Art courtesy of Sophia Zhao.
Before insulin was discovered in 1922 by Sir Frederick Banting and Charles Best, type 1 diabetes—an autoimmune disease that renders the body unable to convert blood sugars to energy—was often a death sentence. Patients with diabetes rarely lived for more than two years after disease onset. This discovery of the insulin treatment was revolutionary: for the first time, patients could survive and manage their illness.
Nearly a century later, a new breakthrough in the field of type 1 diabetes has been achieved. A clinical trial analysis published in Science Translational Medicine, co-authored by Kevan Herold, C.N.H. Long Professor of Immunology and of Internal Medicine at Yale University, and Emily Sims, Assistant Professor of Pediatrics at Indiana University, reported compelling evidence for teplizumab—a drug granted FDA ‘Breakthrough’ status in January 2021. The breakthrough aspect comes from the fact that this drug doesn’t simply address symptoms; it could be able to preemptively delay, or even prevent, type 1 diabetes altogether.
The journey towards teplizumab has been a long and arduous one. “Literally for the past thirty years I’ve been working on this, from doing the pre-clinical mouse work, to doing the early investigator-initiated clinical trials, to eventually leading clinical trials that were done by NIH consortia like the Immune Tolerance Network or TrialNet,” Herold said.
A long and winding road
Even after insulin started to be used as treatment, Herold witnessed the drastic effects that the disease had on the quality of life of patients. “Diabetes is with you twenty-four-seven,” he said. “There’s literally nothing that you do that is not impacted by having the disease, whether it’s deciding to eat or not, whether it’s exercise, whether it’s sleep, whether it’s going to class.”
For Herold, the prospect of conducting research had been appealing since his undergraduate years. Throughout his research trajectory, he has always strived to understand the basic mechanisms, causes, and treatments of type 1 diabetes. Herold’s decades-long commitment to the pursuit of scientific advancement in this area began even before the invention of many essential research techniques scientists often rely on today, such as polymerase chain reaction. “At that time, a lot of what we take for granted now hadn’t even been discovered,” he explained. “Immunology was still in its infancy.”
The research leading up to this breakthrough drug began in 1990 for Herold and his colleague, Jeffrey Bluestone, Professor of Metabolism and Endocrinology at UCSF. In his earlier research, Herold had studied autoreactive T cells—a group of immune white blood cells that turn against our own cells and tissues. By looking at them in mouse models with diabetes, he was led to believe that they could cause type 1 diabetes in humans. With researchers at Johnson & Johnson, Bluestone then developed a human drug, teplizumab, that modifies a certain population of autoreactive T cells that play an important role in killing beta cells—the cells that produce insulin in the pancreas. CD3, a T cell receptor, is involved in activating this population of autoreactive T cells. Teplizumab is an anti-CD3 antibody that binds competitively to CD3—an action thought to prevent the receptor from binding to and activating the autoreactive T cells. Teplizumab thus serves as a regulatory immunosuppressant for an overactive immune system, protecting against the depletion of beta-cells that is characteristically seen in type 1 diabetes.
From gold, to dirt, and back
Teplizumab showed early success in Herold’s first clinical trial in 2002 and was later acquired by biotechnology company MacroGenics. It was also supported by the pharmaceutical company Eli Lilly in phase III clinical trials to evaluate its safety and efficacy. However, this large-scale trial did not end up meeting its target efficacy endpoint, the necessary threshold to move forward. “When that happens in the pharma field, it’s a disaster,” Herold explained. “You’ve basically turned gold into dirt.”
MacroGenics and Eli Lilly both abandoned the project in 2010, and teplizumab was considered a failure. “There was nobody willing to pick it up, and we had no support,” Herold said. Knowing that the drug development process requires substantial resources, Herold and his colleagues traveled across the country and even flew internationally to Germany in pursuit of funding and support. Despite teplizumab having favorable mouse and human trial data, every company, foundation, or potential investor declined—for eight years.
Finally, in 2018, Provention, a biotechnology company founded just two years prior, decided to take on teplizumab anew. Herold cites his belief in the promising science behind the mechanisms of the drug in humans as a large motivating factor in his persistence over the eight long years. “This was literally dead,” he said. “It just goes to show you that if you think something is really worth doing, you [have] got to stick with it no matter how bad it seems, because one turn of the tide could make all the difference in the world.”
