Key points

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple organ systems and whose hallmark is the production of autoantibodies. A diagnosis of SLE relies on the American College of Rheumatology (ACR) criteria; the presence of 4 out of 11 criteria is diagnostic. About 300,000 to 4 million people suffer from SLE in the United States. Two recent studies based on population data sponsored by the Centers for Disease Control and Prevention and local state health departments calculated a prevalence of 73 cases per 100,000. SLE treatments that include antimalarials, nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), cytotoxics, and immune suppressants improve disease activity in SLE patients but put patients at risk for long-term sequelae of low level, active SLE as well as potential serious side effects from the medications. In addition, some patients still develop flares despite what seems to be optimal treatment, and these flares may contribute to the need for increased CS use and subsequent long-term damage. Therefore, there continues to be a need for new therapeutic options, more effective and safer therapies for SLE.

Normally, B cells play an essential role in maintaining a functional immune system: they produce antibodies, serve as antigen-presenting cells, and secrete proinflammatory cytokines in response to foreign antigens. In the pathogenesis of SLE, however, an increasingly large proportion of B cells fail to distinguish foreign and self-antigens and produce antibodies that target self-antigens, leading to an overreactive immune response. B-lymphocyte stimulator (BLyS), a proliferation and survival factor of B cells, is also known as the B-cell activating factor (BAFF). Studies showed an association between BLyS and SLE. SLE patients had significantly greater levels of plasma soluble BLyS than healthy controls or patients with rheumatoid arthritis; circulating BLyS levels were also found to correlate with SLE disease activity measured by the Selena SLEDAI (SS) score. These studies suggested that BLyS is a valid treatment target in SLE.

Belimumab (Benlysta) is a human recombinant monoclonal antibody that targets and inhibits soluble BLyS. The binding between belimumab and BLyS prevents the latter from attaching to its receptor on B cells, leading to apoptosis and reduction of circulating B-cell clones. This BLyS–anti-BlyS structure is subsequently cleared by the immune system. BLyS clinical trials showed that belimumab plus standard SLE treatment reduces peripheral B-cell levels and improves disease activity in some SLE patients. Based on data released to investors by GlaxoSmithKline (GSK), more than 15,000 patients have received at least one infusion of belimumab in the United States. Considering the approximate number of lupus patients to be 300,000, it follows that about 5% of all lupus patients are treated with belimumab. Belimumab treatment is not appropriate for patients with mild SLE; the percentage of belimumab-treated lupus patients among those who would benefit from such treatment can be estimated to be higher.

To further understand the clinical application of belimumab in treating SLE, this article discusses the registration studies and post-marketing experiences and the clinical outcomes of belimumab treatment.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multiple organ systems and whose hallmark is the production of autoantibodies. A diagnosis of SLE relies on the American College of Rheumatology (ACR) criteria; the presence of 4 out of 11 criteria is diagnostic. About 300,000 to 4 million people suffer from SLE in the United States. Two recent studies based on population data sponsored by the Centers for Disease Control and Prevention and local state health departments calculated a prevalence of 73 cases per 100,000. SLE treatments that include antimalarials, nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), cytotoxics, and immune suppressants improve disease activity in SLE patients but put patients at risk for long-term sequelae of low level, active SLE as well as potential serious side effects from the medications. In addition, some patients still develop flares despite what seems to be optimal treatment, and these flares may contribute to the need for increased CS use and subsequent long-term damage. Therefore, there continues to be a need for new therapeutic options, more effective and safer therapies for SLE.

Normally, B cells play an essential role in maintaining a functional immune system: they produce antibodies, serve as antigen-presenting cells, and secrete proinflammatory cytokines in response to foreign antigens. In the pathogenesis of SLE, however, an increasingly large proportion of B cells fail to distinguish foreign and self-antigens and produce antibodies that target self-antigens, leading to an overreactive immune response. B-lymphocyte stimulator (BLyS), a proliferation and survival factor of B cells, is also known as the B-cell activating factor (BAFF). Studies showed an association between BLyS and SLE. SLE patients had significantly greater levels of plasma soluble BLyS than healthy controls or patients with rheumatoid arthritis; circulating BLyS levels were also found to correlate with SLE disease activity measured by the Selena SLEDAI (SS) score. These studies suggested that BLyS is a valid treatment target in SLE.

