belimumab

Belimumab is indicated for the treatment of active systemic lupus erythematosus and active lupus nephritis.

Common adverse effects reported with belimumab include nausea, diarrhea, and fever, as well as hypersensitivity and infusion-site reactions, which were severe in 0.9% of patients. Regulatory agencies recommend that patients be treated with an antihistamine prior to a belimumab infusion.European Medicines Agency: [http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002015/WC500110150.pdf Benlysta Summary of Product Characteristics] {{Webarchive|url=https://web.archive.org/web/20180618210520/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002015/WC500110150.pdf |date=18 June 2018 }}

Because belimumab is an immunosuppressant, more serious infections and deaths were reported among patients treated with the drug than among those treated with placebo.{{cite web|url=http://www.gsk.com/media/pressreleases/2011/2011_us_pressrelease_10017.htm |title=GlaxoSmithKline and Human Genome Sciences announce FDA approval of Benlysta (belimumab) for the treatment of systemic lupus erythematosus |access-date=11 March 2011 |date=9 March 2011 |publisher=GlaxoSmithKline |url-status=dead |archive-url=https://web.archive.org/web/20110317151651/http://www.gsk.com/media/pressreleases/2011/2011_us_pressrelease_10017.htm |archive-date=17 March 2011 }}

No interaction studies have been carried out, but combining belimumab with other immunosuppressants—especially those targeting B lymphocytes, such as anti-CD20 therapies—could increase the risk of severe infections. Likewise, combining belimumab with intravenous cyclophosphamide or live vaccines is not recommended.

File:Belimumab 5Y9K binding BAFF homotrimer.png illustrating three molecules of belimumab (tan/orange) binding a homotrimer of BAFF. {{PDB|5Y9J}}.]]

B lymphocytes (B cells), which are part of the normal immune response, are also responsible for the over-aggressive response seen in autoimmune diseases like systemic lupus erythematosus. B cells develop in the bone marrow and continue to mature peripherally in secondary lymphoid organs and in the gut. When autoimmune B cells attack the body's own tissues, they are normally destroyed by cell suicide (apoptosis). Researchers theorize that systemic lupus erythematosus is caused when autoimmune B cells proliferate and survival factors protect them from cell suicide.{{medcn|date=February 2023}}

B-cell activating factor (BAFF), also called B-lymphocyte stimulator (BLyS), is required for the development and survival of B cells. In systemic lupus erythematosus patients, BAFF is overexpressed, which may cause autoimmune B cell proliferation and survival. Belimumab binds to BAFF and prevents it from binding to B cells. Without BAFF, B cells commit suicide and no longer contribute to the autoimmune damage of systemic lupus erythematosus.{{medcn|date=February 2023}}

BAFF is secreted by a variety of cells: monocytes and macrophages; bone marrow stromal cells; astrocytes in certain glioblastomas; synoviocytes in rheumatoid arthritis; and salivary epithelial cells in Sjögren syndrome. It interacts with three membrane receptors on B lymphocytes:{{medcn|date=February 2023}}

• BAFF-R (BAFF receptor)
• BCMA (B cell maturation antigen)
• TACI (transmembrane activator and calcium modulator and cyclophylin ligand interactor)

When BAFF binds to BAFF-R and BCMA on B cells, levels of Bcl-2, a survival factor, are increased. When all three BAFF receptors are stimulated, levels of NF kappa B, which contributes to cell proliferation and differentiation, are increased in the nucleus.{{medcn|date=February 2023}}

Another B-cell activator similar to BAFF is APRIL (A proliferation-inducing ligand),{{cite journal | vauthors = Schneider P | title = The role of APRIL and BAFF in lymphocyte activation | journal = Current Opinion in Immunology | volume = 17 | issue = 3 | pages = 282–289 | date = June 2005 | pmid = 15886118 | doi = 10.1016/j.coi.2005.04.005 | url = https://serval.unil.ch/notice/serval:BIB_2A4D71FFC1D3 }} but APRIL activates only BCMA and TACI, not BAFF-R.{{medcn|date=February 2023}}

Belimumab reduces the number of circulating B cells, but anti-CD20 monoclonal antibodies reduce the number even more. It is possible that belimumab binds primarily to circulating soluble BAFF and therefore does not induce the antibody-dependent cellular cytotoxicity that could be expected from this IgG1-type antibody.June 2007 European League against Rheumatism symposium..{{better citation needed|date=October 2021}}

