Barriers Persist To Implement Teplizumab In Clinical Practice

Type 1 diabetes (T1D) is caused by an immune-mediated destruction of pancreatic beta-cells. Autoantibodies are produced by B cells and T cell infiltration of pancreatic islet cells, which results in the production of autoreactive T cells. These cells produce inflammatory cytokines and mediators that cause beta cell dysfunction and eventual destruction.¹

The autoimmune process of T1D progresses through 3 stages:²

• Stage 1: presence of 2 or more T1D autoantibodies with normoglycemia
• Stage 2: autoantibodies persist and dysglycemia develops
• Stage 3: symptomatic or clinical T1D develops due to beta-cell destruction

The risk for development of stage 3 T1D in 5 years is 44% in stage 1 and increases to 75% in stage 2.²

Image credit: LStockStudio | stock.adobe.com

The incidence of T1D in 2019 was 18 million individuals worldwide, with 1.6 million in the United States. Additionally, there are an estimated 2.3 million patients with stage 1 or 2 T1D. The estimated cumulative burden for all patients with T1D in the US is $30 billion annually. Per patient, this cumulative annual economic burden is approximately $5960 for pediatric patients and $20,320 for adults.³

Studies among Swedish men and women found a loss of 14.2 life-years among men and 17.7 years among women diagnosed with T1D before the age of 10, and a loss of life expectancy of 11 life years among men and 13 years among women at the age of 20 years.^4,5 Given these burdens, there is an urgent need for methods to delay the onset of T1D. The first FDA-approved agent to delay the onset of Stage 3 T1D was teplizumab (Tzield; Sanofi) in November 2022.⁶

Teplizumab is indicated to delay the onset of Stage 3 T1D in adults and pediatric patients 8 years of age and older with stage 2 T1D, which is defined as at least 2 positive pancreatic islet cell autoantibodies, dysglycemia without overt hyperglycemia using oral glucose tolerance tests (OGTT), and no clinical history that suggests T2D.

Mechanism of Action

Teplizumab is a monoclonal antibody that binds to the CD3 chain of the T-cell receptor complex. This binding causes an increase in regulatory T cells and exhausted CD8-positive T-cells. The delay in the progression to stage 3 T1D is thought to result from partial agonist signaling and deactivation of autoreactive T-cells in the pancreatic beta cells.^6-8

Dosing and Administration

Teplizumab is dministered as an intravenous infusion over 30 minutes once daily for 14 consecutive days using body surface area dosing. Figure 1 reviews this regimen. Patients should pre-medicate with a non-steroidal anti-inflammatory drug, an antihistamine, and an antiemetic, if desired, for the first 5 days.

Figure 1.

Adverse reactions can includecytokine release syndrome, serious infections, lymphopenia, and hypersensitivity reactions.

Clinical Trials

TN-10 was the major study that resulted in the FDA approval for teplizumab to delay the progression to stage 3 T1D.⁹ It was a phase 2, randomized, double-blind, placebo-controlled time-to event trial and patients were randomized 1:1 to receive teplizumab or placebo. Patients were included if they were non-diabetic relatives of patients with T1D, were at least 8 years of age at randomization, had 2 or more diabetes-related autoantibodies detected in 2 samples within 6 months before randomization, and had evidence of dysglycemia on OGTT. Table 1⁹ reviews efficacy outcomes in TN-10 and Table 2⁹ reviews safety outcomes.

Table 1. Efficacy outcomes in TN-10⁹

Table 2. Safety outcomes in TN-10

In an extension trial of the TN-10 trial with a median of 923 days of follow-up, the median time to diagnosis of T1D was 59.3 months in the teplizumab group (n =22) compared with 27.1 months in the placebo group (n = 25).¹⁰ Teplizumab has also been studied for patients recently diagnosed with T1D to delay disease progression, but with mixed results.^11-13 Teplizumab is not currently FDA approved for this indication.

Application to Clinical Practice

As updated in the 2024 American Diabetes Association (ADA) Standards of Care, teplizumab infusion should be considered in select individuals aged 8 years of age or older with stage 2 T1D to delay the onset of symptomatic T1D.¹⁴ The delay in T1D clinical diagnosis by 2 to 3 years with the use of teplizumab, as shown in the TN-10 trials, could have significant impacts on quality of life.

