Belimumab Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:458612180
Type:mab
Mab Type:mab
Source:u
Target:B-cell activating factor (BAFF, BLyS)
Tradename:Benlysta
Dailymedid:Belimumab
Pregnancy Au:C
Pregnancy Au Comment:[1]
Routes Of Administration:Intravenous, subcutaneous
Atc Prefix:L04
Atc Suffix:AG04
Legal Au:S4
Legal Au Comment:[2]
Legal Ca:Rx-only
Legal Ca Comment:/Schedule D[3]
Legal Us:Rx-only
Legal Us Comment:[4]
Legal Eu:Rx-only
Legal Eu Comment:[5]
Cas Number:356547-88-1
Drugbank:DB08879
Chemspiderid:none
Unii:73B0K5S26A
Kegg:D03068
Chembl:1789843
Synonyms:LymphoStat-B
C:6358
H:9904
N:1728
O:2010
S:44

Belimumab, sold under the brand name Benlysta, is a human monoclonal antibody that inhibits B-cell activating factor (BAFF),[6] also known as B-lymphocyte stimulator (BLyS).[7] It is approved in the United States and Canada, and the European Union to treat systemic lupus erythematosus and lupus nephritis.[8]

The most common side effects include bacterial infections, such as bronchitis (infection in the lungs) and infection of the urinary tract (structures that produce or carry urine), diarrhea and nausea (feeling sick).

Medical uses

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

Side effects and interactions

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.[9]

Because belimumab is an immunosuppressant, more serious infections and deaths were reported among patients treated with the drug than among those treated with placebo.[10]

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.

Mechanism of action

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.

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.

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:

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.

Another B-cell activator similar to BAFF is APRIL (A proliferation-inducing ligand),[11] but APRIL activates only BCMA and TACI, not BAFF-R.

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.[12] .

History

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.[13] 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).[14] Six years later, research showing the key role of BLyS in B cell differentiation, survival, and activation was published.[15]

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.[16] 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.[17] Later that year, one of these antibodies was isolated and characterized. It was named LymphoStat-B and subsequently called belimumab.[18]

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.[19]

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.[20] [21]

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.[22]

Clinical trials found belimumab to be safe in treating systemic lupus erythematosus,[23] [24] [25] but the magnitude of benefit was small,[26] 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.[27]

Belimumab was not effective in Phase II clinical trials for rheumatoid arthritis.[28] It was moderately effective in Phase II trials for Sjögren syndrome.[29]

In December 2020, belimumab was approved by the FDA as a treatment for lupus nephritis in combination with standard treatment.[30]

Society and culture

Legal status

Under the brand name Benlysta, belimumab received FDA approval for the treatment of systemic lupus erythematosus in March 2011,[31] 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.[32] [33] 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.[34] [35]

Economics

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.[36]

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).[37]

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.[38]

Research

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.[39]

Rituximab, an anti-CD20 monoclonal antibody, has been approved for some indications. Ocrelizumab, ofatumumab, and "third-generation" anti-CD20 monoclonals are in development.

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.[40]

