Ustekinumab Provides Sustained Decrease of SLE Disease Activity, Phase 2 Trial Shows

One year of treatment with ustekinumab led to sustained reductions in disease activity in systemic lupus erythematosus (SLE) patients, according to a Phase 2 trial.

These benefits were also observed in patients who switched from placebo to Janssen‘s therapy at week 24.

Trial findings were presented in the study, “Efficacy and Safety of Ustekinumab, an Interleukin-12/23 Inhibitor, in Patients with Active Systemic Lupus Erythematosus: 1-Year Results of a Phase 2, Randomized Placebo-Controlled, Crossover Study,” at the recent 2018 American College of Rheumatology (ACR)/Association for Rheumatology Health Professionals (ARHP) Annual Meeting in Chicago.

The global, randomized, placebo-controlled study (NCT02349061) tested ustekinumab in 102 SLE patients, ages 18-75. All patients had active disease despite ongoing standard-of-care therapy with glucocorticoids, immunosuppressants, antimalarials, or angiotensin-converting enzyme inhibitors.

After an initial intravenous (into the vein) dose of 6 mg/kg, patients were randomized to treatment with either a placebo or 90 mg ustekinumab, delivered under the skin every eight weeks, for a total of 24 weeks.

After this period, patients on placebo switched to the treatment candidate for a second phase of the same duration. Both ustekinumab and placebo were given in addition to standard of care. Safety was evaluated through week 56.

In the group taking ustekinumab from the beginning of the study, results showed that 63% had less disease activity, as measured by the SLE Responder Index (SRI)-4. SRI-4 is defined as a decrease in the disease activity index SLEDAI-2K by four points or more, and no worsening in other disease scores.

Rates of changes in SLEDAI-2K were sustained from week 24 (65%) through one year (67%). Similar sustained benefits were observed in the rates of Physician Global Assessment (PGA) and in active joint responses. The response rate of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) — a measure of lupus activity in the skin — also increased from week 24 (53%) to one year (69%).

In the group who switched from placebo to ustekinumab after 24 weeks, 55% had achieved an SRI-4 response at one year.

These findings build on earlier data showing decreased SLE disease activity in a significantly higher proportion of patients receiving ustekinumab at week 24 than those on a placebo (62% vs. 33%).

As for safety results, 15% of the overall patient population experienced serious adverse events, and 7.5% experienced serious infections through week 56. No deaths or cases of cancer, opportunistic infections, or tuberculosis were observed. Overall, the safety data of ustekinumab were consistent with its known safety profile. Long-term safety and efficacy data will be collected through 104 weeks.

“[Ustekinumab] provided sustained clinical benefit in global and organ-specific SLE activity measures through 1 year, with a safety profile consistent with other indications. Thus, ustekinumab] may be an effective therapy for SLE,” the scientists wrote.

The potential SLE medication is a human monoclonal antibody specific for interleukin (IL)-12 and IL-23, two pro-inflammatory molecules implicated in the development of SLE.

“The positive results of this longer-term Phase 2 study further support the role that IL-12 and -23 cytokines may play in the pathophysiology of the disease,” Ronald van Vollenhoven, MD, PhD, the trial’s lead investigator and director of the Amsterdam Rheumatology and Immunology Center (ARC), said in a press release.

Based on these Phase 2 data, Janssen has started the global Phase 3 LOTUS study (NCT03517722), a randomized, placebo-controlled trial of ustekinumab currently enrolling participants. More information can be found here.

“It’s a truly exciting time as these latest findings serve as a catalyst as we advance the programme into Phase 3,” said Jaime Oliver Vigueras, Janssen-Cilag AG’s Europe, Middle East and Africa immunology therapeutic area lead. “Our commitment to innovating on behalf of people with chronic immune diseases is 20 years strong and remains steadfast as we expand our work to help more people in need, including those with lupus.”

In LOTUS, Janssen will collaborate with the Lupus Foundation of America (LFA) to include a disease-monitoring tool called Rapid Evaluation of Activity in Lupus (LFA-REA), which accounts for both clinician and patient input to assess the impact of SLE on patients’ health and daily life.

Janssen will also work with the Lupus Research Alliance (LRA) and its network of lupus experts with the goal of accelerating ustekinumab’s development as a treatment for SLE.

“With such a limited amount of treatment options available for patients with lupus, there is a great need for those living with the disease to have the possibility of additional therapies,”  said Kenneth Farber, LRA’s president and CEO. “We look forward to continuing collaborations with Janssen in the Phase 3 study to further evaluate ustekinumab as a potential treatment option.“

Ustekinumab (sold under the brand name Stelara) is currently approved for the treatment of psoriatic arthritis and Crohn’s disease — a type of inflammatory bowel disease — in adults, and for plaque psoriasis in adults and adolescents.