Belimumab (Lymphostat-Bâ„¢) is safe, biologically active, and at least somewhat effective for patients with rheumatoid arthritis (RA), but the magnitude of its effect may not portend a bright future for the novel anti-BlyS agent, according to the results of a dose-ranging study¹ presented at the 69th Annual Meeting of the American College of Rheumatology in San Diego, California.

With only modest ACR 20 responses at 24 weeks, the results were not deemed impressive by two prominent rheumatologists. Taken together with the agent's failure to meet its primary endpoint in a recent lupus trial, the future of belimumab may be in doubt.

"There was a very modest clinical response, and [the new agent] didn't drop B-cells too much," asserts Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas. "I would think anti-BlyS is not very effective in RA."

Lowest dose most effective?

At week 24, study participants taking 1 mg/kg, the lowest dose of belimumab, were twice as likely to achieve ACR 20 responses compared to those randomly assigned to receive placebo (35% versus 16%, respectively), the study showed. Also, the primary efficacy endpoint of ACR 20 was higher in all treatment groups compared with placebo, with 29% and 16% of patients in all active treatment and placebo groups, respectively, achieving an ACR 20 response at week 24.

"Although the RA results were statistically significant at the 1-mg dose, they were not very dramatic," contends Dr. Fleischmann, who presented data on the rival B-cell-depleting agent rituximab (Rituxan®) at the ACR meeting.

The study researchers, however, disagree with the negative assessment. "Dr. Fleischmann's point regarding the dosage is not valid, as this is the first trial in this population, and it is really a dose-ranging trial," says lead researcher James McKay, DO, a clinical associate professor of medicine at Oklahoma State University Center for Health Science in Tulsa, Oklahoma. "We were trying to determine which was the safest and most effective dose," he tells CIAOMed. "I think [belimumab] has tremendous potential. This is very early on in the drug development, and we are seeing favorable signals."

Dr. Fleishmann stands by his analysis. "If it filled all the receptors and only 29% achieved ACR 20 at 24 weeks and it only reduced B cells by 20% to 30% and RF [rheumatoid factor] by 20% to 30%, why would they think this drug is valuable going forward?" he asks. While he acknowledges that belimumab may have value in diseases other than RA, "if it takes longer than 24 weeks to fully work, how effective is it going to be? Every other drug works within a matter of days to weeks."

Compared with rituximab, belimumab's approach to depleting B cells is milder, Dr. McKay explains. As such, "the time to maximal effects may take longer," he says. "We are used to drugs working quickly, like the TNF inhibitors. I think this drug has a gentle, gradual response over time, so I think we need more data and I don't think we should give up at all."

A fully human monoclonal antibody, belimumab inhibits BlyS, a member of the tumor necrosis factor ligand superfamily. In the new 24-week randomized, double-blind superiority trial, RA patients were randomly assigned to receive either belimumab at 1, 4, or 10 mg/kg or placebo intravenously via a 2-hour infusion on days 0, 14, and 28, and then every 28 days through 24 weeks.

The study population comprised 283 disease-modifying antirheumatic drugs (DMARDs) and biologics-experienced subjects who had failed >1 DMARD with active RA. Approximately 38% of study participants had failed at least one tumor necrosis factor-alpha (TNF-α) inhibitor.

Patients in the study had longstanding disease of at least 10 years and more than 80% were rheumatoid factor (RF) positive. Study patients had >6 swollen joints and >8 tender joints, and were receiving stable standard of care therapy consisting of concomitant 0 to 2 DMARDs, excluding biologics, plus nonsteroidal anti-inflammatory drugs (NSAIDs) and/or prednisone <10 mg/day. Approximately 73% of study participants were receiving background methotrexate (MTX) therapy.

Compound is biologically active

Belimumab demonstrated biological activity by significantly reducing RF from weeks 4 through 24 (P <.001), and all participants who received the study drug also exhibited a significant reduction in CD20+ cells from baseline at weeks 20 through 24, compared to participants taking placebo, according to the study.

Eric Matteson, MD, a professor of medicine at the Mayo Clinic in Rochester, Minnesota, says he agrees with Dr. Fleischmann that the RA trial results are disappointing. "It's biologically active and CD 20 counts go down, and it's also active against the signs and symptoms of RA, but the effect is modest compared to other agents being used in similar groups of patients," he tells CIAOMed. "It shows promise, but there are open questions about whether the magnitude of the therapeutic efficacy is going to carry this drug any further."

Subgroup analysis highlights specific patients who may benefit most

A subgroup analysis showed that a statistically significant improvement versus placebo in the 24-week ACR 20 response was observed at the 1-mg/kg dose of belimumab in patients who were RF-positive at baseline; had a baseline DAS28 score >5.1; were anti-TNF-α-naÏŠve; had previously failed MTX therapy; and were receiving concomitant MTX therapy during the phase II study.

A statistically significant improvement versus placebo in the 24-week ACR 20 response also was observed in all belimumab active-treatment groups in patients who were RF-positive at baseline; were anti-TNF-α-naÏŠve; had previously failed MTX therapy; and were receiving concomitant MTX therapy during the phase II study.

No improvement was observed in RF-negative subjects or in anti-TNF-α experienced subjects, according to the subgroup analysis.

Adverse events and laboratory abnormalities across all active and placebo arms of the current trial were similar. There were no significant differences in the incidence of severe, serious, or infection-related adverse events, the study showed. Sinusitis and pruritus were the only adverse events with significantly higher incidence in a single active-dose group versus placebo, and pneumonia was the only treatment-related serious adverse event. One death due to cardiac arrest occurred in the placebo group.

 "I think [belimumab] will also prove safer than rituximab," Dr. McKay says, adding that an optional extension protocol is ongoing.

As far as the safety of belimumab, "it's possible that it will be safer because it doesn't have any effect," Dr. Fleishmann tells CIAOMed. "If we had a drug that reduces 30% of B cells with the same efficacy as rituximab, one would be very interested in looking at it in terms of long-term safety and efficacy," he says. "The problem with belimumab in RA is that it doesn't appear to be that effective; I was hoping it was going to work."

Disappointing lupus study

The new findings come on the heels of a phase II clinical trial of belimumab in patients with systemic lupus erythematosus (SLE), which found that the new drug did not meet the overall primary efficacy endpoints of increasing the time to first SLE flare over 52 weeks or reducing the signs and symptoms of SLE at week 24, as assessed by validated measures of disease activity.

As far as the lupus data is concerned, Dr. McKay says the study is ongoing and the 1-year data looks good. He suggests that more time may be needed to see the full effects of belimumab in lupus as well as RA.

Reference

1. McKay J, Chwalinska-Sadowska H, Boling E, et al. Belimumab (BmAb), a fully human monoclonal antibody to B-lymphocyte stimulator (BLyS), combined with standard of care therapy reduces the signs and symptoms of rheumatoid arthritis in a heterogenous subject population. Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 1920.