By: Justin Budz, PharmD Candidate c/o 2023

              Diabetes mellitus encompasses both chronic and reversible conditions that affect the body’s ability to utilize glucose. In 2019, about 28.7 million (8.7%) people in the United States (US) had diagnosed diabetes. Of this population, about 1.6 million (5.7%) people ages 20 or older and 244,000 (0.9%) people ages 19 or younger had diagnosed type 1 diabetes (T1D).¹ T1D is characterized by the destruction of insulin-producing pancreatic beta cells, which eventually results in an absolute deficiency of insulin. The majority of T1D is attributable to autoimmune-mediated destruction of beta cells by CD4+ and CD8+ T cells and macrophages that infiltrate the islets of Langerhans.^2,3

Immunotherapy that can directly inhibit beta cell destruction serves as a potential treatment for autoimmune T1D at clinical onset in patients with remaining functional beta cells. Preservation of beta cell function results in prolonged adequate glycemic control to lessen the risk of retinopathy, nephropathy, hypoglycemia, and ketoacidosis.⁴ Anti-CD3 treatment was identified as a potential candidate for treatment of T1D when studies in non-obese diabetic mice showed that injections of an anti-CD3 antibody could reverse disease.⁵ Since those pre-clinical trials, current studies have attempted to achieve the same results using a non-activating humanized monoclonal anti-CD3 agent, such as teplizumab.⁶

On November 17, 2022, the US Food and Drug Administration (FDA) approved Tzield (teplizumab-mzwv) injection to delay the onset of stage 3 T1D in patients 8 years of age and older who currently have stage 2 T1D.⁷ Teplizumab-mzwv is a monoclonal antibody that binds to CD3, a cell surface antigen present on T cells. This anti-CD3 mechanism involves partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T cells. Anti-CD3 activity leads to an increase in the proportion of regulatory T cells and of exhausted CD8+ T cells in peripheral blood, suggesting an augmented immune tolerance.^4,8 The FDA’s recent approval of teplizumab-mzwv affords patients with a delay in the burdens of T1D, extending clinical diagnosis by months to years.

Literature Review of the Phase 2 Clinical Trial Supporting the FDA’s Approval of Teplizumab-mzwv

The FDA based its approval of teplizumab-mzwv from the results of a phase 2, randomized, placebo-controlled, double-blind trial conducted by Herold et al.⁹ The trial was conducted from 2011 through 2018 at sites in the US, Canada, Australia, and Germany.⁹ Eligible patients were between the ages of 8 to 45 with at least one first or second degree relative diagnosed with T1D. Additional inclusion criteria required the presence of at least two diabetes autoantibodies, as well as evidence of dysglycemia confirmed by an oral glucose tolerance test within 7 weeks of the baseline visit.⁹ Patients with previously diagnosed T1D, abnormal laboratory chemical values, evidence of an acute infection, or previous treatment with teplizumab or other monoclonal antibodies within one year of the trial were excluded from the study.⁹

Study investigators recruited 112 potential participants, of which 76 underwent randomization in a 1:1 ratio to receive either teplizumab-mzwv or placebo. Randomization was stratified by age (< 18 years or ≥ 18 years) and second oral glucose-tolerance test results before treatment (impaired tolerance, normal tolerance, or diabetes).⁹ 55 (72%) of the participants included in the trial were less than 18 years of age. The majority of participants were white, and more than half were siblings of patients with T1D.⁹ Upon randomization, 44 patients were assigned to the teplizumab-mzwv group, receiving a 14-day outpatient course of teplizumab-mzwv administered intravenously in a clinical research center. Teplizumab-mzwv was given at a dose of 51 μg/m² of body-surface area on day 0, a dose of 103 μg/m² on day 1, a dose of 207 μg/m² on day 2, a dose of 413 μg/m² on day 3, and a dose of 826 μg/m² on days 4 through 13. For the control group, 32 patients were assigned to receive placebo, following the same 14-day outpatient dosing schedule.⁹

41 (93%) of the participants in the teplizumab-mzwv group and 28 (88%) of the participants in the placebo group completed the 14-day course of their respective agents. The median total dose of teplizumab-mzwv administered was 9.14 mg/m².⁹ The median follow-up duration was 745 days. During this study, the primary end point investigated the elapsed time from randomization to clinical diagnosis of diabetes. The secondary endpoint evaluated the number of participants who experienced adverse effects.⁹

Regarding efficacy data, teplizumab-mzwv, compared to placebo, was able to show statistically significant results in delaying the onset of T1D. In the teplizumab-mzwv group, 19 (43%) participants were diagnosed with T1D, compared to 23 (72%) participants in the placebo group. The annual rates of diagnosis of T1D were 14.9% per year in the teplizumab-mzwv group and 35.9% per year in the placebo group. The median time to diagnosis was 48.4 months in the teplizumab-mzwv group and 24.4 months in the placebo group. The overall hazard ratio (HR) of teplizumab-mzwv compared to placebo was 0.41 (95% confidence interval [CI] 0.22 to 0.78; P = 0.006).⁹ Overall, 42 (55%) participants were diagnosed with T1D. The progression to clinical T1D diagnosis was greater in the first year after trial entry (17 participants, 40%) than in year 2 (10 participants, 24%), year 3 (6 participants, 14%), or year 4 (5 participants, 12%).⁹ Teplizumab-mzwv was found to have its greatest effect in the first year, where diabetes was diagnosed in only 3 participants (7%) in the teplizumab-mzwv group, compared to 14 participants (44%) in the placebo group (HR 0.13; 95% CI 0.05 to 0.34).⁹

