Ustekinumab Fails to Show Efficacy in a Phase III Axial Spondyloarthritis Program: The Importance of Negative Results

Abstract

In this issue of Arthritis & Rheumatology, Deodhar et al report negative phase III study results for ustekinumab in axial spondyloarthritis (SpA) (1). Ustekinumab is an interleukin-12 (IL-12)/IL-23 inhibitor approved for the treatment of psoriasis, psoriatic arthritis (PsA), and Crohn's disease. PsA has close clinical and genetic associations with axial SpA, including genetic association with variants in the IL-23 receptor signaling pathway. In addition, ustekinumab demonstrated promising results in a phase II open-label proof-of-concept study among 20 patients with ankylosing spondylitis (AS). In this previous study, ustekinumab at 90 mg was given subcutaneously (SC) at baseline and at weeks 4 and 16, and 65% of patients met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response) at 24 weeks (2). Many other outcomes also favored ustekinumab, including reduced evidence of inflammation on magnetic resonance imaging (MRI). These results suggested that ustekinumab's benefits may be comparable to those of tumor necrosis factor (TNF) and IL-17 antagonists, 2 classes of agents approved for use in AS. Thus, the negative results of the phase III trial came as a real surprise, notwithstanding that the earlier study was not placebo controlled.The phase III program for ustekinumab was well designed and comprehensive. Three different studies were undertaken: one in patients with radiographic axial SpA (otherwise known as AS) who were naive to biologic therapy; a second in patients with radiographic axial SpA who were intolerant of (or whose disease was refractory to) a single TNF inhibitor (TNFi); and a third in patients with nonradiographic axial SpA who had an inadequate response to nonsteroidal antiinflammatory drugs and could have been exposed to a single TNFi. These are now standard populations for a phase III program in axial SpA. Patients were randomized to receive either 45 mg or 90 mg ustekinumab or placebo administered SC. Sample size estimates for all 3 studies were chosen to achieve 90% power to detect treatment differences between ustekinu mab and placebo for the primary end point at a significance level of 0.05. Estimates of 40% achieving an ASAS40 response in the treatment group and 20% in the placebo group were used for power calculation.What was demonstrated? At 24 weeks in study 1, the ASAS40 responses in the placebo, 45 mg ustekinumab, and 90 mg ustekinumab arms were 28.4%, 31.0%, and 28.1%, respectively, showing no separation between treatment arms and placebo. Other measures, including spine MRI, showed no significant separation between the treatment arms and placebo. Based on these negative results, the decision was made to stop the whole phase III study program; thus, studies 2 and 3 were not completed. Results for patients in those studies who did complete 24 weeks showed a similar lack of difference between placebo and treatment arms.Did biomarker analysis shed any light on the results? In study 1, several analytes at ba...

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“…For treatment of the spondylitis component of PsA, we rely on data from axSpA trials, which also may not be accurately extrapolatable. Trials of the IL-12/23 inhibitor ustekinumab and the IL-23 inhibitor risankizumab have failed in ankylosing spondylitis 13. Even though these agents have demonstrated benefit and been approved for PsA, their ability to benefit the spinal component of PsA remains unproven and needs to be tested.…”

Effects of ustekinumab on spondylitis-associated endpoints in TNFi-naïve active psoriatic arthritis patients with physician-reported spondylitis: pooled results from two phase 3, randomised, controlled trials

“…IL-12/23p409–11 and IL-23p19 inhibitors are effective in PsA22 23 but not AS,13 24 while IL-17 inhibition is effective in AS and PsA, inclusive of axial manifestations 25 26. Specific to AS and PsA, it has been postulated that differing biologic mechanisms in the spine, where IL-23-independent production of IL-17 may occur, versus the periphery results in differential responses to IL-23 inhibition 27 28. Indeed, in a recently conducted prospective evaluation of >2000 patients with AS or PsA, AS patients, with or without psoriasis, differed demographically, genetically, clinically and radiographically from patients with axial PsA, leading the authors to conclude that axial PsA appears to be a distinct entity 29.…”

Precision medicine in psoriatic arthritis: how should we select targeted therapies?

“…In future, a formal evaluation of the functional prediction of a given polymorphism prior to assumption of pathogenetic association would seem prudent. It has also been suggested that perhaps IL-23-independent IL-17A production may be crucial in the observed divergent therapeutic response to two drugs targeting the same pathway though the evidence here is sparse 32,33 . Furthermore, pharmacodynamics and tissue drug penetration remain theoretical challenges or as yet misunderstood pathologic events in axial disease.…”