Blisibimod

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Blisibimod
Clinical data
Pregnancy cat. -
Legal status Investigational
Identifiers
CAS number 1236126-45-6 N
ATC code None
Synonyms A-623
Chemical data
Formula C2836H4376N756O858S26 
Mol. mass 63.6 kDa
 N (what is this?)  (verify)

Blisibimod (also known as A-623, formerly AMG 623) is a selective antagonist of B-cell activating factor (BAFF, also known as B-lymphocyte stimulator or BLyS), being developed by Anthera Pharmaceuticals as a treatment for systemic lupus erythematosus.[1] It is currently under active investigation in clinical trials.[2]

Mechanism[edit]

Blisibimod is a fusion protein consisting of four BAFF binding domains fused to the N-terminus of the fragment crystallizable region (Fc) of a human antibody.[1]

BAFF is involved in B-cell survival, activation, and differentiation.[3] Elevated levels of BAFF have been associated with several B-cell mediated autoimmune diseases, including systemic lupus erythematosus,[4][5][6] lupus nephritis,[7] rheumatoid arthritis,[5][6] multiple sclerosis,[8] Sjögren’s syndrome,[9] Graves’ disease,[10] and Hashimoto's thyroiditis.[10] Blisibimod binds to BAFF and inhibits interaction with BAFF receptors, 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 by Amgen, with Phase I trials demonstrating comparable safety between the blisibimod and placebo treatments.[1] It was subsequently acquired by Anthera Pharmaceuticals,[13] who in 2010 initiated a global Phase 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 presented at several nephrology-centered conferences, including ACR[15] and EULAR.[16] Blisibimod is currently being tested in a Phase 3 study, CHABLIS-SC1, for Systemic Lupus Erythematosus, and a Phase 2 study, BRIGHT-SC, for IgA nephropathy.

References[edit]

  1. ^ a b c d "A-623: BAFF Peptibody for the Treatment of Lupus". Anthera Pharmaceuticals, Inc. Retrieved 2011-07-08. 
  2. ^ a b "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. 
  3. ^ a b Browning, J.L. (July 2006). "B cells move to centre stage: novel opportunities for autoimmune disease treatment.". Nature Reviews Drug Discovery 5 (7): 564–76. doi:10.1038/nrd2085. PMID 16816838. 
  4. ^ Petri, P.; Stohl, W.; Chatham, W.; McCune, W.J.; Chevrier, M.; Ryel, J.; Recta, V.; Zhong, J.; Freimuth, W. (August 2008). "Association of plasma b lymphocyte stimulator levels and disease activity in systemic lupus erythematosus". Arthritis & Rheumatism 58 (8): 2453–9. doi:10.1002/art.23678. PMID 18668552. 
  5. ^ a b Cheema, G.S.; Roschke, V.; Hilbert, D.M.; Stohl, W. (June 2001). "Elevated serum b lymphocyte stimulator levels in patients with systemic immune–based rheumatic diseases". Arthritis & Rheumatism 44 (6): 1313–9. doi:10.1002/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S. PMID 11407690. 
  6. ^ a b Zhang, J.; Roschke, V.; Baker, K.P.; Wang, Z.; Alarcon, G.S.; Fessler, B.J.; Bastian, H.; Kimberly, R.P.; Zhou, T. (January 2001). "Cutting edge: a role for b lymphocyte stimulator in systemic lupus erythematosus". Journal of Immunology 166 (1): 6–10. PMID 11123269. 
  7. ^ Neusser, M.A.; Lindenmeyer, M.T.; Edenhofer, I.; Gaiser, S.; Kretzler, M.; Regele, H.; Segerer, S.; Cohen, C.D. (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. 
  8. ^ Krumbholz, M.; Theil, D.; Derfuss, T.; Rosenwald, A.; Schrader, F.; Monoranu, C.M.; Kalled, S.L.; Hess, D.M.; Serafini, B.; Aloisi, F.; Wekerle, H.; Hohlfeld, R.; Meinl, E. (January 2005). "BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma.". Journal of Experimental Medicine 201 (2): 195–200. doi:10.1084/jem.20041674. PMID 15642740. 
  9. ^ Quartuccio, L.; Fabris, M.; Moretti, M.; Barone, F.; Bombardieri, M.; Rupolo, M.; Lombardi, S.; Pitzalis, C.; Beltrami, C.A.; Curcio, F.; De Vita, S. (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. ^ a b Fabris, M.; Grimaldi, F.; Villalta, D.; Picierno, A.; Fabro, C.; Bolzan, M.; De Vita, S.; Tonutti, E. (January 2010). "BLyS and april serum levels in patients with autoimmune thyroid diseases.". Autoimmunity Reviews 9 (3): 165–9. doi:10.1016/j.autrev.2009.07.005. PMID 19647102. 
  11. ^ Navarra, S.V.; Guzmán, R.M.; Gallacher, A.E.; Hall, S.; Levy, R.A.; Jimenez, R.E.; Li, E.K.M.; Thomas, M.; Kim, H.; León, M. G.; Tanasescu, C.; Nasonov, E.; Lan, J.L.; Pineda, L.; Zhong, Z.J.; Freimuth, W.; Petri, M.A. (February 2011). "Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial.". The Lancet 377 (9767): 721–31. doi:10.1016/S0140-6736(10)61354-2. PMID 21296403. 
  12. ^ Genovese, M.C.; 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. 
  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. 
  14. ^ ClinicalTrials.gov. "PEARL-SC Trial: A Study of the Efficacy, Safety, and Tolerability of A 623 Administration in Subjects With Systemic Lupus Erythematosus.". United States National Institute of Health. Retrieved 2011-07-15. 
  15. ^ "Anthera Announces Additional Data from the Phase 2b PEARL-SC Presented at the ACR/ARHP 2012 Annual Scientific Meeting" (Press release). Anthera Pharmaceuticals, Inc. 2012-11-13. 
  16. ^ "Anthera Pharmaceuticals to Present at Annual Jefferies Healthcare Conference" (Press release). Anthera Pharmaceuticals, Inc. 2013-05-07.