Blisibimod

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 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’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] 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 2 3 4 "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. 1 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. 1 2 Browning JL (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. S2CID 9159761.
  4. ↑ Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, Recta V, Zhong J, Freimuth W (2008). "Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus" (PDF). Arthritis and Rheumatism. 58 (8): 2453–9. doi:10.1002/art.23678. hdl:2027.42/60900. PMID 18668552.
  5. 1 2 Cheema GS, Roschke V, Hilbert DM, Stohl W (2001). "Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases". Arthritis and Rheumatism. 44 (6): 1313–9. doi:10.1002/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S. PMID 11407690.
  6. 1 2 Zhang J, Roschke V, Baker KP, Wang Z, Alarcón GS, Fessler BJ, Bastian H, Kimberly RP, Zhou T (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, Segerer S, Cohen CD (2011). "Intrarenal production of B-cell survival factors in human lupus nephritis" (PDF). 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, Kalled SL, Hess DM, Serafini B, Aloisi F, Wekerle H, Hohlfeld R, Meinl E (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, Lombardi S, Pitzalis C, Beltrami CA, 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. 1 2 Fabris M, Grimaldi F, Villalta D, Picierno A, Fabro C, Bolzan M, De Vita S, Tonutti E (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 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 (2011). "Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial". Lancet. 377 (9767): 721–31. doi:10.1016/S0140-6736(10)61354-2. PMID 21296403. S2CID 28952240.
  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. Archived from the original on 2011-10-02. Retrieved 2011-07-15.
  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 from the original on 2012-03-27. Retrieved 2011-07-15.
  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. ↑ Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, Martin RS, Scheinberg MA (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): 1667–75. doi:10.1136/annrheumdis-2013-205144. PMID 24748629. S2CID 23122293.


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