Yale researchers develop first FDA-approved drug to delay autoimmune diseases

Yale researchers develop first FDA-approved drug to delay autoimmune diseases

Kevan Herold of Yale School of Medicine led clinical trials of teplizumab, a drug that delays the development of type 1 diabetes, which affects about 1.95 million Americans.

Chloe Nield and James Steele

11:59 p.m., November 30, 2022

Staff Journalist and Contributing Journalist

Eric Wang, Senior Photographer

Teplizumab, a drug that delays type 1 diabetes, recently became the first drug to delay an autoimmune disease approved by the FDA. A Yale professor played a crucial role in its development.

Kevan Herold, CNH Long Professor of Immunobiology and Medicine at the Yale School of Medicine, has led clinical trials for drug development for the past three decades. The approval of teplizumab opens a new frontier in diagnosing and treating diabetes and paves the way for future work in the area of ​​disease prevention.

The drug was found to delay the development of type 1 diabetes for a median of 2 years.

“If you’re 8 years old and won’t be diabetic for two years [because of teplizumab treatment], that’s a big deal, because now you’re going to be 10 when you get diabetes, and hopefully a 10-year-old is a bit more mature than an 8-year-old,” Herold said. “Same thing if you’re about to go to college, you’re not going to get diabetes until you’re in high school, or even after high school… [diabetes’] absence, even for a day, is a gift.

Type 1 diabetes is an autoimmune disease where your body destroys cells in the pancreas that secrete insulin. Insulin is a hormone that signals cells to take in sugar which can be used for energy. When insulin-secreting cells are destroyed, blood sugar cannot be absorbed. According to the American Diabetes Association, about 1.9 million Americans have type 1 diabetes. Treatment is with insulin injections, which can be extremely expensive.

Teplizumab, sold under the brand name Tzield, is a monoclonal antibody, a type of antibody made by cloning a white blood cell that has been exposed to a target protein. Teplizumab targets the epsilon chain, which is part of the CD3 receptor protein complex. The CD3 complex is a component of the membrane of T lymphocytes responsible for recognizing the respective targets of this T lymphocyte, which is a type of immune cell.

The exact mechanism of the reaction between teplizumab and the epsilon chain is uncertain, but Herold and colleagues expect that teplizumab sends a signal to the T cell by binding to the epsilon chain. This signal is thought to partially or completely disable the T cells responsible for destroying pancreatic cells that produce insulin in patients with type 1 diabetes.

Even after treatment with teplizumab, the effectiveness of the immune system will not be hampered, Herold explained. The signal created when the CD3 complex encounters a viral antigen is much stronger than the reception signal for teplizumab.

“If you look at the long-term safety profile of people [in trials] who have been treated with the drug, there is no evidence of an infectious disease risk,” Herold said.

Herold predicts that the strength of the signal given by teplizumab is somewhere between that of the antigenic signal and the autoimmune signal. This prevents T cells from destroying beneficial tissues while allowing them to retain their effectiveness in fighting viruses.

While the development and approval of teplizumab has been a long process, Herold has been “very interested in using immunotherapies to change the course of autoimmune diseases, especially diabetes” from the start.

The median age of participants in teplizumab trials is 13 to 14 years; however, many different ages were included in the trials. The participants had not yet been diagnosed with diabetes prior to their participation in the trial and were identified by their family relationship with someone with type 1 diabetes, Herold explained. They were then screened for immune markers typical of type 1 diabetes, and if it was determined they were at risk of developing the disease, they were given teplizumab for two weeks and disease progression was monitored. in the years that followed.

Clinical trials found that, compared to a placebo group, the development of type 1 diabetes was delayed by a median of 2 years in participants who received teplizumab. However, some patients had significantly longer delays than this. One patient even experienced a delayed development of type 1 diabetes by 11 years.

“We are very keen to understand what is the difference between these [patients] who have long answers and who have these short answers, and how we convert these short answers into long answers,” Herold said, explaining that this will be one of the main focuses of future research.

Herold explained that while two years might not seem like a big time frame, that extra time without illness is valuable.

For example, there would be more time for research in the area of ​​treating type 1 diabetes to progress. Herold explained that the way we treat and diagnose diabetes today is different than it was just three years ago.

“Dr. Herold and his colleagues have spent years understanding how a person’s own immune system can destroy beta (or insulin-producing) cells in the pancreas, leading to type 1 diabetes. This work has led to teplizumab trials,” Nancy Brown, dean of the Yale School of Medicine, told The News. “Making discoveries that transform lives and health is what YSM professors strive for.

On November 17, the FDA approved the use of teplizumab as a treatment to delay type 1 diabetes in people age 8 and older. This approval means it is appropriate to start screening patients for type 1 diabetes in order to administer teplizumab treatment.

Herold explained that the patients identified to undergo the treatment should eventually expand to the general public, and not just those identified on the basis of having relatives with type 1 diabetes. This is particularly important, given that the Most people who develop type 1 diabetes have no family history of the disease, according to Herold.

“It’s a new frontier, screening even the general population for a disease that you can prevent, not just after,” Herold said. “I think this is an exciting new area of ​​medical investigation.”

Trialnet is an international network of scientists dedicated to type 1 diabetes research. Yale is one of twenty-two international TrialNet Type 1 Diabetes Clinical Centers at the forefront of type 1 diabetes research. Jennifer Sherr, principal investigator of the TrialNet site at Yale and professor of pediatrics at the Yale School of Medicine, spoke about the importance of the development of teplizumab.

“[The development of teplizumab] opens the door to prioritizing the development of new therapies to slow and stop T1D and brings us one step closer to TrialNet’s ultimate goal: a future without T1D,” Sherr wrote. “Although TrialNet currently has no ongoing teplizumab studies, we will build on the success of the teplizumab prevention study by continuing to find new ways to slow and possibly stop T1D.”

Herold was the third person to serve as president of TrialNet.

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