B-cell activating factor is a naturally occurring protein that was discovered by researchers from National Jewish Health (previously the National Jewish Medical and Research Center) and the University of Colorado, who jointly published a paper detailing their findings in May 1999 and named the protein TALL-1.{{cite journal | vauthors = Shu HB, Hu WH, Johnson H | title = TALL-1 is a novel member of the TNF family that is down-regulated by mitogens | journal = Journal of Leukocyte Biology | volume = 65 | issue = 5 | pages = 680–683 | date = May 1999 | pmid = 10331498 | doi = 10.1002/jlb.65.5.680 | s2cid = 1498303 | doi-access = free }} The same protein was named BAFF in another paper published in June 1999, and in a paper published in July of that year, Human Genome Sciences (HGS) referred to it as BLyS (short for B lymphocyte stimulator).{{cite journal | vauthors = Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM | title = BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator | journal = Science | volume = 285 | issue = 5425 | pages = 260–263 | date = July 1999 | pmid = 10398604 | doi = 10.1126/science.285.5425.260 | first7 = D }} Six years later, research showing the key role of BLyS in B cell differentiation, survival, and activation was published.{{cite journal | vauthors = Crowley JE, Treml LS, Stadanlick JE, Carpenter E, Cancro MP | title = Homeostatic niche specification among naïve and activated B cells: a growing role for the BLyS family of receptors and ligands | journal = Seminars in Immunology | volume = 17 | issue = 3 | pages = 193–199 | date = June 2005 | pmid = 15826824 | doi = 10.1016/j.smim.2005.02.001 }}

In October 2000, HGS and Cambridge Antibody Technology (CAT) agreed to co-develop monoclonal antibodies targeted at BLyS. Under this agreement, CAT would identify antibodies and HGS would select appropriate ones to take into clinical trials.{{cite web |url=http://www.hgsi.com/benlysta-belimumab-3.html |title=Benlysta (belimumab) |publisher=Human Genome Sciences |access-date=11 March 2011 |archive-url=https://web.archive.org/web/20110421233142/http://hgsi.com/benlysta-belimumab-3.html |archive-date=21 April 2011 |url-status=dead }} In 2003, CAT researchers reported that, by using phage display technology, they had elicited an array of more than 1,000 distinct antibodies, half of which inhibited binding of BLyS to its receptor.{{cite journal | vauthors = Edwards BM, Barash SC, Main SH, Choi GH, Minter R, Ullrich S, Williams E, Du Fou L, Wilton J, Albert VR, Ruben SM, Vaughan TJ | title = The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS | journal = Journal of Molecular Biology | volume = 334 | issue = 1 | pages = 103–118 | date = November 2003 | pmid = 14596803 | doi = 10.1016/j.jmb.2003.09.054 }} Later that year, one of these antibodies was isolated and characterized. It was named LymphoStat-B and subsequently called belimumab.{{cite journal | vauthors = Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern WG, Lappin PB, Riccobene T, Abramian D, Sekut L, Sturm B, Poortman C, Minter RR, Dobson CL, Williams E, Carmen S, Smith R, Roschke V, Hilbert DM, Vaughan TJ, Albert VR | title = Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator | journal = Arthritis and Rheumatism | volume = 48 | issue = 11 | pages = 3253–3265 | date = November 2003 | pmid = 14613291 | doi = 10.1002/art.11299 }}

In August 2006, HGS and GlaxoSmithKline (GSK) entered into a co-development and commercialization agreement under which HGS would conduct Phase III trials for belimumab with assistance from GSK. The companies would share equally in Phase III/IV development costs, sales and marketing expenses, and profits of any product commercialized under the agreement. On 13 February 2007, HGS and GSK announced the initiation of the first of two Phase III clinical trials of belimumab in patients with active lupus erythematosus.{{cite press release|title=Human Genome Sciences And Glaxosmithkline Announce Initiation Of Phase 3 Clinical Trial Of Lymphostat-B In Systemic Lupus Erythematosus|date=13 February 2007|publisher=Human Genome Sciences|url=http://www.hgsi.com/latest/human-genome-sciences-and-glaxosmithkline-announce-initiation-of-phase-3-clinical-trial-of-lymphostat-b-reg-in-systemic-lupus-erythema-2.html|access-date=11 March 2011|url-status=dead|archive-url=https://web.archive.org/web/20110425024219/http://hgsi.com/latest/human-genome-sciences-and-glaxosmithkline-announce-initiation-of-phase-3-clinical-trial-of-lymphostat-b-reg-in-systemic-lupus-erythema-2.html|archive-date=25 April 2011}}

