Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Glaxo Group Limited Glaxo Wellcome House Berkeley Avenue Greenford Middlesex UB6 0NN United Kingdom
Pharmacotherapeutic group: Selective immunosuppressants
ATC code: L04AA26
Benlysta is a human IgG1λ monoclonal antibody specific for soluble human B Lymphocyte Stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Benlysta blocks the binding of soluble BLyS, a B cell survival factor, to its receptors on B cells. Benlysta does not bind B cells directly, but by binding BLyS, Benlysta 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. In patients with hypergammaglobulinemia, normalization of IgG levels was observed by Week 52 in 49% and 20% of patients receiving Benlysta and placebo, respectively.
In patients with anti-dsDNA antibodies, 16% of patients treated with Benlysta 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 Benlysta and in 17% and 19% of patients receiving placebo.
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).
A significant reduction of circulating B cells, including naïve, activated, plasma, and the SLE B cell subset was seen at Week 52.
Assay sensitivity for neutralising antibodies and non-specific anti-drug antibody (ADA) is limited by the presence of active drug in the collected samples. The true occurrence of neutralising antibodies and non-specific anti-drug antibody in the study population is therefore not known.
In the two Phase III studies, 4 out of 563 (0.7%) patients in the 10 mg/kg group and 27 out of 559 (4.8%) patients in the 1 mg/kg group tested positive for persistent presence of anti-belimumab antibodies.
Among persistent-positive subjects in the Phase III studies, 1/10 (10%), 2/27 (7%) and ¼ (25%) subjects in the placebo, 1 mg/kg and 10 mg/kg groups, respectively, experienced infusion reactions on a dosing day; these infusion reactions were all non-serious and mild to moderate in severity. Few patients with ADA reported serious/severe AEs. The rates of infusion reactions among persistent-positive subjects were comparable to the rates for ADA negative patients of 75/552 (14%), 78/523 (15%), and 83/559 (15%) in the placebo, 1 mg/kg and 10 mg/kg groups, respectively.
The efficacy of Benlysta was evaluated in 2 randomized, double-blind, placebo-controlled studies in 1,684 patients with a clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Patients had active SLE disease, defined as a SELENA-SLEDAI (SELENA=Safety of Estrogens in Systemic Lupus Erythematosus National Assessment; SLEDAI=Systemic Lupus Erythematosus Disease Activity Index) score ≥6 and positive anti-nuclear antibody (ANA) 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 consisting of (alone or in combination): corticosteroids, anti-malarials, NSAIDs or other immunosuppressives. The two studies were similar in design except that BLISS-76 was a 76-week study and BLISS-52 was a 52-week study. In both studies the primary efficacy endpoint was evaluated at 52 weeks.
Patients who had severe active lupus nephritis and patients who had severe active central nervous system (CNS) lupus were excluded.
BLISS-76 was conducted primarily in North America and Western Europe. Background medicinal products included corticosteroids (76%; >7.5 mg/day 46%), immunosuppressives (56%), and anti-malarials (63%).
BLISS-52 was conducted in South America, Eastern Europe, Asia, and Australia. Background medicinal products included corticosteroids (96%; >7.5 mg/day 69%), immunosuppressives (42%), and anti-malarials (67%).
At baseline 52% of patients had high disease activity (SELENA SLEDAI score ≥10), 59% of patients had mucocutaneous, 60% had musculoskeletal, 16% had haematological, 11% had renal and 9% had vascular organ domain involvement (BILAG A or B at baseline).
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 | BLISS-76 | BLISS-52 | BLISS-76 and BLISS-52 Pooled | |||
|---|---|---|---|---|---|---|
| Placebo* | Benlysta 10 mg/kg* | Placebo* | Benlysta 10 mg/kg* | Placebo* | Benlysta 10 mg/kg* | |
| (n=275) | (n=273) | (n=287) | (n=290) | (n=562) | (n=563) | |
| SLE Responder Index | 33.8% | 43.2%(p=0.021) | 43.6% | 57.6%(p=0.0006) | 38.8% | 50.6%(p<0.0001) |
| Observed difference vs placebo | - | 9.4% | - | 14.0% | - | 11.8% |
| Odds ratio (95% CI) vs placebo | - | 1.52(1.07, 2.15) | - | 1.83(1.30,2.59) | - | 1.68(1.32,2.15) |
Components of SLE Responder Index:
| Percent of patients with reduction in SELENA- SLEDAI ≥4 | 35.6% | 46.9%(p=0.006) | 46.0% | 58.3%(p= 0.0024) | 40.9% | 52.8%(p<0.0001) |
| Percent of patients with no worsening by BILAG index | 65.1% | 69.2%(p=0.32) | 73.2% | 81.4%(p=0.018) | 69.2% | 75.5%(p=0.019) |
| Percent of patients with no worsening by PGA | 62.9% | 69.2%(p=0.13) | 69.3% | 79.7%(p=0.0048) | 66.2% | 74.6%(p=0.0017) |
* plus standard therapy/standard of care
In a pooled analysis of the two studies, the percentage of patients receiving >7.5 mg/day prednisone (or equivalent) at baseline, whose average corticosteroid dose was reduced by at least 25% to a dose equivalent to prednisone ≤7.5 mg/day during Weeks 40 through 52, was 17.9% in the group receiving Benlysta and 12.3% in the group receiving placebo (p=0.0451).
