A623

Blisibimod

Blisibimod

Chemical compound

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]

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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][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, for IgA nephropathy.

References

  1. [1]
    "A-623: BAFF Peptibody for the Treatment of Lupus". Anthera Pharmaceuticals, Inc. Archived from the original on 2011-09-02. Retrieved 2011-07-08.
  2. [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)" (Press release). Anthera Pharmaceuticals, Inc. 29 July 2010. Archived from the original on 3 June 2011. Retrieved 15 July 2011.
  3. [3]
    Browning 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. [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. [5]
    Cheema 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. [6]
    Zhang 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. [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. [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. [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. [10]
    Fabris 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. [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. [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 from the original on 2011-10-02. Retrieved 2011-07-15.
  13. [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 from the original on 2012-03-27. Retrieved 2011-07-15.
  14. [14]
    Clinical trial number NCT01162681 for "PEARL-SC Trial: A Study of the Efficacy, Safety, and Tolerability of A 623 Administration in Subjects With Systemic Lupus Erythematosus" at ClinicalTrials.gov
  15. [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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