The cost of teplizumab is $13,850 per vial, which is equivalent to $194,000 per 14-day course, and is significantly higher than the annual cost burden of diabetes for 2 years ($11,920 for pediatrics; $40,640 for adults).^3,15 The Provention Bio COMPASS Program is a patient assistance program available for teplizumab.¹⁶ In order to qualify for therapy with teplizumab, patients must be screened for T1D autoantibodies before they develop symptoms. The ADA currently recommends that screening for stage 1 or 2 T1D may be done by testing for autoantibodies to insulin, glutamic acid decarboxylase, islet antigen 2, or zinc transporter 8.¹⁴ Previous guidelines recommended autoantibody screening in the setting of a research study or for first-degree family members of a proband with T1D.¹⁷

Despite the high efficacy of teplizumab, its utilization in stage 2 of T1D will likely be limited by the high cost and limited T1D prescreening in clinical practice. Pharmacists should nevertheless be aware of this option and its important impacts for patients.

References

1. Van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011;91(1):79-118. doi:10.1152/physrev.00003.2010

2. Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, Gottlieb PA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015;38(10):1964-74. doi:10.2337/dc15-1419

3. JDRF. Modeling the Total Economic Value of Novel Type 1 Diabetes (T1DM) Therapeutic Concepts. 2020. Accessed January 3, 2023. https://t1dfund.org/wp-content/uploads/2020/02/Health-Advances-T1D-Concept-Value-White-Paper-2020.pdf

4. Rawshani A, Sattar N, Franzén S, et al. Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study. Lancet. 2018;392(10146):477-486. doi:10.1016/S0140-6736(18)31506-X

5. Livingstone SJ, Levin D, Looker HC, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008-2010. JAMA. 2015;313(1):37-44. doi:10.1001/jama.2014.16425

6. Tzield (teplizumab). Package insert. Provention Bio; 2022. Accessed January 6, 2024.

7. Teplizumab. Lexicomp. February 2023. Accessed January 6, 2024. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7289485?cesid=8T3vbTUU2PI&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dteplizumab%26t%3Dname%26acs%3Dtrue%26acq%3Dteplizuma

8. Provention Bio. Teplizumab For the Delay Of Progression To Clinical Stage 3 Type 1 Diabetes In At-risk Patients – Sponsor Briefing Document. Endocrinologic and Metabolic Drugs Advisory Committee. 2021. Accessed January 6, 2024. https://www.fda.gov/media/149389/download

9. Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes [published correction appears in N Engl J Med. 2020 Feb 6;382(6):586]. N Engl J Med. 2019;381(7):603-613. doi:10.1056/NEJMoa1902226

10. Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med. 2021;13(583):eabc8980. doi:10.1126/scitranslmed.abc8980

11. Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011;378(9790):487-497. doi:10.1016/S0140-6736(11)60931-8

12. Herold KC, Gitelman SE, Ehlers MR, et al. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes. 2013;62(11):3766-3774. doi:10.2337/db13-0345

13. Ramos EL, Dayan CM, Chatenoud L, et al. Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes. N Engl J Med. 2023;389(23):2151-2161. doi:10.1056/NEJMoa2308743

14. American Diabetes Association Professional Practice Committee; 3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes—2024. Diabetes Care 1 January 2024; 47 (Supplement_1): S43–S51. https://doi.org/10.2337/dc24-S003

15. Provention prices type 1 diabetes drug Tzield at $194,000. pharmaphorum. Accessed January 6, 2024. https://pharmaphorum.com/news/provention-prices-type-1-diabetes-drug-tzield-at-194000

16. Personalized Support for Patients | TZIELD (teplizumab-mzwv) HCP injection 2mg/2mL. TZIELD HCP. Accessed January 6, 2024. https://www.tzieldhcp.com/patient-support

17. American Diabetes Association Professional Practice Committee; 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2022. Diabetes Care 1 January 2022; 45 (Supplement_1): S17–S38. https://doi.org/10.2337/dc22-S002