Investigative B-Cell Inhibitor Shows Benefit in Systemic Lupus Erythematosus

Paula Moyer, MA

June 18, 2007

June 18, 2007 (Barcelona) — Patients with systemic lupus erythematosus (SLE) show a response in key measurements of disease activity when treated with belimumab ( LymphoStat-B, Human Genome Sciences), according to a team of investigators who presented their findings here at the annual meeting of the European Congress of Rheumatology (EULAR).

"This study showed that treatment with belimumab resulted in sustained improvement in SLE symptoms in patients with serologically active disease," said principal investigator Ellen Ginzler, MD, professor of medicine and chief of rheumatology at State University of New York (SUNY) Downstate, in New York City, in a presentation. "We also confirmed that combining multiple disease-activity measures is a successful way to assess disease activity."

The investigators conducted the study because the heterogeneity of SLE disease manifestations makes it difficult to use a single index to adequately assess whether patients are having a therapeutic response to a treatment in SLE clinical trials. Therefore, in a phase 2 study, they used a new combined responder index to assess whether patients responded to belimumab. Belimumab is an inhibitor of soluble B-lymphocyte stimulator.

The study involved 449 SLE subjects with screenings of at least 4 in the Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA) and the SLE Disease Activity Index (SLEDAI). The 52-week, randomized, double-blind, placebo-controlled trial compared the effects of adding belimumab or placebo to SLE standard-of-care therapy. The patients received belimumab at doses of 1, 4, or 10 mg/kg.

The investigators conducted a separate evaluation of the patients who had baseline serologic activity, defined as an antinuclear antibody level of at least 1:80 or anti-double-stranded (ds)DNA antibodies of at least 30 IU. Using this definition, 71.5% of the original cohort had baseline serologic activity. The investigators evaluated these patients for changes in biomarkers and in several assessments: the SELENA SLEDAI, the Physician's Global Assessment (PGA, 0 to 3 units), the British Isles Lupus Assessment Group (BILAG) scale, and the Health Questionnaire Short Form 36 (SF-36). They then developed a combined end point that incorporated a response parameter and controls against worsening in other organ systems.

At baseline, the patients had an average SELENA SLEDAI score of 9.6. At that time, 68% of subjects had at least 1 BILAG or 2 organ-system scores. Among patients in the belimumab group, the average reduction in the SELENA SLEDAI was 29%, compared with placebo ( P = .044) at week 52; the reduction was an average of 38% at week 76.

There were also significant improvements in the PGA and SF-36 scores, according the investigators ( P = .001 and P < .02, respectively). At week 52, the investigators found that significantly more belimumab-treated subjects had improvements on both the SELENA SLEDAI and PGA scores than did those on placebo ( P < .05). At that point, the investigators' assessments of BILAG 3 results showed that those on treatment had fewer shifts to worse scores on the musculosekeletal ( P < .008), neurological ( P < .038), and cardiovascular-respiratory system subscales ( P = .060). They also had fewer new BILAG 1A or 2B flares ( P < .015).

The combined response analysis defined a response as an improvement of at least 4 on the SELENA SLEDAI score with no new BILAG 1A or 2B flares and no PGA worsening, which consisted of less than a 0.3-point increase. The investigators observed this effect in 46% of those on belimumab and 29% of those on placebo ( P = .006). By week 76, 56% of those on belimumab were considered responders. The analysis showed that responders had a 36%reduction in activated B-cells, compared with a 20% reduction among nonresponders ( P < .05), and that anti-dsDNA was lowered by 53% in responders and 38% in nonresponders ( P < .05). Responders also had an average improvement of 4.1 on the SF-36 physical functioning subscale at week 52, compared with an average increase of 1.0 point among nonresponders ( P < 0.001).

"This is a large study that involved a combined responder index for the first time in lupus," said Dimitrios Boumpas, MD, professor of medicine at the University of Crete, in Heraklion, Greece, in an interview with Medscape. "The investigators were able to use this approach to confirm previous observations that inhibition of B cells can improve outcomes in lupus." Dr. Boumpas chaired the committee that recently developed the European Guidelines for the Management of SLE.

"Clinicians need to know that the effects were significant but modest," he said. "It was not a dramatic effect. In spite of this limitation, the study is useful because it opens the possibility for more treatments for lupus, and a drug like this could perhaps be combined with other treatments for even greater results."

The study was funded jointly by GlaxoSmithKline and Human Genome Sciences, which collaborated in the development of LympoStat-B. Dr. Ginzler reported no relevant financial relationships.

EULAR 2007: Abstract OP0018. Presented June 14, 2007.

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