Apr 24, 2014
B-Cell Targeting Has Benefit in Severe Lupus
By Nancy Walsh, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
• This phase 2b clinical trial was designed to evaluate the efficacy and safety of different doses of subcutaneous blisibimod, an inhibitor of B-cell activating factor, in patients with systemic lupus erythematosus.
• Significant beneficial effects were seen in patients with severe disease at baseline who were randomized to the highest dose of blisibimod compared with pooled placebo.
Although an inhibitor of B-cell activating factor failed to meet the primary endpoint in a phase II trial for lupus, beneficial effects were seen in patients with severe disease at baseline, researchers reported.
On a composite endpoint that required at least a 5-point improvement on a lupus disease activity index, responder rates were 37.2% for pooled groups of patients receiving blisibimod and 35.3% for those receiving placebo (P=0.635), according to Richard A. Furie, MD, of North Shore-Long Island Jewish Health System in Great Neck, N.Y., and colleagues.
However, among patients with high disease activity who were on corticosteroids at baseline, response rates requiring a 7-point improvement were 41.7% for those receiving the highest dose of blisibimod (200 mg weekly) compared with 12.8% among patients given comparable placebo (P=0.002), the researchers reported online in Annals of the Rheumatic Diseases.
In addition, response rates among patients with severe disease given that dosage regimen were 41.7% when an 8-point improvement on the disease activity index was required, compared with 10.6% for placebo (P<0.001).
B-cell activating factor (BAFF) is a "critical survival factor for B cells," which is upregulated in systemic lupus erythematosus (SLE), the researchers explained.
Blisibimod is a selective inhibitor of both soluble and membrane-bound BAFF that was associated with decreases in B cells in a phase I trial.
The Study and the Endpoints
The study design was complex, and reflected the difficulties researchers have faced in assessing new therapies in lupus.
These have included the heterogeneous nature of the disease, its tendency to wax and wane, and the need for aggressive background therapy in placebo groups, which can mask small potential benefits for investigational treatments.
These factors were seen during the clinical development of belimumab (Benlysta), which was the first new FDA-approved drug for use in lupus in more than 50 years when it was licensed in 2011.
Belimumab is an anti-BAFF monoclonal antibody that initially appeared to be ineffective until post-hoc analyses determined that it was most beneficial in the subgroup of patients with high disease activity and ANA and anti-dsDNA autoantibodies.
The use of the composite endpoints and careful attention to biomarkers and baseline factors were an attempt to overcome the obstacles that hampered previous clinical trials, according to the investigators.
The primary endpoint was the SLE Responder Index, or SRI-5. This consisted of a 5-point improvement on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI), plus no worsening on the physician's global assessment.
In addition, there could be no new "A" scores on the British Isles Lupus Assessment Group (BILAG) organ system domain and no more than one new BILAG "B" score. An "A" score represents worsening that needs high-dose steroids or additional cytotoxic agents, while a "B" score indicates a requirement for low-dose steroids or antimalarials.
Additional outcomes in the trial included the SRI-6, -7, and -8, which represented greater points of improvement on the SELENA-SLEDAI.
"The use of higher thresholds of improvement in SELENA-SLEDAI score is consistent with the American College of Rheumatology-recommended measures of disease activity, which defines an improvement in the SELENA-SLEDAI score greater than 7 or a worsening of more than 8 points as clinically meaningful," Furie and colleagues explained.
Severe disease was defined as a SELENA-SLEDAI score of 10 or higher, plus the use of corticosteroids.
Severe flare was defined as an increase of 12 points or more on the SELENA-SLEDAI, an increase in daily prednisone dose of 0.5 mg/kg, the need for a new immunosuppressive agent, an increase above 2.5 on the physician global assessment, or hospitalization for lupus.
In this study, 547 patients who had autoantibodies to antinuclear antigens (ANA) or double-stranded DNA (anti-dsDNA) were randomized to receive blisibimod, 100 mg once weekly, 200 mg once weekly, 200 mg once monthly, or matched placebos for 6 months.
Patients' mean age was 37, mean disease duration was 6 years, and more than 90% were women. High titers of ANA were detected in almost 80%, and high levels of anti-dsDNA were present in almost 70%.
Immunosuppressive drugs were being taken by 33% to 52%, antimalarials by about 70%, and corticosteroids by approximately 90% and in mean doses of 11 mg per day.
The mean baseline SELENA-SLEDAI score was 9.9.
A total of 81% of patients completed the 6-month randomized phase of the study, and 382 entered the open-label extension phase.
Although the primary endpoint wasn't met, between weeks 12 and 36, the number of responders in the 200 mg weekly group was greater than in the placebo groups.
In the modified intent-to-treat population, SRI-7 responses were seen in 25% of patients given 200 mg every week compared with 8.7% of the corresponding placebo group (P=0.003), while SRI-8 responses were seen in 25% versus 7.6% (P=0.001).
Percentages of patients with no new BILAG scores was high, at 74.7% of those receiving placebo, and was 78.3% among those in the highest-dose blisibimod group. Similarly, 72.9% and 76.1% of patients receiving placebo and weekly 200 mg blisibimod had no deterioration on the physician global assessment.
The time to first severe flare was 232 days in the placebo groups, 330 days for the pooled blisibimod groups, and 348 days for the 200 mg weekly blisibimod group.
Other findings included "modest" increases in the number of patients who were able to taper their corticosteroids and greater decreases in proteinuria.
As expected, there were significant decreases in B cells in the active treatment groups that were accompanied by reductions in anti-dsDNA autoantibodies and increases in complement C3 and C4. Levels of immunoglobulins also fell, and with no notable increase in rates of infection.
Safety of the Treatment
The treatment "was generally safe and well tolerated at all dose levels," the investigators observed.
Adverse events were similar overall in the blisibimod and placebo groups, while fewer serious adverse events occurred in the blisibimod groups (11.1% versus 15.8%).
Seven deaths were reported -- three in patients receiving placebo and four in those given blisibimod, which were septic shock in two, myocardial infarction in one, and respiratory failure in another.
In the current study, baseline disease severity and the combined SRI endpoint appeared to be "critical" components of the drug evaluation, according to the investigators.
"Specifically, in addition to identifying a safe, well tolerated, efficacious, and convenient dose of blisibimod (200 mg weekly), this study established a patient population likely to benefit from blisibimod therapy (severe SLE: SELENA-SLEDAI ≥10 and receiving a corticosteroid), and an endpoint (SRI-8) that optimizes the ability to discern clinical benefit over background therapy," they wrote.
The study findings support the further development of blisibimod, particularly for patients with severe disease. "A focus on subjects with severe SLE is especially important as current treatment options for this patient subset include drugs with unacceptable toxicities," they concluded.
A limitation of the study was the use of other medications including immunosuppressive agents, which were less frequently used among patients in the blisibimod groups, so they "theoretically may have had a treatment disadvantage."
The study was sponsored by Anthera Pharmaceuticals.
The authors disclosed relevant financial relationships with Anthera.