselkumab, whether administered every 4 weeks or every 8 weeks, elicited significant improvements in skin psoriasis, physical function, and health-­related quality of life, all of which influence mental health, work produc­tivity, and the economic burden of psoriatic arthritis,” DISCOVER-2 said.

An accompanying Comment in the journal said there was a continued unmet need for new therapies.

“With its broad effects on arthritis, psoriasis, and extra- articular manifestations, inhibition of the IL-23 p19 subunit is an exciting therapeutic principle that will add to the landscape of psoriatic arthritis, and probably also change it over time because of its efficacy profile.”

“Ultimately, however, guselkumab will be required to show evidence from head-to-head studies against TNF inhibitors, and maybe even against IL-17 inhibitors (or possibly both), in order to establish a clinical preference for treatment choices.”

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