LONDON, United Kingdom — In patients with diabetic nephropathy, reductions in albuminuria are greater when CCX140-B, a novel selective chemokine receptor inhibitor, is added to standard care, a phase 2 proof-of-concept trial suggests.

"Even with optimal current care, the residual risk for a further decrease in renal function in diabetic nephropathy is still extremely high," said Dick de Zeeuw, MD, from University Hospital Groningen in the Netherlands.

"We found that CCX140-B, at a dose of 5 mg, is safe and effective for improving albuminuria over a year of treatment, and could become a valuable addition to standard treatments to prevent diabetic renal progression in type 2 diabetes," he reported during a news conference here at the European Renal Association–European Dialysis and Transplant Association 52nd Congress.

The randomized double-blind placebo-controlled trial was conducted in a number of countries in Europe and the United Kingdom.

The 332 study participants had type 2 diabetes accompanied by proteinuria, an albumin to creatinine ratio at first morning void of 100 to 3000 mg/g, and an estimated glomerular filtration rate (eGFR) of at least 25 mL/min per 1.73 m².

At baseline, all patients were on an antidiabetic regimen that included either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Mean baseline albumin to creatinine ratio was 363 mg/g.

Two doses of CCX140-B were evaluated; 110 patients received 5 mg/day and 111 received 10 mg/day. The remaining 111 patients received placebo.

The intent-to-treat analysis included 192 patients.

At 52 weeks, the albumin to creatinine ratio was 10% lower in the 10 mg group than in the placebo group (P = 0.087), and was a significant 16% lower in the 5 mg group (P = .010).

Even with optimal current care, the residual risk for a further decrease in renal function in diabetic nephropathy is still extremely high.

In addition, reductions in eGFR were minimal in the 10 mg, 5 mg, and placebo groups (3.8 vs 2.4 vs 2.6 mL/min per 1.73 m²), and were not significantly different between groups. Given that renoprotective agents such as the angiotensin receptor blockers require longer than 52 weeks to affect eGFR, no changes were expected, Dr de Zeeuw explained.

CCX140-B did not affect blood pressure, suggesting that changes in albuminuria might have been mediated by a reduction in renal inflammation.

"There were also no differences in adverse events or serious adverse events between the three treatment arms," Dr de Zeeuw reported. "And there were no significant differences in other end points, including changes in hemoglobin A1c."

The maximum effect of CCX140-B was observed at week 12, when there was a 24% decrease in the albumin to creatinine ratio; however, this effect was only maintained in the 5 mg group.

The monocyte chemoattractant protein (MCP)-1 and its receptor, CCR2, are involved in the pathogenesis of diabetic nephropathy. By intersecting this pathway, the CCR2 receptor inhibitor can inhibit mechanisms other than the renin–angiotensin system that contribute to the disease, he explained.

"For this reason, it would be really interesting to target the inflammatory pathways of renal progressive disease to see what else it may bring," Dr de Zeeuw added.

Unmet Clinical Need

There is an unmet clinical need to reduce albuminuria to a greater extent than is currently possible using standard-of-care agents, said session cochair Johannes Mann, MD, from the University of Erlangen–Nuremberg in Germany.

The residual risk for progressive loss in renal function in patients with diabetic nephropathy is related to residual albuminuria, he told Medscape Medical News.

"However, changes in albuminuria and proteinuria do not qualify to get a drug approved, while changes in eGFR probably will," Dr Mann said.

The other problem with the study was that there was no dose-response relation between the 5 mg and 10 mg doses of CCRX140-B; in fact, the 10 mg dose was actually less effective than the 5 mg dose, he pointed out.

"And we still don't know whether 2.5 mg or any other dose under 5 mg would be effective," he said. That is a major deficiency of the study.

The study was funded by ChemoCentryx. Dr de Zeeuw is a consultant for and receives honoraria from AbbVie, Astellas, ChemoCentryx, Eli Lilly, Janssen, Fresenius, and Merck Darmstadt. Dr Mann has disclosed no relevant financial relationships.

European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 52nd Congress. Abstract LBA-3544. Presented May 29, 2015.


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