Sirukumab did not demonstrate efficacy or acceptable safety in patients with active lupus nephritis concomitantly receiving immunosuppressant therapy, according to a study published in Arthritis & Rheumatology.
Among patients with systemic lupus erythematosus (SLE), lupus nephritis (LN) is associated with increased mortality. There is an unmet need for improving LN treatment since current therapies, such as cyclophosphamide and mycophenolate mofetil, often result in slow or incomplete responses.
Preclinical studies suggest that interleukin (IL)-6 inhibition improves kidney-related outcomes and survival in LN. Brad H. Rovin, MD, of Ohio State University Wexner Medical Center, and colleagues evaluated sirukumab, a high-affinity IL-6 targeted human monoclonal antibody, for treatment of LN in a randomized, controlled, proof-of-concept study (ClinicalTrials.gov identifier: NCT01273389).
Patients with class III or IV LN and proteinuria (>0.5 g/day) on immunosuppressive therapy were assigned to sirukumab (10 mg/kg) or placebo in a 5:1 ratio. Study drug was administered intravenously once every 4 weeks for a period of 24 weeks.
High Yield Data Summary
- In this proof-of-concept trial,
IL-6 inhibition with the monoclonal antibody sirukumab did not reduce proteinuria in most patients with persistently active LN concomitantly receiving maintenance immunosuppressive therapy
The primary outcome was reduction in proteinuria, as measured by protein-to-creatinine (P:C) ratio in a 12-hour urine collection, at 24 weeks compared with baseline.
Of 25 participants, 19 (76%) completed all 24 weeks of study treatment. At 24 weeks, sirukumab did not improve proteinuria (0% median percent change from baseline), and placebo treatment was associated with increased proteinuria from baseline (median percent reduction -43.3%).
However, 5 patients in the sirukumab group demonstrated ≥50% improvement in proteinuria by week 28.
Of 6 (24%) patients who discontinued study treatment before 24 weeks, 5 did so because of adverse events, which included pneumonia and neutropenia. Nearly half of all patients receiving sirukumab experienced at least 1 serious adverse event, most commonly infections and worsened LN. In contrast, no serious adverse events were reported in the placebo group.
“Despite the overall lack of clinical benefit, there was an intriguing improvement of ≥50% in the P:C ratio in a small subset of 5 patients identified as responders,” the authors wrote.
“There were certain baseline patient characteristics that were enriched in this retrospectively defined subset of responders, including a preponderance of men, negative anti-dsDNA status, class IV disease, and nonnephrotic levels of proteinuria, although these characteristics were not unique to the responding patients. The data indicate that it would be difficult to identify potential responders based on their clinical characteristics alone,” they added.
Summary and Clinical Applicability
Active LN in patients with SLE is associated with lower survival, and current treatment regimens often produce inadequate responses. Because IL-6 inhibition has been shown in animal models to improve renal outcomes in LN, sirukumab was evaluated as a potential new treatment for LN.
“This proof-of-concept study did not demonstrate the anticipated efficacy nor did it demonstrate an acceptable safety profile for sirukumab treatment in this population of patients with active LN receiving concomitant immunosuppressive treatment,” the authors concluded.
Limitations and Disclosures
- The study enrolled a small number of patients and was not powered to identify potentially significant differences in efficacy and safety between the sirukumab and placebo groups
- Patients were selected based on renal biopsy results within 14 months prior to enrollment. Renal histologic features may have changed between the time of biopsy and the time of enrollment as the result of disease progression or concurrent immunosuppressive therapy
Rovin BH, van Vollenhoven RF, Aranow C, et al. A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of treatment with sirukumab (CNTO 136) in patients with active lupus nephritis. Arthritis Rheumatol. 2016;68(9):2174-83. doi: 10.1002/art.39722