Research & Development

C-peptide:  Biology

C-peptide is a 31 amino acid residue peptide derived from proinsulin (see schematic below), which is synthesized in the pancreatic beta cells. In healthy individuals, C-peptide and insulin are co-secreted in equimolar amounts into the portal circulation. In type 1 diabetes, autoimmune destruction of the beta cells results in deficiency of both insulin and C-peptide. These patients routinely receive insulin injections to compensate for the lack of endogenous insulin production, but no replacement of C-peptide is given. Scientists working at Cebix have identified C-peptide as a biologically active endogenous peptide hormone implicated in vascular homeostasis in several tissues. Therefore, C-peptide deficiency, together with elevated blood glucose levels, contributes to the development of microvascular complications in the nerves, the kidneys, and the retina. Replacement of C-peptide in type 1 diabetes patients and in animal models of diabetes has been shown to prevent or retard the progression of long-term complications.

Schematic representation of human proinsulin. C-peptide is indicated in yellow and insulin’s A- and B- chains in red.

During the past decade, proinsulin C-peptide has emerged as a bioactive peptide. In vivo studies in animal models of type 1 diabetes have established that C-peptide administration results in significant improvements in nerve and kidney function. Thus, in animals with early signs of diabetes-induced neuropathy, C-peptide treatment in replacement dosage results in improved peripheral nerve function, as evidenced by increased nerve conduction velocity, and significant amelioration of nerve structural changes. Likewise, C-peptide administration in animals with nephropathy improves renal function and structure; it decreases urinary albumin excretion and prevents or decreases diabetes-induced glomerular changes.

C-peptide:  Mechanism of Action

C peptide binds to a membrane structure, most likely a G-protein coupled membrane receptor, eliciting a rise in intracellular Ca2+ concentration and subsequent activation of at least two enzyme systems, Na+,K+ ATPase and endothelial nitric oxide synthase (eNOS).  Both enzyme systems are essential for the normal function of cells and are known to be deficient in diabetes. Na+,K+ ATPase maintains normal cellular energy status, electrolyte concentrations, and fluid balance.  Nitric oxide, its formation being stimulated by eNOS in cells in the blood vessel walls, is of crucial importance for normal blood flow regulation and vascular homeostasis in tissues.  It is hypothesized that C peptide replacement in type 1 diabetes will serve to improve energy status and electrolyte balance (Na+,K+ ATPase effects) and improve blood flow in critical tissues (eNOS effects), thereby preventing or retarding the development of long-term microvascular complications.  In addition, C-peptide has been shown to be capable of activating gene transcription and enhance expression of neurotrophic factors.  The following schematic outlines the cellular actions and downstream effects of endogenous C-peptide.

C-peptide:  Development Plan

The C-peptide development program undertaken by Cebix is unique to start-up companies because substantial clinical data already exist.  Based on the clinical studies conducted to date in approximately 200 type 1 diabetes patients, C-peptide replacement therapy has an excellent safety profile with no drug-related adverse events; this is to be expected for an endogenous peptide when administered to patients at concentrations found in healthy (non-diabetic) persons.  Following initial evaluation of C-peptide for the treatment of diabetic neuropathy in type 1 patients, we plan to investigate C-peptide replacement therapy in type 1 diabetic nephropathy and retinopathy.

In the clinical studies previously conducted, C-peptide was administered subcutaneously at a frequency of four times a day.  To make C-peptide more patient-friendly as a marketed drug product, the next stage of clinical development will incorporate a dosing regimen of weekly or monthly subcutaneous depot injections.  The technical feasibility of formulating C-peptide as a depot for injection is currently being assessed by Cebix in collaboration with contract vendors that offer varied proprietary approaches.  The primary objective of this work is to develop a small-volume depot injection of C-peptide that is physically stable and provides a controlled release of peptide at therapeutic levels over the desired time frame (week or month).  The C-peptide drug product for clinical supplies will be manufactured according to federal and international regulations, and appropriate toxicological assessments will be done prior to clinical testing.

A Phase 2 study of C-peptide in type 1 diabetic patients with mild to moderate neuropathy is planned for initiation in early 2011.  When available, information pertaining to this clinical study will be posted on www.clinicaltrials.gov.  The goal of the study will be to evaluate the ability of C-peptide to slow the progression of neuropathy, or possibly improve it, based on sensory measurements such as nerve conduction velocity.  Results from this Phase 2 study will guide the development of future clinical studies on the safety and efficacy of C-peptide in patients with neuropathy, nephropathy, and retinopathy.