SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by periods of illness and remissions in which the immune system produces antibodies to cells within the body leading to widespread inflammation and tissue damage. Immunologic abnormalities, especially the production of a number of antinuclear antibodies (ANA), are a prominent feature of the disease. SLE has a variety of clinical manifestations, and it can affect joints, skin, brain, lungs, kidneys, and blood vessels. Individuals with SLE may experience fatigue, pain or swelling in joints, skin rashes, and fevers.
On March 9, 2011, the US Food and Drug Administration (FDA) approved belimumab (Benlysta) for intravenous (IV) use in individuals with active, autoantibody positive SLE who are receiving standard therapy, including corticosteroids, antimalarials, immunosuppressives, and nonsteroidal anti-inflammatory drugs (NSAIDs). It is the first inhibitor intended to target B-lymphocyte stimulator (BLyS) protein, which may reduce the number of abnormal B cells. BLyS is overexpressed in patients with SLE and other autoimmune diseases. After subsequent studies using the IV formulation, the FDA granted approval in pediatric individuals ages five years and older. Additionally, a subcutaneous formulation of belimumab (Benlysta) for use in adults was also FDA approved.
LUPUS NEPHRITIS (LN)
Lupus nephritis (LN) is the most common organ-threatening manifestation of SLE and can result in significant morbidity and mortality. It adversely affects individuals with SLE in terms of individual and renal survival rates as well as quality of life and work disability. Improved outcomes in members with LN can result from treatment of both the underlying SLE as well as the renal disease. The presence of renal disease can be demonstrated with multiple methods including serum and urine laboratory tests. The presence of nephritis can be identified with a kidney biopsy. Standard therapy includes treatment with corticosteroids along with induction and maintenance medications. On December 16, 2020, the FDA approved belimumab (Benlysta) for IV use in individuals, age 18 and older, with active LN who are receiving standard therapy, which can include corticosteroids with 1) mycophenolate for induction followed by mycophenolate for maintenance, or 2) cyclophosphamide for induction followed by azathioprine for maintenance.
Systemic Lupus Erythematosus (SLE)
Two clinical studies involving 1,684 individuals with lupus demonstrated the safety and effectiveness of belimumab (Benlysta) for IV use. The studies diagnosed individuals with active lupus and randomized them to receive belimumab (Benlysta) for IV use plus standard therapy, or an inactive infused solution (placebo) plus standard therapy. The studies excluded anyone who had received prior B-cell targeted therapy or IV cyclophosphamide, and those who had active lupus involving the kidneys or central nervous system.
The individuals treated with belimumab (Benlysta) for IV use and standard therapies experienced less disease activity than those who received a placebo and standard-of-care medicines. Results suggested, but did not definitively establish, that some patients had a reduced likelihood of severe flares, and some reduced their steroid doses.
Subsequent safety and efficacy results for subjects treated up to seven years continue to support disease control and safety profile in individuals with active SLE taking belimumab (Benlysta) plus standard therapy.
The safety and efficacy of the use of IV belimumab
(Benlysta) in pediatric individuals was evaluated in a phase 2, randomized,
placebo-controlled, double-blind study involving 93 participants. These
participants were divided into 3 cohorts. Cohort 1 enrolled 12 individuals ages
12 to 17, in a 5:1 ratio, to receive belimumab (Benlysta) or placebo on days 0,
14, 28, then every 28 days until week 48. The pharmacokinetics of the drug in
the pediatric individuals were compared to the pharmacokinetics of the drug in
adult individuals from previous clinical trials. When it was confirmed that
these were similar, Cohorts 2 and 3 began to enroll. In Cohort 2, 13 individuals
ages 5 to 11 years were enrolled in a 5:1 ratio to receive belimumab (Benlysta) or placebo in the same
manner as Cohort 1. Cohort 3 enrolled 68 pediatric individuals ages 5 to 17 and
randomized them 1:1 to receive belimumab (Benlysta) or placebo according to age
and Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease
Activity Index (SELENA-SLEDAI) scores. The primary efficacy endpoint was the
SLE Responder Index (SRI-4) score at week 52. Some secondary endpoints included
change in SELENA-SLEDAI scores by week 52, change in proteinuria, and adverse
events. Because of the difficulty in enrolling enough participants to enable
significance levels, the results were discussed descriptively. The percentage
of individuals who experienced a 4 or more point reduction in SELENA-SLEDAI
scores was 55 percent for the belimumab (Benlysta) group and 44 percent for the
placebo group. The number of individuals with higher levels of proteinuria was
1.43 for the belimumab (Benlysta) group and 6.13 for the placebo group. The
incidence of adverse events was similar between the treatment group and the
placebo group with 79.2 percent versus 82.5 percent, respectively. One death
occurred in the placebo group, but none in the treatment group.
Lupus Nephritis (LN)
A clinical study involving 448 individuals with active proliferative and/or membranous LN demonstrated the safety and effectiveness of belimumab (Benlysta) for IV use. The individuals had a clinical diagnosis of SLE according to American College of Rheumatology classification criteria; biopsy-proven LN Class III, IV, and/or V; and had active renal disease at screening requiring standard therapy: corticosteroids with 1) mycophenolate for induction followed by mycophenolate for maintenance, or 2) cyclophosphamide for induction followed by azathioprine for maintenance.
The proportion of individuals achieving Primary Efficacy Renal Response (PERR) at week 104 was significantly higher in individuals receiving belimumab (Benlysta) plus standard therapy compare with placebo plus standard therapy (p=0.031). The major secondary endpoints also showed significant improvement with belimumab (Benlysta) plus standard therapy compared with placebo plus standard therapy. In descriptive subgroup analyses, the PERR and Complete Renal Response (CRR) rates were examined by induction therapy (mycophenolate or cyclophosphamide), biopsy class (Class III or IV, Class III + V or Class IV + V, or Class V), and urine protein:creatinine ratio (uPCR) levels at baseline (<3 g/g or 3 g/g or greater; post-hoc analysis). In descriptive subgroup analyses of time to renal-related event or death, results were consistent with the overall endpoint regardless of induction therapy (mycophenolate or cyclophosphamide), biopsy class (Class III or IV, Class III + V or Class IV + V, or Class V; post-hoc analysis), and baseline proteinuria (<3 g/g or 3 g/g or greater; post-hoc analysis). The treatment differece was primarily driven by the renal worsening and renal-related treatment failure components of the endpoint.
The safety, effectiveness, and pharmacokinetics of belimumab (Benlysta) in children ages 5 to 17 was supported by evidence from adequate and well-controlled studies of belimumab (Benlysta) in the following scenarios: adults with SLE, adults with LN, and pediatric individuals ages 5 to 17 with SLE. The pharmacokinetic data from pediatric individuals was found to be similar to the pharmacokinetic data in adult individuals. It would be expected that the pharmacokinetic exposure would be comparable to adults in pediatric individuals with LN.
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