Tackling Type One: Teplizumab and Early Detection 

by Nicole Rodriguez

Imagine waking up each morning, pricking your finger, and self-administering an injection of medicine—all before eating breakfast. Now, envision having to count and log all the carbohydrates within each of your delicious breakfast creations. How would you feel if you had to do this for every meal for the rest of your life? This is the reality of the 8.4 million people worldwide living with type one diabetes mellitus (T1DM).  

T1DM is an autoimmune disease characterized by high blood sugar due to insulin insufficiency. Insulin is produced by pancreatic ß cells and is the hormone responsible for initiating transport of carbohydrates from the bloodstream into the body’s cells. In T1DM, ß cells are damaged by the immune system, therefore less insulin is produced and carbohydrates begin to accumulate in the bloodstream, resulting in high blood sugar, known as hyperglycemia. During a hyperglycemic episode, a person feels unusually tired, is excessively thirsty, urinates repeatedly, and experiences blurred vision. If left untreated, continuous hyperglycemia can culminate into a life-threatening condition called ketoacidosis.  

Genetic factors, such as the inheritance of a mutated human leukocyte antigen (HLA) gene, and environmental factors, including vitamin D deficiencies and infections, are major risk factors for the onset of the condition. Currently, the standard treatment for T1DM consists of repetitive blood sugar monitoring, carbohydrate counting, and insulin replacement therapy using insulin injections. Injections of exogenous insulin promote carbohydrate uptake by cells and lower blood sugar. People with T1DM use sugar levels and total carbohydrates to inform the dosage of these injections. Overadministration of insulin can lead to hypoglycemia, which has its own host of mild to severe symptoms, including trembling, nausea, and seizures. Hence, it is crucial for people with T1DM to have a curated routine for measuring blood sugar, tracking carbohydrate consumption, and adjusting their insulin dosages accordingly. With the average age of diagnosis for the disease being 24, those diagnosed with T1DM often must make substantial changes to their already-established lifestyles to manage their condition. This includes finding time to carefully plan meals, monitor sugar levels, administer insulin, and regularly meet with their primary care physician, endocrinologist, dietician, and ophthalmologist. As a result, diagnosis is often coupled with abrupt and significant routine changes that can be difficult to implement and maintain.  

What if there was a medication that could slow down the onset of T1DM and offer people more time to adopt the necessary lifestyle changes to properly manage this condition? 

In 2022, the U.S. Food and Drug Administration approved Teplizumab as a treatment that can delay the progression of T1DM. The development of Teplizumab is a notable advancement in care because, unlike the conventional treatment of insulin injections, this medication takes a preventive approach to T1DM.  

To understand how Teplizumab delays the condition’s course, it is important to understand the pathology of T1DM. T1DM is considered an autoimmune disease because individuals with the condition produce molecules, called autoantibodies, that attach to ß cells and mark them for attack by immune system cells, such as cytotoxic T lymphocytes (CTLs). CTLs release molecules, like interleukin-1 and tumor necrosis factor alpha, that are toxic to ß cells. However, not all immune cells target ß cells. Regulatory T cells (Tregs) are known to reduce the activity of CTLs, and consequently reduce the amount of damage to pancreatic cells. Although the mechanism of Teplizumab is only partly understood, the medication reliably results in the proliferation of Tregs and a decrease in the number CTLs, reducing the intensity of the immune system attack on ß cells. Therefore, Teplizumab delays the severity of T1DM by extending the time required for significant damage to ß cells to occur.  

