Belimumab: A B-lymphocyte stimulator inhibitor for-systemic lupus erythematosus

April 1, 2011

Belimumab is a monoclonal antibody that inhibits B-lymphocyte stimulator that has been FDA approved for the treatment of systemic lupus erythematosus. It is the first new drug for the treatment of SLE approved in more than 50 years.

Key Points

Abstract

Belimumab is a monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS) that has been FDA approved for the treatment of systemic lupus erythematosus (SLE). It is the first new drug for the treatment of SLE approved in more than 50 years. Currently available treatment for SLE often involves symptomatic relief. Because belimumab modifies the proliferation of B cells, it has shown efficacy in reducing disease activity and flares in serologically active patients when combined with standard therapy versus placebo. In clinical trials, belimumab was administered by 2-hour continuous intravenous (IV) infusion every 2 weeks for the first month, then monthly thereafter. Current data indicate that belimumab does not increase the risk of infection, but additional long-term studies are needed. (Formulary. 2011;46:118,127–129.)

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by exacerbations and remissions.1 Patients most commonly experience a mixture of skin, musculoskeletal, hematologic, and serologic symptoms.1 Women are more commonly affected than men and the disease is primarily diagnosed in patients aged 15 to 45 years.1 Currently available therapies for SLE are usually given in response to symptoms within specific organ systems and include nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine, systematic corticosteroids, or methotrexate.2 T cells, B cells, and cytokines all have a role in SLE.3 The involvement of B cells in the clinical presentation of SLE suggests that they are a potential target for drug therapy.

CHEMISTRY AND PHARMACOLOGY

Proinflammatory cytokines (such as tumor necrosis factor-alpha, interleukin-6, and interleukin-10) and autoantibodies contribute to many of the symptoms of SLE.3 Autoantibodies are released by proliferating B cells, which have been stimulated by autoreactive T cells and the freely circulated BLyS, which is a cytokine in the tumor necrosis factor family.1 The overexpression of BLyS in patients with SLE is thought to contribute to the excessive B cell proliferation.3

Belimumab is a recombinant, fully human IgG monoclonal antibody that specifically recognizes and binds to soluble BLyS to inhibit its activity.5 By preventing BLyS from binding to B cell surfaces, the proliferation of B cells is halted and the B cells undergo apoptosis.5 This process then stops the production of autoantibodies, thereby decreasing the disease activity of SLE and the resulting symptoms.5

PHARMACOKINETICS

Belimumab exhibits linear pharmacokinetics upon IV administration over a dose range of 1 to 20 mg/kg.6 The peak plasma concentration is approximately 20 µg/mL per 1 mg/kg dose of belimumab.6 Clearance is approximately 7 mL/day per kg and the volume of distribution ranges from 69 to 112 mL/kg.6 The elimination half-life ranges from 8.5 to 14.1 days, and is not affected by renal function.6 The metabolism of belimumab is unknown. Belimumab pharmacokinetics have not been affected by the coadministration of immunosuppressants, hydroxychloroquine, or prednisone.6

CLINICAL TRIALS

Randomized, controlled clinical trials of belimumab have measured clinical outcomes with various SLE-specific measuring instruments and scales. The Safety of Estrogens in Lupus Erythematosus: National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) ranges from a score of 0 to 105, with 0 indicating inactive disease.7 The Physicians' Global Assessment (PGA) in SLE ranges from 0 to 3, with 0 indicating inactive disease.8 The SELENA-SLEDAI flare index incorporates the SELENA-SLEDAI score, assessment of new or worsening disease activity, medication changes, hospitalizations, and PGA score.9

The SELENA-SLEDAI flare index defines a mild to moderate flare as at least 1 of the following events:

A severe flare is defined by a change in at least 1 of the following:

The British Isles Lupus Activity Group (BILAG) is another type of scoring system, where each organ system is given an alphabetical score of A (most active), B (moderate activity), C (minor activity), D (stable), or E (never present).8 Major flares are classified by moves to A scores and minor flares by moves to B scores.9

