PARIS – The investigational interleukin-6 blocker sirukumab provided no benefit to patients with lupus nephritis but put them at a very high risk of developing a serious infection in a small, randomized, placebo-controlled trial.
Based on the study results, the study sponsor, Janssen, has shut down its program for the lupus nephritis indication, Dr. Ronald van Vollenhoven said at the annual European Congress of Rheumatology.
"While a few patients did experience a reduction in proteinuria, we had an unacceptably high rate of adverse events," said Dr. van Vollenhoven, chief of the Unit for Clinical Therapy Research, Inflammatory Diseases, at the Karolinska Institute, Stockholm. "Based on these findings, we will not be advancing any further investigation of sirukumab for patients with active lupus nephritis."
Dr. Ronald van Vollenhoven
The company continues to develop the drug for rheumatoid arthritis.
In the trial, 21 patients received intravenous sirukumab 10 mg/kg once every 4 weeks for 24 weeks, and 4 received placebo. During the trial and a 16-week safety observation follow-up period, 48% of those who took the investigational IL-6 blocker developed a serious adverse event, including infections serious enough to require hospital admission.
While not specifying the infections, which occurred in 10 patients, Dr. van Vollenhoven noted that five patients taking the drug discontinued it because of adverse events, which included Haemophilus influenzae pneumonia, elevated liver enzymes, anaphylactic reaction after the first dose, worsening nephritis, and severe neutropenia.
Overall, 19 patients completed the study. In addition to the five who quit because of adverse events, one additional patient withdrew voluntarily. All had active lupus nephritis of about 50 months’ duration, with a mean daily proteinuria of more than 2 g; about a third of the group had nephrotic proteinuria. The mean Systemic Lupus Erythematosus Disease Activity Index 2000 was about 16. All were taking concomitant mycophenolate mofetil or azathioprine.
At the end of the treatment period, there was no significant between-group difference in proteinuria, Dr. van Vollenhoven said. Four of those in the active group experienced at least a 50% reduction in proteinuria over baseline, while none of those in the placebo group experienced this change. However, this difference was not statistically significant. There were no significant changes in the patient or physical global assessment for either group.
Serious adverse events occurred in 48% of those taking the drug, including serious infections (30%) as well as renal/urinary (19%), blood (9.5%), and gastrointestinal (9.5%) events. None occurred in the placebo group.
Among patients in the sirukumab group, there was one grade 4 lymphocytopenia, one grade 4 neutropenia, and two grade 3 neutropenias. One patient had a grade 2 liver enzyme elevation.
Dr. van Vollenhoven was on the study steering committee and is a consultant and speaker for Janssen, as well as other drug manufacturers. Four coauthors are employees of Janssen.