Status: FDA approval in March 2011; EU approval in May 2013

Organizations involved:

Human Genome Sciences Inc. - Manuf.; R&D; Tech.; World mark.

GlaxoSmithKline plc - World mark.

National Jewish Medical and Research Center –R&D; Tech.

Lonza AG - Manuf.

DRI Capital - Tech.

Biogen-Idec - Tech.; Former

University of Colorado – Tech.

Cambridge Antibody Technology – R&D

MedImmune, Inc. – Parent

AstraZeneca plc – Parent

Genentech/Roche – Patent dispute

Eli Lilly & Co. – Patent dispute

Description: Benlysta (formerly LymphoStat-B) is a lyophilized (freeze-dried) formulation of belimumab, a recombinant fully IgG1gamma human monoclonal antibody directed against a soluble B-lymphocyte stimulator, BLyS (previously described by HGSI as B-cell-activating factor of BAFF; also reported as TALL-1) expressed by an unspecified "mammalian cell expression system." Belimumab binds to soluble BLyS with high affinity and prevents the binding of BLyS to its receptors. Belimumab has a molecular weight of approximately 147 kDa.

Benlysta is supplied as a sterile preservative-free, powder for reconstitution, dilution, and intravenous infusion provided in single-use glass vials with a latex-free rubber stopper and a flip-off seal. Each 5-mL vial contains 120 mg of belimumab. Each 20 mL vial contains 400 mg of belimumab.. Upon reconstitution with Sterile Water for Injection, USP, each single-use vial delivers 80 mg/mL belimumab in 0.16 mg/mL citric acid, 0.4 mg/mL polysorbate 80 (Tween 80), 2.7 mg/mL sodium citrate, and 80 mg/mL sucrose, with a pH of 6.5. Vials are stored refrigerated between 2-8°C (36-46°F).

Nomenclature: B-cell-activating factor Mab, rDNA [BI]; belimumab [USAN INN]; Benlysta [TR]; LymphoStat-B [TR former]; Immunoglobulin G1, anti-(human cytokine BAFF) (human monoclonal LymphoStat-B heavy chain), disulfide with human monoclonal LymphoStat-B l-chain, dimer [CAS]; 356547-88-1 [CAS RN]; D03068 [SY]; NDC 49401-101-01 and NDC 49401-102-01 [NDC]

Bioloigical: Belimumab potently inhibits BLyS-induced proliferation of B cells in vitro and prevents human BLyS-induced increases in splenic B-cell numbers and serum IgA titers in mice. In cynomolgus monkeys treated with belimumab, reductions as great as 75% were observed in the number of lymphoid tissue and peripheral blood CD20+ B cells and CD21+ plasmacytoid cells. Intravenous doses of up to 50 mg/kg delivered every 2 weeks over 6 months were well tolerated in cynomolgus monkeys. On discontinuation of belimumab in cynomolgus monkeys, the numbers of peripheral blood CD20+ B cells recovered to normal levels within 3 to 5 months.

Belimumab is the first in a new class of pharmaceuticals called BLyS-specific inhibitors. It is a human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS (note, a trademark for "BLyS" is claimed/application pending), previously described by HGSI as BAFF (B-cell-activating factor). BLyS is a naturally occurring protein discovered by HGSI that is required for the development of B-lymphocyte cells into mature plasma B cells. BLyS plays a role in B-cell maturation and survival, as well as immunoglobulin (Ig) class switching. These plasma B cells produce antibodies.

The BLyS protein was discovered by researchers from the National Jewish Medical and Research Center and the University of Colorado and announced in 1999.

