CCX-354

The chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease.

Since the introduction of biologic therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small molecule immune modulators would be developed that would have a risk : benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compounds over the past year.

Additional information has become available in the past year on five oral compounds including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib.

Compounds that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk : benefit ratio. It is too early to tell about inhibitors of other pathways.