Ustekinumab Reduces Severe Flares in Patients with Active SLE, Trial Shows

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with ustekinumab leads to significant reductions in severe flares in systemic lupus erythematosus (SLE) patients with active disease, 1-year data from a Phase 2 trial shows. Biomarker analyses of the same data also provided clues about how ustekinumab works in SLE.

The data were presented at the 2019 Annual European Congress of Rheumatology (EULAR 2019) by the Janssen Pharmaceutical Companies of Johnson & Johnson, which makes ustekinumab,  approved as Stelara for people with Crohn’s disease and psoriasis.

The oral presentations were titled “Maintenance of Efficacy and Safety and Reduction of BILAG Flares with Ustekinumab, an Interleukin-12/23 Inhibitor, in Patients with Active Systemic Lupus Erythematosus (SLE): 1-Year Results of a Phase 2, Randomized Placebo-Controlled, Crossover Study,” and “Biomarker Profiling Reveals Novel Mechanistic Insights into Ustekinumab Therapeutic Responses in Systemic Lupus Erythematosus.”

Ustekinumab is a monoclonal antibody that binds to and neutralizes a protein called IL-12/23 p40, which is important for the activation of a kind of immune cell called T-helper 1 (Th1) cells. These cells, in turn, create inflammatory signals that can drive SLE disease progression.

The new data come from a Phase 2 clinical trial (NCT02349061), which included 102 adults with SLE who had active disease despite receiving standard-of-care treatment. They were randomized 3:2 to receive either ustekinumab or a placebo, in addition to continuing to receive standard-of-care treatment (steroids, antimalarial drugs, etc.).

Previously, results at 24 weeks were reported and showed that, compared to those on placebo, patients on ustekinumab had significantly less disease activity.

After the 24-week period, patients on placebo were switched to ustekinumab, and all patients were monitored for an additional 24 weeks. The presentations focused on results from this long-term period (48 weeks), with an emphasis on severe disease flares.

In the initial 24-week period, severe flares occurred at a rate of 2.1/10,000 patient-days in the ustekinumab group and 8.4/10,000 patient-days in the placebo group.

In the subsequent 24-week period, the rates were 1.1 and 4.6/10,000 patient-days, respectively, for patients who initially had been given ustekinumab or a placebo (although, during this time period, all patients were receiving Stelara).

The continued decrease in severe flare rate in the group continuing to receive Stelara, as well as the decrease in severe flare rate in those who switched over from placebo, support the idea that Stelara can reduce SLE flares.

“SLE flares are very unpredictable and have a major impact on patients’ quality of life. As such, these results present an impactful and clinically relevant finding, and suggest ustekinumab could in the future offer patients a valuable new treatment option,” Ronald van Vollenhoven, MD, PhD, a professor at the Amsterdam University Medical Center and one of the investigators of the clinical trial, said in a press release.

In addition to presenting data on flares, an analysis of biomarkers in this same population was also presented. Over the initial 24 weeks of the study, blood samples were collected from patients divided into three groups: those on ustekinumab who responded to treatment, those on ustekinumab who did not respond to treatment, and those on placebo.

The researchers measured levels of various immunological signaling proteins thought to be involved in lupus to see whether any were associated with patients being more or less likely to respond to the treatment.

Patients who had reduced levels of one such protein, interferon-gamma (IFN-γ), after ustekinumab treatment were more likely to be responders. Levels of other proteins, including the related IFN-I, were not associated with patients’ response to the treatment.

“This is an important finding because SLE drivers have, until recently, been considered to be led by IFN-I,” said George Tsokos, MD, a rheumatologist at Boston’s Beth Israel Deaconess Medical Center and one of the researchers involved in the study.

“These results suggest that the classical model suspected to be functioning in SLE may be supported by an alternative mechanism of disease via IL-12/-23-dependent T-helper-1 cell differentiation and IFN-γ. It might be this pathway helping to improve clinical disease activity and reduce severe flares, which are currently challenging to manage with lupus,” he said.

A Phase 3 clinical trial, called LOTUS (NCT03517722), is ongoing to validate these findings. The study is recruiting 500 participants with severe SLE despite receiving standard treatment. More information can be found here.