C-peptide Seen as Key Biomarker for Type 1 Diabetes Drug Trials

C-peptide is an important biomarker that is critical to developing new disease-modifying therapies for type 1 diabetes. For more than 40 years, C-peptide has been known as a biomarker for beta cell function, and in recent years the FDA has stated that C-peptide could be used as a reasonably likely surrogate endpoint that could support accelerated approval.

Type 1 diabetes is defined by hyperglycemia due to autoimmune destruction of the insulin-producing beta cells in the pancreas, leading to insulin deficiency, and accounts for 5% to 10% of all cases of diabetes. Type 1 diabetes affects approximately 2 million people in the US and 8.4 million people worldwide and is associated with microvascular and macrovascular complications such as retinopathy, nephropathy, neuropathy, and cardiovascular disease.

C-peptide is a fragment generated during the process of making the active form of insulin that gets released from the pancreas into the body, and it can be easily measured in the blood or urine. If it is low, or there is none, it indicates that the pancreas is producing little or no insulin.

A biomarker can be used as a clinical trial endpoint only if it is a surrogate endpoint, meaning the biomarker has been proven to predict a clinical benefit. Regulators at the FDA and other regulatory agencies around the world classify surrogate endpoints based on the strength of the evidence that they can predict clinical benefit. A reasonably likely surrogate endpoint has good but not conclusive evidence and can support accelerated approval with post-marketing studies needed to confirm benefit, while a validated surrogate endpoint has definitive evidence and can support full approval.

Regulators have said the endpoints that can be used for drug approval in type 1 diabetes trials today are HbA1c, low blood-sugar events, and rates of disease complications. For disease-modifying therapies, reaching these endpoints in clinical trials can be a major challenge, especially when tested in people recently diagnosed with type 1 diabetes. Measuring the effects of a new drug on HbA1c levels is difficult because insulin therapy can also cause improvements in HbA1c, low blood-sugar events are relatively uncommon, and complications take years to develop, so trials that use these endpoints often require prohibitively large numbers of enrolled subjects and long follow-up.

For 25 years, the research field has agreed C-peptide should also be used as a validated surrogate endpoint to predict clinical benefits in disease-modifying therapy clinical trials. Using C-peptide, 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 type 1 diabetes, when insulin therapy is needed, who currently do not have any options to preserve beta cells and delay disease progression.

Despite widespread scientific consensus, regulators do not yet agree that C-peptide is a validated surrogate endpoint that can support full approval. Without C-peptide, it will be incredibly difficult for disease-modifying therapies to move through the drug development pipeline at a reasonable pace.

People with type 1 diabetes require lifelong insulin replacement, which can be administered via subcutaneous injection or insulin pump. Randomized clinical trials have demonstrated that continuous glucose monitors with insulin pumps, which automatically adjust insulin delivery in response to glucose levels, result in less hypoglycemia and improved hemoglobin A1c levels.