Blisibimod

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

Blisibimod (also known as A-623, formerly AMG 623) is a selective peptibody 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

Blisibimod is a peptibody consisting of four novel 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

Blisibimod was initially developed by Amgen, with Phase I trials demonstrating comparable safety between the blisibimod and placebo treatments.[1] Blisibimod was acquired by Anthera Pharmaceuticals,[13] who in 2010 initiated a global Phase II study entitled PEARL-SC to investigate the efficacy, safety, and tolerability of blisibimod in subjects with systemic lupus erythematosus.[2][14] As of 2011, this study is ongoing.

References

  1. ^ a b c d "A-623: BAFF Peptibody for the Treatment of Lupus". Anthera Pharmaceuticals, Inc.. http://www.anthera.com/products_a623.asp/. 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. http://investor.anthera.com/releasedetail.cfm?ReleaseID=493946. 
  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. http://www.nature.com/nrd/journal/v5/n7/full/nrd2085.html. 
  4. ^ Petri, P.; Stohl, W.; Chatham, W.; McCune, W.J.; Chevrier, M.; Ryel, J.; Recta, V.; Zhong, J. et al. (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; Alarcon; Fessler; Bastian; Kimberly et al. (January 2001). "Cutting edge: a role for b lymphocyte stimulator in systemic lupus erythematosus.". Journal of Immunology 166 (1): 6–10. PMID 11123269. http://www.jimmunol.org/content/166/1/6.full. 
  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. http://www.nature.com/modpathol/journal/v24/n1/abs/modpathol2010184a.html. 
  8. ^ Krumbholz, M.; Theil, D.; Derfuss, T.; Rosenwald, A.; Schrader, F.; Monoranu, C.M.; Kalled, S.L.; Hess, D.M. et al. (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. http://jem.rupress.org/content/201/2/195.long. 
  9. ^ Quartuccio, L.; Fabris, M.; Moretti, M.; Barone, F.; Bombardieri, M.; Rupolo, M.; Lombardi, S.; Pitzalis, C. 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2577948. 
  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. et al. (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. doi:10.1016/S0140-6736(10)61354-2. PMID 21296403. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61354-2/abstract. 
  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. http://www.abstracts2view.com/eular/view.php?nu=EULAR10L_OP0052&terms. 
  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. http://investor.anthera.com/releasedetail.cfm?ReleaseID=423193. 
  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. http://clinicaltrials.gov/ct2/show/NCT01162681. Retrieved 2011-07-15.