When the FDA approved belimumab for treatment of lupus, based on its effectiveness and safety in the 1,684 patients enrolled in the two BLISS studies (Study of Belimumab in Subjects With Systemic Lupus Erythematosus), FDA reviewers and others brought up several concerns:
1. The study criteria disqualified patients with renal and central nervous system complications, so it selected for patients with less severe disease.
2. The studies found no effect among African American patients. (Sponsor Human Genome Sciences, now a division of GlaxoSmithKline, attributed that to the small number of African-American subjects.)
3. Although BLISS-52 and BLISS-76 both concluded that adverse event rates were similar in the belimumab and placebo groups, those reported were worrisome, including serious infections and three suicides.
Presentations at the American College of Rheumatology meeting next week will address related issues with the best available data.
A post hoc multivariate analysis of BLISS data shows that belimumab was also effective in those with more severe disease. A main entry criterion for the BLISS studies was a SELENA-SLEDA score ≥ 6. The later analysis showed belimumab most effective in patients with SELENA-SLEDA scores ≥ 10, low complement, anti-dsDNA positivity, or corticosteroid use. In the EULAR journal Annals of the Rheumatic Diseases, Ronald van Vollenhoven of Karolinska University Hospital in Sweden and colleagues have already reported on analysis of the 876 patients who met the complement/dsDNA criteria, and the (overlapping) 877 patients who met the SELENA-SLEDA criteria. In a poster session at the forthcoming ACR meeting on Tuesday, Ann E. Clarke MD of McGill University Health Center in Quebec will give further analysis of the 877 patients with SELENA-SLEDA scores ≥10 (Abstract #2241). Van Vollenhoven and Michelle A. Petri of Johns Hopkins University will also present posters on predicting flares in the BLISS placebo groups (Abstracts #164 and #615, respectively).
Belimumab was effective in African-American patients. On Wednesday, Christopher E. Collins MD of Washington Hospital Center in Washington, DC, will give a presentation on outcomes among African-American patients with SLE in a multi-center cohort study (Abstract #2617). Rheumatologists are evaluating randomly identified patients with ≥8 belimumab infusions six months before and six months after treatment. Collins' interim analysis evaluated a subset of 58 of these patients who are African-Americans, 93% of them women, being treated by 31 rheumatologists in 18 states. A majority of them had clinical improvements and steroid sparing. (A definitive answer will have to wait for the EMBRACE study, a 52-week phase III trial of 816 black patients, which is scheduled to begin recruiting soon and to report results in 2018.)
Belimumab was safe and maintained its effectiveness in a long-term study. On Wednesday, Joan T. Merrill MD of the Oklahoma Medical Research Foundation will give a presentation on results of more than 1,745 patient-years of belimumab treatment for SLE (Abstract #2621). In a randomized phase II study, 449 patients with SELENA-SLEDA scores ≥4 were given 1, 4 or 10 mg/kg of belimumab or placebo for 52 weeks. In a continuation study, 296 patients were all given belimumab at up to 10 mg/kg. After seven years, 190 patients remained. Of patients who were positive for anti-dsDNA, 45.8% became negative. Many patients had normalized complement, and corticosteroid use decreased by a median 55%. The drug was well tolerated. Seven patients died during the study, but no cause of death predominated.
The major question of belimumab’s effectiveness for lupus nephritis will not be answered until the conclusion of BLISS-LN, a phase III two-year trial of 464 patients that has just begun recruiting.
Also from ACR2012:
“Magic Bullet” Approaching for Systemic JIA: But Which One?
FDA Panel on Biosimilars: Analytics Should Trump Clinical Trials
Rheumatic Drug Safety Updates 2012: FDA at the ACR Meeting
Briefer Two-Drug Regimen Offers Dramatic Results in Lupus Case Series