Additionally, subgroup analyses were conducted to compare the effects of teplizumab-mzwv based on human leukocyte antigens (HLA) type and autoantibodies.⁹ Among the participants in the teplizumab-mzwv group, 21 (49%) had HLA-DR3 and 28 (65%) had HLA-DR4 major histocompatibility complex (MHC) molecules. The presence of HLA-DR4 and the absence of HLA-DR3 were both associated with greater responses to teplizumab-mzwv (HR of 0.20 [95% CI 0.09 to 0.45] and HR of 0.18 [95% CI 0.07 to 0.45], respectively).⁹ The response to teplizumab-mzwv was also greater among participants without anti–zinc transporter 8 (ZnT8) antibodies (HR 0.07; 95% CI 0.02 to 0.26).⁹ The presence or absence of other autoantibodies was not associated with a clinical response from teplizumab-mzwv.⁹

Regarding safety data, the most common adverse event categories (those occurring ≥ 5%) associated with teplizumab-mzwv included blood/bone marrow, dermatologic, pain, infection, gastrointestinal, metabolic/laboratory, pulmonary/upper respiratory, constitutional symptoms, and allergy/immunologic.⁹ The most common adverse reactions were lymphopenia, rash, leukopenia and headache. A total of 15 lymphopenia events occurred in the teplizumab-mzwv group during the first 30 days after administration, with lymphocyte counts decreasing to a nadir over 5 days. Lymphopenia resolved by day 45 in all participants except one. In that one participant, lymphocyte counts returned to normal by day 105. Additionally, a spontaneously resolving rash occurred in 16 participants in the teplizumab-mzwv group.⁹

Conclusion

This phase 2 trial indicates that a single course of teplizumab-mzwv significantly slows the progression to clinical diagnosis of T1D.⁹ Those who received teplizumab-mzwv were able to achieve a median delay in the diagnosis of diabetes by 4 years. At the conclusion of this trial, the majority of diabetes-free participants were in the teplizumab-mzwv group (57%) compared to the placebo group (28%).⁹ The identification of specific HLA types and autoantibodies may be beneficial prior to initiating teplizumab-mzwv, as subgroup analyses showed differing responses to teplizumab-mzwv depending on participant characteristics.⁹ It is also important to consider that this trial only evaluated the effects of teplizumab-mzwv from one course of treatment. It is unknown whether repeated dosing may provide additional benefits such as a prolonged therapeutic effect, or create potential risks such as the development of antidrug antibodies.⁹

Currently, teplizumab-mzwv is approved for patients 8 years of age and older with a diagnosis of stage 2 T1D. Prior to initiating teplizumab-mzwv, the stage 2 T1D must be confirmed with documentation of at least two positive pancreatic islet cell autoantibodies and dysglycemia using an oral glucose tolerance test. A complete blood count and liver enzyme test must also be obtained to prevent contraindications based on certain abnormal lab findings. Teplizumab-mzwv is administered once daily for a 14-day course via intravenous infusion over a minimum of 30 minutes. Teplizumab-mzwv is dosed by body surface area at 65 μg/m² on day 1, 125 μg/m² on day 2, 250 μg/m² on day 3, 500 μg/m² on day 4, and 1,030 μg/m² on days 5 through 14. Patients must premedicate prior to infusion for the first 5 days of teplizumab-mzwv treatment with either a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, along with an antihistamine and/or an antiemetic.⁸

Overall, the delay of progression to T1D achieved by teplizumab-mzwv is clinically important, especially in pediatric patients where the diagnosis of diabetes is often associated with adverse outcomes. Complications include cardiovascular disease, neuropathy, nephropathy, retinopathy, and osteoporosis.¹⁰ Diagnosis of diabetes in pediatric patients is also associated with challenges in daily management of the disease. Based on the child’s age, early management of diabetes may be very overwhelming as the child and parents must learn how to give injections, count carbohydrates, and monitor blood glucose.¹⁰ Teplizumab-mzwv, along with future investigational immunotherapies, may hopefully pave the way for a future where patients are able to be treated, or at the very least, significantly delayed, from the clinical diagnosis of T1D.

References

1. Prevalence of diagnosed diabetes. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-diabetes.html. Last Updated 09/30/2022.
2. Maahs DM, West NA, Lawrence JM, et al. Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am. 2010;39(3):481-497. doi:10.1016/j.ecl.2010.05.011
3. Gillespie KM. Type 1 diabetes: pathogenesis and prevention. CMAJ. 2006;175(2):165-170. doi:10.1503/cmaj.060244
4. Hagopian W, Ferry RJ Jr, Sherry N, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial. Diabetes. 2013;62(11):3901-3908. doi:10.2337/db13-0236
5. Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A. 1994;91(1):123-127. doi:10.1073/pnas.91.1.123
6. Wallberg M, Recino A, Phillips J, et al. Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity [published correction appears in Immunology. 2017 Aug;151(4):481]. Immunology. 2017;151(2):248-260. doi:10.1111/imm.12729
7. FDA approves first drug that can delay onset of type 1 diabetes. U.S. Food & Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes. Last Updated 11/17/2022.
8. Tzield (teplizumab-mzwv) [package insert]. Red Bank, NJ; Provention Bio, Inc.; Revised 11/01/2022.
9. 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
10. American Diabetes Association. (11) Children and adolescents. Diabetes Care. 2015 Jan;38 Suppl:S70-6. doi: 10.2337/dc15-S014.

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