Diabetic Nephropathy

Kidney disease is common among patients with Type 2 diabetes and hypertension. It is characterized by a persistent and usually progressive decline in renal function as measured by glomerular filtration rate and/or albuminuria. Given the rise in the incidence of obesity, Type 2 diabetes and hypertension, the associated incidence of diabetic nephropathy has reached epidemic proportions in industrialized nations. Treatment of patients with diabetic nephropathy (DN) includes treatment of the underlying Type 2 diabetes and hypertension. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are commonly prescribed to control hypertension and slow the progression of DN. Nevertheless, about 20% of patients eventually progress to end-stage renal disease (ESRD) and require hemodialysis, peritoneal dialysis, or renal transplant. Therefore, we believe an unmet medical need for safe and convenient treatments to retard or reverse the progression of DN persists.

Data from nonclinical studies indicate that CCX140 is a potent and selective antagonist of the chemokine receptor known as CCR2 that is found in macrophages and believed to play an important role in the inflammatory process. Because CCX140 blocks the monocyte/macrophage migration from blood to tissues that occurs only during inflammation, it is anticipated that administration of CCX140 will provide selective therapeutic benefit without compromising general immune surveillance.

Hyperglycemia and hypertension in patients with Type 2 diabetes are major determinants of the development of DN. While historically considered as a non-inflammatory disease, there is now clear evidence of the role of macrophages in DN. Renal biopsies from patients with DN display elevated glomerular infiltration of macrophages that is not secondary to fibrosis, and tubular interstitial damage is strongly correlated with monocyte/macrophage cell infiltration. Experimental studies in preclinical diabetic models have clarified that monocyte infiltration occurs at early stages of disease and this infiltration correlates with renal injury.

Recent work has focused on CCR2 as the main driver of monocyte infiltration into diseased kidneys. Levels of MCP-1 (also called chemokine ligand 2 (CCL2)), the main ligand for CCR2, are elevated in the kidneys of patients with DN. MCP-1 is produced by renal parenchymal cells in vitro when exposed to the diabetic stressors (i.e., high glucose, stretching/hypertension). Advanced glycation end products are also capable of stimulating MCP-1 production by renal cells in vitro. Levels of urinary MCP-1 are considered strong indicators of renal damage and correlate well with albuminuria and interstitial macrophage numbers.

Data generated by ChemoCentryx scientists show that, in addition to a salutary effect on glycemic parameters, CCR2 blockade leads to improvement in urinary albumin excretion, serum creatinine and blood urea nitrogen, or BUN, in models.

As a precursor to our clinical trials in patients with diabetic nephropathy, in January 2011, we completed a 159-patient randomized Phase II clinical trial to assess the safety and tolerability of CCX140 in patients with Type 2 diabetes, the most common cause of diabetic nephropathy. CCX140 is currently in two Phase II clinical trials in diabetic nephropathy and we expect to complete these clinical trials by the end of 2012, provided that we do not increase the sample size or add additional dose groups to one of the Phase II clinical trials.

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