A well-established treatment for psoriasis, psoriatic arthritis, and Crohn’s disease failed to work in axial spondyloarthritis patients, a study shows. But the study's failure may tell us more than not.
A well-established treatment for psoriasis, psoriatic arthritis (PsA), and Crohn’s disease failed to demonstrate similar efficacy in a phase one and phase two trial for axial spondyloarthritis (SpA), a study shows.
Led by Atul Deodhar, M.D., of Oregon Health and Science University in Portland and published in the February issue of Arthritis and Rheumatology, ustekinumab failed to meet its primary and secondary endpoints.
In theory, it would make sense that it would work. After all, PsA and SpA share a genetic variant along the IL-23 pathway. There was other evidence pointing in the direction of ustekinumab as a successful treatment for SpA. Previous studies showed that it inhibited radiographic progression and doctors have reported that patients with spondylitis receiving ustekinumab reported improvements in their condition.
A phase two open-label proof-of-concept study of 20 patients with ankylosing spondylitis (AS) showed that 65% of patients achieved an ASAS40 response at 24 weeks with ustekinumab administered subcutaneously.
"These results suggested that ustekinumab’s benefits may be comparable to those of tumor necrosis factor (TNF) and IL-17 antagonists, two classes of agents approved for use in ankylosing spondylitis. Thus, the negative results of the phase three trial came as a real surprise, notwithstanding that the earlier study was not placebo controlled," wrote Philip Mease, M.D., in an editorial published with the study.
These were three studies: Study one included 346 patients: 116 were assigned to the placebo group; 116 received 45 mg ustekinumab and 114 received 90 mg ustekinumab for up to 24 weeks. Researchers decided that the outcomes for study one would determine whether they would proceed with studies two and three. They found that study one failed to meet both the primary and secondary end points (ASAS40 response), so the study was stopped and soon after, they stopped studies two and three before patients were fully enrolled in the trials. Neither of the three studies showed clinically meaningfully improvements in patients over placebo.
“Despite both the scientific and clinical rationale for supporting initiation of these phase three studies of ustekinumab in axial SpA, including an openâlabel study of patients with AS and improvement in PsA patients with physicianâreported spondylitis, questions remain as to why ustekinumab was not effective. A recent review highlighted differences in axial disease in AS and PsA, suggesting that spondylitis may be driven by different mechanisms in these two diseases. Additional research is needed to better understand the pathogenic mechanisms and the cytokine pathways that manifest as axial SpA,” wrote Dr. Deodhar and colleagues.
In his editorial, Dr. Mease said the "phase three program for ustekinumab was well designed and comprehensive." He also explored possible explanations for the negative results, including the high placebo response rate of study one.
“Whatever the reason or reasons, whether biologic mechanisms, high placebo response rate, inadequate dose, or combination thereof, we now have two axial SpA studies of IL- 23 inhibitory drugs which have shown negative results. There is currently an axial SpA trial underway with tildrakizumab, an IL- 23p19 inhibitor. We await with interest the results of this trial to learn whether it too demonstrates a negative result, or, for reasons to be determined, shows otherwise. Publication of these negative studies is important to further our understanding of the complex immunologic mechanisms of diseases such as axial SpA and to help us appreciate their differences from related conditions such as PsA, psoriasis, and IBD, as well as to provide evidence for effective and ineffective treatment pathways," he wrote.
Philip Mease, M.D., "Ustekinumab Fails to Show Efficacy in a Phase III Axial Spondyloarthritis Program: The Importance of Negative Results," Arthritis and Rheumatology. Vol. 71, No. 2, February 2019, pp 179–181. DOI 10.1002/art.40759
Deodhar A, Gensler LS, Sieper J, et al. "Three Multicenter, Randomized, Double-Blind, Placebo-Controlled Studies Evaluating the Efficacy and Safety of Ustekinumab in Axial Spondyloarthritis," Arthritis and Rheumatology. ePub Dec. 29, 2018; print February 2019. DOI: 10.1002/art.40728.
The featured study was sponsored by Janssen Research & Development, LLC.