C-peptide: Everything you need to know

Biomarkers and surrogate endpoints 

A biomarker, or a biological marker, is anything that can be used to measure what’s going on in the body.

Biomarkers are used by doctors to help monitor your health and 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 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 surrogate endpoint for the risk of diabetes-related eye, kidney, or nerve complications. Surrogate endpoints are important because they allow us to see the effects of a drug much faster, easier, and sometimes more clearly than other endpoints.

Regulators at the U.S. Food and Drug Administration (FDA) and other regulatory agencies around the world classify surrogate endpoints based on the strength of the evidence that they can predict clinical benefit. See below for the different categories of surrogate endpoints and what each means.

For example, it is very well established that HbA1c is a good predictor of diabetes-related complications. The evidence is robust enough that HbA1c is considered a validated surrogate endpoint, and it has been used to support approval of many T1D therapies.

Challenges with current T1D clinical trial endpoints

Regulators have said the endpoints that can be used for drug approval in T1D trials today are HbA1c, low blood-sugar events, and rates of disease complications. For disease-modifying therapies (DMTs)—those that can change the course of T1D—reaching these endpoints in clinical trials can be a major challenge, especially when tested in people recently diagnosed with T1D.

There are multiple reasons for this. First, measuring the effects of new drug on HbA1c levels is difficult because insulin therapy can also cause improvements in HbA1c, and we need to distinguish between the effects of the two. Second, low blood-sugar events are relatively uncommon, especially if someone experiences a honeymoon period after diagnosis. Third, complications take years to develop, and trials would have to be decades long to directly see a drug’s effects on long-term outcomes. Therefore, trials that use these endpoints often require prohibitively (1) large numbers of enrolled subjects and/or (2) long follow-up, which makes moving DMTs through the pipeline more challenging than ever. Compounding the challenge, large or lengthy trials are expensive, which could hinder industry investment in T1D therapies.

Why C-peptide is important

Using C-peptide, DMT studies could require fewer participants, take less time, and cost less money, all while still being able to demonstrate the clinical benefits of a new therapy. This is especially critical for emerging therapies aimed at people in stage 3 T1D—when insulin therapy is needed—who currently don’t have any options to preserve beta cells and delay disease progression. Ultimately, C-peptide as a validated surrogate endpoint would unlock DMTs for the T1D community. In fact, without C-peptide, it will be incredibly difficult for DMTs to move through the drug development pipeline at a reasonable pace—or at all.

Despite widespread scientific consensus, regulators do not yet agree that C-peptide is a validated surrogate endpoint that can support full approval. In recent years, the FDA has stated that C-peptide could be used as a reasonably likely surrogate endpoint that could support accelerated approval. If granted accelerated approval, additional post-marketing studies are required to confirm the drug’s benefits. And the confirmatory trials must use the same old endpoints that are so challenging to study: HbA1c, low blood sugar events, or disease complications. This is a big step forward, but for many companies, the bar is still too high to invest in T1D therapies.

Based on FDA recommendations, almost every DMT trial in stage 3 T1D uses C-peptide as the study endpoint, and the FDA recently agreed to consider C-peptide as a reasonably likely surrogate endpoint that could support accelerated approval for two different therapies from two different companies.

First, the FDA agreed that C-peptide data from the DIAGNODE-3 trial, which investigated whether retogatein (rhGAD65) could preserve beta cells, could potentially support accelerated approval. Second, the FDA is currently reviewing data from the Tzield PROTECT study, which also assessed C-peptide to see if Tzield could preserve beta cells, and the FDA has granted Tzield priority review for stage 3 T1D. Each of these examples demonstrate that regulators believe in the potential of DMTs to change the lives of the T1D community, and they opened the door for C-peptide to accelerate the pace of these therapies. While the interim results from DIAGNODE-3 were negative and the Tzield review is still ongoing, we see clear signs that C-peptide makes the development of DMTs possible.

However, regulators don’t yet consider C-peptide 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?   

The story 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 of 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: A consensus-driven 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 drugs that showed the beneficial effects of preserving beta cell function (measured by C-peptide), and some of the most important studies could not definitively prove that C-peptide predicted benefits. Regulators needed more data. 

Many more clinical trials

Now, there have been dozens of clinical trials of disease-modifying therapies in stage 3 T1D, and nearly all of them use C-peptide, which scientists can rely on to demonstrate the beneficial effects of preserving beta cells. 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 stage 3 T1D. This, said the authors, “support[s] the use of C-peptide as a surrogate endpoint in clinical trials.”  

Breakthrough T1D is a founding member of the Critical Path Institute’s (C-Path) Type 1 Diabetes Consortium. C-Path is a nonprofit organization dedicated to improving and streamlining the process of drug development, and with support from Breakthrough T1D, launched its T1D Consortium (T1DC) in 2017. Initially, the T1DC worked to get regulatory endorsement of diabetes-related autoantibodies as biomarkers to be used in the development of therapies that can delay or prevent T1D. This was achieved by receiving regulatory qualification from the European Medicines Agency (EMA) and published acceptance from FDA. Now, the T1DC is working to develop clinical trial simulation tools to improve T1D prevention and new-onset T1D clinical trials, as well as generating new evidence for the role of C-peptide in clinical trials.  

Making the case for C-peptide

A publication, authored by world-renowned investigators (one of which was in the publication that followed the 2001 ADA workshop!) and five Breakthrough T1D employees, summarizes the totality of evidence to date for C-peptide as a validated surrogate that predicts clinical benefits of DMTs 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 clinical trials of DMTs 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.

Even more, for the first time ever, last year the FDA participated in a public workshop about C-peptide with researchers, scientists, Breakthrough T1D, companies, and people living with T1D. During this workshop, the FDA gave clear directions to the research community about the evidence needed for them to consider C-peptide a validated surrogate endpoint that can be used for DMT approvals.

As a result of this workshop, C-Path’s T1DC spun out a C-peptide data analytics working group with the key players in the field—including the FDA—that has been working hard over the past year to compile the evidence that the FDA requested. Right now, the FDA is reviewing the statistical analysis plan for C-peptide data. Once approved, the group will move forward, put their analysis plan into action, and submit their results.