Belimumab: Novel biologic DMARD for the treatment of systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, the underlying cause of which is not fully known. Recently, biologic disease-modifying anti-rheumatic drugs (DMARDs) have started to be considered for the treatment of SLE due to their improved tolerability profiles compared with conventional therapies. This report profiles belimumab, a novel biologic DMARD, which has been approved for use in the treatment of certain patients with SLE.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. The underlying cause is yet to be fully elucidated. It appears clinically as a heterogeneous disorder, with disease activity ranging from indolent to fulminant and a variable course of symptom flares and remission. [PubMed Health. Systemic lupus erythematosus. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001471/] The classic presentation consists of fever, joint pain and rash, typically in women of childbearing age. Fatigue is also an almost universal symptom. Other manifestations include arthritis (although rarely erosive or deforming), malar rash, photosensitivity, renal disease, neuropsychiatric disorders, pleuritis, gastrointestinal symptoms, pericarditis, stroke, anemia and thrombocytopenia. [Ther Clin Risk Manag 2012;8:33-43; BMJ Open 2013;3:e002852] SLE can be both debilitating and life-threatening, hence can significantly impair quality of life. Because it can compromise major organs including brain, heart, lungs and kidneys, SLE is associated with one of the highest rates of mortality among autoimmune diseases. [Pharmacy Therapeutics 2012;37:212-26]
Symptom control and suppression of disease activity are the goals of treatment for SLE. The European League Against Rheumatism (EULAR) recommends that glucocorticoids and antimalarial agents be used in patients with SLE and no major organ involvement. [Ann Rheum Dis 2008;67:195-205] Non-steroidal anti-inflammatory drugs should only be used short term and in those patients with a low risk of complications due to these agents. In those who do not respond to steroids at long-term maintenance doses or those experiencing a disease flare, immunosuppressive agents may be considered. [Ann Rheum Dis 2010;69:1269-1274] It should be noted however, that many of the drugs used to treat lupus are ‘off-label’, that is, without regulatory approval for an SLE indication.
More recently, biologic disease-modifying anti-rheumatic drugs (DMARDs) have started to be considered for SLE. There is a strong rationale for their development given the side effect profile of current therapies (which includes weight gain, hypertension, increased susceptibility to infection and osteoporosis for corticosteroids and increased infection risk, malignancy and infertility for immunosuppressants). Some patients with refractory disease require prolonged high-dose corticosteroids and/or long-term immunosuppression to maintain remission. In an attempt to avoid this unfavorable risk–benefit profile, several biologic DMARDs have been explored for the treatment of SLE. The existing DMARDs that inhibit tumor necrosis factor (TNF) were not viable options since these drugs are known to induce SLE. One DMARD that has been explored is rituximab – a monoclonal antibody that reacts with the CD20 antigen expressed on B lymphocytes. This drug has been shown to be effective for rheumatoid arthritis, however results have been mixed in SLE. While some small uncontrolled trials and case series suggested that rituximab may be effective and steroid-sparing in severe, refractory SLE, an exploratory phase II/III study found no difference between rituximab and placebo. [Lupus 2009;18:767-76, Arthritis Rheum 2010;62:222-233] In contrast, the clinical trial program for belimumab – an IgG1 monoclonal antibody that inhibits the activity of the soluble cytokine BLyS (B lymphocyte stimulator) – has demonstrated efficacy and resulted in the first regulatory approval of a biologic DMARD for SLE.
Pharmacology and pharmacokinetics
The pathogenesis of SLE involves a complex interplay of activation and dysregulation of the innate and adaptive immune responses. B lymphocytes play a central role in the disease, primarily by producing autoantibodies but also by producing cytokines and presenting antigens to T cells. One of the key players in the process is BLys, also known as B cell activating factor (BAFF). BLyS is a member of the TNF family of cytokines and plays a crucial role in B cell selection, maturation and survival. [Ther Adv Chronic Dis 2012;3:11-23] Belimumab binds to soluble BLys, thereby inhibiting the survival and differentiation of B cells. [Ann Rheum Dis 2008;67:195-205] Phase I dose-ranging studies of belimumab showed that it has a terminal half-life of 19-20 days, a small volume of distribution and slow clearance rate. [BMJ Open 2013; 3: e002852]
The feasibility and safety of belimumab therapy for SLE was demonstrated by a 12-week, phase I, double-blind, randomized, placebo-controlled study (n=70) which showed no difference in the rate of adverse events and reductions in peripheral B cell levels (although this study was not designed to test efficacy). [Arthritis Res Ther 2008;10:R109] Belimumab was then tested in a larger cohort of patients with SLE (n=449) in a 52-week, phase II, double-blind, randomized, placebo-controlled study on a background of standard care – that is, a stable regimen of steroids, antimalarials, or other immunosuppressants for 60 days prior to the first belimumab infusion. This investigation failed to show any significant improvement in the primary endpoints of disease activity at week 24 and time to first SLE flare over 52 weeks. [Arthritis Rheum 2009;61:1168-1178] However in a post-hoc analysis of the subgroup of patients with serologically active disease at study entry (n=321) did show a significant improvement in several secondary endpoints with belimumab. [Arthritis Rheum 2009;60(Suppl. 10):1149]
Investigation of belimumab for SLE then moved into phase III, with two multicenter, randomized, double-blind trials; Belimumab In Subjects with Systemic lupus erythematosus (BLISS-52 and BLISS-76). Patients enrolled had relatively high disease activity (SELENA–SLEDAI score ≥6) and were seropositive with anti-nuclear antibodies (ANAs) and/or antibodies to double-stranded DNA (dsDNA) detected at two independent time points. Treatment consisted of belimumab 1 mg/kg or 10 mg/kg for 52 weeks or placebo for 76 weeks. In the BLISS-52 study at 52 weeks (n=865), active treatment at 10 mg/kg was associated with disease activity reduction in a significantly greater proportion of patients compared with placebo (58 percent vs 44 percent, respectively; p<0.001). Belimumab was also associated with a significant improvement in physician’s global assessment scores at week 24 relative to placebo (–7.07 vs –14.3, p≤0.05). [Lancet 2011;377:721-731] Similarly, in the BLISS-76 study (n=819), the proportion of patients with significantly reduced disease activity was also greater with belimumab 10 mg/kg compared with placebo at 52 weeks (43 percent vs 34 percent, p=0.021). [Arthritis Rheum 2010;62(Suppl. 10):1454] A combined analysis of data from the BLISS-52 and BLISS-76 trials concluded that the evidence suggests belimumab is clinically effective for SLE, however differences in the trial populations limit the generalizability of these results. [Pharmacy Therapeutics 2012;37:212-226] This is reflected in the narrower approved indication in Europe, where it is restricted to SLE patients with a high degree of disease activity as evidenced by the presence of anti-dsDNA antibodies and low complement levels despite standard therapy. In contrast, the FDA-approved indication is broader, namely, patients with autoantibody-positive SLE. [Pharmacy Therapeutics 2012;37:212-226]
The most commonly reported AEs in clinical trials with 10 mg/kg of belimumab were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, extremity pain, depression, migraine and pharyngitis. Serious infections (most commonly upper respiratory infections) occurred in 6 percent of patients receiving belimumab compared with 5.2 percent of those in the placebo arm.
The recommended dosage regimen for belimumab is 10 mg/kg at 2-week intervals for the first three doses and at 4-week intervals thereafter. It is administered as an intravenous infusion over a period of 1 hour. Consideration should be given to coadministration of premedication for prophylaxis against infusion reactions and hypersensitivity reactions. [Belimumab Prescribing Information]