Phase 2 clinical trial. A phase 2 randomized, double-blind, placebo controlled trial evaluated a range of belimumab doses in patients with SLE (n=476).8 Patients were eligible for enrollment if they were adults (aged ≥18 years) with active SLE defined by a SELENA-SLEDAI score ≥4; had a history of measurable autoantibodies; and were receiving a stable regimen of prednisone (5 to 40 mg/day), antimalarials, or immunosuppressive agents for at least 60 days prior to enrollment.8 Patients were randomly assigned to 1, 4, or 10 mg/kg belimumab or placebo by IV infusion over 2 hours on days 1, 14, and 28, then every 28 days for 52 weeks. Patients maintained their regular treatment regimens throughout the study.8

At 24 weeks there were no significant differences between any individual belimumab-treated group and placebo, or between belimumab treatment and placebo overall in terms of SELENA-SLEDAI score changes.8 There also were no significant differences between belimumab treatment and placebo on SELENA-SLEDAI score at 52 weeks.8

Significantly greater improvements were seen on PGA scores among belimumab-treated patients than in placebo-treated patients at 52 weeks (P=.0019).8 No differences were seen between belimumab- and placebo-treated patients in rates of mild/moderate or severe SLE flares at 24 or 52 weeks.8 The median time for first SLE flare was not significantly different between the belimumab and placebo groups at 52 weeks.8 Patients receiving belimumab had a significantly longer time to first SLE flare between 24 and 52 weeks than placebo patients (154 vs 108 days, P=.0361), suggesting that belimumab may have stabilized the disease.8

This phase 2 trial also evaluated outcomes in a serologically active subgroup (n=321) defined as having positive production of antinuclear autoantibodies (ANA).8 In this subgroup, belimumab-treated patients had greater reductions in SELENA-SLEDAI score than placebo-treated patients at week 52 (P=.0435).8 Belimumab-treated patients also exhibited greater improvements in PGA score versus placebo at 52 weeks (P=.0011).8 No significant differences were seen between belimumab and placebo in the number of SLE flares or time to first flare in this subgroup.8

Phase 3 clinical trials. Belimumab in Subjects With Systemic Lupus Erythematosus (BLISS)-52 was a phase 3 randomized, double-blind, placebo controlled trial comparing 2 doses of belimumab in patients with SLE (n= 865) for 52 weeks.10 Patients were eligible for enrollment if they had a baseline SELENA-SLEDAI score ≥6, were serologically active, and were receiving stable standard of care therapy for at least 30 days prior to study entry.10

BLISS-76 was a phase 3 randomized, double-blind, placebo-controlled trial comparing belimumab 1 mg/kg or 10 mg/kg in patients with SLE (n=819) for 76 weeks.11 Patients were all serologically active and receiving stable standard of care therapy.11 Patients were randomly assigned to receive belimumab or placebo in addition to their current regimens by IV infusion on days 0, 14, 28, and then every 28 days through week 72, with final evaluation at week 76.11

The primary end point was the SRI at week 52.11 Secondary end points included the SRI at week 76, proportion of patients with 4-point improvements in SELENA-SLEDAI score, and mean change in PGA.11 Only data from the SRI end points at week 52 and 76 have been reported. Belimumab 10 mg/kg resulted in better attainment of the SRI end point than placebo at week 52 (P=.017).11 There was no significant difference between belimumab 10 mg/kg and placebo in SRI at week 76.11 Belimumab 1 mg/kg versus placebo yielded no significant differences in SRI at either week 52 or week 76 (see Table 1).11

ADVERSE EVENTS

In the phase 2 dose-ranging trial, rates of adverse events were similar between groups.8 Urticaria was statistically more frequent in belimumab-treated patients versus placebo-treated patients (4% vs 0%).8 Infection rates were not significantly different between belimumab and placebo groups (75.6% vs 72.6%, respectively).8

In the phase 3 trials, rates of overall adverse events, infections, or discontinuations due to adverse events were not statistically different between groups.10,11 In BLISS-52, there were more cases of diarrhea in the belimumab groups (9.7% for 1 mg/kg, 10.3% for 10 mg/kg, 7.0% for placebo).10 In BLISS-76, 7 cases of malignancy were reported; 4, 2, and 1 in the belimumab 1 mg/kg, belimumab 10 mg/kg, and placebo groups, respectively.11 Details about the types of malignancy have not yet been reported. No cases of malignancy were reported in BLISS-52.9 In both phase 3 trials, a total of 12 deaths were reported; 4, 5, and 3 deaths in the belimumab 1 mg/kg, belimumab 10 mg/kg, and placebo groups, respectively.10,11 Nine of the deaths were in the BLISS-52 trial; 2, 4, and 3 deaths in the belimumab 1 mg/kg, belimumab 10 mg/kg, and placebo groups respectively.10 Causes were only reported for a portion of the deaths in BLISS-52; three of the deaths in the belimumab groups were due to infections and one patient in the placebo group died of cardiac arrest following sepsis.10 Causes of death from BLISS-76 have not been reported.

DRUG INTERACTIONS

Currently, there is limited data available regarding potential drug interactions with belimumab. A phase 1 trial evaluated the use of belimumab concomitantly with other standard SLE therapies such as prednisone, antimalarials, NSAIDs, methotrexate, azathioprine, and mycophenolate mofetil and no changes in pharmacokinetic parameters were observed.6 However, an increased risk of infection when administered with other immunosuppressants cannot be ruled out.

DOSING AND ADMINISTRATION

Clinical trials have evaluated belimumab administered via IV continuous infusion over 2 hours.6,8,10,11 Patients were given doses at days 0, 14, and 28, and then every 28 days thereafter. Phase 3 trials evaluated 1 mg/kg and 10 mg/kg.10,11 The approved dose is 10 mg/kg at 2-week intervals for the first 3 weeks and at 4-week intervals. It is administered as an IV infusion only, over 1 hour. Patients should be monitored for anaphylaxis reaction.12 Belimumab is not renally eliminated, so it is unlikely that dosing adjustments are needed for patients with renal insufficiency.6 The necessity for dosage adjustment in patients with hepatic insufficiency is unknown at this time.

FORMULARY CONSIDERATIONS

Belimumab is the first in the class of BLyS inhibitors recently FDA approved for the treatment of adult patients with active, autoantibody-positive SLE, who are receiving standard therapy. In phase 3 randomized controlled trials, belimumab 10 mg/kg was superior to placebo when added to stable standard SLE therapy. No head-to-head trials comparing belimumab to other B-cell active monoclonal antibodies have been published. Patients generally tolerated belimumab well, with urticaria being more commonly reported compared with placebo in phase 2 trials. Clinical trials show no increases in infection rates with belimumab treatment, but long-term studies may be necessary to detect its downstream impact on infection rate.

The wholesale acquisition cost of a 120-mg vial of belimumab is $443, and for a 400-mg vial, it is $1,477. In serologically active SLE patients already taking the standard treatment regimen, belimumab may be an add-on option that may reduce disease activity and prevent flares. Data are not yet available to identify any additional subgroups of patients who would derive the most benefit from belimumab therapy.

Dr. Phung is assistant professor of pharmacy practice at the Western University of Health Sciences College of Pharmacy, Pomona, Calif.

Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.

REFERENCES

1. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Arthritis Rheum. 2008;58:15-25.

2. Francis L, Peri A. Pharmacotherapy of systemic lupus erythematosus. Expert Opin Pharmacother. 2009;10:1481-1494.

3. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358:929-939.

4. FDA. FDA approves Benlysta to treat lupus. [press release]. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm246489.htm. Accessed March 25, 2011.

5. Zhang J, Roschke V, Baker KP, et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol. 2001;166:6-10.

6. Furie R, Stohl W, Ginzler EM, et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther. 2008;10:R109.

7. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005;353:2550-2558.

8. Wallace DJ, Stohl W, Furie RA. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61:1168-1178.

9. Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical trials. Lupus. 1999;8:685-691.

10. Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled, phase 3 trial. Lancet. 2011;377:721-731.

11. Van Vollenhoven RF, Zamani O, Wallace DJ, et al. Belimumab, a BLyS-specific inhibitor, reduces disease activity and severe flares in seropositive SLE patients: BLISS-76 study. Presented at: the European League Against Rheumatism Meeting; July 16-19, 2010; Rome, Italy. Abstract OP0068.

12. Benlysta [package insert]. Rockville, MD: Human Genome Sciences; 2011.

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