Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic group: Selective immunosuppressants
ATC code: L04AA26
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.
Median IgG levels at Week 52 were reduced by 11% in patients receiving Benlysta 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 Benlysta compared with 41% in patients receiving placebo. In patients with anti-dsDNA antibodies at baseline, by Week 52, 18% of patients treated with Benlysta 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 Benlysta and in 21% and 20% of patients receiving placebo, respectively.
Benlysta 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 Benlysta 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.
In the subcutaneous study where serum samples from more than 550 patients with SLE were tested, no anti-belimumab antibodies were detected during or after treatment with belimumab 200 mg subcutaneously.
The efficacy of Benlysta administered subcutaneously was evaluated in a randomised, double-blind, placebo-controlled 52-week Phase III study (HGS1006-C1115; BEL112341) in 836 adult patients with a clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥8 and positive anti-nuclear antibody (ANA or anti-dsDNA) test results (ANA titre ≥1:80 and/or a positive anti-dsDNA [≥30 units/ml]) at screening. Patients were on a stable SLE treatment regimen (standard of care) consisting of any of the following (alone or in combination): corticosteroids, anti-malarials, NSAIDs or other immunosuppressives. Patients were excluded from the study if they had severe active central nervous system lupus or severe active lupus nephritis.
This study was conducted in the US, South America, Europe and Asia. Patient median age was 37 years (range: 18 to 77 years), and the majority (94%) were female. Background medicinal products included corticosteroids (86%; >7.5 mg/day prednisone equivalent 60%), immunosuppressives (46%), and anti-malarials (69%). Patients were randomised in a 2:1 ratio to receive belimumab 200 mg or placebo subcutaneously once weekly for 52 weeks.
At baseline 62.2% of patients had high disease activity (SELENA SLEDAI score ≥10), 88% of patients had mucocutaneous, 78% had musculoskeletal, 8% had haematological, 12% had renal, and 8% had vascular organ involvement.
The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response as meeting each of the following criteria at Week 52 compared with baseline:
The SLE Responder Index measures improvement in SLE disease activity, without worsening in any organ system, or in the patient’s overall condition.
Table 1. Response rate at week 52:
| Response | Placebo (n=279) | Benlysta 200 mg weekly (n=554) |
|---|---|---|
| SLE responder index | 48,4% | 61,4% (p=0,0006) |
| Observed difference vs placebo | 12,98% | |
| Odds ratio (95% CI) vs placebo | 1,68 (1,25, 2,25) | |
| Components of SLE responder index | ||
| Percent of patients with reduction in SELENA-SLEDAI ≥4 | 49,1% | 62,3% (p=0,0005) |
| Percent of patients with no worsening by BILAG index | 74,2% | 80,9% (p=0,0305) |
| Percent of patients with no worsening by PGA | 72,8% | 81,2% (p=0,0061) |
All patients received standard therapy.
The differences between the treatment groups were apparent by Week 16 and sustained through Week 52 (Figure 1).
Figure 1. Proportion of SRI responders by visit:
Flares in SLE were defined by the modified SELENA SLEDAI SLE Flare Index. The risk of first flare was reduced by 22% during the 52 weeks of observation in the group receiving Benlysta compared with the group receiving placebo (hazard ratio=0.78; p=0.0061). The median time to the first flare among patients having a flare was delayed in patients receiving Benlysta compared with placebo (190 days vs. 141 days).
Severe flares were observed in 10.6% of patients in the group receiving Benlysta compared with 18.2% of patients in the group receiving placebo over the 52 weeks of observation (observed treatment difference = -7.6%). The risk of severe flares was reduced by 49% during the 52 weeks of observation in the group receiving Benlysta compared with the group receiving placebo (hazard ratio=0.51; p=0.0004). The median time to the first severe flare among patients having a severe flare was delayed in patients receiving Benlysta compared with placebo (171 days vs. 118 days).
The percentage of patients receiving greater than 7.5 mg/day prednisone (or equivalent) at baseline whose average corticosteroid dose was reduced by at least 25% from baseline to a dose equivalent to prednisone ≤7.5 mg/day during Weeks 40 through 52, was 18.2% in the group receiving Benlysta and 11.9% in the group receiving placebo (p=0.0732).
Benlysta demonstrated improvement in fatigue compared with placebo measured by the FACIT-Fatigue Scale. The adjusted mean change of score at Week 52 from baseline is significantly greater with Benlysta compared to placebo (4.4 vs. 2.7, p=0.0130).
Subgroup analysis of the primary endpoint demonstrated that the greatest benefit was observed in patients with higher disease activity at baseline including patients with SELENA SLEDAI scores ≥ 10 or patients requiring steroids to control their disease or patients with low complement levels.
An additional, previously identified serologically active group, those patients with low complement and positive anti-dsDNA at baseline, also demonstrated a greater relative response, see Table 2 for results of this example of a higher disease activity group.
Table 2. Patients with low complement and positive anti-dsDNA at baseline:
| Subgroup | Anti-dsDNA positive AND low complement | |
|---|---|---|
| Placebo | Benlysta 200 mg weekly | |
| (n=108) | (n=246) | |
| SRI response rate at week 52 (%) | 47,2 | 64,6 (p=0,0014) |
| Observed treatment difference vs. placebo (%) | 17,41 | |
| Severe flares over 52 weeks: | (n=108) | (n=248) |
| Patients experiencing a severe flare (%) | 31,5 | 14,1 |
| Observed treatment difference vs. placebo (%) | 17,4 | |
| Time to severe flare [Hazard ratio (95% CI)] | 0,38 (0,24, 0,61) (p<0,0001) | |
| (n=70) | (n=164) | |
| Prednisone reduction by ≥25% from baseline to ≤7.5 mg/day during weeks 24 through 52* (%) | 11,4 | 20,7 (p=0,0844) |
| Observed treatment difference vs. placebo (%) | 9,3 | |
| FACIT-fatigue score improvement from baseline at week-52 (mean): | 2,4 | 4,6 (p=0,0324) |
| Observed treatment difference vs. placebo (median difference) | 2,1 | |
* Among patients with baseline prednisone dose >7.5 mg/day
There were too few patients ≥65 years of age or black patients enrolled in the controlled clinical trials with subcutaneous Benlysta to draw meaningful conclusions about the effects of age or race on clinical outcomes.
The safety and efficacy of Benlysta administered intravenously have been studied in black patients. The currently available data are described in the Summary of Product Characteristics of Benlysta 120 mg and 400 mg powder for concentrate for solution for infusion.
The European Medicines Agency has deferred the obligation to submit the results of studies with Benlysta subcutaneous administration in one or more subsets of the paediatric population in SLE (see section 4.2 for information on paediatric use).
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 Benlysta subcutaneously.
Benlysta in pre-filled pen or pre-filled syringe is administered by subcutaneous injection.
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.
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.
No pharmacokinetic data are available for subcutaneous administration of Benlysta in paediatric patients.
Benlysta 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, Benlysta 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 Benlysta subcutaneously; 770 patients with mild renal impairment, 261 patients with moderate renal impairment and 14 patients with severe renal impairment received Benlysta 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 were not considered clinically meaningful. There was no significant impact on efficacy and safety based on weight. Therefore, no dose adjustment is recommended.
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 (see section 4.2).
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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