C-Peptide as an Endpoint in Clinical Trials: Its Time Has Come

It was identified in the late 1960s. Since then, studies have shown that it is a biomarker for beta-cell function. In other words, it’s a measure of beta cell health and insulin secretion. If it’s in between the normal range, you don’t have type 1 diabetes (T1D). If it’s low (or you have none), it indicates that your pancreas is producing little or no insulin. There was even a test to measure it in humans 50 years ago.  

What is it?  

C-peptide. It is a fragment generated during the process of making the active insulin that gets released into the body.

Biomarkers and Surrogate Endpoints   

A biomarker is anything that can be used to measure what’s going on in the body. Biomarkers are often used by researchers to study how the body responds to new therapies. In some cases, biomarkers can be used as a clinical trial endpoint, something that is measured in a clinical study to objectively determine if a therapy is effective.   

To be used as a clinical trial endpoint, a biomarker must be a validated surrogate endpoint, meaning the biomarker has been proven to predict a clinical benefit (that is to say the biomarker is a surrogate for other clinical benefits). For example, HbA1c is a validated surrogate endpoint for the risk of diabetes-related eye, kidney, or nerve disease.   

For more than 40 years, C-peptide has been known as a biomarker for beta-cell function. However, regulators don’t yet consider it to be a validated surrogate endpoint, and it therefore can’t be used to approve a new drug.   

So why isn’t C-Peptide a validated surrogate endpoint?   

It goes back more than 20 years. 

Early Consensus 

In 2001, the American Diabetes Association (ADA) held a workshop to identify appropriate outcome measures in T1D clinical trials. Clinicians and researchers at the workshop agreed that C-peptide is not just a measure of beta-cell function, but also directly predicts benefits on other outcomes, including improved HbA1c, lower risk of low blood sugar (called hypoglycemia), and lower risk of diabetic eye disease.  

Researchers concluded that drugs that can preserve C-peptide, and therefore beta-cell function, would also improve these other clinical outcomes. The results were clear: The unanimous conclusion determined that C-peptide is the appropriate outcome measure for T1D clinical trials to preserve beta-cell function.  

Unfortunately, regulators were not convinced. At the time, researchers could only point to a few investigational drugs¹ that showed the beneficial effects of preserving beta-cell function (measured by C-peptide), and regulators wanted more validation. 

Many More Clinical Trials

Now, there are at least 21 clinical trials² of disease-modifying therapies in the new-onset stage, which scientists can rely on to demonstrate the beneficial effects of preserving beta-cell function as measured by C-peptide. A meta-analysis, funded by Breakthrough T1D and Diabetes UK through the Critical Path Institute’s Trial Outcome Marker Initiative (TOMI), showed that disease-modifying therapies that preserve beta-cell function are effective at improving metabolic outcomes in new-onset T1D. This, said the authors, “support[s] the use of C-peptides as a surrogate endpoint in clinical trials.”  

Breakthrough T1D is a founding member of the Critical Path Institute (C-Path)—a nonprofit organization dedicated to improving and streamlining the process of drug development—T1D Consortium (T1DC) in 2017. Initially, the T1DC worked to qualify diabetes-related autoantibodies as biomarkers to be used in the development of therapies for the treatment and prevention of T1D. This was achieved by receiving regulatory endorsement from the European Medicines Agency (EMA). Now, the T1DC is working to develop clinical trial simulation tools to improve T1D prevention and new-onset trials.  

Large Clinical Trials vs. Rapid Progress in Development  

Regulators have said the endpoints that can be used for drug approval in T1D trials are HbA1c, low blood-sugar events, and complications. Showing benefits of new disease-modifying therapies in new-onset T1D using these endpoints is a challenge.  

A new drug’s effect on HbA1c can be difficult to determine while insulin is also being used. Low blood-sugar events are uncommon, and complications take years to develop. Therefore, trials that use these endpoints often require prohibitively (1) large numbers of enrolled subjects and/or (2) long follow-up, which makes developing drugs difficult.  

Instead, by using validated surrogate endpoints that predict clinical benefits, clinical trials can be smaller or shorter while still being able to demonstrate the benefits of a drug. In this way, validated surrogate endpoints accelerate the drug development process and help bring new therapies to people with T1D faster.  

A new publication, authored by world-renowned investigators (one of which was in the publication that followed the 2001 ADA workshop!) and five Breakthrough T1D employees, provides more evidence for C-peptide as a validated surrogate to predict clinical benefits of disease-modifying therapies in T1D. This publication summarizes data from many different types of studies to make the case for C-peptide. The research presented includes: 

• Longitudinal studies (Diabetes Control and Complications Trial (DCCT/EDIC))  
• Cross-sectional studies (Scottish Diabetes Research Network Type 1 Bioresource Study (NT1BIO))  
• Beta cell transplantation studies (Collaborative Islet Transplant Registry)  
• Meta-analysis of disease-modifying therapies to preserve beta-cell function (TOMI Study)  
  

All of these have identified benefits from the preservation or restoration of beta-cell function as measured by C-peptide.  

The greatest opportunity to intervene with disease-modifying therapies exists early in the autoimmune process. It requires, therefore, an endpoint that can identify clinically meaningful impacts in early-stage disease. C-peptide is that. 

Breakthrough T1D hopes that regulators will agree.  

¹ The drugs used were:  

• anti-CD3 monoclonal antibody (which would become Tzield™ (teplizumab) more than 20 years after they highlighted it at the ADA workshop)  
• azathioprine plus steroids  
• cyclosporin
• heat-shock protein peptide DiaPep277 

² The medications and interventions used were: