More on the anti-BLyS approach: Belimumab in RA

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More on the anti-BLyS approach: Belimumab in RA



Dec 2, 2005



Zosia Chustecka



San Diego, CA - Progress with the development of belimumab

(LymphoStat-B, Human Genome Sciences) is being followed with some

interest, as the drug offers a novel approach to the treatment of

autoimmune disease, pioneering a route that focuses on B-lymphocyte

stimulator BLyS (also known as BAFF). Successful completion of a

phase 2 trial in rheumatoid arthritis (RA) was reported earlier this

year, but details of the results were presented for the first time at

the 2005 ACR/ARHP Annual Scientific Meeting [1].

Efficacy in RA

The phase 2 study in RA was conducted in 283 patients with active

moderate-to-severe disease who had failed prior treatment; on

average, participants had failed 2.2 disease-modifying antirheumatic

drugs (DMARDs), and 38% had failed at least one TNF inhibitor.

Patients continued with current therapy, receiving up to two DMARDS

(but no biologics) and/or 10-mg/day prednisolone; the majority (73%)

of participants were on background methotrexate.

Belimumab was administered intravenously on day 0, 14, and 28 and

then every 28 days for 24 weeks. Three doses (1, 4, and 10 mg/kg)

were compared with placebo. The primary efficacy end point was the

ACR20 response at 24 weeks, and a significant result was seen with

the lowest dose: 35% patients on 1 mg/kg compared with 16% on placebo

(p=0.0097). The other two doses showed a trend toward benefit but did

not reach significance, and there was no dose-response relationship.

A subgroup analysis found no improvement in patients who were

rheumatoid factor negative (RF-) or in those who had previously been

treated with anti-TNF products. The study is continuing in an

extension phase.

These results show that the drug is safe and well tolerated and that

it has a statistically significant beneficial effect on reducing RA

activity, warranting further studies for this indication. In a

company press release, lead investigator Dr McKay (Oklahoma

State University, Tulsa) says these data support additional studies

in RA. Dr Stump, Human Genome Sciences executive vice president

of drug development, commented, " The relatively low placebo response

rate suggests this was a somewhat refractory population to treat. "

However, several RA experts have commented that the efficacy observed

was rather modest, and in view of the fact that there are very

effective drugs for RA already available, some are wondering how

clinically useful this anti-BLyS approach will turn out to be. The

cynics also point to the recently announced less-than-successful

phase 2 trial in lupus. Belimumab missed its primary end point in

that trial, but the company says the drug showed " substantial

evidence of clinical activity, " and so further development in this

indication is still under consideration, as previously reported by

rheumawire.

But Dr Matteson (Mayo Clinic, Rochester, MN), who acts as an

editorial consultant to jointandbone.org, points out that belimumab

demonstrated clinical efficacy in a group of patients with very

active disease and the results by ACR20-response criteria are similar

to that seen in trials with other biologic agents. " While some see

the effect as modest, the safety profile of the drug was excellent,

and it may well find a place in the therapeutic armamentarium for

management of rheumatoid arthritis and related conditions if further

studies demonstrate a consistent and significant pattern of

efficacy, " he tells rheumawire.

Another presentation at the ACR meeting, based on blood samples taken

from participants in the above trial, showed the effect that

belimumab was having an effect on B-cell populations [2]. Results for

all participants taking the drug (all dosage groups combined) show a

reduction of 20% or more in CD20+, CD19+, naïve B cells, and

activated B cells compared with placebo. No change was seen in plasma

B cells, and an increase was seen in memory B cells by day 28, which

persisted through week 24. No dose response was observed with these

changes in B-cell levels. There was also a modest reduction in

immunoglobulins. The company notes that elevated serum levels of BLyS

at baseline modestly but significantly correlated with the severity

of disease activity and with elevated levels of rheumatoid factor and

inflammatory markers, suggesting a role for BLyS in the pathogenesis

of RA.

Belimumab was created through a collaboration with Cambridge Antibody

Technology, after the discovery of BlyS by Human Genome Sciences. It

is being developed under a deal with GlaxoKline, which has an

agreement to share equally phase 3/4 trials and then sales and

marketing.







Sources



McKay J, Chwalinska-Sadowska H, Boling E, et al. Belimumab, a fully

human monoclonal antibody to B-lymphocyte stimulator (BLyS), combined

with standard care of therapy reduces the signs and symptoms of

rheumatoid arthritis in a heterogeneous subject population. 2005 ACR/

ARHP Annual Scientific Meeting; Nov. 12-17, 2005; San Diego, CA.

Abstract 1920.

Stohl W, Chatham W, Weisman M, et al. Belimumab, a novel fully human

monoclonal antibody to B-lymphocyte stimulator (BLyS), selectively

modulates B-cell subpopulations and immunoglobulins in a

heterogeneous rheumatoid arthritis subject population. 2005 ACR/ARHP

Annual Scientific Meeting; Nov. 12-17, 2005; San Diego, CA. Abstract

1160.