Is Insulin Enough? Developing C-Peptide Therapy

Since insulin was first given to diabetics in the 1920s, it has been cast as the magical elixir of type 1 diabetes.  As far as the big picture goes, it is, since it keeps those of us without  healthy beta cells from dying.   As diabetes care advances, however, and moves beyond the “Let’s just try to keep ’em alive,” stage, some are beginning to question the sufficiency of insulin replacement alone.

Symlin, made by Amylin Pharmaceuticals, was one of the first non-insulin hormone replacements to reach type 1 diabetics. Symlin is an analogue of the naturally occurring hormone amylin, which is secreted by beta cells along with insulin. Diabetics without functioning beta cells lack amylin just as they lack insulin, and so Amylin Pharmaceuticals argues that Symlin should become part of the diabetic regimen as well, a helpful complement of insulin.

But even amylin does not complete the picture, and one company, Cebix Incorporated, based in San Diego, California, has started looking at another missing component of beta cell secretion: C-peptides.

C-peptide is an important part of the insulin assembly process of beta cells in the pancreas. When insulin is made in the body, it is first formed as a long chain of 110 amino acids. After the chain is assembled, it is folded and relocated within the beta cell, and ultimately cleaved into three parts– the insulin A chain, the insulin B chain, and the C-peptide in the middle. The two short insulin A and B chains bind to form a single insulin protein, and then both entities– the insulin protein and the short C-peptide– are released by beta cells into circulations.

When C-peptide was first discovered in 1967 as part of the insulin synthesis process, it was assumed to primarily serve as a facilitator for the formation of insulin itself– a short strand of middle-man amino acids that helped insulin to fold and be cleaved as necessary. In fact, C-peptide’s main role in medicine thus far has been as adjunct-to-insulin; when testing whether a patient still has beta cells and the ability to produce insulin, C-peptide levels are often measured. This allows doctors to determine how much proinsulin, and therefore insulin, is being manufactured by the body even in patients who the doctors suspect have impaired beta-cell function.

Recently, this role of C-peptide as a measure of natural insulin production made national headlines when Joslin Diabetes Center researchers found by measuring C-peptide levels that some type 1 diabetics were still making insulin, even after fifty years of diabetes. To the Joslin researchers, the C-peptide levels were interesting mainly as indication of continuing beta cell function and its relation to long-term control for diabetics.

For some researchers, however, including those at Cebix, the C-peptide levels are interesting not just as a side effect of insulin production.  And although originally belittled as merely an insulin functionary, C-peptide is now being reevaluated, and a new, biologically active role for C-peptides is being explored.

For Dr. John Wahren, this exploration is old news. Wahren first started looking at C-peptide in the 1980s in Sweden. By the 1990s, Wahren and others had published quite a bit of research attesting to the benefits of C-peptide, showing that C-peptide administration improved muscle vasculature [1] and renal function [2] in rats, and that C-peptide replacement had measurable effects on nervous function [3] and blood flow for diabetics [4].

Tracing the root of these widespread effects, the researchers found that contrary to original assumptions, C-peptide did a lot more than help insulin fold. Once it is released into circulation by beta cells, C-peptide, like insulin, has a direct effect on cellular signaling. Though the entirety of molecular interactions caused by C-peptides are yet to be discovered, current research [5] shows that C-peptides bond to a receptor on the surface of cells and initiate a cascade of signals that cause the cell to take in more calcium, regulate gene transcription and cell cycle progression, and increase nitric oxide levels in blood vessels. All of these activities are crucial to cell survival, and as a result the potential effects of varying C-peptide levels are far reaching.

This research into C-peptide action, initially funded in large part by the Swedish government, led Wahren to formalize a plan for the development of therapeutic drugs for diabetic neuropathy, or nerve damage that results as a complication of diabetes, based on C-peptide replacement. In the late 90s, Wahren sold the rights to the idea to his then-employer, Schwarz Pharma AG (since acquired by UCB Pharmaceuticals ). With Schwarz’s backing and their $10 million in funding, Wahren set about trying to prove C-peptide would be a clinically effective therapeutic agent for diabetics who no longer made the peptide naturally.