BLyS is a member of the tumor necrosis factor (TNF) ligand superfamily of cytokines that is expressed and secreted by monocytes, macrophages, dendritic cells, and granulocyte colony-stimulating factor activated neutrophils. BLyS exists in both membrane-bound and soluble forms. BLyS is expressed as a 285 amino acid type II membrane-bound polypeptide and a soluble 152 amino acid polypeptide. The biologically active, soluble form of BLyS is enzymatically cleaved from the cell membrane and can bind to any of three receptors: TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor); BCMA (B-cell Maturation Antigen); and BAFF-R (B-cell lymphocyte activating factor receptor)/BLyS receptor 3, localized primarily on B lymphocytes. BLyS contributes to B-cell proliferation and differentiation, and it is important in immunoglobulin class switching. Constitutive over-expression of BLyS in transgenic mice results in the development of an autoimmune-like disease that is characterized by hypergammaglobulinemia, autoantibody production, and glomerulonephritis. In murine lupus, treatment with a BLyS antagonist significantly reduces the occurrence of proteinuria and prolongs survival. Elevated BLyS blood levels have been found in some patients with SLE, and observational studies show that BLyS concentrations change over time in the majority of SLE patients. Increases in BLyS levels correlate with increased disease activity and were predictive of future disease activity, suggesting that BLyS may be a biomarker for SLE.

In lupus, rheumatoid arthritis, and certain other autoimmune diseases, such as systemic lupus erythematosus (SLA), 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 presence of autoantibodies appears to correlate with disease severity. Preclinical and clinical studies demonstrate that B-cell antagonists can reduce autoantibody levels and help control autoimmune disease activity.

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 show that BLyS antagonists, such as Benlysta, can reduce autoantibody levels in SLE. It is conjectured that belimumab binds primarily to circulating soluble BLyS.

HGSI discovered BLyS or B-lymphocyte stimulator in 1997 and published a preliminary description of its activity in Science in July 1999. Belimumab is a fully human monoclonal antibody that HGSI generated through a collaboration with Cambridge Antibody Technology (CAT, now part of MedImmune, a subsidiary of AstraZenaca), using CAT's proprietary phage display-based antibody generation and screening technology.

Companies.: Benlysta was initially developed and is manufactured by Human Genome Sciences Inc. (HGSI), CBER/FDA est. no. 1820. Most manufacturing is being initially performed by HGSI, with this considered satisfactory to meet demand for 2-3 years after launch. Human Genome Sciences reportedly spent 15 years developing developing Benlysta.

In August 2006, HGSI entered into a definitive co-development and co-commercialization agreement with GlaxoSmithKline plc (GSK). HGSI has responsibility for conducting the Phase III trials, with assistance from GSK. The companies will share equally in Phase III/IV development costs, sales and marketing expenses, and profits of any product commercialized under the agreement.

In July 2010, HGSI contracted with Lonza AG for additional manufacturing capacity for Benlysta.

Manufacture: HGSI in collaboration with Cambridge Antibody Technology (Cambridge, UK; subsequently acquired by AstraZeneca in 2006), originally screened a human single-chain antibody (scFv) phage library to detect scFvs that bind to human BLyS (Fig. 2). This initial screening resulted in ~3,000 scFvs with BLyS-binding activity, of which ~1,200 displayed significant BLyS inhibitory activity. HGSI then used its high-throughput sequencing capabilities to determine the heavy- and light-chain variable sequences used by each clone. Based on inhibitory activity and VH/VJ family homology, a select number (~50) of scFvs were cloned into expression vectors containing IgG1 heavy and lambda light chain constant region sequences (that is, converted to full-length human immunoglobulins). Subsequent rounds of affinity maturation, conversion and functional analyses yielded two fully human mAbs, each of which bound BLyS with high affinity and antagonized its ability to interact with its cognate cellular receptors. One of these clones was selected for further development and initially called ‘LymphoStat B’, a name that was eventually replaced by belimumab.

In Sept. 2012, Biogen-Idec sold its patent-related royalty interest in Benlysta to DRI Capital (formerly Drug Royalty Corporation Inc.). Human Genome Sciences and Glaxo Group Limited will make royalty payments directly to DRI instead of to Biogen Idec. Human Genome Sciences and Glaxo Group Limited will make royalty payments directly to DRI instead of to Biogen Idec. DRI will in turn pay Biogen Idec a multiple of certain of the royalties received for the period covering October 2011 to September 2014. Following that period, DRI will retain the royalty payments from the sales of BENLYSTA, with certain exceptions, including a one-time contingency payment that could be triggered if the cumulative royalties to DRI exceed an agreed amount. The multiple paid by DRI to Biogen Idec will vary by year and territory in which the royalties are generated. The initial payment by DRI to Biogen Idec, covering the royalty period from October 1, 2011 to March 30, 2012 is approximately $18.3 million.

