Science

C-peptide, the connecting peptide of proinsulin, is being developed by Cebix as an investigational drug for the treatment of long-term complications of diabetes. The peptide is a 31 amino acid cleavage product of proinsulin, formed in the biosynthesis of insulin within the pancreatic beta-cells. Patients with type 1 diabetes lack both circulating insulin and C-peptide; the former is replaced but not the latter.

Pioneering work by the scientific community and Cebix scientists strongly suggests that lack of endogenous C-peptide, together with hyperglycemia, is an important contributing factor in the pathogenesis of long-term complications of type 1 diabetes (1). Studies in animal models of type 1 diabetes and early phase clinical trials in patients with type 1 diabetes demonstrated a protective effect of C-peptide treatment in diabetes-induced microcirculation abnormalities of the kidneys, peripheral nerves, and central nervous system (2-5). Furthermore, the functional improvements occurred despite both unchanged glycemic control and blood pressure. In patients with type 1 diabetes, C-peptide administration in physiological replacement doses was safe and well tolerated. These results identify C-peptide as a promising novel therapeutic candidate in the treatment of type 1 diabetes.

In clinical trials conducted to date, C-peptide has been administered as an aqueous solution requiring subcutaneous injection four times daily. Recent efforts by the company have produced a C-peptide for upcoming clinical studies that is a modified C-peptide with extended half-life in the plasma enabling once weekly subcutaneous injections. In this modified form, C-peptide is covalently bound to polyethylene glycol (PEG) resulting in an increased half-life from approximately 1 hour to three days. Data shows that the long-acting PEGylated C-peptide (investigational drug CBX129801) exerts biological effects that are comparable to those of the unmodified native C-peptide. Native C-peptide has been administered to more than 250 type 1 diabetes patients and has accumulated an attractive safety profile. Likewise, PEG is used as a modifying agent in several currently marketed pharmaceuticals and is not associated with toxic effects during approved use.

Cebix plans to initiate a Phase 1 study with CBX129801 in the United States in the first quarter of 2011. If this trial confirms that CBX129801 is safe and well tolerated in type 1 diabetes patients, the company plans to initiate a large pivotal Phase 2b study in the United States, Canada, and the European Union with CBX129801 for the treatment of mild to moderate peripheral neuropathy in type 1 diabetes patients. This trial will be designed to validate with PEGylated C-peptide the earlier observations (2,6) of the restorative effects of C-peptide replacement on nerve function.

This project is the first of its kind to explore a treatment that targets primary mechanisms in the development of peripheral neuropathy in type 1 diabetes. As such, CBX129801 has the opportunity if successful through clinical testing to marketing approval of becoming a disease-modifying therapy with the goal to alter the chronic prognosis of millions of patients worldwide with type 1 diabetes. Cebix also plans to support clinical studies in diabetic nephropathy in type 1 diabetes patients within the next 18 months in the European Union.

References 1. Hills CE, Brunskill NJ. Clin Sci 116:565-574, 2009 2. Hills CE, Brunskill NJ, Squires PE. Am J Nephrol 31:389-397, 2010 3. Samnegård B, Jacobson SH, Wahren J, Sjöquist M. et al Nephrol Dial Transplant 20:532-538, 2005 4. Ekberg K, Brismar T, Bolinder J, Wahren J. et al Diabetes Care 30:71-76, 2007 5. Johansson BL, Borg K, Fernqvist-Forbes E, Kernell A, Odergren T, Wahren J. Diabet Med 17:181-189, 2000 6. Ekberg K, Brismar T, Johansson BL, Jonsson B, Lindstrom P, Wahren J. Diabetes 52:536-541, 2003