Markolf Hanefeld, Ernest Schell, Ioanna Gouni-Berthold, Martin Melichar, Ivana Vesela, Dan Johnson, Shichang Miao, Tim J Sullivan, Juan C Jaen, Thomas J Schall, Pirow Bekker and The CCX140-B Diabetes Study Group
Study background: Inflammatory macrophages expressing the C-C chemokine receptor 2 (CCR2) accumulate in adipose tissue and contribute to insulin resistance. CCX140-B is an orally-administered antagonist of CCR2 expressed on monocytes and macrophages and blocks infiltration of these cells into adipose tissue. A pilot Phase 2 clinical trial was conducted in patients with type 2 diabetes with the primary objective to evaluate the safety and tolerability of CCX140-B. Key secondary objectives included assessment of glycemic parameters, fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c).
Methods: This is a randomized, double-blind, clinical trial of CCX140-B in 159 subjects with type 2 diabetes on stable metformin for at least 8 weeks prior to study entry. HbA1c was 6.5 to 10% and FPG 135 to 270 mg/dL at study entry. Randomized subjects received double-blind placebo (N=32), 5 mg CCX140-B (N=63), 10 mg CCX140-B (N=32), or pioglitazone 30 mg (N=32) once daily orally for 4 weeks, with a 4-week follow-up period.
Results: CCX140-B was well tolerated. No serious adverse events occurred with CCX140-B. FPG showed a CCX140-B dose-dependent decrease, with 10 mg CCX140-B showing a similar decrease to pioglitazone (leastsquares mean change at week 4 of -16.1 vs. -21.4 mg/dL, respectively). HbA1c least-squares mean changes from baseline to week 4 for the placebo, 5 mg CCX140-B, 10 mg CCX140-B, and pioglitazone groups were -0.09%, -0.09%, -0.23% (p=0.045 vs. placebo), and -0.13% (NS vs. placebo), respectively. No detrimental changes were seen in plasma monocyte chemoattractant protein-1 or blood monocyte counts with CCX140-B.
Conclusion: CCX140-B, an orally administered, specific CCR2 antagonist was found to be well tolerated and safe in this Phase 2 clinical trial and showed evidence of a beneficial effect on glycemic parameters. If confirmed, CCX140-B might be beneficial in treatment of patients with type 2 diabetes. (Clinical Trial Registry: clinicaltrials.gov identifier NCT01028963).
