Mechanism of Action
BENLYSTA is a BLyS-specific inhibitor that 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.
In Trial 1 and Trial 2 in which B cells were measured, treatment with BENLYSTA significantly reduced circulating CD19+, CD20+, naive, and activated B cells, plasmacytoid cells, and the SLE B-cell subset at Week 52. Reductions in naive and the SLE B-cell subset were observed as early as Week 8 and were sustained to Week 52. Memory cells increased initially and slowly declined toward baseline levels by Week 52. The clinical relevance of these effects on B cells has not been established.
Treatment with BENLYSTA led to reductions in IgG and anti-dsDNA, and increases in complement (C3 and C4). These changes were observed as early as Week 8 and were sustained through Week 52. The clinical relevance of normalizing these biomarkers has not been definitively established.
The pharmacokinetic parameters displayed in Table 2 are based on population parameter estimates which are specific to the 563 patients who received belimumab 10 mg/kg in Trials 2 and 3 [see Clinical Studies
Table 2. Population Pharmacokinetic Parameters in Patients with SLE after Intravenous Infusion of BENLYSTA 10 mg/kg
(n = 563)
|Peak concentration (Cmax, µg/mL)
|Area under the curve (AUC0-âˆž, dayâˆ™Î¼g/mL)
|Distribution half-life (t½, days)
|Terminal half-life (t½, days)
|Systemic clearance (CL, mL/day)
|Volume of distribution (Vss, L)
Drug Interactions: No formal drug interaction studies have been conducted with belimumab. Concomitant use of mycophenolate, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and HMG-CoA reductase inhibitors did not significantly influence belimumab pharmacokinetics. Coadministration of steroids and angiotensin-converting enzyme (ACE) inhibitors resulted in an increase of systemic clearance of belimumab that was not clinically significant because the magnitude was well within the range of normal variability of clearance. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated.
The following information is based on the population pharmacokinetic analysis.
Age: Age did not significantly influence belimumab pharmacokinetics in the study population, where the majority of subjects (70%) were between 18 and 45 years of age. No pharmacokinetic data are available in pediatric patients. Limited pharmacokinetic data are available for elderly patients as only 1.4% of the subjects included in the pharmacokinetic analysis were 65 years of age or older [see Use in Specific Populations
Gender: Gender did not significantly influence belimumab pharmacokinetics in the largely (94%) female study population.
Race: Race did not significantly influence belimumab pharmacokinetics. The racial distribution was 53% white/Caucasian, 16% Asian, 16% Alaska native/American Indian, and 14% black/African-American.
Renal Impairment: No formal studies were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. Belimumab has been studied in a limited number of 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). Although increases in creatinine clearance and proteinuria (>2 g/day) increased belimumab clearance, these effects were within the expected range of variability. Therefore, dosage adjustment in patients with renal impairment is not recommended.
Hepatic Impairment: No formal studies were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Belimumab has not been studied in patients with severe hepatic impairment. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of belimumab. The mutagenic potential of belimumab was not evaluated.
Effects on male and female fertility have not been directly evaluated in animal studies.
The safety and effectiveness of BENLYSTA were evaluated in three randomized, double-blind, placebo-controlled studies involving 2133 patients with SLE according to the American College of Rheumatology criteria (Trial 1, 2, and 3). Patients with severe active lupus nephritis and severe active CNS lupus were excluded. Patients were on a stable standard of care SLE treatment regimen comprising any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs, and immunosuppressives. Use of other biologics and intravenous cyclophosphamide were not permitted.
Trial 1: BENLYSTA 1 mg/kg, 4 mg/kg, 10 mg/kg
Trial 1 enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg BENLYSTA plus standard of care compared with placebo plus standard of care over 52 weeks in patients with SLE. Patients had to have a SELENA-SLEDAI score of ≥4 at baseline and a history of autoantibodies (anti-nuclear antibody (ANA) and/or anti-double-stranded DNA (anti-dsDNA), but 28% of the population was autoantibody negative at baseline. The co-primary endpoints were percent change in SELENA-SLEDAI score at Week 24 and time to first flare over 52 weeks. No significant differences between any of the BENLYSTA groups and the placebo group were observed. Exploratory analysis of this study identified a subgroup of patients (72%), who were autoantibody positive, in whom BENLYSTA appeared to offer benefit. The results of this study informed the design of Trials 2 and 3 and led to the selection of a target population and indication that is limited to autoantibody-positive SLE patients.
Trials 2 and 3: BENLYSTA 1 mg/kg and 10 mg/kg
Trials 2 and 3 were randomized, double-blind, placebo-controlled trials in patients with SLE that were similar in design except duration - Trial 2 was 76 weeks duration and Trial 3 was 52 weeks duration. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥6, and positive autoantibody test results at screening. Patients were excluded from the study if they had ever received treatment with a B-cell targeted agent or if they were currently receiving other biologic agents. Intravenous cyclophosphamide was not permitted within the previous 6 months or during study. Trial 2 was conducted primarily in North America and Europe. Trial 3 was conducted in South America, Eastern Europe, Asia, and Australia.
