Benlysta® has now been approved for patients with lupus. Read below to learn more about the clinical trials leading to its approval by the FDA.
On July 20, 2009, Human Genome Sciences and GlaxoSmithKline announced positive results from their Phase-III, double-blind, placebo-controlled lupus clinical trial.
This 52-week study, also known as BLISS-52, enrolled 865 patients in 13 countries outside North America and randomized active lupus patients to 10mg/kg active drug (Belimumab, also known as Benlysta®), 1 mg/kg active drug, or placebo (not containing active drug) in addition to their standard lupus medications.
Patients had to fulfill the American College of Rheumatology lupus criteria, have active lupus, and remain on a stable treatment regimen (excluding other biologic therapies or cyclophosphamide) in order to be eligible for the trial. Patients with severe lupus kidney disease and lupus-related neurologic problems were excluded. The study medication was given intravenously (through the veins) two weeks apart for the first two doses, and then every four weeks.
The study was successful in meeting its predetermined primary outcome, which was the percentage of patients with improvement by four or more points in their SELENA SLEDAI score (a validated composite clinical index measuring lupus activity in various organs) without worsening in two other clinical instruments for disease activity (physician global assessment (PGA) and BILAG (another clinical index to measure disease activity).
The response rates were 57.6%, 51.7% and 43.6% for Benlysta® 10mg/kg, 1 mg/kg, and placebo, respectively (the response rates were significantly better in the active drug arms). In addition to improvement in various clinical measurements of disease activity, patients were also able to reduce steroid dosages. Notably, the drug was tolerated well and the safety profile, including the infection rate, was comparable to the placebo arm.
Benlysta® is a fully human monoclonal antibody that blocks the activity of a protein called B lymphocyte stimulator (BLyS). This protein has the ability to activate B-cells to produce autoantibodies (antibodies against self), which promote tissue damage in lupus.
The study findings show that Benlysta® has the potential to become the first new approved lupus drug in decades for people living with lupus. The findings are exciting for both lupus patients and physicians, given that there is currently a paucity of medications that are both safe and effective for lupus.
Based on the information we have from the study, Benlysta® is likely to be used to treat patients with lupus that have an inadequate response to one or more of currently available drugs, such as hydroxychloroquine, mycophenolate mofetil, and/or azathioprine. It is unknown at this point whether Benlysta® will also be effective in Lupus Nephritis and lupus affecting the nervous system, two of the most severe manifestations of lupus.
The developer of Benlysta®, Human Genome Sciences, is sharing development and marketing of the drug with GlaxoSmithKline. They conducted a second Phase-III trial (BLISS-76, conducted in North America and Europe, in which Hospital for Special Surgery was one of the participating centers). The companies are planning to apply for regulatory approval in the first half of next year.
The results of BLISS-76 were announced on November 2, 2009. This trial took place in North America and Europe, and was identical in design to the BLISS-52 trial, except for the fact that the study period was 76 weeks. There were 275 patients in the placebo arm, 271 in the Belimumab 1mg/Kg arm, and 273 in the Belimumab 10 mg/Kg arm. Similar to BLISS-52, only patients with positive serology for ANA (= 1:80 titer) and/or anti-dsDNA autoantibodies were included in the trial.
The primary outcome was the percentage of patients that responded by the SLE Responder Index (defined as improvement by four or more points in their SELENA SLEDAI score without clinically significant worsening in the physician’s global assessment and BILAG) at week 52. The response rates were 43.2%, 40.6% and 33.8% for Benlysta® 10mg/kg, Benlysta®1 mg/kg, and placebo, respectively. Only the higher dose of Benlysta® was significantly more effective than placebo.
Secondary outcomes, including ability to reduce steroid dosage also favored the active drug but were not as strong as in the BLISS-52 trial. The drug was tolerated well and its safety profile, including the infection rate, was comparable to the placebo arm.
The positive results of both Benlysta® trials are welcomed by the rheumatology community as a big step forward in the treatment of lupus. Based on these trials, it is expected that the FDA will approve this drug for SLE in the near future, which is exciting news for patients and physicians. Even more importantly, these trials have opened the way for better designed lupus clinical trials and it is expected that other novel therapeutic agents will follow suit soon.
1. FDA Advisory Committee recommends approval of Benlysta®.
2. More positive clinical trial data presented at the November 2010 ACR meeting.
On 11/16/10, the Arthritis Advisory Committee, after a day of scientific presentations, public hearings and detailed discussions, deliberated in an open forum, and voiced its opinion that it recommends (by a vote of 13 to 2) that the Food and Drug Administration (FDA) approve belimumab for the proposed indication of reducing disease activity in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE). If approved, belimumab, made by Human Genome Sciences (HGS) and its partner GlaxoSmithKline (GSK), will be the first new lupus drug in more than 50 years.
While the FDA is not required to follow the Committee’s recommendation, it typically does. The FDA is expected to make its decision about approving belimumab for marketing by the end of the year.
“Lupus patients and their families, along with lupus investigators who have worked long and hard to understand this most complex disease, are encouraged by important progress in lupus drug development,” says Dr. Peggy Crow, Chair of the Scientific Advisory Board of the Alliance for Lupus Research (ALR). “Today’s decision represents a significant milestone in lupus research. We are hopeful that the decision made today on behalf of the Arthritis Advisory Committee will not only support the FDA approval of belimumab, which will be the first new option for people affected by lupus in more than five decades, but will also provide guidance and insights to help further other research into additional new therapeutic options for people with lupus.”(3)
More good news about Benlysta® came at the national American College of Rheumatology (ACR) Meeting held in Atlanta in November, 2010. More specifically, upon post-hoc sensitivity analysis in the BLISS-76 trial, application of more stringent response criteria (modified SRI for drops of SELENA-SLEDAI of 5-7 points) led to statistically significant improved rates of response, by about 10%, at 76 weeks for the Benlysta® 10mg/kg dose group of patients, but also the 1mg/Kg dose group (SRI 7 only). Furthermore, pooled analysis of 1684 patients from both BLISS-52 and BLISS-76 trials, showed that both reduction and no increases in prednisone doses occurred more frequently in the Benlysta® arms of the trials compared to placebo treated patients. Notably, severe SELENASLEDAI flares in the second half of the trial were almost half as likely in active arm. Clinical responses were accompanied by serologic responses with decreases in several auto-antibodies and increases in depressed complement levels. Although the majority of treated patients had manifestations from their mucocutaneous (skin) and musculoskeletal (joints) systems, improvements were noted in other organ systems. Importantly, the safety profile was similar to placebo. Although activated B cells, including the SLE B cells (CD19-/CD27BRIGHT/CD38BRIGHT), decreased, the Memory B cells (CD20+/CD27+) were preserved, along with protective titers of previous immunizations.
Based on these data, we believe that when this medication is finally approved for lupus, it will provide a reliable and relatively safe therapeutic option for SLE patients with active disease despite already existing therapies. It will also facilitate a reduction in glucocorticoid (steroid) doses in patients with evidence or high risk of toxicity from these medications. More data are needed before this medication can be recommended for the therapy of more severe lupus disease, especially those with nephritis and neurologic disease - as such patients were excluded from the BLISS trials.
1. FDA approves Benlysta®.
On March 9, 2011, the FDA approved Benlysta® for use in patients with lupus.