High expectations for ustekinumab in SLE after positive Phase 2 trial

Positive results for ustekinumab in systemic lupus erythromatosus have been shown in a small Phase 2 trial of the anti-interleukin 12/23 antibody as add-on treatment.

In a randomised controlled trial in 102 patients with active SLE, ustekinumab (Stelara) proved to be significantly better than placebo in improving clinical parameters of the disease.

Published in the Lancet, the trial led by Professor Ronald van Vollenhoven and colleagues at the University of Amsterdam, showed that ustekinumab was superior to placebo in terms of the primary endpoint of SLE disease activity index 2000 responder index (SRI-4).

The international multicentre trial, which included patients from Australia, found that at 24 weeks, 37 of 60 patients (62%) in the ustekinumab group achieved an SRI-4 response compared to 33% in the placebo group. The treatment involved an initial IV infusion of ustekinumab followed by subcutaneous injections every eight weeks.

Ustekinumab-treated patients also showed better global response (SRI-5 or SRI-6) than placebo and also showed benefits in terms of endpoints for joint and mucocutaneous disease and clinical biomarkers of SLE activity such as anti-dsDNA and C3.

However the BILAG-Based Combined Lupus Assessment (BICLA) responses were not different between groups.

The adverse effect profile of ustekinumab was similar to that seen in previous larger trials of the agent for other indications such as Crohn’s disease, with no difference in severe adverse events between the drug and placebo. Infections were the most common, with two cases of severe infection in the ustekinumab group and none in the placebo.

The study authors said the findings showed potential for ustekinumab in SLE, a condition for which there is a considerable unmet need for tolerable and effective treatments.

They said it was particularly promising that ustekinumab showed efficacy in SLE because it raised the possibility of a potential new cytokine mechanism of action  – via interleukin-12 and 23 -to modulate the disease.

However an accompanying editorial sounded a word of caution, noting that other agents such as epratuzumab had shown positive results in phase 2 trials in SLE but then gone on to give disappointing findings in larger phase 3 studies.

The editorial, written by Nathalie Costedoat-Chalumeau and Frederic Houssiau of France, also questioned whether patients in the ustekinumab arm of the trial had all received optimal standard of care treatment. They noted that 31% were not treated with antimalarials such as hydroxychloroquine and only 2% of those with active arthritis were taking methotrexate. Likewise, only half those taking glucocorticoids received a steroid sparing immunosuppressant.

“These minor criticisms should not detract from the eager expectation with which patients and lupologists await prospective candidates for systemic lupus erythematosus therapy. The trial reported by van Vollenhoven and colleagues is indeed a step forward,” they concluded.

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