Ustekinumab as Add-on Therapy Was Seen to Benefit SLE Patients in Phase 2 Trial

Ustekinumab as an add-on to standard of care was seen to significantly increase the number of systemic lupus erythematosus (SLE) patients with a reduction in disease activity compared to standard of care alone, results from a Phase 2 trial show.

Patients were also less likely to experience a disease flare and experienced more meaningful improvements in their joints if they were receiving ustekinumab, researchers showed.

The study, “Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study,” was published in The Lancet.

SLE, an autoimmune disease that affects multiple organs, is characterized by multiple inflammatory mechanisms.

The pro-inflammatory molecules IL-12 and IL-23 have been implicated in the development of SLE, with mouse models of the disease showing a lessened disease severity if they lack these genes.

Consistently, a recent meta-analysis has pointed an inhibitor of both IL-12 and IL-23 — called ustekinumab — as the No. 1 candidate for repurposing in SLE. Ustekinumab (sold under the brand name Stelara) is currently approved for the treatment of psoriatic arthritis and Crohn’s disease in adults, and for plaque psoriasis in adults and adolescents.

Given its established safety in other auto-immune conditions, researchers now aimed to assess the safety and effectiveness of ustekinumab in SLE patients in a Phase 2 trial (NCT02349061).

“To the best of our knowledge, this study is the first to report efficacy and safety of an anti-IL-12 and IL-23 antibody in systemic lupus erythematosus,” researchers wrote.

The study included 102 patients ages 18-75 who had moderate-to-severe disease activity despite conventional treatment — glucocorticoids, immunosuppressants, antimalarials, or ACE inhibitors. Recruitment took place at 44 private and academic centers in Argentina, Australia, Germany, Hungary, Mexico, Poland, Spain, Taiwan, and the U.S.

Patients were randomly assigned ustekinumab or a placebo, both in combination with standard SLE therapies.

The first ustekinumab dose was adjusted according to a patient’s weight: 260 mg for patients weighing less than 121 pounds; 390 mg for patients weighing between 121 pounds and 187 pounds; and 520 mg for patients weighing more than 187 pounds. Then all patients received 90 mg ustekinumab or a placebo every eight weeks.

The study’s primary goal was to determine the proportion of patients achieving a Systemic Lupus Erythematosus Responder Index (SRI-4) Composite Response, a measure of disease activity, after 24 weeks on treatment. Essentially, SRI-4 is defined as a reduction in the disease activity index SLEDAI-2K by four points or more, and no worsening in other disease scores.

The trial met its primary endpoint, with 62% of patients receiving ustekinumab achieving an SRI-4 response at week 24, compared to 33% in the control group. The benefits started at week 12 and were consistent across several patient subgroups.

The proportion of patients experiencing improvements in the BILAG-based Combined Lupus Assessment (BICLA), another measure of disease activity, was similar in both groups. But more patients receiving ustekinumab had no worsening in this measure.

“Improvements in patients in the ustekinumab group compared with those in the placebo group were also observed across additional measures of disease activity,” researchers wrote. In fact, ustekinumab reduced the number of disease flares and reduced the number of joints with tenderness and swelling.

Researchers noted, however, that these improvements were likely not related to changes in interferon-related genes, which are known players in SLE.

Adverse events were more common among those receiving ustekinumab (78%) than in the control group (67%), with urinary tract infection, cold, infections of the upper respiratory tract, and headache being the most common adverse events. One patient had a reaction to ustekinumab and discontinued treatment, but no deaths occurred during the trial.

These were “similar to those seen in previous trials of ustekinumab in patients with psoriasis, psoriatic arthritis, and Crohn’s disease,” researchers explained.

“In this randomised controlled trial, a significantly greater proportion of ustekinumab-treated patients achieved the SRI-4 primary endpoint at week 24 than those who received placebo, when added to standard-of-care therapy,” researchers wrote.

“The results of this study confirm the importance of IL-12 and IL-23 in this disease, and indicate that ustekinumab might be an effective therapy for systemic lupus erythematosus.”