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.
h3 ®. Subcutaneous administration
Median IgG levels at Week 52 were reduced by 11% in patients receiving belimumab compared with an increase of 0.7% in patients receiving placebo.
In patients with anti-dsDNA antibodies at baseline, median anti-dsDNA antibodies levels at Week 52 were reduced by 56% in patients receiving belimumab compared with 41% in patients receiving placebo. In patients with anti-dsDNA antibodies at baseline, by Week 52, 18% of patients treated with belimumab had converted to anti-dsDNA negative compared with 15% of the patients receiving placebo.
In patients with low complement levels, normalization of C3 and C4 was observed by Week 52 in 42% and 53% of patients receiving belimumab and in 21% and 20% of patients receiving placebo, respectively.
Belimumab significantly reduced circulating overall, transitional, naïve, and SLE B cells, as well as plasma cells at Week 52. Reductions in naïve and transitional B cells, as well as the SLE B cell subset were observed as early as Week 8. Memory cells increased initially and slowly declined toward baseline levels by Week 52.
The B cell and IgG response to long term treatment with intravenous belimumab was assessed in an 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.
h3 ®. Intravenous administration
Changes in biomarkers were seen in clinical trials with belimumab administered intravenously. In adult patients 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 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 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 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 one study in paediatric patients (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 who received belimumab 10 mg/kg 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.
Following intravenous infusion 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).
The pharmacokinetic parameters are based on individual parameter estimates from a population pharmacokinetic analysis of 53 patients from a study in paediatric patients. Following intravenous administration of 10 mg/kg on Days 0, 14 and 28, and at 4-week intervals thereafter, belimumab exposures were similar between paediatric and adult SLE subjects. Steady-state geometric mean Cmax, Cmin, and AUC values were 305 μg/mL, 42 μg/mL, and 2569 day•μg/mL in the 5- to 11-year-old-group, and 317 μg/mL, 52 μg/mL, and 3126 day•μg/mL in the 12- to 17-year-old-group (n=43).
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 administrated intravenously was studied in patients with SLE and renal impairment (261 subjects with moderate renal impairment, creatinine clearance ≥30 and <60 ml/min; 14 subjects with severe renal impairment, creatinine clearance ≥15 and <30 ml/min). The reduction in systemic clearance estimated by population PK modelling for patients at the midpoints of the renal impairment categories relative to patients with median creatinine clearance in the PK population (79.9 ml/min) were 1.4% for mild (75 ml/min), 11.7% for moderate (45 ml/min) and 24.0% for severe (22.5 ml/min) renal impairment. Although proteinuria (≥2 g/day) increased belimumab clearance and decreases in creatinine clearance decreased belimumab clearance, these effects were within the expected range of variability. 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 were not considered clinically meaningful. There was no significant impact on efficacy and safety based on weight. Therefore, no dose adjustment is recommended.
Weight-normalised belimumab dosing leads to decreased exposure for underweight subjects (BMI <18.5) and to increased exposure for obese subjects (BMI ≥30) after intravenous administration. BMI-dependent changes in exposure did not lead to corresponding changes in efficacy. Increased exposure for obese subjects receiving 10 mg/kg belimumab did not lead to an overall increase in AE rates or serious AEs compared to obese subjects receiving placebo. However, higher rates of nausea, vomiting and diarrhoea were observed in obese patients. None of these gastrointestinal events in obese patients were serious. No dose adjustment is recommended for underweight or obese subjects.
SLE patients transitioning from 10 mg/kg intravenously every 4 weeks to 200 mg subcutaneously weekly 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 PK parameters the steady-state average belimumab concentrations for 200 mg subcutaneous every week were similar to 10 mg/kg intravenous every 4 weeks.
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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