Notes and References

  1. Web site: Belimumab (Benlysta) Use During Pregnancy . Drugs.com . 5 February 2020 . 29 July 2020 . 4 December 2020 . https://web.archive.org/web/20201204112426/https://www.drugs.com/pregnancy/belimumab.html . live .
  2. Web site: BENLYSTA (GlaxoSmithKline Australia Pty Ltd) . Therapeutic Goods Administration (TGA) . 11 November 2022 . 15 April 2023.
  3. Web site: Benlysta Product information . Health Canada . 22 October 2009 . 17 March 2023.
  4. Web site: Benlysta- belimumab injection, powder, lyophilized, for solution Benlysta- belimumab solution . DailyMed . 17 January 2020 . 29 July 2020 . 25 September 2020 . https://web.archive.org/web/20200925225748/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2fa3c528-1777-4628-8a55-a69dae2381a3 . live .
  5. Web site: Benlysta EPAR . European Medicines Agency (EMA) . 17 September 2018 . 29 July 2020 . 25 October 2020 . https://web.archive.org/web/20201025193634/https://www.ema.europa.eu/en/medicines/human/EPAR/benlysta . live .
  6. Bossen C, Schneider P . BAFF, APRIL and their receptors: structure, function and signaling . Seminars in Immunology . 18 . 5 . 263–275 . October 2006 . 16914324 . 10.1016/j.smim.2006.04.006 .
  7. Kaveri SV, Mouthon L, Bayry J . Basophils and nephritis in lupus . The New England Journal of Medicine . 363 . 11 . 1080–1082 . September 2010 . 20825323 . 10.1056/NEJMcibr1006936 .
  8. GlaxoSmithKline . Benlysta now approved in Canada in addition to standard therapy for treatment of active lupus nephritis in adult patients . Newswire . 30 July 2021 . 17 March 2023.
  9. [European Medicines Agency]
  10. Web site: GlaxoSmithKline and Human Genome Sciences announce FDA approval of Benlysta (belimumab) for the treatment of systemic lupus erythematosus . 11 March 2011 . 9 March 2011 . GlaxoSmithKline . dead . https://web.archive.org/web/20110317151651/http://www.gsk.com/media/pressreleases/2011/2011_us_pressrelease_10017.htm . 17 March 2011 .
  11. Schneider P . The role of APRIL and BAFF in lymphocyte activation . Current Opinion in Immunology . 17 . 3 . 282–289 . June 2005 . 15886118 . 10.1016/j.coi.2005.04.005 .
  12. June 2007 European League against Rheumatism symposium.
  13. Shu HB, Hu WH, Johnson H . TALL-1 is a novel member of the TNF family that is down-regulated by mitogens . Journal of Leukocyte Biology . 65 . 5 . 680–683 . May 1999 . 10331498 . 10.1002/jlb.65.5.680 . 1498303 . free .
  14. 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 . BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator . Science . 285 . 5425 . 260–263 . July 1999 . 10398604 . 10.1126/science.285.5425.260 . D .
  15. Crowley JE, Treml LS, Stadanlick JE, Carpenter E, Cancro MP . Homeostatic niche specification among naïve and activated B cells: a growing role for the BLyS family of receptors and ligands . Seminars in Immunology . 17 . 3 . 193–199 . June 2005 . 15826824 . 10.1016/j.smim.2005.02.001 .
  16. Web site: Benlysta (belimumab) . Human Genome Sciences . 11 March 2011 . https://web.archive.org/web/20110421233142/http://hgsi.com/benlysta-belimumab-3.html . 21 April 2011 . dead .
  17. 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 . The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS . Journal of Molecular Biology . 334 . 1 . 103–118 . November 2003 . 14596803 . 10.1016/j.jmb.2003.09.054 .
  18. 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 . Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator . Arthritis and Rheumatism . 48 . 11 . 3253–3265 . November 2003 . 14613291 . 10.1002/art.11299 .
  19. Human Genome Sciences And Glaxosmithkline Announce Initiation Of Phase 3 Clinical Trial Of Lymphostat-B In Systemic Lupus Erythematosus. 13 February 2007. Human Genome Sciences. 11 March 2011. dead. 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. 25 April 2011.
  20. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/UCM241199.pdf Summary Minutes of the Arthritis Advisory Committee Meeting November 16, 2010
  21. https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisDrugsAdvisoryCommittee/ucm203434.htm 2010 Meeting Materials, Arthritis Advisory Committee
  22. Andrew Pollack, "F.D.A. Approves Benlysta, a New Lupus Drug", The New York Times, 9 March 2011
  23. 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 . Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial . Lancet . 377 . 9767 . 721–731 . February 2011 . 21296403 . 10.1016/S0140-6736(10)61354-2 . 31 October 2012 . live . BLISS-52 Study Group . 28952240 . https://web.archive.org/web/20121017121223/http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61354-2/fulltext . 17 October 2012 .
  24. 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 . A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus . Arthritis and Rheumatism . 63 . 12 . 3918–3930 . December 2011 . 22127708 . 5007058 . 10.1002/art.30613 . BLISS-76 Study Group .
  25. Lee YH, Song GG . 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 . Lupus . 27 . 1 . 112–119 . January 2018 . 28592201 . 10.1177/0961203317713143 . 26026994 . free .
  26. 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
  27. Web site: Should Belimumab Have Been Approved? Stephen Paget, Medscape Rheumatology, Mar 24, 2011 . 27 April 2013 . 16 November 2015 . https://web.archive.org/web/20151116220815/http://www.medscape.com/viewarticle/739330_2 . live .
  28. .
  29. Web site: Efficacy and Safety of Belimumab in Subjects With Primary Sjögren's Syndrome (BELISS) . July 2012 . 1 November 2012 . 18 October 2012 . https://web.archive.org/web/20121018230037/http://www.clinicaltrials.gov/ct2/show/NCT01160666 . live .
  30. News: FDA Approves Belimumab & Voclosporin for Lupus Nephritis. The Rheumatologist. 24 March 2021. 3 May 2021. 5 May 2021. https://web.archive.org/web/20210505201535/https://www.the-rheumatologist.org/article/fda-approves-belimumab-voclosporin-for-lupus-nephritis/. live.
  31. FDA approves Benlysta to treat lupus . https://web.archive.org/web/20110311142824/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm246489.htm . dead . 11 March 2011 . 9 March 2011 . U.S. Food and Drug Administration (FDA) .
  32. http://www.medpagetoday.com/Rheumatology/Lupus/23324 FDA Questions Safety, Efficacy of Belimumab
  33. Web site: Pollack A . Benlysta, Lupus Treatment, Endorsed by F.D.A. . . 16 November 2010 . 29 July 2020 . 9 November 2020 . https://web.archive.org/web/20201109033133/http://www.nytimes.com/2010/11/17/health/17drug.html . live .
  34. Benlysta granted Orphan Drug Designation by US FDA for the potential treatment of systemic sclerosis . 9 February 2023 . GSK . 9 February 2023 . 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/ . live .
  35. Web site: GSK Says Benlysta Granted Orphan Drug Designation By FDA . 9 February 2023 . MarketScreener . February 2023 . 9 February 2023 . 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/ . live .
  36. https://finance.yahoo.com/news/hgsi-cuts-loss-benlysta-sales-184526054.html HGSI Cuts Loss on Benlysta Sales
  37. Hahn BH . Belimumab for systemic lupus erythematosus . The New England Journal of Medicine . 368 . 16 . 1528–1535 . April 2013 . 23594005 . 10.1056/NEJMct1207259 .
  38. http://www.nice.org.uk/newsroom/pressreleases/SystemicLupusBelimumabFAD.jsp NICE publishes draft guidance on belimumab for systemic lupus erythematosus
  39. 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 . A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys . The American Journal of Pathology . 168 . 2 . 476–489 . February 2006 . 16436662 . 1606502 . 10.2353/ajpath.2006.050600 .
  40. Kappos L, Hartung HP, Freedman MS, Boyko A, Radü EW, Mikol DD, Lamarine M, Hyvert Y, Freudensprung U, Plitz T, van Beek J . Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial . The Lancet. Neurology . 13 . 4 . 353–363 . April 2014 . 24613349 . 10.1016/S1474-4422(14)70028-6 . ATAMS Study Group . 38926361 .

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