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Blisibimod

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
Blisibimod
Clinical data
Other namesA-623
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC2836H4376N756O858S26
Molar mass63624.20 g·mol−1
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Blisibimod (also known asA-623, formerlyAMG 623) is a selective antagonist ofB-cell activating factor (BAFF, also known as B-lymphocyte stimulator or BLyS), being developed byAnthera Pharmaceuticals as a treatment forsystemic lupus erythematosus.[1] It is currently under active investigation in clinical trials.[2]

Mechanism of action

[edit]

Blisibimod is afusion protein consisting of four BAFFbinding domains fused to theN-terminus of thefragment crystallizable region (Fc) of a humanantibody.[1]

BAFF is involved inB-cell survival, activation, and differentiation.[3] Elevated levels of BAFF have been associated with several B-cell mediatedautoimmune diseases, including systemic lupus erythematosus,[4][5][6]lupus nephritis,[7]rheumatoid arthritis,[5][6]multiple sclerosis,[8]Sjögren syndrome,[9]Graves' disease,[10] andHashimoto's thyroiditis.[10] Blisibimod binds to BAFF andinhibits interaction with BAFFreceptors, thus decreasing B-cell survival and proliferation throughout the body.[1][3] Improvements in disease activity have been observed in patients with systemic lupus erythematosus[11] and rheumatoid arthritis[12] following treatment with BAFF inhibitors in clinical trials.

Development

[edit]

Blisibimod was initially developed byAmgen, withPhase I trials demonstrating comparable safety between the blisibimod andplacebo treatments.[1] It was subsequently acquired by Anthera Pharmaceuticals,[13] who in 2010 initiated a globalPhase II study called PEARL-SC to investigate the efficacy, safety, and tolerability of blisibimod in subjects with systemic lupus erythematosus.[2][14] The PEARL-SC study, completed in April 2012, yielded data that has been published.[15] Blisibimod is currently being tested in a Phase 3 study, CHABLIS-SC1, for systemic lupus erythematosus, and a Phase 2 study, BRIGHT-SC, forIgA nephropathy.

References

[edit]
  1. ^abcd"A-623: BAFF Peptibody for the Treatment of Lupus". Anthera Pharmaceuticals, Inc. Archived fromthe original on 2011-09-02. Retrieved2011-07-08.
  2. ^ab"Anthera Initiates Expanded and Extended PEARL-SC Phase 2b Clinical Study in Lupus With A-623 - A Subcutaneous Dual Inhibitor of Membrane and Soluble B-Cell Activating Factor (BAFF or BLyS)" (Press release). Anthera Pharmaceuticals, Inc. 29 July 2010. Archived fromthe original on 3 June 2011. Retrieved15 July 2011.
  3. ^abBrowning JL (July 2006). "B cells move to centre stage: novel opportunities for autoimmune disease treatment".Nature Reviews. Drug Discovery.5 (7):564–576.doi:10.1038/nrd2085.PMID 16816838.S2CID 9159761.
  4. ^Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, et al. (August 2008). "Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus".Arthritis and Rheumatism.58 (8):2453–2459.doi:10.1002/art.23678.hdl:2027.42/60900.PMID 18668552.
  5. ^abCheema GS, Roschke V, Hilbert DM, Stohl W (June 2001)."Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases".Arthritis and Rheumatism.44 (6):1313–1319.doi:10.1002/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S.PMID 11407690.
  6. ^abZhang J, Roschke V, Baker KP, Wang Z, Alarcón GS, Fessler BJ, et al. (January 2001)."Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus".Journal of Immunology.166 (1):6–10.doi:10.4049/jimmunol.166.1.6.PMID 11123269.
  7. ^Neusser MA, Lindenmeyer MT, Edenhofer I, Gaiser S, Kretzler M, Regele H, et al. (January 2011)."Intrarenal production of B-cell survival factors in human lupus nephritis".Modern Pathology.24 (1):98–107.doi:10.1038/modpathol.2010.184.PMID 20890272.S2CID 11795623.
  8. ^Krumbholz M, Theil D, Derfuss T, Rosenwald A, Schrader F, Monoranu CM, et al. (January 2005)."BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma".The Journal of Experimental Medicine.201 (2):195–200.doi:10.1084/jem.20041674.PMC 2212784.PMID 15642740.
  9. ^Quartuccio L, Fabris M, Moretti M, Barone F, Bombardieri M, Rupolo M, et al. (2008)."Resistance to rituximab therapy and local BAFF overexpression in Sjögren's syndrome-related myoepithelial sialadenitis and low-grade parotid B-cell lymphoma".The Open Rheumatology Journal.2:38–43.doi:10.2174/1874312900802010038.PMC 2577948.PMID 19088870.
  10. ^abFabris M, Grimaldi F, Villalta D, Picierno A, Fabro C, Bolzan M, et al. (January 2010). "BLyS and April serum levels in patients with autoimmune thyroid diseases".Autoimmunity Reviews.9 (3):165–169.doi:10.1016/j.autrev.2009.07.005.PMID 19647102.
  11. ^Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. (February 2011). "Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial".Lancet.377 (9767):721–731.doi:10.1016/S0140-6736(10)61354-2.PMID 21296403.S2CID 28952240.
  12. ^Genovese M, Bojin S, Biagini M, Mociran E, Cristei D, Georgescu L, Sloan-Lancaster J (June 2010)."Effects on B cells, safety, and efficacy of LY2127399, a novel anti-BAFF MAB, in patients with active rheumatoid arthritis".Annals of the Rheumatic Diseases.69 (Suppl3): 69. Archived fromthe original on 2011-10-02. Retrieved2011-07-15.
  13. ^"Anthera Pharmaceuticals acquires the worldwide rights to a BAFF inhibitor for the treatment of lupus and other autoimmune diseases" (Press release). Anthera Pharmaceuticals, Inc. 2008-01-08. Archived fromthe original on 2012-03-27. Retrieved2011-07-15.
  14. ^Clinical trial numberNCT01162681 for "PEARL-SC Trial: A Study of the Efficacy, Safety, and Tolerability of A 623 Administration in Subjects With Systemic Lupus Erythematosus" atClinicalTrials.gov
  15. ^Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, et al. (September 2015). "A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study".Annals of the Rheumatic Diseases.74 (9):1667–1675.doi:10.1136/annrheumdis-2013-205144.PMID 24748629.S2CID 23122293.
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