Flares in SLE were defined by the modified SELENA SLEDAI SLE Flare Index. The median time to the first flare was delayed in the pooled group receiving belimumab compared to the group receiving placebo (110 vs 84 days, hazard ratio=0.84, p=0.012). Severe flares were observed in 15.6% of the Benlysta group compared to 23.7% of the placebo group over the 52 weeks of observation (observed treatment difference = -8.1%; hazard ratio=0.64, p=0.0011).
Benlysta demonstrated improvement in fatigue compared with placebo measured by the FACIT-Fatigue scale in the pooled analysis. The mean change of score at Week 52 from baseline is significantly greater with Benlysta compared to placebo (4.70 vs 2.46, p=0.0006).
Univariate and multivariate analysis of the primary endpoint in pre-specified subgroups demonstrated that the greatest benefit was observed in patients with higher disease activity including patients with SELENA SLEDAI scores ≥ 10, patients requiring steroids to control their disease, and patients with low complement levels.
Post-hoc analysis has identified high responding subgroups such as those patients with low complement and positive anti-dsDNA at baseline, see Table 2. Of these patients, 64.5% had SELENA SLEDAI scores ≥ 10 at baseline.
Table 2 – Patients with low complement and positive anti-dsDNA at baseline:
| Subgroup | Anti-dsDNA positive AND low complement | |
|---|---|---|
| BLISS-76 and BLISS-52 pooled data | Placebo(n=287) | Benlysta 10 mg/kg (n=305) |
| SRI response rate at Week 52 (%) | 31.7 | 51.5 (p<0.0001) |
| Observed treatment difference vs placebo (%) | - | 19.8 |
| SRI response rate (excluding complement and anti-dsDNA changes) at Week 52 (%) | 28.9 | 46.2 (p<0.0001) |
| Observed treatment difference vs placebo (%) | - | 17.3 |
| Severe flares over 52 weeks | ||
| Patients experiencing a severe flare (%) | 29.6 | 19.0 |
| Observed treatment difference vs placebo (%) | - | 10.6 |
| Time to severe flare [Hazard ratio (95% CI)] | - | 0.61 (0.44, 0.85)(p=0.0038) |
| Prednisone reduction by ≥25% from baseline to ≤7.5 mg/day during Weeks 40 through 52* (%) | (n=173) | (n=195) |
| 12.1 | 18.5 (p=0.0964) | |
| Observed treatment difference vs placebo (%) | - | 6.3 |
| FACIT-fatigue score improvement from baseline at Week-52 (mean) | 1.99 | 4.21 (p=0.0048) |
| Observed treatment difference vs placebo (mean difference) | - | 2.21 |
| BLISS-76 Study only | Placebo(n=131) | Benlysta 10 mg/kg (n=134) |
| SRI response rate at Week-76 (%) | 27.5 | 39.6 (p=0.0160) |
| Observed treatment difference vs placebo (%) | - | 12.1 |
* Among patients with baseline prednisone dose >7.5 mg/day
The European Medicines Agency has deferred the obligation to submit the results of studies with Benlysta in one or more subsets of the paediatric population in SLE (see section 4.2 for information on paediatric use).
There were too few patients over 65 years of age, or black/African American patients enrolled in the controlled clinical trials to draw meaningful conclusions about the effects of age or race on clinical outcomes.
The pharmacokinetic parameters quoted below are based on population parameter estimates for the 563 patients who received Benlysta 10 mg/kg in the two Phase III studies.
Benlysta is administered by 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 distributed to tissues with an overall volume of distribution of 5.29 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.
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).
Paediatric population: No pharmacokinetic data are available in paediatric patients.
Elderly (older than or equal to 65 years of age): Benlysta has been studied in a limited number of elderly patients. Within the overall SLE intravenous study population, age did not affect belimumab exposure in the population pharmacokinetic analysis. However, given the small number of subjects 65 years or older, an effect of age cannot be ruled out conclusively.
Renal impairment: No specific studies have been conducted to examine the effects of renal impairment on the pharmacokinetics of Benlysta. During clinical development Benlysta 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.
Hepatic 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.
Body weight/BMI: Weight-normalised belimumab dosing leads to decreased exposure for underweight subjects (BMI <18.5) and to increased exposure for obese subjects (BMI ≥30). 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.
Nonclinical 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 Benlysta 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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