FDA class: Biologics BLA

Approvals: Date = 20110309, full BLA (BL 125370)

Indications: [full text of the " "Indications and USAGE" section of the product insert/labeling]:

BENLYSTA is a B-lymphocyte stimulator (BLyS)-specific inhibitor indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus who are receiving standard therapy.

Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

Status: Benlysta received EU EMA approval on July 14, 2011. Benlysta 10mg/kg was approved as an add-on therapy in adult patients with active autoantibody-positive systemic lupus erythematosus (SLE), with a high degree of disease activity (e.g. positive anti-dsDNA and low complement), despite standard therapy. Approval was granted by Health Canada on July 12, 2011

The Benlysta BLA has received priority review and Fast Track designation, and has been selected for participation in the FDA's Continuous Marketing Application Pilot 2 Program.

In Oct. 2009, HGSI received a Special Protocol Assessment (SPA) from FDA agreeing to the company's Phase III clinical development program for LymphoStat-B for treatment of active systemic lupus erythematosus (SLE). The program includes a primary efficacy endpoint that emerged directly from the previously reported results of a Phase II clinical trial -- a combined patient response rate that includes elements of the SELENA SLEDAI and BILAG disease activity indices, as well as the Physician's Global Assessment index. These measures are well known to clinical investigators with experience in SLE. HGSI (and GSK) had previously met with the European Agency for the Evaluation of Medicinal Products (EMEA) received agreement on the major components of the Phase III clinical development program, including the primary efficacy endpoint, target patient population, and dose selection.

On June 4, 2010, GSK submitted a Marketing Authorization Application to the European Medicines Agency, seeking approval to market belimumab in Europe for treatment of autoantibody-positive patients with SLE, and HGS submitted a BLA seeking approval to market belimumab in the United States. No new treatment for lupus has been approved by regulatory authorities in more than 50 years.

On June 9, 2010, HGSI filed the BLA including the results of two pivotal Phase III clinical trials that treated a total of 1,684 autoantibody-positive patients with SLE. In Aug. 2010, FDA granted a priority review designation to Benlysta as a potential treatment for systemic lupus erythematosus (SLE), with a Prescription Drug User Fee Act (PDUFA) target date of Dec. 9, 2010.

In Nov. 2010, an FDA advisory committee voted voted 13 to 2 in favor of approval. However, some panelists were troubled by the fact that Benlysta appears to be less than efficacious or perhaps could even harm African American patients. Nearly every member called on the FDA to reword the labeling to convey that it was not tested on all forms of lupus. Many panelists also said key data, such as deaths during treatment and the impact on African American patients, should continue to be monitored. FDA reviewers had noted that Benlysta might have only a modest effect on lupus symptoms and might raise the risk of death, infection, or psychiatric problems including suicide. Two patients treated with Benlysta during clinical trials killed themselves, while there were no suicides with a placebo.

In making its final decision on approval, FDA and HGSI need to reach an agreement on (1) how to label the product against the pent-up expectations of a poorly treated patient group to enforce some restraint against immediate, wide use of the product post-approval; and (2) how to add a post-approval randomized study and labeling information to address a sign of poor performance in African-Americans – a significant lupus subpopulation. That study was not part of the initial HGSI Phase IV study planning; and the company apparently added a commitment to conduct the study in the run-up to the Nov. 16 advisory committee meeting. Whatever labeling restrictions emerge, they are likely to have minimal impact on the patient demand to try the first new approved therapy in fifty years for lupus.

Perhaps the most difficult concern for FDA approval stemmed from a reversal of treatment effect in the 72 patients of African-American heritage or Indigenous American heritage in the 10 mg dosage part of the major North American study. FDA interpreted the lower efficacy as tied to more drop-outs at the higher dosage in the African-American population, which raised the concern that Benlysta might be toxic in that key subpopulation at higher doses. The drop-outs might signal a hidden toxicity. FDA may want to push labeling restrictions to try to cut off extensive use of the product in this patient group outside of any Phase IV study. This is the type of discussion/dilemma that was expected to push the approval past the PDUFA date of Dec. 9, 2010.

