Rania Habib, MD, DDS (Host): The Endocrinology team at Children's Health is a leader in care for children with Type 1 diabetes. They focus on groundbreaking, innovative technologies and treatments to make sure their patients have access to the best care. Currently, Children's Health is the only pediatric hospital in the entire DFW area that offers the newly FDA approved drug teplizumab, also known as Tzield.

This is Pediatric Insights, Advances and Innovation with Children's Health, where we explore the latest in pediatric care and research. I'm your host, Dr. Rania Habib. Joining me today is Dr. Abha Choudhary, a Board Certified Pediatric Endocrinologist at Children's Health and Associate Professor at UT Southwestern. She is here to discuss the importance of Tzield as an innovative treatment for Type 1 diabetes in children. Welcome, Dr. Choudhary. We are very excited to delve into this fascinating topic.

Abha Choudhary, MD: Thank you for having me here today.

Host: Teplizumab was approved by the FDA in January of 2023. Can you share more about Tzield and how it's administered?

Abha Choudhary, MD: Absolutely. Let me start with some basics of Type 1 diabetes. So Type 1 diabetes is characterized by autoimmune destruction of the pancreatic beta cells, which leads to loss of insulin production, and hence elevated blood glucoses. The beta cell destruction starts long before blood glucose levels can be measured as abnormal.

This is the pre-symptomatic stage of diabetes, where there is evidence of autoimmunity, but without measurable abnormalities in blood glucose values. Evidence of autoimmunity is established by presence of two or more diabetes related auto antibodies. These auto antibodies include insulin, islet cell, zinc transporter, and glutamic acid decarboxylase, and these can be measured in any commercial lab.

There are three stages of diabetes. Stage 1 and stage 2 are the pre-symptomatic stages, and stage 3 is when the individual presents with symptoms and are diagnosed with clinical diabetes. Stage 1 is the presence of autoimmunity with normal glucose levels. Stage 2 is the presence of autoimmunity with evidence of dysglycemia or abnormal blood glucose levels.

And Stage 3 is the symptomatic phase where individuals are brought to medical attention with signs and symptoms of diabetes, such as polyuria, polydipsia, and weight loss. Teplizumab, or Tzield, is the first disease modifying agent approved in Stage 2 Type 1 diabetes, and this was approved by the FDA in November of 2022.

It is approved for ages 8 and older, and it is administered as an IV infusion for 14 consecutive days.

Host: How do you determine who is a good candidate for Tzield? And, I know you mentioned a child needs to be around 8. Why is that?

Abha Choudhary, MD: So the studies have been done for ages 8 and older, and there are several other studies looking at younger age groups at this time. so, A good candidate for Tzield is somebody who's 8 years and older with stage 2 diabetes. And just as a reminder, stage 2 diabetes is characterized by 2 or more positive pancreatic antibodies with evidence of dysglycemia. Dysglycemia can be established by the following criteria. 1. Fasting plasma glucose between 100 and 125 milligrams per deciliter, OGTT, 2 hours postprandial glucose, which is during an oral glucose tolerance test between 140 to 199 milligrams per deciliter. 3. Is hemoglobin A1c between 5.7 to 6.4 percent or a 10 percent or greater increase in hemoglobin A1C. And some centers have also been using the continuous glucose monitoring criteria, which is time above 140 milligrams per deciliter greater than equal to 20%.

Host: Can you share a little bit more about how this drug delays the onset of Type 1 diabetes?

Abha Choudhary, MD: Sure. So let's talk about some basic immunology. Type one diabetes is caused by autoimmune destruction of the insulin producing beta cells. And there are three steps in this process. Step 1 is recognition of beta cell autoantigens by the T-cells. The recognition starts with expression of a series of molecule on the surface of the antigen presenting cell, which presents the autoantigen to the T cell.

CD3 is a molecule on the surface of the T effector cells associated with antigen recognition. Step 2 is there is proliferation and differentiation of the T cells into pathogenic effectors which attacks the beta cells. And step 3 is the beta cell attack. And we know that this occurs over time and eventually leads to beta cell death.

Tzield is an anti CD3 monoclonal antibody. And this targets the CD3 molecule, which is on the surface of the T effector cells. This modifies the T effector cells and leads to delayed decline in the beta cell function. A landmark study was published in New England Journal of Medicine in August of 2019.

And this was a multi center, double blinded, randomized trial which included 76 subjects who were relatives of patients with Type 1 diabetes in stage 2 Type 1 diabetes. They were randomized to a 14 day outpatient course of teplizumab or placebo. The results showed that the median time of diagnosis was significantly longer in the teplizumab group at 48.4 months versus 24.4 months in the placebo group. So, the authors concluded that a two week course of teplizumab delayed the onset of diabetes in high risk participants by a median of two years compared to placebo.

Host: That is absolutely fantastic, and the fact that they did such a large scale, multi center study to prove that, really shows that that is such an effective drug. What should doctors know about this drug before recommending it to a patient's family?

