Blisibimod Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:477373423
Legal Status:Investigational
Cas Number:1236126-45-6
Unii:114VP6C6ES
Atc Prefix:none
Synonyms:A-623
Chemspiderid:none
Kegg:D10311
C:2836
H:4376
N:756
O:858
S:26

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 of action

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 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] 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] The PEARL-SC study, completed in April 2012, yielded data that has been published.[14] 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.

Notes and References

  1. Web site: A-623: BAFF Peptibody for the Treatment of Lupus. Anthera Pharmaceuticals, Inc.. 2011-07-08. dead. https://web.archive.org/web/20110902022559/http://www.anthera.com/products_a623.asp. 2011-09-02.
  2. 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). 29 July 2010. Anthera Pharmaceuticals, Inc.. 15 July 2011. https://web.archive.org/web/20110603133749/http://investor.anthera.com/releasedetail.cfm?ReleaseID=493946. 3 June 2011. dead.
  3. Browning JL . B cells move to centre stage: novel opportunities for autoimmune disease treatment . Nature Reviews. Drug Discovery . 5 . 7 . 564–576 . July 2006 . 16816838 . 10.1038/nrd2085 . 9159761 .
  4. Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, Recta V, Zhong J, Freimuth W . 6 . Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus . Arthritis and Rheumatism . 58 . 8 . 2453–2459 . August 2008 . 18668552 . 10.1002/art.23678 . free . 2027.42/60900 .
  5. Cheema GS, Roschke V, Hilbert DM, Stohl W . Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases . Arthritis and Rheumatism . 44 . 6 . 1313–1319 . June 2001 . 11407690 . 10.1002/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S . free .
  6. Zhang J, Roschke V, Baker KP, Wang Z, Alarcón GS, Fessler BJ, Bastian H, Kimberly RP, Zhou T . 6 . Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus . Journal of Immunology . 166 . 1 . 6–10 . January 2001 . 11123269 . 10.4049/jimmunol.166.1.6 . free .
  7. Neusser MA, Lindenmeyer MT, Edenhofer I, Gaiser S, Kretzler M, Regele H, Segerer S, Cohen CD . 6 . Intrarenal production of B-cell survival factors in human lupus nephritis . Modern Pathology . 24 . 1 . 98–107 . January 2011 . 20890272 . 10.1038/modpathol.2010.184 . 11795623 . free .
  8. Krumbholz M, Theil D, Derfuss T, Rosenwald A, Schrader F, Monoranu CM, Kalled SL, Hess DM, Serafini B, Aloisi F, Wekerle H, Hohlfeld R, Meinl E . 6 . 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 . January 2005 . 15642740 . 2212784 . 10.1084/jem.20041674 .
  9. Quartuccio L, Fabris M, Moretti M, Barone F, Bombardieri M, Rupolo M, Lombardi S, Pitzalis C, Beltrami CA, Curcio F, De Vita S . 6 . 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 . 2008 . 19088870 . 2577948 . 10.2174/1874312900802010038 . free.
  10. Fabris M, Grimaldi F, Villalta D, Picierno A, Fabro C, Bolzan M, De Vita S, Tonutti E . 6 . BLyS and April serum levels in patients with autoimmune thyroid diseases . Autoimmunity Reviews . 9 . 3 . 165–169 . January 2010 . 19647102 . 10.1016/j.autrev.2009.07.005 .
  11. 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 . 6 . 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 . 28952240 .
  12. Genovese M, Bojin S, Biagini M, Mociran E, Cristei D, Georgescu L, Sloan-Lancaster J . 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. June 2010. 2011-07-15. https://web.archive.org/web/20111002070706/http://www.abstracts2view.com/eular/view.php?nu=EULAR10L_OP0052&terms. 2011-10-02. dead.
  13. Anthera Pharmaceuticals acquires the worldwide rights to a BAFF inhibitor for the treatment of lupus and other autoimmune diseases.. 2008-01-08. Anthera Pharmaceuticals, Inc.. 2011-07-15. https://web.archive.org/web/20120327172621/http://investor.anthera.com/releasedetail.cfm?ReleaseID=423193. 2012-03-27. dead.
  14. Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, Martin RS, Scheinberg MA . 6 . 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 . September 2015 . 24748629 . 10.1136/annrheumdis-2013-205144 . 23122293 .

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