In 2019, Herold led a phase II clinical trial, sponsored by TrialNet, testing the effectiveness of teplizumab. He found that it successfully delayed the onset of type 1 diabetes in high-risk patients by approximately two years. Herold then proposed a new question: how does teplizumab affect beta-cell function? “We ask this question all the time in people who have diabetes, but we really never had the opportunity to answer it in people at risk for diabetes,” he explained. “They don’t yet have the disease, but we know that they’re going to develop it.”
Delaying the onset of diabetes
For Sims, conducting research was not always a priority. “I always thought I wanted to be a doctor, and I always loved kids, so I thought I was going to be a pediatrician,” Sims said. She found the physiology of endocrinology interesting and intuitive, so she decided to specialize in pediatric endocrinology. She was first exposed to basic science research during these years.
Almost immediately, the inherent cross-applications of research and medicine became apparent. “Working in the lab gave me this really cool opportunity to ask questions that were relevant to what you see in the patients you’re treating,” she said. Referencing a line from Aaron Burr in the musical Hamilton, she explained that research is like “being in the room where it happens.” In Sims’ many interactions with children diagnosed with type 1 diabetes, she witnessed the toll of this disease on her patients and their families. “When you get that diagnosis, your life changes,” she said.
Herold and Sims are both involved in the NIH consortium TrialNet. Sims’ expertise studying beta-cells and analyzing metabolic data drew her to join Herold in pursuit of a better understanding of the effects of teplizumab on beta-cell function.
In their 2021 study, published in Science Translational Medicine this March, Sims and Herold suggested that there is progressive depletion of beta-cells in the years preceding type 1 diabetes diagnosis. During this period, the level of metabolic dysfunction, which is a sign of autoimmunity, defines the stages of the disease. Stage 1 consists of the period before glucose abnormalities arise; stage 2 makes these abnormalities more evident; and stage 3 is the typical definition of diabetes––the phase defined by clinical presentation of high blood sugar.
Sims and Herold investigated whether teplizumab would delay stage 3 clinical diagnosis in seventy-six individuals at stage 2 of the disease. They found that a single fourteen-day teplizumab treatment program could have enduring effects: the teplizumab group had a median time of five years before stage 3 onset compared to just two for the placebo group. Moreover, eighteen percent of teplizumab-treated individuals treated were not diagnosed with stage 3 at all in more than five years, which is the time during which follow-up data was being collected, compared to just six percent for the placebo group. The study also found that teplizumab improved beta-cell function, even in individuals who did not develop diabetes. The drug could also reverse declines in insulin secretion.
Sims and Herold’s paper outlined that teplizumab led to an improvement in metabolic responses and delay of diabetes. It is the first drug of its kind to ever do so. “If you’re eight years old and get treated for the disease, you’re not going to develop it for five years until you’re thirteen,” Herold said. “The maturation of a child during that period of time is extensive, and you’re probably better able to manage the disease when [you’re] older. Same thing if you’re going into middle school and you’re not going to get it until after graduating high school. That’s a big deal!”
The Food and Drug Administration (FDA) has recently granted teplizumab “Breakthrough Therapy Designation,” which bodes well for its approval this summer. If the drug is approved, an important next step is to identify those who are eligible for and could benefit from the treatment. Sims explained that TrialNet screens the relatives of patients with diabetes, but most people who develop diabetes do not actually have family members with the disease. “We have to think big: now we have a reason to screen people at risk for diabetes, because there is something we can do about it,” Herold stated.
Current insulin treatments act as retroactive “band-aids,” making it possible for diabetes patients to manage their symptoms and survive. Teplizumab, on the other hand, targets the underlying mechanisms of type 1 diabetes before its onset. This means that it could modify the disease’s trajectory. With teplizumab, the playing field for type 1 diabetes has completely shifted—what was once a waiting game now holds options for delay, or even prevention, of the disease.
About the Author:
Alex Dong is a first-year student from Canada in Benjamin Franklin college interested in studying Biomedical Engineering on the pre-med track. On YSM, Alex is a copy editor, staff writer, layout designer, photographer, and artist. Outside of YSM, Alex is a Senator for the Yale College Council and a poet for the Yale Layer.
The author would like to thank Dr. Kevan Herold and Dr. Emily Sims for taking the time to discuss their experiences and research with him.
Herold, K. C., Bundy, B. N., Long, S. A., Bluestone, J. A., DiMeglio, L. A., Dufort, M. J., … & Greenbaum, C. J. (2019). An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. New England Journal of Medicine, 381(7), 603-613.
Sims, E. K., Bundy, B. N., Stier, K., Serti, E., Lim, N., Long, S. A., … & Type 1 Diabetes TrialNet Study Group. (2021). Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Science Translational Medicine, 13(583).