Chemical formula: C₆₇₁₄H₁₀₄₂₈O₂₁₀₂S₅₂
Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B Lymphocyte Stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab blocks the binding of soluble BLyS, a B cell survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.
BLyS levels are elevated in patients with SLE and other autoimmune diseases. There is an association between plasma BLyS levels and SLE disease activity. The relative contribution of BLyS levels to the pathophysiology of SLE is not fully understood.
Changes in biomarkers were seen in clinical trials with belimumab administered intravenously. In adult patients with SLE with hypergammaglobulinemia, normalization of IgG levels was observed by Week 52 in 49% and 20% of patients receiving belimumab and placebo, respectively.
In patients with SLE with anti-dsDNA antibodies, 16% of patients treated with belimumab converted to anti-dsDNA negative compared with 7% of the patients receiving placebo by Week 52.
In patients with SLE with low complement levels, normalization of C3 and C4 was observed by Week 52 in 38% and 44% of patients receiving belimumab and in 17% and 18% of patients receiving placebo, respectively.
Of the anti-phospholipid antibodies, only anti-cardiolipin antibody was measured. For anti-cardiolipin IgA antibody a 37% reduction at Week 52 was seen (p=0.0003), for anti-cardiolipin IgG antibody a 26% reduction at Week 52 was seen (p=0.0324) and for anti-cardiolipin IgM a 25% reduction was seen (p = NS, 0.46).
Changes in B cells (including naïve, memory and activated B cells, and plasma cells) and IgG levels occurring in patients with SLE during ongoing treatment with intravenous belimumab were followed in a long-term uncontrolled extension study. After 7 and a half years of treatment (including the 72-week parent study), a substantial and sustained decrease in various B cell subsets was observed leading to 87% median reduction in naïve B cells, 67% in memory B cells, 99% in activated B cells, and 92% median reduction in plasma cells after more than 7 years of treatment. After about 7 years, a 28% median reduction in IgG levels was observed, with 1.6% of subjects experiencing a decrease in IgG levels to below 400 mg/dL. Over the course of the study, the reported incidence of AEs generally remained stable or declined.
In patients with active lupus nephritis, following treatment with belimumab (10 mg/kg intravenously) or placebo, there was an increase in serum IgG levels which was associated with decreased proteinuria. Relative to placebo, smaller increases in serum IgG levels were observed in the belimumab group as expected with the known mechanism of belimumab. At Week 104, the median percent increase from baseline in IgG was 17% for belimumab and 37% for placebo. Reductions in autoantibodies, increases in complement, and reductions in circulating total B cells and B-cell subsets observed were consistent with the SLE studies.
In one study in paediatric patients with SLE (6 to 17 years of age) the pharmacodynamic response was consistent with the adult data.
The subcutaneous pharmacokinetic parameters below are based on population parameter estimates from 661 subjects, comprised of 554 SLE patients and 107 healthy subjects, who received belimumab subcutaneously.
The intravenous pharmacokinetic parameters quoted below are based on population parameter estimates for the 563 patients with SLE who received belimumab 10 mg/kg body weight in the two Phase III studies.
Following subcutaneous administration the bioavailability of belimumab was approximately 74%. Steady-state exposure was reached after approximately 11 weeks of subcutaneous administration. The maximum serum concentration (Cmax) of belimumab at steady state was 108 μg/ml.
Maximum serum concentrations of belimumab were generally observed at, or shortly after, the end of the infusion. The maximum serum concentration was 313 µg/mL (range: 173-573 µg/mL) based on simulating the concentration time profile using the typical parameter values of the population pharmacokinetic model.
Belimumab was distributed to tissues with steady-state volume (Vss) of distribution of approximately 5 litres.
Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.
Following subcutaneous administration, belimumab had a terminal half-life of 18.3 days. The systemic clearance was 204 ml/day.
Following intravenous infusion, serum belimumab concentrations declined in a bi-exponential manner, with a distribution half-life of 1.75 days and terminal half-life 19.4 days. The systemic clearance was 215 mL/day (range: 69-622 mL/day).
A population pharmacokinetic analysis was conducted in 224 adult patients with lupus nephritis who received belimumab 10 mg/kg intravenously (Days 0, 14, 28, and then every 28 days up to 104 weeks). In patients with lupus nephritis, due to renal disease activity, belimumab clearance was initially higher than observed in SLE studies; however, after 24 weeks of treatment and throughout the remainder of the study, belimumab clearance and exposure were similar to that observed in adult patients with SLE who received belimumab 10 mg/kg body weight intravenously.
Based on population pharmacokinetic modelling and simulation, the steady-state average concentrations of subcutaneous administration of belimumab 200 mg once weekly in adults with lupus nephritis are predicted to be similar to those observed in adults with lupus nephritis receiving belimumab 10 mg/kg body weight intravenously every 4 weeks.