Two Phase III clinical studies were conducted, involving a total of 1,684 patients with scores of ≥6 on the SELENA-SLEDAI assessment of lupus activity. The primary end point was a reduction of ≥4 on the SELENA-SLEDAI assessment, and several other factors, after 52 weeks. Belimumab significantly improved the response rate, reduced disease activity and severe flares, and was well tolerated. Among patients treated with belimumab (10mg/kg) in addition to standard therapy, 58% had SELENA-SLEDAI scores reduced by ≥4 points over 52 weeks, compared with 46% of patients treated with placebo. However, patients of African-American or African descent did not respond significantly to belimumab.[https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM241199.pdf Summary Minutes of the Arthritis Advisory Committee Meeting November 16, 2010] {{Webarchive|url=https://web.archive.org/web/20170304123931/https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisdrugsadvisorycommittee/ucm241199.pdf |date=4 March 2017 }} U.S. Food and Drug Administration (FDA)[https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/ucm203434.htm 2010 Meeting Materials, Arthritis Advisory Committee] {{Webarchive|url=https://web.archive.org/web/20120329221010/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/ucm203434.htm |date=29 March 2012 }} U.S. Food and Drug Administration (FDA)

These trials did not include patients with the most severe forms of systemic lupus erythematosus, which involve active damage to the kidneys or central nervous system. Subjects with active kidney disease were included in Phase II trials.Andrew Pollack, [http://prescriptions.blogs.nytimes.com/2011/03/09/f-d-a-approves-new-lupus-drug/ "F.D.A. Approves Benlysta, a New Lupus Drug"] {{Webarchive|url=https://web.archive.org/web/20201112013844/https://prescriptions.blogs.nytimes.com/2011/03/09/f-d-a-approves-new-lupus-drug/ |date=12 November 2020 }}, The New York Times, 9 March 2011

Clinical trials found belimumab to be safe in treating systemic lupus erythematosus,{{cite journal | vauthors = Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, León MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA | title = Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial | journal = Lancet | volume = 377 | issue = 9767 | pages = 721–731 | date = February 2011 | pmid = 21296403 | doi = 10.1016/S0140-6736(10)61354-2 | url = http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961354-2/fulltext | access-date = 31 October 2012 | url-status = live | collaboration = BLISS-52 Study Group | s2cid = 28952240 | archive-url = https://web.archive.org/web/20121017121223/http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61354-2/fulltext | archive-date = 17 October 2012 }}{{cite journal | vauthors = Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzová D, Sanchez-Guerrero J, Schwarting A, Merrill JT, Chatham WW, Stohl W, Ginzler EM, Hough DR, Zhong ZJ, Freimuth W, van Vollenhoven RF | title = A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus | journal = Arthritis and Rheumatism | volume = 63 | issue = 12 | pages = 3918–3930 | date = December 2011 | pmid = 22127708 | pmc = 5007058 | doi = 10.1002/art.30613 | collaboration = BLISS-76 Study Group }}{{cite journal | vauthors = Lee YH, Song GG | title = Comparative efficacy and safety of intravenous or subcutaneous belimumab in combination with standard therapy in patients with active systemic lupus erythematosus: a Bayesian network meta-analysis of randomized controlled trials | journal = Lupus | volume = 27 | issue = 1 | pages = 112–119 | date = January 2018 | pmid = 28592201 | doi = 10.1177/0961203317713143 | s2cid = 26026994 | doi-access = free }} but the magnitude of benefit was small,[http://www.hopkinsarthritis.org/arthritis-news/lupus-news/belimumab-the-1st-drug-to-be-fda-approved-for-the-treatment-of-lupus-since-1955/ Belimumab: The first drug to be FDA approved for the treatment of lupus since 1955] {{Webarchive|url=https://web.archive.org/web/20210913120358/https://www.hopkinsarthritis.org/arthritis-news/lupus-news/belimumab-the-1st-drug-to-be-fda-approved-for-the-treatment-of-lupus-since-1955/ |date=13 September 2021 }}, By Rebecca Manno, Johns Hopkins Arthritis Center, 15 July 2011 and Phase III trials excluded the most severe cases of systemic lupus erythematosus, involving kidney and brain damage. Reviewers at the US Food and Drug Administration (FDA) expressed concern that the drug was only "marginally" effective, and that there were more deaths in the treatment group. Defenders said that in addition to its modest efficiency, belimumab allowed patients to significantly reduce their use of corticosteroids.{{cite web |url=http://www.medscape.com/viewarticle/739330_2 |title=Should Belimumab Have Been Approved? Stephen Paget, Medscape Rheumatology, Mar 24, 2011 |access-date=27 April 2013 |archive-date=16 November 2015 |archive-url=https://web.archive.org/web/20151116220815/http://www.medscape.com/viewarticle/739330_2 |url-status=live }}

