Chronic Kidney Disease

Diabetic nephropathy (DN) is a way of life for about 40 percent of all people who have Type 2 diabetes. Right now, many patients with DN, a form of chronic kidney disease, are prescribed medications, mostly just common blood pressure medications, that are intended to slow its progress. But at ChemoCentryx we are developing therapies aiming to not just slow, but perhaps even halt this disease’s progression. Our hope is that patients do not have to travel along the path to renal failure.  Instead they may continue living a higher quality of life.
Our lead drug candidate, CCX140, is an orally-administered inhibitor of the chemokine receptor known as CCR2 and has been evaluated in a Phase II placebo-controlled, clinical trial in patients with diabetic nephropathy. CCX140 treatment in these patients resulted in a statistically significant reduction in proteinuria. Reduction in proteinuria is widely considered as a beneficial outcome in the treatment of chronic kidney disease (CKD) including Focal Segmental Glomerulosclerosis (FSGS), and experts regard the reduction of proteinuria as the likely registration endpoint for a new therapeutic in FSGS.

In December 2016, we expanded our existing kidney health alliance with Vifor Pharma to include the development and commercialization of CCX140 for renal diseases. The alliance will initially focus on the joint development of CCX140 in rare kidney diseases, with Vifor Pharma retaining an option to solely develop and commercialize CCX140 in more prevalent forms of chronic kidney disease (CKD). Under the agreement, ChemoCentryx retains marketing rights for rare renal disease in the U.S. and China, while Vifor Pharma has commercialization rights in the rest of the world.

We have successfully completed Phase II clinical development of CCX140 in patients with diabetic nephropathy. In December 2014, we announced positive top-line 52-week data from this trial, indicating that the study met its primary endpoint by demonstrating that treatment with 5mg of CCX140 given orally once daily added to standard of care treatment (an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)) resulted in a statistically significant (p=0.01) reduction in Urinary Albumin Creatinine Ratio (UACR), beyond that achieved with standard of care alone over a 52 week treatment period.

A reduction in protein in the urine is an important clinical result, as studies show that this is a precursor to long term renoprotective effects like reduction in incidence of end-stage renal disease (ESRD). CCX140 was well-tolerated and no safety issues were observed that would prevent further clinical development of CCX140 in diabetic nephropathy.

Diabetic nephropathy is a form of chronic kidney disease, characterized by the gradual loss of kidney function.  It is most common among people with Type 2 diabetes and hypertension and affects 26 million American adults.

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The chemokine receptor known as CCR2 has been identified as a main driver of inflammatory monocyte and macrophage recruitment into diseased kidneys. Various cell types in glomeruli also appear to express CCR2, which drives some of the renal impairment in diabetic nephropathy. Levels of MCP-1 (also known as CCL2), the main ligand for CCR2, are elevated in the kidneys of patients with diabetic nephropathy. MCP-1 is produced by kidney cells in response to such factors as high blood glucose levels and physical stresses. As a result, levels of MCP-1 in the urine are strong indicators of renal damage and correlate well with albuminuria and interstitial macrophage numbers.

In preclinical studies conducted by ChemoCentryx and other independent researchers, CCR2 inhibition leads to pronounced reduction in albuminuria, as well as improvement in markers of renal function such as serum creatinine and blood urea nitrogen (BUN). CCX140 has been shown to be a potent and selective inhibitor of CCR2, which is required for monocytes to infiltrate the kidney, where they differentiate into macrophages. Preclinical model data suggest that once these damage-promoting cells are inhibited, the kidney is thought to be able to function in a healthier state, and perhaps even restore certain renal function.

Efficacy in Diabetic Nephropathy in a Phase II Clinical Trial of Chemokine Receptor 2 Inhibitor CCX140-B, Richard J. Glassock, Elena Henkel, Heidrun Mehling, Christoph Hasslacher, Ioanna Gouni-Berthold, Vladimir Tesar, Antonia Potarca, Pirow Bekker, Thomas J. Schall. Presented at the American Society of Nephrology Annual Kidney Week Meeting, 2015.

The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial Dick de Zeeuw, Pirow Bekker, Elena Henkel, Christopher Hasslacher, Ioanna Gouni-Berthold, Heidrun Mehling, Antonia Potarca, Vladimir Tesar, Hiddo J Lambers Heerspink, Thomas J Schall, for the CCX140-B Diabetic Nephropathy Study Group. The Lancet Diabetes & Endocrinology, Published online August 10, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00261-2

CCR2 inhibition: a panacea for diabetic kidney disease? Weir MR, The Lancet Diabetes & Endocrinology, published online August 10, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00286-7

Hanefeld M, Schell E, Gouni-Berthold I, et al. Orally-administered chemokine receptor CCR2 antagonist CCX140-B in type 2 diabetes: a pilot double-blind, randomized clinical trial. J Diabetes Metab 2012; 3: 225. DOI:10.4172/2155-6156.1000225.

Diabetes and associated co-morbidities as an inflammatory syndrome. Jaen JC, Powers JP, Sullivan TJ. Ann. Reports Med. Chem. 2012, 47:159–175.

Sullivan TJ, Miao Z, Zhao BN, et al. Experimental evidence for the use of CCR2 antagonists in the treatment of type 2 diabetes. Metabolism 2013; 62:1623-1632.

Sullivan T, Miao Z, Dairaghi DJ, et al. CCR2 antagonist CCX140-B provides renal and glycemic benefi ts in diabetic transgenic human CCR2 knockin mice. Am J Physiol Renal Physiol 2013; 305: F1288–97.

Chemokines and chemokine receptors as therapeutic targets in chronic kidney disease. Vielhauer V, Anders H-J. Frontiers in Bioscience, Scholar Edition 2009; S1(1):1-12.

The role of chemokines in glomerulonephritis. Wada T, Matsushima K, Kaneko S. Frontiers in Bioscience 2008; 13:3966-3974.

Kidney diseases and chemokines. Panzer U, Steinmetz OM, Stahl RAK, Wolf G. Current Drug Targets 2006; 7(1):65-80.

CCR2 inhibition improves renal function in diabetic BTBR ob/ob mice. Sullivan T; Miao Z; Berahovich R; Zhao N; Ertl L; Baumgart T; Krasinski A; Dang T; Miao S;; Powers JP; Jaen JC; Schall T. 48th Annual Meeting – European Association for the Study of Diabetes (EASD), Berlin (Germany); October 1-5, 2012 (selected for oral presentation).

CCR2 inhibition improves renal function in diabetic BKS db/db mice. Sullivan TJ, Miao Z, Zhao N, Berahovich R, Powers JP, Ertl L, Jaen JC, Schall TJ. 72nd American Diabetes Association Scientific Sessions, Philadelphia (PA); June 8-12, 2012. Abstract # 517-P.