Baseline concomitant medications included corticosteroids (Trial 2: 76%, Trial 3: 96%), immunosuppressives (Trial 2: 56%, Trial 3: 42%; including azathioprine, methotrexate and mycophenolate), and antimalarials (Trial 2: 63%, Trial 3: 67%). Most patients (>70%) were receiving 2 or more classes of SLE medications.
In Trial 2 and Trial 3, more than 50% of patients had 3 or more active organ systems at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (82% in both studies); immunology (Trial 2: 74%, Trial 3: 85%); and musculoskeletal (Trial 2: 73%, Trial 3: 59%). Less than 16% of patients had some degree of renal activity and less than 7% of patients had activity in the vascular, cardio-respiratory, or CNS systems.
At screening, patients were stratified by disease severity based on their SELENA-SLEDAI score (≤ 9 vs ≥10), proteinuria level (< 2 g/24 hr vs ≥ 2 g/24 hr), and race (African or Indigenous-American descent vs. other), and then randomly assigned to receive BENLYSTA 1 mg/kg, BENLYSTA 10 mg/kg, or placebo in addition to standard of care. The patients were administered study medication intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for 48 weeks in Trial 3 and for 72 weeks in Trial 2.
The primary efficacy endpoint was a composite endpoint (SLE Responder Index or SRI) that defined response as meeting each of the following criteria at Week 52 compared with baseline:
- ≥ 4-point reduction in the SELENA-SLEDAI score, and
- no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores, and
- no worsening (< 0.30-point increase) in Physician's Global Assessment (PGA) score.
The SRI uses the SELENA-SLEDAI score as an objective measure of reduction in global disease activity; the BILAG index to ensure no significant worsening in any specific organ system; and the PGA to ensure that improvements in disease activity are not accompanied by worsening of the patient's condition overall.
In both Trials 2 and 3, the proportion of SLE patients achieving an SRI response, as defined for the primary endpoint, was significantly higher in the BENLYSTA 10 mg/kg group than in the placebo group. The effect on the SRI was not consistently significantly different for the BENLYSTA 1 mg/kg group relative to placebo in both trials. The 1 mg/kg dose is not recommended. The trends in comparisons between the treatment groups for the rates of response for the individual components of the endpoint were generally consistent with that of the SRI (Table 3). At Week 76 in Trial 2, the SRI response rate with BENLYSTA 10 mg/kg was not significantly different from that of placebo (39% and 32%, respectively).
Table 3. Clinical Response Rate in Patients with SLE After 52 Weeks of Treatment
||Placebo + Standard of Care
(n = 275)
1 mg/kg + Standard of Care
(n = 271)
10 mg/kg + Standard of Care
(n = 273)
(n = 287)
1 mg/kg +
(n = 288)
10 mg/kg +
(n = 290)
|SLE Responder Index
(p = 0.104)
(p = 0.021)
(p = 0.013)
(p < 0.001)
(95% CI) vs.
|Components of SLE Responder Index
|Percent of patients with reduction in SELENA-SLEDAI ≥4
|Percent of patients with no worsening by BILAG index
|Percent of patients with no worsening by PGA
The reduction in disease activity seen in the SRI was related primarily to improvement in the most commonly involved organ systems namely, mucocutaneous, musculoskeletal, and immunology.
Effect in Black/African-American Patients:
Exploratory sub-group analyses of SRI response rate in patients of black race were performed. In Trial 2 and Trial 3 combined, the SRI response rate in black patients (N=148) in the BENLYSTA groups was less than that in the placebo group (22/50 or 44% for placebo, 15/48 or 31% for BENLYSTA 1 mg/kg, and 18/50 or 36% for BENLYSTA 10 mg/kg). In Trial 1, black patients (N = 106) in the BENLYSTA groups did not appear to have a different response than the rest of the study population. Although no definitive conclusions can be drawn from these subgroup analyses, caution should be used when considering BENLYSTA treatment in black/African-American SLE patients.
Effect on Concomitant Steroid Treatment:
In Trial 2 and Trial 3, 46% and 69% of patients, respectively, were receiving prednisone at doses > 7.5 mg/day at baseline. The proportion of patients able to reduce their average prednisone dose by at least 25% to ≤ 7.5 mg/day during Weeks 40 through 52 was not consistently significantly different for BENLYSTA relative to placebo in both trials. In Trial 2, 17% of patients receiving BENLYSTA 10 mg/kg and 19% of patients receiving BENLYSTA 1 mg/kg achieved this level of steroid reduction compared with 13% of patients receiving placebo. In Trial 3, 19%, 21%, and 12% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg, and placebo, respectively, achieved this level of steroid reduction.
Effect on Severe SLE Flares:
The probability of experiencing a severe SLE flare, as defined by a modification of the SELENA Trial flare criteria which excluded severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated for both Trials 2 and 3. The proportion of patients having at least 1 severe flare over 52 weeks was not consistently significantly different for BENLYSTA relative to placebo in both trials. In Trial 2, 18% of patients receiving BENLYSTA 10 mg/kg and 16% of patients receiving BENLYSTA 1 mg/kg had a severe flare compared with 24% of patients receiving placebo. In Trial 3, 14%, 18%, and 23% of patients receiving BENLYSTA 10 mg/kg, BENLYSTA 1 mg/kg and placebo, respectively, had a severe flare.