Belimumab
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[8] and Canada,[9] and the European Union[5] to treat systemic lupus erythematosus and lupus nephritis.[10]
Fab fragment of belimumab. PDB: 5Y9K. | |
| Monoclonal antibody | |
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| Type | Whole antibody |
| Source | Human |
| Target | B-cell activating factor (BAFF, BLyS) |
| Clinical data | |
| Trade names | Benlysta |
| Other names | LymphoStat-B |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a611027 |
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| Routes of administration | Intravenous, subcutaneous |
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| Formula | C6358H9904N1728O2010S44 |
| Molar mass | 144121.90 g·mol−1 |
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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).[5]
Medical uses edit
Belimumab is indicated for the treatment of active systemic lupus erythematosus and active lupus nephritis.[4][5]
Side effects and interactions edit
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.[11]
Because belimumab is an immunosuppressant, more serious infections and deaths were reported among patients treated with the drug than among those treated with placebo.[12]
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.[4][11]
Mechanism of action edit
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.[medical citation needed]
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.[medical citation needed]
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:[medical citation needed]
- 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.[medical citation needed]
Another B-cell activator similar to BAFF is APRIL (A proliferation-inducing ligand),[13] but APRIL activates only BCMA and TACI, not BAFF-R.[medical citation needed]
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.[14].[better source needed]
History edit
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.[15] 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).[16] Six years later, research showing the key role of BLyS in B cell differentiation, survival, and activation was published.[17]
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.[18] 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.[19] Later that year, one of these antibodies was isolated and characterized. It was named LymphoStat-B and subsequently called belimumab.[20]
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.[18] 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.[21]
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.[22][23] However, patients of African-American or African descent did not respond significantly to belimumab.[24][25][26]
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.[27]
Clinical trials found belimumab to be safe in treating systemic lupus erythematosus,[22][23][28] but the magnitude of benefit was small,[8] 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.[29]
Belimumab was not effective in Phase II clinical trials for rheumatoid arthritis.[30] It was moderately effective in Phase II trials for Sjögren syndrome.[31]
In December 2020, belimumab was approved by the FDA as a treatment for lupus nephritis in combination with standard treatment.[32]
Society and culture edit
Legal status edit
Under the brand name Benlysta, belimumab received FDA approval for the treatment of systemic lupus erythematosus in March 2011,[33] 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.[24][34] It was subsequently approved in Canada and the European Union as well.[9][5]
In February 2023, belimumab was given orphan drug designation by the FDA for the potential treatment of systemic sclerosis.[35][36]
Economics edit
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.[8] Sales rose to $31.2 million in the first quarter of 2012.[37]
The total cost for the first year of treatment with belimumab is $28,000.[38] 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).[38]
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.[39]
Research edit
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.[40]
Rituximab, an anti-CD20 monoclonal antibody, has been approved for some indications. Ocrelizumab, ofatumumab, and "third-generation" anti-CD20 monoclonals are in development.[citation needed]
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.[41][42]
References edit
- ^ "Belimumab (Benlysta) Use During Pregnancy". Drugs.com. 5 February 2020. from the original on 4 December 2020. Retrieved 29 July 2020.
- ^ "BENLYSTA (GlaxoSmithKline Australia Pty Ltd)". Therapeutic Goods Administration (TGA). 11 November 2022. Retrieved 15 April 2023.
- ^ "Benlysta Product information". Health Canada. 22 October 2009. Retrieved 17 March 2023.
- ^ a b c "Benlysta- belimumab injection, powder, lyophilized, for solution Benlysta- belimumab solution". DailyMed. 17 January 2020. from the original on 25 September 2020. Retrieved 29 July 2020.
- ^ a b c d e "Benlysta EPAR". European Medicines Agency (EMA). 17 September 2018. from the original on 25 October 2020. Retrieved 29 July 2020.
- ^ Bossen C, Schneider P (October 2006). "BAFF, APRIL and their receptors: structure, function and signaling" (PDF). Seminars in Immunology. 18 (5): 263–275. doi:10.1016/j.smim.2006.04.006. PMID 16914324.
- ^ Kaveri SV, Mouthon L, Bayry J (September 2010). "Basophils and nephritis in lupus". The New England Journal of Medicine. 363 (11): 1080–1082. doi:10.1056/NEJMcibr1006936. PMID 20825323.
- ^ a b c Belimumab: The first drug to be FDA approved for the treatment of lupus since 1955 13 September 2021 at the Wayback Machine, By Rebecca Manno, Johns Hopkins Arthritis Center, 15 July 2011
- ^ a b DrugBank DB08879
- ^ "Benlysta now approved in Canada in addition to standard therapy for treatment of active lupus nephritis in adult patients" (Press release). GlaxoSmithKline. 30 July 2021. Retrieved 17 March 2023 – via Newswire.
- ^ a b European Medicines Agency: Benlysta Summary of Product Characteristics 18 June 2018 at the Wayback Machine
- ^ . GlaxoSmithKline. 9 March 2011. Archived from the original on 17 March 2011. Retrieved 11 March 2011.
