Integrated analysis confirms benefits of 45-mg and 90-mg dosing
By Wayne Kuznar
San Diego, CA— Ustekinumab (Stelara), a human monoclonal antibody against interleukin (IL)-12 and IL-23, was approved by the US Food and Drug Administration in September 2013, alone or in combination with methotrexate, for the treatment of adults with active psoriatic arthritis. A new integrated analysis of 2 phase 3 clinical trials was presented at the 2013 meeting of the American College of Rheumatology, showing that ustekinumab reduces radiographic progression of joint disease in patients with active psoriatic arthritis.
Impeding joint damage is an important part of the long-term management of psoriatic arthritis, said the study’s lead investigator Iain B. McInnes, FRCP, PhD, Professor of Medicine, University of Glasgow, Scotland.
The IL-23/IL-17 axis mediates pathways that have the potential to drive inflammation and matrix destruction, said Dr McInnes.
The integrated analysis incorporated patients enrolled in the Phase 3 Multicenter, Randomised, Double-blind, Placebo-controlled Trials of Ustekinumab, a Fully Human Anti-IL-12/23 p40 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Psoriatic Arthritis (PSUMMIT) I and PSUMMIT II. In PSUMMIT I, the 615 participants had inadequate response to methotrexate and no exposure to tumor necrosis factor (TNF)-alpha inhibitors. Previous anti–TNF-alpha therapy was permitted in PSUMMIT II, in which 312 patients were enrolled. The integrated analysis included 927 patients with active disease despite previous treatment.
In both trials, patients were randomized to ustekinumab 45 mg or 90 mg or to placebo at weeks 0 and 4 and then every 12 weeks. Patients with no response to placebo (defined as <5% improvement in the tender and swollen joint count from baseline) at week 16 were crossed over to ustekinumab 45 mg. All remaining patients who were randomized to placebo crossed over at week 24 to ustekinumab 45 mg. The patients randomized to ustekinumab 45 mg who had no response had their dose of ustekinumab increased to 90 mg starting at week 16.
Radiographic progression was a secondary end point of the analysis. It was assessed in the hands and the feet by the change from baseline to 24 weeks in modified Sharp/van der Heijde (SHS) scores.
At 24 weeks, patients randomized to ustekinumab 45 mg and 90 mg had mean changes from baseline in total SHS scores of 0.40 and 0.39, respectively, compared with a mean change of 0.97 for patients receiving placebo (P = .017 and P <.001, respectively). The favorable effect of ustekinumab on radiographic progression continued to week 52.
The treatment effect on radiographic progression of disease was expected to be similar for the 2 studies. Although results from PSUMMIT I showed significant inhibition of structural damage at week 24 for both ustekinumab doses, the effect of ustekinumab on inhibiting the progression of structural damage could not be ascertained in the smaller PSUMMIT II study. There was a higher proportion of dropouts in the placebo group in PSUMMIT II, which required that missing x-ray data be imputed as no progression of disease. This rule may have obscured any true difference between the groups in radiographic progression in PSUMMIT II, said Dr McInnes.
Nevertheless, “the combined x-ray analysis met the prespecified major radiographic end point,” he said. “The overall x-ray data are supportive of inhibition of progression of structural damage in patients with psoriatic arthritis at both the 45-mg and the 90-mg dose of ustekinumab.”