Clinical Overview: Teplizumab for Type 1 Diabetes Mellitus

New research results have been published on the possibility of using teplizumab (Tzield; Provention Bio) in preventing the development of type 1 diabetes in patients at high risk for the disease. Experts emphasize that the FDA decision to approve teplizumab provides a new and important treatment option.¹

Type 1 diabetes belongs to a group of autoimmune diseases. This disease most often manifests in young people with a genetic predisposition, in whom the autoimmune process was initiated by the action of environmental factors. Patients may develop disease at any age. Per the US Centers of Disease Control and Prevention, the peak age for being diagnosed with type 1 diabetes is around 13 or 14 years of age.²

In the development of the disease process, there is a gradual loss of the secretory capacity of pancreatic beta cells, which results in absolute insulin deficiency. At the beginning of disease progression, the number of beta cells in the pancreas covers the need for insulin and the only sign of the disease at this early stage is the presence of autoimmune antibodies. As the disease progresses, T cell-mediated destruction of pancreatic beta cells leads to the loss of insulin production, impaired glycemic control, and reliance on exogenous insulin.³

Teplizumab is a humanized IgG1κ Fc-nonbinding anti-CD3 monoclonal antibody that blocks T cells, preventing them from attacking beta cells. It is, therefore, an immune therapy indicated in people at high risk of type 1 diabetes who have antibodies indicating an immune attack and whose glucose tolerance is not normal.

Teplizumab targets T cells through antibodies against the T cell receptor (TCR) component CD3. The Fc-nonbinding anti-CD3 monoclonal antibody induces apoptosis of activated human T cells.⁴

That type of mechanism was previously used to prevent graft-versus-host-disease in organ transplantation, but more recently has been tested to prolong the onset of stage 3 type 1 diabetes in adults and pediatric patients aged 8 years and older with stage 2 type 1 diabetes.⁵

Teplizumab is given as intravenous infusion once a day for 14 days. Clinical trials have shown that a 14-day course of treatment delays the onset of type 1 diabetes by an average of 2 years, although there are cases of delay of the onset of the disease even longer.

The efficacy and safety of teplizumab was assessed in a randomized, double-blind, event-driven and placebo-controlled study, which included a high-risk group of 76 patients, of whom 55 patients were under 18 years of age and 21 adults over 18. Patients were randomized to receive teplizumab or a placebo.

The results showed that during the follow-up, which lasted an average of 51 months, 45% of the 44 patients receiving the drug were later diagnosed with type 1 diabetes in stage 3. The average time from randomization to diagnosis was 50 months for those taking teplizumab and 25 months for those taking placebo.

The subjects were then randomly assigned to the drug and placebo groups. During the intervention period, study participants received teplizumab or placebo for 2 weeks, and then the glucose tolerance test (OGTT) was performed every 6 months.

In the study, 69 patients (93%) completed the 14-day intervention period. The median total dose administered was 9.14 mg/m³ and the median follow-up time was 745 days. The median time to diabetes diagnosis was 48 months in the study group and 24 months in the control group.

Ultimately, the disease was diagnosed in 43% of patients who received teplizumab and in 72% of those in the placebo group, with the highest efficacy of therapy observed in the first year. During this period, diabetes was diagnosed in 7% of people from the study group and as much as 44% of people from the control group. The results of the conducted studies showed that patients receiving teplizumab had a half lower risk of developing diabetes compared to the placebo group (15% vs 36% per year).⁶

The use of the drug comes with FDA precautions, which includes monitoring for symptoms of cytokine release syndrome, risk of serious infections, decreased lymphocyte counts, risk of drug hypersensitivity, the need for all age-appropriate vaccinations prior to use, as well as avoidance of concomitant use of mRNA-containing vaccines with teplizumab.⁵

This clinical achievement raises new questions about timely manner of diabetes mellitus type 1 screening. It is time to introduce accurate screening tests into routine care. The immunotherapy can slow the progression to type 1 diabetes and we are looking forward to additional studies on how to extend the benefits of teplizumab to the general population.

References

1. US Food and Drug Administration. FDA approves first drug that can delay onset of type 1 diabetes. News release. November 17, 2022. Accessed November 22, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes.
2. Centers of Disease Control and Prevention (CDC) website. Accessed November 22, 2022. https://www.cdc.gov/diabetes/basics/diabetes-type-1-diagnosis.html#:~:text=The%20peak%20age%20for%20being,older%20(even%20over%2040).
3. Dayan CM, Korah M, Tatovic D, Bundy BN, Herold KC. Changing the landscape for type 1 diabetes: the first step to prevention. Lancet. 2019 Oct 5;394(10205):1286-1296. doi: 10.1016/S0140-6736(19)32127-0.
4. Gaglia J, Kissler S. Anti-CD3 Antibody for the Prevention of Type 1 Diabetes: A Story of Perseverance. Biochemistry. 2019 Oct 8;58(40):4107-4111. doi: 10.1021/acs.biochem.9b00707.
5. Tzield. Package Insert. Provention Bio, Inc.; 2022. Accessed November 22, 2022. https://static1.squarespace.com/static/5f4574ed93f3456c76f3a95d/t/6376c9452abcde44dd5d8ae5/1668729158250/tzield-prescribing-information-and-medication-guide.pdf
6. Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019;381(7):603-613. doi: 10.1056/NEJMoa1902226