Benlysta received full BLA approval on March 9, 2011. The application had received priority review and Fast Track designation and went through 1 approval cycle, with the PDUFA date met (after the extension by the sponsor filing a major BLA amendment).

With its approval, FDA noted that "African American patients and patients of African heritage participating in the two studies did not appear to respond to treatment with Benlysta. The studies lacked sufficient numbers to establish a definite conclusion. To address this concern, the sponsor has agreed to conduct an additional study of people with those backgrounds to further evaluate the safety and effectiveness of Benlysta for this subgroup of lupus patients."

EMA.EU approval was granted in May 2013.

Tech. transfer: BLyS-related patents include U.S. 6,475,987, " Tall-1 receptor homologues,: assigned to the National Jewish Medical and Research Center (with the Univ. of Colorado also reported as involved).

Belimumab-related patents assigned to HGSI include 7,605,236, granted in 2009 (filed in 2005; exp. in 2025), " Antibodies that immunospecifically bind to B lymphocyte stimulator protein;" 7,220,840, "Antibodies that immunospecifically bind to B lymphocyte stimulator protein;" and 7,138,501, "Antibodies that immunospecifically bind BLyS." As shown by the inclusion of many court and other filings listed in the "Other References" section of 7,605,236, BLyS has been the subject of multiple patent disputes.

In Feb. 2010, in a case brought by Eli Lilly & Co., UK’s Court of Appeals upheld an earlier ruling invalidating a U.K. patent claiming the gene sequence for belimumab. GSK responded that this would not halt Benlysta marketing, with the product protected by a number of other patents.

In April 2011, Genentech (Roche) and the City of Hope filed a patent infringement suit against HGSI, GSK and Lonza alleging infringement of 7,923,221, " Methods of Making Antibody Heavy and Light Chains Having Specificity for a Desired Antigen," more commonly known as Cabilly II (see the Monoclonal Antibodies, recombinant entry). This patent broadly covers recombinant antibody expression and expires in 2018.

Trials: Under the terms of the Special Protocol Assessment, the Phase III development program includes two double- blind, placebo-controlled, multi-center superiority trials, BLISS-52 and BLISS-76, which evaluate the efficacy and safety of Benlysta plus standard of care, versus placebo plus standard of care, in the treatment of patients with active systemic lupus erythematosus (SLE). The primary efficacy endpoint of both studies is the patient response rate at Week 52, as defined by: a reduction from baseline in the SELENA SLEDAI score of at least 4 points; no worsening in Physician's Global Assessment (with worsening defined as an increase in PGA of more than 0.30 points from baseline); no new BILAG A organ domain score and no more than 1 new BILAG B organ domain score from baseline. The total duration of the two studies differs, at 52 weeks (BLISS-52) and 76 weeks (BLISS-76), respectively. Aside from duration, the two studies will have similar protocols. In each of the two Phase III trials, approximately 810 patients were enrolled and randomized to 1 of 3 treatment groups (1 mg/kg LymphoStat-B, 10 mg/kg LymphoStat-B, or placebo). Patients were dosed intravenously on Days 0, 14 and 28, then every 28 days. To be eligible for enrollment in the Phase 3 trials, patients must be serologically active, with unequivocal antinuclear antibody (ANA) test results assessed at 2 independent time points (HEp-2 ANA of at least 1:80 and/or anti-dsDNA of at least 30 IU/mL). Background SLE medications must be stable for a period of at least 30 days prior to Day 0. Important secondary endpoints include the patient response rate at Week 76, the SF-36 Health Survey physical component summary score, fatigue measures, and the percentage of patients with reduction from baseline in average prednisone dose at Weeks 40-52.