Belimumab was not effective in Phase II clinical trials for rheumatoid arthritis.{{ClinicalTrialsGov|NCT00071812|A Safety and Efficacy Study of LymphoStat-B (Monoclonal Anti-BLyS Antibody) in Subjects With Rheumatoid Arthritis}}. It was moderately effective in Phase II trials for Sjögren syndrome.{{cite web |url=http://clinicaltrials.gov/ct2/show/NCT01160666 |title=Efficacy and Safety of Belimumab in Subjects With Primary Sjögren's Syndrome (BELISS) |date=July 2012 |access-date=1 November 2012 |archive-date=18 October 2012 |archive-url=https://web.archive.org/web/20121018230037/http://www.clinicaltrials.gov/ct2/show/NCT01160666 |url-status=live }}

In December 2020, belimumab was approved by the FDA as a treatment for lupus nephritis in combination with standard treatment.{{cite news|url=https://www.the-rheumatologist.org/article/fda-approves-belimumab-voclosporin-for-lupus-nephritis/|title=FDA Approves Belimumab & Voclosporin for Lupus Nephritis|publisher=The Rheumatologist|date=24 March 2021|access-date=3 May 2021|archive-date=5 May 2021|archive-url=https://web.archive.org/web/20210505201535/https://www.the-rheumatologist.org/article/fda-approves-belimumab-voclosporin-for-lupus-nephritis/|url-status=live}}

Under the brand name Benlysta, belimumab received FDA approval for the treatment of systemic lupus erythematosus in March 2011,{{cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm246489.htm | archive-url = https://web.archive.org/web/20110311142824/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm246489.htm | url-status = dead | archive-date = 11 March 2011 | date = 9 March 2011 | title = FDA approves Benlysta to treat lupus | publisher = U.S. Food and Drug Administration (FDA) }} despite concerns among advisory committee members that the improvement of 4 points on the SELENA-SLEDA scale was marginal, and despite reservations about additional deaths in the treatment group.[http://www.medpagetoday.com/Rheumatology/Lupus/23324 FDA Questions Safety, Efficacy of Belimumab] {{Webarchive|url=https://web.archive.org/web/20210303145232/https://www.medpagetoday.com/Rheumatology/Lupus/23324 |date=3 March 2021 }}, By Emily P. Walker, Washington Correspondent, MedPage Today, 12 November 2010{{cite web | vauthors = Pollack A | title=Benlysta, Lupus Treatment, Endorsed by F.D.A. | website=The New York Times | date=16 November 2010 | url=https://www.nytimes.com/2010/11/17/health/17drug.html | access-date=29 July 2020 | archive-date=9 November 2020 | archive-url=https://web.archive.org/web/20201109033133/http://www.nytimes.com/2010/11/17/health/17drug.html | url-status=live }} It was subsequently approved in Canada and the European Union as well.

In February 2023, belimumab was given orphan drug designation by the FDA for the potential treatment of systemic sclerosis.{{cite press release |title=Benlysta granted Orphan Drug Designation by US FDA for the potential treatment of systemic sclerosis |url=https://www.gsk.com/en-gb/media/press-releases/benlysta-granted-orphan-drug-designation-by-us-fda-for-the-potential-treatment-of-systemic-sclerosis/ |access-date=9 February 2023 |website=GSK |archive-date=9 February 2023 |archive-url=https://web.archive.org/web/20230209100018/https://www.gsk.com/en-gb/media/press-releases/benlysta-granted-orphan-drug-designation-by-us-fda-for-the-potential-treatment-of-systemic-sclerosis/ |url-status=live }}{{cite web |title=GSK Says Benlysta Granted Orphan Drug Designation By FDA |url=https://www.marketscreener.com/quote/stock/GSK-PLC-9590199/news/GSK-Says-Benlysta-Granted-Orphan-Drug-Designation-By-FDA-42862719/ |access-date=9 February 2023 |website=MarketScreener |date=February 2023 |archive-date=9 February 2023 |archive-url=https://web.archive.org/web/20230209101524/https://www.marketscreener.com/quote/stock/GSK-PLC-9590199/news/GSK-Says-Benlysta-Granted-Orphan-Drug-Designation-By-FDA-42862719/ |url-status=live }}

