The monoclonal antibody belimumab (Benlysta) may have potential as a corticosteroid-sparing drug when added to standard-of-care treatment for systemic lupus erythematosus (SLE), a post-hoc analysis suggested.
In pooled data from two large randomized controlled trials, this blocker of B-lymphocyte stimulator was moderately associated with a higher probability of corticosteroid dose reduction and a greater average dose reduction over 52 weeks. Dose reduction occurred in 38.5% of belimumab users versus 30.9% of placebo recipients, while dose augmentation occurred in 18.4% versus 30.7%, according to Ronald F. van Vollenhoven, MD, PhD, of the Academic Medical Center in Amsterdam, and colleagues.
An overall increase in corticosteroid dose occurred in 22.6% of patients on belimumab compared with 35% of patients on placebo. In addition, the dose decreased in more patients receiving belimumab than placebo (37.0% versus 29.7%), the researchers reported in Arthritis & Rheumatology.
"A number of studies have demonstrated that corticosteroid use is a key factor in organ damage accrual in patients with SLE, and the risk of organ damage increases with increasing corticosteroid dose," they said. "Thus, one of the major goals of SLE therapy is to reduce the overall cumulative corticosteroid exposure."
Belimumab was approved for use in SLE 5 years ago, despite the fact that a multicenter phase II trial failed to meet its primary endpoints. The investigators conducted post-hoc analyses looking for potential subgroups who might benefit, and found that those who were seropositive had twice the decrease in disease activity as those who were seronegative.
Another possible role suggested for this agent was as a steroid-sparing treatment, so van Vollenhoven and associates analyzed data from BLISS (Study of Belimumab in Subjects with SLE)-52 and BLISS-76 who were taking corticosteroids at baseline and were randomized to infusions of belimumab 10 mg/kg or placebo, plus standard care.
At baseline, 966 out of 1,125 BLISS patients (86%) were taking corticosteroids, and of these, 478 received regular infusions of belimumab (10 mg/kg every 4 weeks) and 488 received a placebo. Most patients were female (94%), and the mean age was 37.1. The average corticosteroid dose (prednisone equivalent) was 12.5 mg/day.
The cohort had a fairly high level of disease activity, with a mean Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index score of 9.8, and 71.5% of patients were seropositive for anti-double stranded DNA. High disease activity was similarly prevalent in both arms, with 275 in the belimumab group and 262 in the placebo group.
More placebo patients (7.6%) than belimumab patients (6.3%) withdrew before 24 weeks, the cut-off date for corticosteroid dose changes, while 17.5% and 13.4%, respectively, withdrew at or after 24 weeks.
Use of the monoclonal antibody also correlated with a smaller average increase in all corticosteroids and in oral corticosteroids specifically. While corticosteroid doses increased in both groups over the study year, belimumab users had a smaller mean cumulative increase than placebo recipients did, at 531.2 mg versus 916.3 mg (P<0.0001). Mean changes in daily doses were 1.5 mg and 2.5 mg for those in the belimumab and placebo groups, respectively (P<0.0001).
"The numerical differences were not dramatic, which may be related to the fact that this trial was not designed with the primary goal of examining steroid-sparing properties for belimumab," the investigators wrote. They added that a forced steroid-taper design might more clearly demonstrate the corticosteroid-sparing efficacy of belimumab.
The mean of all decreases in cumulative corticosteroid dose was higher in the belimumab group (P=0.0165), and the mean of all increases was lower (P=0.0005). Adverse and serious adverse events were comparable in both arms.
As for the increase in corticosteroid exposure emerging from both treatment groups in the BLISS trials, the authors were not surprised: "The patient population in these trials had longstanding, moderate to highly active SLE despite ongoing background therapy with antimalarials, immunosuppressives, and corticosteroids. Such patients are at considerable risk of disease flare and during the trials flares were commonly treated with increases in corticosteroid dose."
Regarding the study's limitations, van Vollenhoven and colleagues mentioned the post-hoc nature of the analyses, the fact that the protocol did not prescribe corticosteroid dose changes in detail, the mixing of oral and parenteral corticosteroids in some analyses, and the lack of power for detecting uncommon corticosteroid-related side effects.
The study was funded by Human Genome Sciences and GlaxoSmithKline.
The authors reported financial relationships with GlaxoSmithKline, AbbVie, Bristol-Myers Squibb, Pfizer, Roche, USB, Biotest, Crescendo, Janssen, Lilly, Merck, and Vertex. Several are employees of GlaxoSmithKline.
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