Soon afterwards, though, Schwarz Pharm began a strategic shift in company goals, deciding to focus on neurology and urology.  Although the project had advanced through pre-clinical and phase I trials, Schwarz decided to drop Wahren’s C-peptide unit, and returned the rights to him. Wahren sought another funding source, and ultimately landed another $10 million from the Swedish venture capital group HealthCap. The HealthCap funding carried the project through phase 2a trials for neuropathy, but, as a result of a few strategic mistakes during the trial process, the funds ran out in the mid 2000s, and Wahren and his C-peptides were again left looking for a home.

Wahren took his idea to his friend and former colleague in the pharmaceutical industry, Lars Ekman. Ekman, like Wahren, had spent some time with Schwarz Pharma, but had since moved on to become the President of Research and Development at the Irish pharmaceutical company Elan. Leading one of Elan’s multinational projects, Ekman had ended up in San Diego, and was very interested in finding new opportunities and pharmaceutical prospects. Convinced by Wahren’s passion and research, Ekman helped to raise another $28 million in venture capital funding for C-peptides from mid-level venture capital groups like Sofinnova Ventures, Thomas McNerney and Partners, and Interwest Partners, among others. He also chose to lead the next stage of development as the CEO of the company created to bring C-peptide treatment to market, Cebix Inc.

Ekman pulled in a core team to lead the company, including James Callaway, and Elan colleague, as President of Cebix. The team, though, was kept very small, with only a handful of people in San Diego, and Wahren continuing to direct research in Sweden. To keep this streamlined profile, any additional help and resources that were needed were obtained from consultants and through connections at Elan.

Given the decades of research showing C-peptides to be biologically active, the Cebix team sees far-reaching potential for C-peptide treatment for type 1 diabetics. Nonetheless, to ensure they have defined  attainable business goals, especially for the initial requirements they face with FDA approval, Cebix has continued with trials and research focused on the relatively narrow but unserved area of mild to moderate diabetic neuropathy.

According to the National Institutes of Health, diabetic neuropathy can be any one of a family of nerve disorders that together affect about 60 to 70 percent of diabetics. The symptoms of neuropathy range from numbness to extreme pain, and can occur as a result of nerve damage to any organ or tissue. The exact causes of neuropathy are still being discovered, but common causes include poor blood glucose control over many years, genetic susceptibility, and nerve damage incurred as a result of chronic autoimmune inflammation.

So what does C-peptide have to do with neuropathy? Though the exact receptors and total effects of C-peptides are still being researched, Cebix has found that there are significant benefits to administering C-peptide to type 1 diabetics who do not make it on their own.  Throughout the course of the research into C-peptides, a total of nineteen clinical studies have been carried out with about 300 patients, and the initial results indicate that C-peptide increases nerve conduction and perception of vibration in both humans and animals.

In a 2003 study of type 1 diabetics without any symptoms of neuropathy [6], Wahren and fellow researchers looked at the velocity of nerve conduction as compared to non-diabetics. Nerve conduction velocity is a measure of the speed at which electrical signals are passed through the nervous system, and is used to assess nerve damage and sensory responsiveness. The diabetic patients, even without evidence of neuropathy, showed slower nerve conduction velocities than the non-diabetic controls at the beginning of the trials. With twelve weeks of C-peptide replacement, however, the diabetic patients showed significant improvement in nerve conduction speeds as compared to diabetics given a placebo. Vibration perception also showed improvement, though perception of hot and cold remained unchanged. Subsequent studies support these findings, and the Wahren’s group showed in 2007 [7] that C-peptide improved nerve conduction and vibration perception in patients already showing symptoms of diabetic neuropathy.

Given this and similar evidence of C-peptide’s beneficial therapeutic effects for type 1 diabetics who otherwise lack the hormone, Cebix has developed an injectable formulation of C-peptide that it hopes to market for treatment of type 1 diabetes. Ultimately, Cebix believes that the sensory nervous system improvements seen in studies warrants replacement therapy for all type 1 diabetics, but, in the interest of taking one solid step at a time, Cebix is targeting the immediate apparent need first– type 1 diabetics with mild to moderate diabetic neuropathy.

Unfortunately, there is no solution for diabetic neuropathy right now; symptoms can be treated with pain relievers, and further damage can be slowed by ensuring tight blood sugar control, but there is no cure for diabetic neuropathy. As a result, the possibility that C-peptide may actually improve nerve conduction for patients and return some lost sensory perception qualifies Cebix’s drug formulation for accelerated approval by the FDA under Subpart H, a regulation that delineates special-case approval for products that “have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments.” In other words, C-peptide is a naturally-occurring hormone thus far shown to be both effective and perfectly safe in treated an untreated disease, so the FDA can be more lenient with the requirements for approval. For Cebix, this means that Pivotal Phase clinical trials can use a surrogate measure– nerve conduction tests– to show the effectiveness of the drug, rather than more difficult-to-quantify measures like patient perception and tactile sensation.

The trick for Cebix, though, even with patients with diabetic neuropathy, is formulating C-peptide in a way that diabetics will be willing to take it. Another injection? To prevent nerve damage and improve sensory perception, but still– who wants another needle?

Cebix has not found a way to deliver C-peptide effectively without injection, but they have done as much as possible to make the process relatively painless and low-frequency. After trying several different means of formulation and delivery, Cebix is currently looking at two options that would require only one weekly injection from a 27-gauge-or-smaller needle. The once-a-week delivery, Cebix hopes, will mean that the potential benefits of the drug for patients with neuropathy– and perhaps eventually for all type 1 diabetics– will outweigh the pain and hassle of taking another shot.

With both the delivery mechanism and the FDA pathway defined, Cebix hopes to move forward with clinical trials for C-peptide replacement therapy in diabetic neuropathy, and then to continue with trials for treatment of diabetic nephropathy and other complications. It will still be several years at the least, then, before Cebix has any C-peptide commercially available, and until that time they will be testing the efficacy and safety of the treatment. Nonetheless, the emerging picture for diabetics is clear– insulin isn’t the only color in the crayon in the box anymore, and Cebix and others are working hard to supply diabetics with the missing colors.

1. Lindström K, Johansson C, Johnsson E, Haraldsson B: Acute effects of C-peptide on the microvasculature of isolated perfused skeletal muscle and kidneys in rat. Acta. Physiol. Scand. 156:19-25, 1996

2. Ohtomo Y, Aperia A, Sahlgren B, Johansson B-L, Wahren J: C-peptide stimulates rat renal tubular Na+,K+ATPase activity in synergism with neuropeptide Y. Diabetologia 39:199-205, 1996

3. Johansson B-L, Borg K, Fernqvist-Forbes E, Odergren T, Remahl S, Wahren J: C-peptide improves autonomic nerve function IDDM patients. Diabetologia 39:687-695, 1996

4. Johansson B-L, Linde B, Wahren J: Effects of C-peptide on blood flow, capillary diffusion capacity and glucose utilization in the exercising forearm of Type I (insulin-dependent) diabetic patients. Diabetologia 35:1151-1158, 1992

5. Johansson J, Ekberg K, Shafqat J, Henriksson M, Chibalin A, Wahren J, Jörnvall H: Molecular effects of proinsulin C-peptide. Biochemical & Biophysical Research Communications 295:1035-1040, 2002

6. Ekberg K, Brismar T, Johansson BL, Jonsson B, Lindström P, Wahren J.

Amelioration of sensory nerve dysfunction by C-Peptide in patients with type 1

diabetes. Diabetes. 2003 Feb;52(2):536-41. PubMed PMID: 12540632. http://diabetes.diabetesjournals.org/content/52/2/536.full

7. Ekberg K, Brismar T, Johansson BL, Lindström P, Juntti-Berggren L, Norrby A,

Berne C, Arnqvist HJ, Bolinder J, Wahren J. C-Peptide replacement therapy and

sensory nerve function in type 1 diabetic neuropathy. Diabetes Care. 2007

Jan;30(1):71-6. PubMed PMID: 17192336.

*C-Peptide image by JaGa (self-made using BKChem and Inkscape) via Wikimedia Commons

Karmel Allison

Karmel was born in Southern California, diagnosed with Type 1 Diabetes at the age of nine, and educated at UC Berkeley. Karmel now lives in San Diego with her husband, where she is loving the sunshine, working in computational biology at the University of California, San Diego, and learning to use the active voice when talking about her diabetes.

Karmel Allison

Karmel was born in Southern California, diagnosed with Type 1 Diabetes at the age of nine, and educated at UC Berkeley. Karmel now lives in San Diego with her husband, where she is loving the sunshine, working in computational biology at the University of California, San Diego, and learning to use the active voice when talking about her diabetes.