The Protege study, which was a phase three clinical study conducted at 83 academic and medical institutions across North America, Europe, and Asia, observed that treating people recently diagnosed with T1DM with a single course of Teplizumab improved insulin production for up to twelve months afterward. A separate randomized control trial conducted across six medical centers in the United States found that a two-course treatment of Teplizumab reduced the need for insulin injections and improved C-peptide levels, which are correlated with more insulin production and better ß cell function, up to two years after treatment within recently diagnosed individuals. Currently, Teplizumab is marketed and clinically approved as a medication for individuals who are already diagnosed with T1DM; however, the results of a recent multicenter phase two clinical trial suggest that the medication can have a preventative effect for healthy people without diabetes who are genetically predisposed to developing the condition. Notably, healthy individuals with a first relative with T1DM have a 15 times greater chance of developing the condition. The trial recruited healthy participants who had either a parent or sibling with T1DM, administered either Teplizumab or a placebo, and monitored the development of T1DM over time. The follow-up revealed that 50% of the Teplizumab group later developed T1DM with onset occurring an average of 59.6 months after treatment, compared to the 76% of the placebo group who developed the condition 27.1 months after receiving an inert treatment. Additionally, members of the Teplizumab group had lower C-peptide levels and more ß cells insulin secretion compared to the placebo group.  

These studies support that Teplizumab can delay the course of T1DM by an average of three years by preserving cell function and promoting natural insulin production. Not only does Teplizumab provide people with more time to make the necessary lifestyle changes to manage their new diagnosis, Teplizumab is also expected to attenuate the long-term complications of living with T1DM, including cardiovascular, kidney, and nerve damage. 

However, for Teplizumab to be effective, it must be prescribed early within the T1DM pathological process, specifically before a person enters stage three T1DM. T1DM has a predictable trajectory with three distinct stages. Although the course of T1DM is anticipated, the time of stage onset and the duration of each stage is variable. For example, the onset of T1DM symptoms has been observed in ages 2–34 and stages can last anywhere from a couple of months to several years.  

During stage one, a person produces at least two of the four major autoantibodies that target ß cells. However, blood sugar levels remain within normal range and no symptoms are present. With the advancement to stage two, they present with dysregulated blood sugar in addition to autoantibodies. Finally, during stage three, people present with autoantibodies, hyperglycemia, and hyperglycemic symptoms.  

Currently, Teplizumab is prescribed to people with stage two T1DM to slow down the progression to stage three. Therefore, to mobilize the postponing power of Teplizumab, we need a reliable method of diagnosing T1DM during its early stages.  

Unfortunately, longitudinal screenings for T1DM are not a routine part of primary care visits like vision tests, mammograms, and prostate exams. About 95% of people with T1DM are diagnosed at stage three, after seeking medical care for hyperglycemic symptoms. Shockingly, about 30% of people with T1DM presented with ketoacidosis, one of the most severe symptoms of hyperglycemia, at the time of their diagnosis.  

This reality poses an immense barrier to the utility of Teplizumab because many T1DM diagnoses are made too late for the medication to be applied. Although the biomedical side of treatment development is important and exciting, the scientific community must also anticipate and actively address obstacles to the implementation of medications during therapy development. 

Longitudinal studies on T1DM progression provide important insight for the creation of new screening protocols that are conducive to early-stage diagnosis and that can improve the application of T1DM. The results of the The Environmental Determinants of Diabetes (TEDDY) study, a multicenter study conducted across the U.S., Germany, Finland, and Sweden, found that recurring pediatric screenings are an effective method for tracking the development of T1DM in people at genetic risk for the condition. Beginning at the age of three months until the age of 15, individuals enrolled in the study were tested for the presence of autoantibodies and blood sugar levels every third month. The health outcomes of this highly monitored group were compared to the outcomes of the public. During the time of T1DM diagnosis, the group of highly monitored children were less likely to present with ketoacidosis compared to children who received conventional monitoring for the condition. The early detection success of the TEDDY study suggests that incorporating screening methods such as genetic risk assessment, family history  review, and autoantibody monitoring into primary care visits will enable early stage T1DM identification and Teplizumab treatment.  

The development of Teplizumab presents a breakthrough approach to managing T1DM, however, further analysis of the underdeveloped diagnostic approach for T1DM unearths substantial limitations to the therapy’s value. Until diagnostic procedures are adequate to identify early-stage T1DM, the usefulness of Teplizumab will remain restricted. This issue highlights the need for collaboration between pharmaceutical scientists, public health professionals, and medical professionals during therapy development to yield biochemically effective medications that can be applied within real-world contexts.