The pharmacokinetic parameters of belimumab administered subcutaneously are based on a population pharmacokinetic analysis of 25 patients from a Phase II pharmacokinetic study in paediatric patients with SLE receiving belimumab subcutaneously and the Phase II study in paediatric patients with SLE receiving belimumab intravenously. Following subcutaneous administration of 200 mg of belimumab in paediatric patients 5 to less than 18 years of age [weekly (patients weighing ≥50 kg), every 10 days (patients weighing 30 to <50 kg) or every 2 weeks (patients weighing 15 to <30 kg)], the steady state average belimumab concentration is estimated to be similar to that of adult SLE subjects following subcutaneous administration of 200 mg belimumab weekly, and similar to that of paediatric SLE subjects following intravenous administration of belimumab 10 mg/kg body weight on Days 0, 14 and 28, and at 4-week intervals thereafter. Simulated steady-state geometric mean Cmax, Cavg, Cmin, and AUC (calculated over the dosing interval) are estimated to be 124 μg/mL, 119 μg/mL, 111 μg/mL and 834 day•μg/mL for paediatric patients weighing ≥50 kg receiving belimumab once weekly, 114 μg/mL, 105 μg/mL, 91 μg/mL and 1051 day•μg/mL for paediatric patients weighing 30 to <50 kg receiving belimumab every 10 days, and 119 μg/mL, 103 μg/mL, 79 μg/mL and 1438 day•μg/mL for paediatric patients weighing 15 to <30 kg receiving belimumab every 2 weeks.
Belimumab has been studied in a limited number of elderly patients. Age did not affect belimumab exposure in the subcutaneous population pharmacokinetic analysis. However, given the small number of subjects ≥65, an effect of age cannot be ruled out conclusively.
No specific studies have been conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. During clinical development, belimumab was studied in a limited number of SLE patients with mild (creatinine clearance [CrCl] ≥60 and <90 ml/min), moderate (CrCl ≥30 and <60 ml/min), or severe (CrCl ≥15 and <30 ml/min) renal impairment: 121 patients with mild renal impairment and 30 patients with moderate renal impairment received belimumab subcutaneously; 770 patients with mild renal impairment, 261 patients with moderate renal impairment and 14 patients with severe renal impairment received belimumab intravenously.
No clinically significant reduction in systemic clearance as a result of renal impairment was observed. Therefore, no dose adjustment is recommended for patients with renal impairment.
No specific studies have been conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue and changes in hepatic function are unlikely to have any effect on the elimination of belimumab.
The effects of body weight and BMI on belimumab exposure after subcutaneous administration in adults were not considered clinically meaningful. There was no significant impact on efficacy and safety based on weight. Therefore, no dose adjustment in adults is recommended.
The effects of body weight on belimumab exposure after subcutaneous administration in paediatric patients have been determined using a population pharmacokinetic model. Paediatric patients with lower body weight have lower belimumab clearance and volume of distribution resulting in increased exposure. To ensure belimumab exposures remain within acceptable limits and are consistent across the paediatric weight range, patients with lower body weight are dosed belimumab less frequently.
Patients with SLE transitioning from 10 mg/kg body weight intravenously every 4 weeks to a 200 mg subcutaneous regimen using a 1 to 4 week switching interval had pre-dose belimumab serum concentrations at their first subcutaneous dose close to their eventual subcutaneous steady-state trough concentration. Based on simulations with population pharmacokinetic parameters, the steady-state average belimumab concentrations for 200 mg subcutaneous every week (in adult patients, and in paediatric patients 5 to under 18 years of age and ≥50 kg), every 10 days (in paediatric patients 5 to under 18 years of age and 30 to <50 kg) or every 2 weeks (in paediatric patients 5 to under 18 years of age and 15 to <30 kg), were similar to 10 mg/kg body weight intravenous every 4 weeks.
One to 2 weeks after completing the first 2 intravenous doses, patients with lupus nephritis transitioning from 10 mg/kg body weight intravenously to 200 mg subcutaneously weekly, are predicted to have average belimumab serum concentrations similar to patients dosed with 10 mg/kg body weight intravenously every 4 weeks based on population pharmacokinetic simulations.
Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity and toxicity to reproduction.
Intravenous and subcutaneous administration to monkeys resulted in the expected reduction in the number of peripheral and lymphoid tissue B cell counts with no associated toxicological findings.
Reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab 150 mg/kg by intravenous infusion (approximately 9 times the anticipated maximum human clinical exposure) every 2 weeks for up to 21 weeks, and belimumab treatment was not associated with direct or indirect harmful effects with respect to maternal toxicity, developmental toxicity, or teratogenicity.
Treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of life in infant monkeys; IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.
Effects on male and female fertility in monkeys were assessed in the 6-month repeat dose toxicology studies of belimumab at doses up to and including 50 mg/kg. No treatment-related changes were noted in the male and female reproductive organs of sexually mature animals. An informal assessment of menstrual cycling in females demonstrated no belimumab-related changes.
As belimumab is a monoclonal antibody no genotoxicity studies have been conducted. No carcinogenicity studies or fertility studies (male or female) have been performed.
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