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Belimumab May Be First Biologic Okayed for SLE


 

ROME — What a difference a year makes.

At last year's rain-drenched EULAR gathering in Copenhagen, earlier optimism regarding the prospects for biologic therapies for systemic lupus erythematosus gave way to a pervasive pessimism. Highly encouraging studies had been followed by a rash of negative major clinical trials, which dashed many observers' hopes that biologics would have a clinically meaningful impact in SLE. But that was then.

“It's a year later now. The sun has been shining every day in Rome, and I can tell you that there are now a lot of reasons to think biologics are going to make a real difference in the treatment of lupus,” Dr. Ronald van Vollenhoven said. Clearly, the most exciting recent development is that the anti–B cell cytokine agent belimumab (Benlysta) achieved its primary end points in two separate, exceptionally large phase III clinical trials.

“Safety was excellent in those trials; that's really a great component of the story. So I think belimumab is very likely to become the first registered biologic for SLE,” predicted Dr. van Vollenhoven, senior physician in the department of rheumatology and chief of the clinical trials unit of the Karolinska Institute, Stockholm.

If so, belimumab would also be the first new therapy of any sort approved for SLE in more than 40 years.

Dr. van Vollenhoven, who was on the steering committees of both the BLISS-76 (Belimumab in Subjects With Systemic Lupus Erythematosus–76) and BLISS-52 trials, characterized the demonstrated treatment effect of the anti–B cell cytokine agent as “modest.” But he noted that there is a caveat.

“If the effect size isn't so big, how relevant is the treatment clinically? It's a reasonable question. I think the modest effect size is a function of the primitive outcome measures we have for SLE. The [problem with the lupus trials has been]—and still is—that our instruments aren't very good,” the rheumatologist said. “I think we're picking up a signal and the signal is weak, but it's not because the true effect is weak. It's just because our instruments are blunt. The true effect is probably much better than we think.”

Atacicept, another anti–B cell cytokine agent, is now in a phase III randomized clinical trial for SLE, he said.

There is further encouraging news. At the Rome congress, Dr. Daniel J. Wallace presented positive results from the phase IIB EMBLEM trial of epratuzumab, a humanized anti-CD22 monoclonal antibody. Unlike rituximab, an anti-CD20 monoclonal antibody that completely obliterates B cells, epratuzumab reduced them by about half in the study.

The EMBLEM trial was a 12-week, multicenter, double-blind, randomized study involving 227 patients with moderate to severe SLE who were already on standard therapy. The key finding was that patients who received a cumulative intravenous dose of 2,400 mg of epratuzumab—either as 600 mg weekly (37 people) or 1,200 mg every other week (37 people)—had a responder rate twice that of controls on placebo (38 people).

EMBLEM's responder rate index end point was a novel composite outcome measure that was aimed at overcoming the sort of limitations Dr. van Vollenhoven cited. It's defined as a reduction of all baseline BILAG grade A disease to grade B-D, and BILAG grade B to grade C or D, in all body systems; no BILAG worsening in other organ systems; no deterioration in SLEDAI or physicians' global disease activity assessments; and no increase in corticosteroids and/or immunosuppressive agents over baseline levels. Overall, the responder rate index was 43.2 for the 74 patients on a total of 2,400 mg of epratuzumab vs. 21.1 for those on placebo. Especially impressive were the epratuzumab-induced reductions in neuropsychiatric and cardiorespiratory symptoms of SLE, which are often particularly resistant to conventional therapies, observed Dr. Wallace of the University of California, Los Angeles.

“This is a very encouraging result from a relatively small first trial that needs to be confirmed,” Dr. van Vollenhoven said. “The size of the treatment effect is pretty impressive. There was a strong positive effect for a total dose of 2,400 mg, but 3,600 mg was not effective. That's a little bit strange. I can't quite put my head around that.”

Dr. van Vollenhoven offered the following updates on the status of other major classes of biologic agents in terms of their prospects as SLE therapies:

Anti–interferon-alpha. High serum levels of interferon-alpha are present in SLE. It is produced by plasmacytoid dendritic cells in response to stimulation by immune complexes. Several companies currently have anti–interferon-alpha agents in clinical trials for SLE. The key issue will be safety: Interferon-alpha plays key roles in viral immunity and tumor defenses, Dr. van Vollenhoven noted.

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