- ^ Schneider P (June 2005). "The role of APRIL and BAFF in lymphocyte activation". Current Opinion in Immunology. 17 (3): 282–289. doi:10.1016/j.coi.2005.04.005. PMID 15886118.
- ^ June 2007 European League against Rheumatism symposium.
- ^ Shu HB, Hu WH, Johnson H (May 1999). "TALL-1 is a novel member of the TNF family that is down-regulated by mitogens". Journal of Leukocyte Biology. 65 (5): 680–683. doi:10.1002/jlb.65.5.680. PMID 10331498. S2CID 1498303.
- ^ Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. (July 1999). "BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator". Science. 285 (5425): 260–263. doi:10.1126/science.285.5425.260. PMID 10398604.
- ^ Crowley JE, Treml LS, Stadanlick JE, Carpenter E, Cancro MP (June 2005). "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. doi:10.1016/j.smim.2005.02.001. PMID 15826824.
- ^ a b . Human Genome Sciences. Archived from the original on 21 April 2011. Retrieved 11 March 2011.
- ^ Edwards BM, Barash SC, Main SH, Choi GH, Minter R, Ullrich S, et al. (November 2003). "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. doi:10.1016/j.jmb.2003.09.054. PMID 14596803.
- ^ Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern WG, et al. (November 2003). "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. doi:10.1002/art.11299. PMID 14613291.
- ^ (Press release). Human Genome Sciences. 13 February 2007. Archived from the original on 25 April 2011. Retrieved 11 March 2011.
- ^ a b Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzová D, et al. (BLISS-76 Study Group) (December 2011). "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. doi:10.1002/art.30613. PMC 5007058. PMID 22127708.
- ^ a b FDA Questions Safety, Efficacy of Belimumab 3 March 2021 at the Wayback Machine, By Emily P. Walker, Washington Correspondent, MedPage Today, 12 November 2010
- ^ Summary Minutes of the Arthritis Advisory Committee Meeting November 16, 2010 4 March 2017 at the Wayback Machine U.S. Food and Drug Administration (FDA)
- ^ 2010 Meeting Materials, Arthritis Advisory Committee 29 March 2012 at the Wayback Machine U.S. Food and Drug Administration (FDA)
- ^ Andrew Pollack, "F.D.A. Approves Benlysta, a New Lupus Drug" 12 November 2020 at the Wayback Machine, The New York Times, 9 March 2011
- ^ Lee YH, Song GG (January 2018). "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. doi:10.1177/0961203317713143. PMID 28592201. S2CID 26026994.
- ^ "Should Belimumab Have Been Approved? Stephen Paget, Medscape Rheumatology, Mar 24, 2011". from the original on 16 November 2015. Retrieved 27 April 2013.
- ^ Clinical trial number NCT00071812 for "A Safety and Efficacy Study of LymphoStat-B (Monoclonal Anti-BLyS Antibody) in Subjects With Rheumatoid Arthritis" at ClinicalTrials.gov.
- ^ "Efficacy and Safety of Belimumab in Subjects With Primary Sjögren's Syndrome (BELISS)". July 2012. from the original on 18 October 2012. Retrieved 1 November 2012.
- ^ "FDA Approves Belimumab & Voclosporin for Lupus Nephritis". The Rheumatologist. 24 March 2021. from the original on 5 May 2021. Retrieved 3 May 2021.
- ^ (Press release). U.S. Food and Drug Administration (FDA). 9 March 2011. Archived from the original on 11 March 2011.
- ^ Pollack A (16 November 2010). "Benlysta, Lupus Treatment, Endorsed by F.D.A." The New York Times. from the original on 9 November 2020. Retrieved 29 July 2020.
- ^ "Benlysta granted Orphan Drug Designation by US FDA for the potential treatment of systemic sclerosis". GSK (Press release). from the original on 9 February 2023. Retrieved 9 February 2023.
- ^ "GSK Says Benlysta Granted Orphan Drug Designation By FDA". MarketScreener. February 2023. from the original on 9 February 2023. Retrieved 9 February 2023.
- ^ HGSI Cuts Loss on Benlysta Sales 7 April 2019 at the Wayback Machine, By Zacks Equity Research, 26 April 2012
- ^ a b Hahn BH (April 2013). "Belimumab for systemic lupus erythematosus". The New England Journal of Medicine. 368 (16): 1528–1535. doi:10.1056/NEJMct1207259. PMID 23594005.
- ^ NICE publishes draft guidance on belimumab for systemic lupus erythematosus 12 September 2012 at the Wayback Machine, press release, 26 April 2012
- ^ Vugmeyster Y, Seshasayee D, Chang W, Storn A, Howell K, Sa S, et al. (February 2006). "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. doi:10.2353/ajpath.2006.050600. PMC 1606502. PMID 16436662.
- ^ Clinical trial number NCT00642902 for "Atacicept in Multiple Sclerosis, Phase II" at ClinicalTrials.gov
- ^ Kappos L, Hartung HP, Freedman MS, Boyko A, Radü EW, Mikol DD, et al. (ATAMS Study Group) (April 2014). "Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial". The Lancet. Neurology. 13 (4): 353–363. doi:10.1016/S1474-4422(14)70028-6. PMID 24613349. S2CID 38926361.