LISBON – A novel investigational chemokine receptor antagonist produced a statistically significant decrease in hemoglobin A1c and a higher percentage of HbA1c responders, compared with placebo after 4 weeks of treatment in a phase II multinational study of 159 patients with type 2 diabetes who were already taking metformin.
The compound, ChemoCentryx’s CCX140-B, works by blocking the infiltration and activation of certain monocytes/macrophages and other cells bearing chemokine receptor 2 that occur during inflammation and are implicated in the development of insulin resistance in type 2 diabetes. The agent is designed to provide selective treatment without compromising other immune functions, said Dr. Markolf Hanefeld, director of the Centre for Clinical Studies, Technical University Dresden (Germany).
The subjects had been on stable metformin treatment for at least 8 weeks before study entry. They had a mean age of 59 years, were 64% male, had a mean body mass index of 32 kg/m2, median diabetes duration of 5.8 years. At baseline, they had a mean hemoglobin A1c value of 7.5% and mean fasting plasma glucose of 170 mg/dL. They were randomized to receive 5 mg/day CCX140-B, 10 mg/day CCX140-B, placebo, or open-label 30 mg/day pioglitazone as an active comparator.
Reductions in HbA1c from baseline at week 4 were 0.09 percentage points with both placebo and the 5 mg CCX140-B group, 0.23 for the 10 mg CCX140-B group, and 0.13 with pioglitazone. The difference, compared with placebo, was significant for 10 mg CCX140-B (P = .045) but not for pioglitazone. The percentage of patients who had a decrease in HbA1c from baseline to week 4 was 58% for placebo, 51% for 5mg CCX140-B, 82% for 10 mg CCX140-B, and 77% for pioglitazone. Again, the difference from placebo was significant for 10 mg CCX140-B (P = 0.45) but not for 5 mg CCX140-B or pioglitazone, Dr. Hanefeld reported.
Treatment with CCX140-B also showed a dose-dependent decrease in fasting glucose through week 4, he noted.
There were no safety concerns regarding laboratory hematology, chemistry, or urinalysis. In contrast to what has been seen with other CCR2 agonists in animal studies, there were no significant changes in plasma MCP-1 or blood monocyte count with CCX140-B. There were also no significant changes in body weight or any evidence of hemodilution or peripheral edema, and there was no effect on HDL cholesterol or LDL cholesterol. There was a slight decrease in triglycerides with pioglitazone but not with CCX140-B, he said.
In a separate rodent study presented at EASD, CCX140-B significantly improved metabolic/renal parameters including hyperglycemia, insulin sensitivity, serum adiponectin, glucosuria, albuminuria, and serum markers (creatine and BUN) of renal function. The metabolic improvements correlated with a significant reduction in adipose tissue macrophage numbers. ChemoCentryx will soon be initiating phase II clinical studies of CCX140-B for the treatment of diabetic nephropathy, according to a company statement.
Dr. Hanefeld has received lecture honoraria from Bayer AG, Takeda Pharmaceutical, GlaxoSmithKline, Sanofi-Aventis, and Boehringer-Ingelheim. He is also a consultant for Sanofi-Aventis and Eli Lilly.