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CC-5013 (Revimid)

Immunomodulatory drugs (IMiDs) are potent thalidomide derivatives, which markedly stimulate T-cell proliferation, as well as IL-2 and IFN-a production, but do not inhibit phosphodiesterase 4 (PDE-4)[1]. CC-5013 (Revimid™) is 50 to 2000 times more potent than thalidomide in stimulating T-cell proliferation triggered via the T-cell receptor (TCR), and 50 to 100 times more potent than thalidomide in augmenting IL-2 and IFN-a production. In addition, CC-5013 triggers dose-dependent decreased secretion of TNF-a, IL-1b, and IL-6; and triggers increased secretion of IL-10. The IC50 of CC-5013 for inhibiting LPS induced TNF-a secretion by PBMC is ~100 nM (25.9 ng/mL), whereas thalidomide has an IC50 of ~194 M (50.2 g/mL)[2]. Based upon these more potent effects of IMiDs than thalidomide on normal cells, their relative anti-MM activities have also been compared. In vitro studies show an IC 50 of 0.4 M (103.6 ng/ml) for CC-5013 against MM cell lines and patient cells[3] which are resistant to conventional therapy; in contrast, even at concentrations up to 100 M (25.8 g/mL), thalidomide decreases MM cell proliferation by only 15 or 20%[4]. These studies further demonstrate that CC-5013 decreases binding of MM cells to bone marrow stromal cells (BMSCs); inhibits the production in the BM milieu of cytokines (IL-6, VEGF, TNF-a) mediating growth and survival of MM cells; blocks angiogenesis; and stimulates host anti-MM NK cell immunity[5], [6]. In addition, CC-5013 inhibits tumor growth, decreases angiogenesis, and prolongs host survival in a human plasmacytoma mouse model[7]. These preclinical studies suggest that CC-5013 may overcome drug resistance, even to thalidomide, in MM cells. The remarkable in vitro and in vivo activity of CC-5013 against resistant MM cells in pre-clinical studies provided the framework for a Phase I dose-escalation trial of CC- 5013 in patients with relapsed/refractory MM. Importantly, CC-5013 achieved either response or stabilization of disease in 19 of 24 (79%) evaluable patients (90%CI: 61%, 91%) and demonstrated a favorable toxicity profile. The dose-limiting toxicity was neutropenia after the first 28 days at the 50 mg a day dose. Dose reduction and the addition of growth factors allowed for continuation of therapy in all patients. In addition, myeloma responses were observed in all dose groups, including the 5 mg daily dose group.

References:

[1] Corral LG, Haslett PAJ, Muller GW, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-_. J Immunol. 1999; 163:380-386

 [2] Muller G, Chen R, Huang SY, et al. Amino-substituted thalidomide analogs: potent inhibitors of TNF-a production. Bioorg. Med. Chem. Lett. 1999; 9:1625-1630.

 [3] Teoh G, Urashima M, Greenfield EA, et al. The 86 kD subunit of Ku autoantigen mediates homotypic and heterotypic adhesion of multiple myeloma cells. J Clin Invest. 1997;101:1379-1388

 [4] Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96:2943-2950.

[5] Gupta D, Treon SP, Shima Y, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia. 2001;15:1950-1961

 [6] Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001; 98:210-216.

 [7] Lentzsch S, LeBlanc R, Podar K, et al. Thalidomide and its immunomodulatory analogs inhibit human multiple myeloma cell growth and angiogenesis in vivo. 2001;submitted  

 
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