Belimumab (Benlysta) is a human recombinant monoclonal antibody that targets and inhibits soluble BLyS. The binding between belimumab and BLyS prevents the latter from attaching to its receptor on B cells, leading to apoptosis and reduction of circulating B-cell clones. This BLyS–anti-BlyS structure is subsequently cleared by the immune system. BLyS clinical trials showed that belimumab plus standard SLE treatment reduces peripheral B-cell levels and improves disease activity in some SLE patients. Based on data released to investors by GlaxoSmithKline (GSK), more than 15,000 patients have received at least one infusion of belimumab in the United States. Considering the approximate number of lupus patients to be 300,000, it follows that about 5% of all lupus patients are treated with belimumab. Belimumab treatment is not appropriate for patients with mild SLE; the percentage of belimumab-treated lupus patients among those who would benefit from such treatment can be estimated to be higher.

To further understand the clinical application of belimumab in treating SLE, this article discusses the registration studies and post-marketing experiences and the clinical outcomes of belimumab treatment.

Registration studies

To evaluate the safety and biologic activity of belimumab, a randomized, multicenter, double-blind, placebo-controlled study (phase I) was conducted in 70 patients with stable mild/moderate SLE disease activity for at least 2 months before screening, with measurable SLE-related autoantibodies, and on a stable treatment regimen of immunosuppressant, antimalarials, NSAIDS, and low-dose CS (≤15 mg prednisone). Four escalating doses of intravenous belimumab (1.0, 4.0, 10, or 20 mg/kg) plus standard of care (SOC) were tested and compared with placebo in 8 cohorts. Cohorts1 to 4 received one single infusion of placebo or belimumab, whereas Cohorts 5 to 8 received 2 identical infusions of placebo or belimumab with the second one administrated after 3 weeks of receiving the first dose. Of the 70 patients, 13 received placebo and 57 received belimumab. Data on adverse events (AEs)/serious AEs, SLE disease activity, hematologic changes, serum belimumab concentrations, and peripheral B-cell counts were evaluated at 84 days and 105 days after the last infusion. Both the placebo and belimumab groups had similar incidence of AEs. Belimumab-treated patients in single- and double-dose cohorts had a significant reduction of peripheral B cells and reduced serum immunoglobulin level, compared with the placebo group. These data suggested that belimumab was well tolerated and effectively reduced peripheral B-cell counts in patients with SLE.

To further evaluate the safety and efficacy of adding belimumab to SOC, a double-blind, placebo-controlled, randomized, dose-ranging study (phase II) was conducted in 449 patients with active SLE. Patients had to have a diagnosis of SLE based on the following ACR criteria: an SS score greater than or equal to 4 at screening, a history of measurable SLE-related autoantibodies, and a stable treatment regimen of immunosuppressant, antimalarials, NSAIDs, and/or CSs. Eligible patients were stratified based on their screening SS score (4–7 vs 8). In addition to SOC SLE medications, patients received infusions of 1, 4, or 10 mg/kg belimumab or placebo at days 0, 14, and 28, and every 28 days thereafter for 52 weeks. Data on Physician Global Assessment (PGA), SS scores, the SELENA-SLEDAI flare index (SFI), British Isles Lupus Assessment Group index (BILAG), and hematological and immunologic variables were collected and compared between baseline, week 24 and 52. The change in the SS score by week 24 and time to first flare during the study period were the 2 primary endpoints, whereas the changes in SS and BILAG scores between week 24 and 52, CS doses, and immunologic parameters were secondary endpoints.