Abha Choudhary, MD: Teplizumab is a 14 day consecutive infusion. It can cause side effects such as rashes, low lymphocyte count, abnormalities in liver functions, nausea, diarrhea, nasopharyngitis. It can also cause cytokine release syndrome, which is characterized by flu like symptoms. And this is seen in about 10 percent of treatments. And this is characterized by joint, muscle aches, fever, nausea, and rash. So, these side effects are not trivial, and the infusions are 14 consecutive days. We have trained infusion staff here at our center, and we are closely monitoring these patients for side effects during the infusions. Some of the barriers to treatment include travel to the site of infusion if it is not offered in your city, lodging, time off, time post infusion, et cetera.

Insurance benefits and coverage also plays a huge role in the approval of the medication. We have to submit prior authorizations and often do a peer to peer appeal for approval of Tzield. It is not recommended if a child has stage 3 Type 1 diabetes. Not recommended in somebody with Type 2 diabetes or if someone has active serious infection or chronic active infections.

If they have lab or clinical evidence of acute infection with Epstein Barr virus or cytomegalovirus, the Tzield infusions are not recommended. If there is evidence of hepatic compromise, such as elevated liver enzymes, or if there is evidence of hematologic compromise, such as low lymphocyte count, platelet or hemoglobin count, this medication is not recommended.

Host: Thank you for clarifying those details. How do you think Tzield will change the future diabetic screening process for patients?

Abha Choudhary, MD: The first degree relatives like parents or siblings are at a 15 times higher risk compared to the general population. The risk in general population is about 1 in 300 for the development of Type 1 diabetes. The individuals with other autoimmune conditions, such as celiac disease or autoimmune thyroid disease, are at an elevated risk as well.

Screening is crucial for high risk populations because early detection can lead to smooth progression into diagnosis of Type 1 diabetes, which is often referred to as soft landing. It also minimizes the risk that a child will be in diabetic ketoacidosis. The approval of teplizumab or Tzield has made screening more attractive because now we have something to offer to delay the onset of symptomatic disease if these individuals are discovered in earlier stages of Type 1 diabetes.

Some have also advocated for universal screening for Type 1 diabetes because the benefits listed above for high risk populations should theoretically be applicable to the general population as well. So what can a pediatrician do? If a physician is concerned about their patients because they are at high risk due to family history or presence of autoimmunity, they can order pancreatic autoantibodies in the commercial lab, either LabCorp or Quest, or refer to TrialNet.

TrialNet is an international network of leading academic institutions and they offer risk screening for relatives of patients with Type 1 diabetes and clinical studies testing ways to slow down and prevent disease progression. They can screen individuals who are two and a half years and older and they follow them over time.

They communicate the results to the parents and also the Endocrinologist if an abnormality is noted. Alternatively, the primary care physician can also reach out to me or the on call Endocrinologist at Children's Medical Center. We are fully set up for Tzield infusions at Children's Medical Center, Plano Campus.

We infused our very first Tzield patient in September of 2023. Our patient was one of the first 100 pediatric patients to receive this infusion in the country. Local infusion centers are also offering Tzield for individuals who are 13 and older, and home infusion options are available as well. However, with the side effect profile, we definitely prefer watching these patients for side effects in our center and having our infusion facility do the infusions.

Host: Dr. Choudary, obviously this is a very innovative drug. When patients want to be referred to your center, how do other providers send them to your center? Could you provide that information for us?

Abha Choudhary, MD: Absolutely. So the providers can call us and refer their patients. The numbers to call are 214-456-5959. Or 469-303-2406.

Host: Dr. Choudary, is there anything else you would like to add for our listeners today?

Abha Choudhary, MD: So, there is a study called PROTECT study, and that is a phase 3 randomized, double blinded, placebo controlled, multi center study, which is designed to determine whether two courses of teplizumab can preserve beta cell function in individuals who have already been diagnosed with Type 1 diabetes, or stage 3 Type 1 diabetes.

So, the study showed that the participants treated with Tzield had significantly greater stimulated C peptide levels, and C peptide is a measure for insulin secretion compared with placebo. There were no significant differences between the groups in the key secondary clinical endpoints such as insulin dose, change in A1C, percent time in range and clinically important hypoglycemic events. So the authors concluded that Tzield has the potential to slow the progression of stage three Type one diabetes and improve clinical parameters in newly diagnosed individuals. This has not been approved by the FDA in stage three Type one diabetes yet. So more to come on this.

Host: Well, we thank you so much for your time, Dr. Choudhary. We are very impressed with the innovative work that you and the Endocrinology department are performing at Children's Health. These children are very lucky to have you.

Abha Choudhary, MD: Thank you.

Host: Thank you so much for your time with us today and to our audience for listening to Pediatric Insights, Advances and Innovation with Children's Health, where we explore the latest in pediatric care and research. I'm your host, Dr. Rania Habib. You can find more information at children's.com/endocrinology. If you found this podcast helpful, please rate and review or share the episode and please follow Children's Health on all of your social channels.