Following Yale Investigator-led Trials, FDA Approves First Drug To Delay Onset of Type 1 Diabetes

On November 17, the FDA approved teplizumab, the first drug with the ability to change the course of type 1 diabetes, or any autoimmune disease. Yale School of Medicine played a crucial role in the drug’s trials, most of which were led by Kevan Herold, MD, C.N.H. Long Professor of Immunobiology and of Medicine (Endocrinology).

Type 1 diabetes is one of the most common chronic diseases of childhood, impacting between one in 300 to one in 600 school-aged children. It’s a lifelong condition that requires constant diet management and insulin therapy. Now, the availability of teplizumab for at-risk patients will help delay the onset of the disease. Herold is excited about the valuable, disease-free years the drug can offer.

“Diabetes is a disease that’s with you literally every minute of the day. You don’t sleep, exercise, or eat without thinking about your metabolic control,” says Herold. “People with diabetes will tell you that any time without the disease is a gift, particularly for young children and their parents.”

Each year, around 30,000 new individuals are diagnosed with type 1 diabetes in the United States. The disease is caused by immune-mediated killing of beta cells. These cells are found in the pancreas and make insulin, which is essential for life. A hundred years ago, before the discovery of insulin in 1922, type 1 diabetes was a lethal diagnosis. Over the past century, says Herold, insulin delivery methods have substantially improved, and there is a lot of work at Yale focused on insulin pump development. However, he continues, children and adults alike rarely meet the American Diabetes Association’s (ADA’S) Standards of Medical Care in Diabetes, which was established to try and prevent the end-stage complications of the disease.

“Although you don’t die from the immediate lack of insulin, chronic exposure to high blood sugar levels leads to complications such as blindness, kidney disease, renal failure, vascular disease, stroke, and heart disease,” Herold says.

Teplizumab is a modified antibody that binds to immune cells called T lymphocytes [T cells], which are what attack the insulin-producing beta cells in type 1 diabetes patients. The drug specifically attaches to a molecule called CD3, the “cognate” component of the T cell, says Herold, that upon being triggered activates the T cell. The binding of teplizumab to the CD3 molecule modulates the immune cells in a way that prevents autoimmunity and prolongs the pancreas’ ability to create insulin.

Screening for immune markers of type 1 diabetes has been available, but until now, there was nothing that could be done for those at risk. The new drug could allow a broader screening in school aged children and prevent new diabetes cases in the youngest of patients.

Herold’s work on type 1 diabetes stems back 30 years to when he was a research fellow at the University of Chicago studying the treatment of the disease in mice. Since then, he has been at the forefront of the teplizumab development. While at Columbia University, he conducted an investigator-initiated trial in 2002 showing the efficacy of the drug. Shortly after that, he moved to Yale, where he conducted a second and third trial, as well as a prevention trial that proved its ability to delay autoimmune disease. “Nearly every study that’s ever been done with this drug has been done at Yale,” says Herold, whose lab also investigates the immune mechanisms that underlie type 1 diabetes.

The prevention trial showed that the median time the onset of type 1 diabetes was delayed was two years. “Some people ask, ‘If you’re still going to get diabetes, what’s the big deal?’” says Herold. “But if you’re an eight-year-old child, and the diagnosis of type 1 diabetes, the time at which you need to take insulin and follow a prescribed diet and monitor your blood sugar is delayed for two more years, that’s huge.” In childhood, a few years can make a substantial difference in terms of maturity—a high schooler, for instance, may be better equipped to handle the burden of a challenging chronic disease than a middle schooler. The delay also reduces the amount of exposure a patient has to the high blood sugars responsible for a wide range of complications. And as therapies for diabetics continue to evolve, there will likely be more improved and convenient options for patients by the time their disease manifests.

For half of the patients, he continues, their delays will be much longer than that. One high school student in his trial was diabetes free for 11 years after treatment, allowing him to attend college, business school, move to New York, and find employment without the burden of the disease.

Herold believes that this drug is simply “the foot in the door.” As researchers continue to study the drug and make modifications, he hopes patients will continue to see better results. “Now we can start to add things to it to prolong the response and enhance the number of people who are responding to the drug,” he says.

Herold once asked a diabetes educator whom he worked with what he would do if he didn’t have the disease. The educator responded that he would do nothing: “I would go sit on a bench and not think about what time it is, when I just ate, what activity I just did, what my blood sugar is—is it going up or is it going down, or even what I need to do in the next few minutes to manage?”

“Don’t underestimate the importance of this for patients,” says Herold. “It’s hard to appreciate the significance of not having the disease unless you have it, but time without the disease is life changing.”