SAN DIEGO – While use of the investigational agent blisibimod did not meet the primary endpoint in a phase 3 trial in systemic lupus erythematosus (SLE), it was associated with steroid sparing, decreased urine protein, a trend toward decreased anti–double-stranded DNA antibodies, and significant decreases in anticardiolipin antibodies and immunoglobulin levels.
Thosewere reported from trial, a randomized (5:4), double-blind, placebo-controlled phase 3 study of 442 patients, and were presented by , at the annual meeting of the American College of Rheumatology. Blisibimod is a subcutaneously injected inhibitor of B-cell activating factor.
The SRI-6 primary endpoint at 52 weeks was met by 44% of patients on blisibimod, compared with 42% on placebo. But the SRI-6 endpoint widened when the most common features at entry were excluded (mucocutaneous and musculoskeletal), suggesting the possibility that blisibimod affects the more objective and potentially organ-threatening renal endpoint.
To be eligible for the trial, patients had to have a Safety of Estrogen in Lupus Erythematosus National Assessment Group–SLE Disease Activity Index () score of 10 or greater and be receiving steroids. The SRI-6 primary endpoint also required no worsening on the British Isles Lupus Assessment Group ( ) disease activity index or Physician Global . Key secondary endpoints included proteinuria and achievement of steroid taper.
Patients in the study were required to be receiving stable doses of prednisone or an equivalent steroid at less than or equal to 0.5 mg/kg or 40 mg daily for at least 28 days prior to randomization. Other permitted standard-of-care oral medications included methotrexate up to 25 mg weekly, azathioprine up to 300 mg daily, mycophenolate mofetil or sodium salt up to 3 mg daily, leflunomide up to 40 mg daily, hydroxychloroquine up to 400 mg daily, and nonsteroidal drugs within locally approved dose ranges.
Of the 442 patients enrolled, 245 received blisibimod, and 197 received placebo. They were well matched in demographics and baseline disease characteristics. “There were very few patients of African descent in this trial,” Dr. Merrill noted. “Also, about 30% of patients had some renal involvement. In fact, patients with stable, active renal disease were encouraged to participate in this trial.” The mean prednisone dose at entry was between 15 and 16 mg daily, and about 60% of patients were taking an antimalarial. An equal proportion of patients in both groups discontinued the study (22%). “A few more patients withdrew due to adverse events in the blisibimod group, and a few more patients withdrew due to lack of efficacy in the placebo group,” she said.
Of 135 patients with a baseline urine protein-to-creatinine ratio equal to or greater than 0.5, blisibimod treatment led to significantly greater improvement in proteinuria at several time points than did treatment with placebo, which also showed improvement in proteinuria.
Treatment with blisibimod also was associated with a reduction in anti–double-stranded DNA antibodies, as well as significant reductions in peripheral B-cell lineages, anticardiolipin antibodies, and immunoglobulins, and with significant increases in complement C3 and C4. “The expected pharmacodynamic markers were [also] met ... and more patients treated with blisibimod were able to achieve a prednisone milestone of reduction to less than or equal to 7.5 mg/day, compared with those in the placebo group,” she said. “This was statistically significant over time at multiple time points.”
Adverse events were balanced between treatment arms except for injection site reactions, which occurred in 7.3% of blisibimod-treated patients versus 2.6% of placebo patients. There were no major safety issues in the study.
Dr. Merrill hypothesized that the higher mean doses of corticosteroid at baseline could have contributed to the higher-than-usual placebo response rates and failure to meet the primary SRI-6 endpoint.
The study was supported by Anthera. Dr. Merrill disclosed that she has received research support from Anthera, Amgen, EMD Serono, GlaxoSmithKline. and Novartis.