"March 9, 2011 -- The FDA has approved Benlysta, the first new lupus treatment in 50 years.
An FDA advisory panel last November voted 13-2 in favor of approval. But the panel noted that Benlysta is no wonder drug. Overall, it offered a"...
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+, na´ve, and activated B cells, plasmacytoid cells, and the SLE B-cell subset at Week 52. Reductions in na´ve 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 BENLYSTA 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/kga
|Pharmacokinetic Parameter||Population Estimates
(n = 563)
|Peak concentration (Cmax, mcg/mL)||313|
|Area under the curve (AUC0-∞, day•mcg/mL)||3,083|
|Distribution half-life (t½, days)||1.75|
|Terminal half-life (t½, days)||19.4|
|Systemic clearance (CL, mL/day)||215|
|Volume of distribution (Vss, L)||5.29|
|a Intravenous infusions were administered at 2-week intervals for the first 3 doses and at 4-week intervals thereafter.|
No formal drug interaction studies have been conducted with BENLYSTA. 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 trial population, where the majority of subjects (70%) were aged between 18 and 45 years. 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 aged 65 years or older [see Use In Specific Populations].
Gender: Gender did not significantly influence belimumab pharmacokinetics in the largely (94%) female trial 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 trials were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. BENLYSTA 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 trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics.
The safety and effectiveness of BENLYSTA were evaluated in 3 randomized, double-blind, placebo-controlled trials involving 2,133 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 groups receiving BENLYSTA and the group receiving placebo were observed. Exploratory analysis of this trial identified a subgroup of patients (72%), who were autoantibody positive, in whom BENLYSTA appeared to offer benefit. The results of this trial 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 trial 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 the trial. 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 trials); immune (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 trial 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 group receiving BENLYSTA 10 mg/kg than in the group receiving placebo. The effect on the SRI was not consistently significantly different for patients receiving BENLYSTA 1 mg/kg 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).15
Table 3: Clinical Response Rate in Patients with SLE
after 52 Weeks of Treatment
|Responsea||Trial 2||Trial 3|
|Placebo + Standard of Care
(n = 275)
|BENLYSTA 1 mg/kg + Standard of Careb
(n = 271)
|BENLYSTA 10 mg/kg + Standard of Care
(n = 273)
|Placebo + Standard of Care
(n = 287)
|BENLYSTA 1 mg/kg + Standard of Careb
(n = 288)
|BENLYSTA 10 mg/kg + Standard of Care
(n = 290)
|SLE Responder Index||34%||41%
(P = 0.104)
(P = 0.021)
(P = 0.013)
(P < 0.001)
|Odds Ratio (95% CI) vs. placebo||1.3 (0.9, 1.9)||1.5 (1.1, 2.2)||1.6 (1.1, 2.2)||1.8 (1.3, 2.6)|
|Components of SLE Responder Index|
|Percent of patients w ith reduction in SELENA-SLEDAI ≥ 4||36%||43%||47%||46%||53%||58%|
|Percent of patients with no worsening by BILAG index||65%||75%||69%||73%||79%||81%|
|Percent of patients with no worsening by PGA||63%||73%||69%||69%||79%||80%|
|a Patients dropping out of the trial early or
experiencing certain increases in background medication were considered as
failures in these analyses. In both trials, a higher proportion of placebo
patients were considered as failures for this reason as compared with the
groups receiving BENLYSTA.
b The 1-mg/kg dose is not recommended.
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 immune.
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 groups receiving BENLYSTA was less than that in the group receiving placebo (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 groups receiving BENLYSTA did not appear to have a different response than the rest of the trial population. Although no definitive conclusions can be drawn from these subgroup analyses, caution should be used when considering treatment with BENLYSTA 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.
Last reviewed on RxList: 3/22/2016
This monograph has been modified to include the generic and brand name in many instances.
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