Belimumab is primarily used in people with systemic lupus erythematosus. When it was introduced in 2011, it was the first new drug approved to treat lupus in 56 years. Sales rose to $31.2 million in the first quarter of 2012.[https://finance.yahoo.com/news/hgsi-cuts-loss-benlysta-sales-184526054.html HGSI Cuts Loss on Benlysta Sales] {{Webarchive|url=https://web.archive.org/web/20190407204253/https://finance.yahoo.com/news/hgsi-cuts-loss-benlysta-sales-184526054.html |date=7 April 2019 }}, By Zacks Equity Research, 26 April 2012

The total cost for the first year of treatment with belimumab is $28,000. Belimumab is much more expensive than other drugs used to treat lupus, including prednisone ($140 per year), hydroxychloroquine ($132), oral methotrexate ($432), azathioprine ($468), and mycophenolate mofetil ($1,224).{{cite journal | vauthors = Hahn BH | title = Belimumab for systemic lupus erythematosus | journal = The New England Journal of Medicine | volume = 368 | issue = 16 | pages = 1528–1535 | date = April 2013 | pmid = 23594005 | doi = 10.1056/NEJMct1207259 }}

In the United Kingdom, the National Institute for Health and Care Excellence calculated the cost of belimumab at £61,200 per quality-adjusted life year (QALY). This is more than the normally accepted cost of £20,000 to £30,000 per QALY. The manufacturer offered the UK National Health Service a discount of a confidential amount, which still did not bring it into the acceptable range.[http://www.nice.org.uk/newsroom/pressreleases/SystemicLupusBelimumabFAD.jsp NICE publishes draft guidance on belimumab for systemic lupus erythematosus] {{Webarchive|url=https://web.archive.org/web/20120912161720/http://www.nice.org.uk/newsroom/pressreleases/SystemicLupusBelimumabFAD.jsp |date=12 September 2012 }}, press release, 26 April 2012

Blisibimod, an inhibitor of both soluble and membrane-bound BAFF, has demonstrated similar reductions of B cells in clinical trials and is being investigated in a Phase II clinical study for patients with lupus.

BR3-Fc, a recombinant fusion protein built with the extracellular ligand-binding portion of BAFF-R, blocks activation of this receptor by BLyS and is in early-stage pharmaceutical development.{{cite journal | vauthors = Vugmeyster Y, Seshasayee D, Chang W, Storn A, Howell K, Sa S, Nelson T, Martin F, Grewal I, Gilkerson E, Wu B, Thompson J, Ehrenfels BN, Ren S, Song A, Gelzleichter TR, Danilenko DM | title = A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys | journal = The American Journal of Pathology | volume = 168 | issue = 2 | pages = 476–489 | date = February 2006 | pmid = 16436662 | pmc = 1606502 | doi = 10.2353/ajpath.2006.050600 }}

Rituximab, an anti-CD20 monoclonal antibody, has been approved for some indications. Ocrelizumab, ofatumumab, and "third-generation" anti-CD20 monoclonals are in development.{{cn|date=February 2023}}

Other drugs addressing B lymphocyte hyperactivity include atacicept, a recombinant fusion protein that is built with the extracellular ligand binding portion of TACI and blocks activation of TACI by APRIL and BLyS. It failed a Phase II trial for multiple sclerosis.{{ClinicalTrialsGov|NCT00642902|Atacicept in Multiple Sclerosis, Phase II}}{{cite journal | vauthors = Kappos L, Hartung HP, Freedman MS, Boyko A, Radü EW, Mikol DD, Lamarine M, Hyvert Y, Freudensprung U, Plitz T, van Beek J | title = Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial | journal = The Lancet. Neurology | volume = 13 | issue = 4 | pages = 353–363 | date = April 2014 | pmid = 24613349 | doi = 10.1016/S1474-4422(14)70028-6 | collaboration = ATAMS Study Group | s2cid = 38926361 }}

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