In July 2009, positive preliminary data were reported from BLISS-52. Benlysta met the primary endpoint in BLISS-52, with belimumab plus standard of care acheiving a clinically and statistically significant improvement in patient response rate at Week 52, compared with standard of care alone. A 10mg/kg dose of Benyslsta, in combination with standard care, improved patient response rates by 43% at week 52, compared with a 34% response rate in placebo. Study results also showed that Benlysta was generally well tolerated, with adverse event rates comparable between belimumab and placebo treatment groups. Benlysta met the primary endpoint at a robust level of statistical significance. Benlysta also significantly reduced SLE disease activity versus placebo based on a number of other measures, including SELENA SLEDAI and Physician’s Global Assessment. A greater percentage of patients receiving Benlysta also achieved a clinically meaningful reduction in steroid dose.

In Nov. 2009, HGSI reported that Benlysta had met the primary endpoint in BLISS-76, the second of two Phase III trials in patients with systemic lupus erythematosus (SLE). The 819-patient study showed that a statistically significant improvement was shown in patient response rate for belimumab plus standard of care, versus placebo plus standard of care (43.2% for 10 mg/kg Benlysta, 40.6% for 1 mg/kg Benlysta) and 33.8% for placebo). Benlysta also met “prespecified major secondary efficacy endpoints.” For example, 46.9% and 42.8% of patients taking Benlysta 10 mg/kg and 1 mg/kg respectively, experienced an improvement in symptoms as measured by the Selena Sledai scale, compared with 35.6% of patients on standard of care, plus placebo. Benlysta swas generally well-tolerated, with rates of overall adverse events and infections being comparable between treatment groups. At the time, the trial still was expected to run 24 months.

In May 2010, HGSI reported that Benlysta did not meet its secondary goals in the late-stage BLISS-76 trial. This included showing statistically significant improvement at 76 weeks of treatment, and Benlysta failed to reach statistical significance in several other secondary goals. Benlysta had earlier met the main study goal of improving patient conditions at 52 weeks of treatment, and most analysts presumed the secondary findings would not affect prospects for approval (and the trial was likely underpowered at 76 weeks).

Also in May 2012, the German Institute for Quality and Efficiency in Health Care rejected use of Benlysta based on its lack of cost-effectiveness.

Disease: Estimates vary on the number of lupus sufferers in the United States ranging from approximately 300,000 to 1.5 million people. People of all races can have the disease; however, African American women have a 3 times higher incidence (number of new cases) than Caucasian women (with lack of efficacy in Blacks in U.S. trials a major concern to FDA, which is requiring post-approval trials to resolve this).

Medical: The recommended dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter. It should be reconstituted, diluted and administerd as an intravenous infusion only, over a period of 1 hour.

Patients commonly experience infusion reactions, so pre-treatment with anantihistamine should be considered.

Market: Benlysta become the first new treatment for SLE in over 50 years. Some analysts originally projected peak sales of $3 billion/year or more. In Nov. 2010, a Thomson Reuters consensus forecast reported Benlysta annual sales may hit $2.2 billion globally in 2014. some analysts predict peak sales as high as $3 billion to $4 billion a year. Summer Street Research Partners has projected global Benlysta sales to reach $2 billion in 2015.

Benlysta's costs about $35,000 per year. Ths is in line with many other auto-immune disease treatments, but it's more expensive than older therapies, and payers may want to make sure patients first aren't able to get relief on cheaper drugs.

The U.S. launch involved a sales force of 150, about 90% of the reps having experience selling biologics to rheumatologists, the specialists who tend to treat lupus patients.

By the end of 2011, with only $52.3 million in sales reported for the year, it was becoming very clear that Benlysta would not attain blockbuster sales, and that is eventual peak sales would be much less than originally projected.     

In April 2012, final draft guidances issued by the National Institute for Health and Clinical Excellence NICE), U.K., and the Scottish Medicines Consortium concluded that Benlysta (belimumab) could not be considered a cost-effective use of NHS resources for patients with active autoantibody positive systemic lupus erythematosus with a high degree of disease activity despite standard therapy.

In early 2013, it was obvious that Benlysta would not become the multi-$billion blockbuster as many had projected. Sales projections were generally modified to be about $700 million or otherwise <$1 billion/year.