The changes in SS scores, in a dose-independent manner across belimumab treatment groups, were similar between placebo and individual treatment groups at 24 and 52 weeks. Although no significant difference was observed in the time to first flare over the study duration, the time to first flare and the rate of severe flares during 24 to 52 weeks differed significantly between the treatment and placebo groups (154 vs 108 days; 12 vs 17%, respectively). Also, belimumab treatment groups had a significant reduction in prednisone dose (−19.9%) between 38 and 52 weeks when compared with the placebo group (−11.7%), especially in patients who received 10 mg/kg belimumab (−40.5%). Starting at week 4, significant improvement in PGA scores was noted in all treatment groups (−31%) compared with the placebo group (−14%), with the most improvement observed in the 10 mg/kg belimumab group. The belimumab and placebo groups had similar rates of AEs. Despite the fact that the primary endpoints were not met, these results supported the biologic activity and safety of belimumab and allowed for a better understanding of the pharmacodynamics of belimumab, SLE disease activity, and clinical trial design. The modifications to study design suggested by these groups include the following: (1) despite the early improvements in B-cell, PGA score reduction suggested that a longer study period was needed for clinical benefits to be reflected in SS and SFI scores; (2) it was noted that 71.5% of the cohort had a positive antinuclear antibodies and/or dsDNA at baseline, and a subset analysis showed that serologically active patients responded to belimumab more effectively than serologically negative patients; (3) changes in concomitant medications could also confound the efficacy of belimumab; (4) given the heterogeneity of SLE, the use of dichotomous measures such as the SS and BILAG was not able to fully capture the partial changes in disease activity. Based on data from the earlier trial, the SLE Responder Index (SRI), a novel outcome measure, was developed to better assess the efficacy of belimumab in SLE patients. The SRI was defined as a combination of a minimum 4 points reduction in SS score, either no new BILAG A or 2 new BILAG Bs, and a maximum 0.3 point increase in PGA score from baseline.

To understand the long-term effects of belimumab on B cells, 21 patients from this clinical trial enrolled in a substudy and received their previous dose or 10 mg/kg of belimumab plus SOC every 28 days for 80 weeks. Patients could subsequently roll over into an open-label mechanistic extension study and receive 10 mg/kg belimumab. Blood samples were collected on days 0, 84, 168, and every 180 days thereafter; data on 17 patients were available for analysis. This extension study further confirmed the critical role of BLyS in B-cell survival and that belimumab reduced circulating naïve B cells.

The long-term safety and efficacy data were recently evaluated in 296 patients who entered the phase II continuation study over 7 years. Of 177 patients who remained in the study after 7 years, 135 initially had positive serologies. Patients had sustained improvement in disease activity, decreased flares, and reductions in autoantibodies and CSs, indicating stable efficacy over time. Seven deaths were observed with no cause predominating. The safety of long-term belimumab treatment was reassuring and similar to the safety profile reported in the same cohort at the 4-year follow-up.

BLISS-52 and BLISS-76 were 2 multicenter, randomized, placebo-controlled, clinical trials conducted in different geographic sites to assess the safety and efficacy of belimumab plus SOC in patients with active SLE (phase III). To participate in the studies, patients had to be seropositive at screening and baseline, receive a stable SLE treatment regimen, meet at least 4 of the 11 ACR criteria, and have an SS score greater than or equal to 6 at screening. In addition to SOC, both studies randomized patients to receive infusions of 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo on days 0, 14, 28, and every 28 days thereafter. The primary efficacy endpoint was the change from baseline in SRI at 52 weeks. Secondary endpoints included a minimum 4 points reduction in SS score at 52 weeks, improvements in PGA and Short Form-36 at 24 weeks, and tapering in prednisone dose by at least 25% from baseline and to less than or equal to 7.5 mg/d during 40 to 52 weeks. Differences between groups were noted starting at week 16 in the 10 mg/kg belimumab group and week 38 in the 1 mg/kg group.

Eight hundred sixty-seven patients from Eastern Europe, Asia, and Latin America were enrolled in BLISS-52 and received SOC plus belimumab or placebo for 52 weeks. The primary endpoint of the study was met: both the 1 mg/kg (51%) and 10 mg/kg (58%) belimumab groups had significantly higher SRI response rates than the placebo group (44%) at 52 weeks. BLISS-76 included 819 patients from the Europe and North America, who were followed for 76 weeks. This study also met its primary endpoint: both the 1 mg/kg (40.6%) and10 mg/kg (43.2%) belimumab groups had higher percent responders than the placebo group (33.5%), with the only latter being statistically significant at 52 weeks. Exploratory endpoints analysis in BLISS-52 and BLIS-76 showed that both belimumab plus SOC treatment groups had significantly reduced rate of disease flares, increased time to the first flare, no worsening in PGA scores, tapered prednisone dose, and decreased serologic activity when compared with the placebo (SOC) group. Based on the data collected from these 2 clinical trials, it was suggested that patients with greater disease activity, lower complement, higher anti-dsDNA levels and current prednisone use have greater therapeutic benefits from belimumab treatment. Overall, these 2 clinical trials confirmed the safety and efficacy of belimumab in treating SLE. No significant differences in safety signals were noted between the groups.