What is Benlysta?
BENLYSTA is an investigational human monoclonal antibody drug and the first in a new class of drugs called BLyS-specific inhibitors. It is being developed for the treatment of antibody-positive patients with systemic lupus erythematosus (SLE) by HGS and GlaxoSmithKline (GSK) under a co-development and commercialization agreement entered into in 2006 [1-2]. BENLYSTA has successfully met its primary endpoint in two pivotal Phase 3 trials in systemic lupus [3-16]. In June 2010, HGS and GSK submitted regulatory applications seeking approval to market BENLYSTA in the United States and Europe [17-18]. The FDA has granted BENLYSTA a priority review designation with a Prescription Drug User Fee Act (PDUFA) target date of December 9, 2010 – so it is possible that BENLYSTA could receive regulatory approval in the United States before the end of 2010 . It could become the first new approved drug for people living with lupus in more than 50 years.
How BENLYSTA Works
BENLYSTA inhibits the biological activity of B-lymphocyte stimulator, or BLyS. BLyS is a naturally occurring protein discovered by HGS , which is required for the survival and development of B-lymphocyte cells into mature plasma B cells. Plasma B cells produce antibodies, the body’s first line of defense against infection. In lupus and certain other autoimmune diseases, elevated levels of BLyS are believed to contribute to the production of autoantibodies – antibodies that attack and destroy the body’s own healthy tissues. The results of clinical, nonclinical and prospective observational studies show a significant correlation of elevated levels of BLyS with SLE disease activity [21-29].
BENLYSTA acts by:(1) specifically recognizing and binding to BLyS, (2) inhibiting BLyS’s stimulation of B-cell development, and (3) restoring the potential for autoantibody-producing B cells to undergo the normal process of apoptosis (programmed cell death). Preclinical and clinical studies demonstrated that BENLYSTA reduced autoantibody levels in SLE [3-29]. The results of two pivotal Phase 3 trials, BLISS-52 and BLISS-76, demonstrated that BENLYSTA reduced SLE disease activity [3-16].
Figure 1. BENLYSTA (belimumab) specifically binds to and inhibits the biological activity of BLyS, thus restoring the potential of autoantibody-producing B cells to undergo the normal process of programmed call death. Preclinical and clinical results to date demonstrated that BENLYSTA reduced autoantibody levels in SLE. The results of two pivotal Phase 3 trials demonstrated that BENLYSTA reduced SLE disease activity.
Collaboration with GlaxoSmithKline
In August 2006, HGS and GSK entered into a co-development and commercialization agreement under which HGS has conducted the BENLYSTA Phase 3 trials, with assistance from GSK. The companies will share equally in Phase 3/4 development costs, sales and marketing expenses, and profits of any product commercialized under the agreement. [1-2]
Potential Treatment Settings
HGS and GSK are working closely together to develop BENLYSTA (belimumab) as a potential new treatment for antibody-positive systemic lupus erythematosus (SLE) and other autoimmune diseases. SLE is a chronic, life-threatening autoimmune disease. Approximately five million people worldwide, including approximately 1.5 million in the United States, suffer from various forms of lupus, including SLE.
HGS and GSK are also examining a range of potential additional indications for BENLYSTA that might be explored in Phase 2 clinical trials, including vasculitis and post-renal transplant. In addition, a number of small proof-of-concept studies are already ongoing or imminent in Sjögren’s syndrome, Waldenstrom’s disease, pre-transplant and idiopathic thrombocytopenic purpura (ITP).
Figure 2. In healthy people, the body signals autoantibody-producing B cells to kill themselves through apoptosis. In patients with autoimmune diseases, such as lupus, the BLyS protein stimulates B-cell hyperactivity and inhibits apoptosis. This allows autoantibody-producing B cells to mature and release autoantibodies into the body. Autoantibodies then attack the body’s own tissues, causing autoimmune diseases like lupus.
Phase 3 Clinical Development Program
The Phase 3 development program for belimumab included two double-blind, placebo-controlled, multi-center Phase 3 superiority trials – BLISS-52 and BLISS-76 – to evaluate the efficacy and safety of belimumab plus standard of care, versus placebo plus standard of care, in antibody-positive (HEp-2 ANA > 1:80 and/or anti-dsDNA > 30 IU/mL) patients with SLE [30-35]. Both BLISS-52 and BLISS-76 have now been completed. This is the largest clinical trial program ever conducted in lupus patients. BLISS-52 randomized and treated 865 patients at 90 clinical sites in 13 countries, primarily in Asia, South America and Eastern Europe. BLISS-76 randomized and treated 819 patients at 136 clinical sites in 19 countries, primarily in North America and Europe.
The design of the two trials was similar, but the duration of therapy in the two studies was different – 52 weeks for BLISS-52 and 76 weeks for BLISS-76. The data from the BLISS-76 Phase 3 study were analyzed after 52 weeks in accord with the study protocol, in support of the BLA and MAA submissions. The BLISS-76 study then continued for an additional 24 weeks through the full 76-week treatment period, with the objective of generating additional information about belimumab based on a variety of secondary endpoints. HGS designed the Phase 3 program for belimumab in collaboration with GSK and leading international SLE experts, and the program is being conducted under a Special Protocol Assessment agreement with FDA .
Clinical Progress to Date
BENLYSTA (belimumab) has met the primary efficacy endpoint in two pivotal Phase 3 trials, as specified by Special Protocol Assessment agreement with FDA [3-16, 33]. The efficacy of treatment with BENLYSTA plus standard of care was superior to placebo plus standard of care in both BLISS-52 and BLISS-76, with overall adverse event rates comparable to placebo plus standard of care. In June 2010, HGS and GSK submitted regulatory applications seeking approval to market BENLYSTA in the United States and Europe [17-18]. The FDA granted BENLYSTA a priority review designation with a Prescription Drug User Fee Act (PDUFA) target date of December 9, 2010 – so it is possible that BENLYSTA could receive regulatory approval in the United States before the end of 2010 .