LEARNING OBJECTIVES
After completing Module 9, the learner should be able to:
1. Describe the clinical trial findings leading to approval of teplizumab to delay the onset of Stage 3 T1D.
2. Describe current eligibility criteria for teplizumab therapy.
3. Name the most common and most serious side effects of teplizumab therapy.
FDA-Approved Treatment for Pre-Symptomatic T1D
09 |
Module Authors: Kimber Simmons, Patricia Gesualdo
Teplizumab-mzwv Approval
On November 17, 2022, a landmark moment occurred when the Food and Drug Administration approved teplizumab-mzwv as the first drug to delay the onset of Stage 3 T1D in individuals ages 8 and older with Stage 2 T1D (see Module 1). On April 22, 2026, approval was expanded to include children aged one year and above with Stage 2 T1D.
Now, when a patient is identified as having Stage 2 T1D at nearly any age, there are three options:
1. Continue to engage in clinical follow up to monitor for disease progression.
2. Enroll in an available clinical research trial (clinicaltrials.gov, see Module 10).
3. Seek teplizumab treatment to delay the onset of type 1 diabetes (if age 1 or older).
FIGURE 1 Teplizumab Delays T1D Diagnosis
2-year delay of clinical T1D (Stage 3) onset in those at high risk for developing disease (relatives, 2+ T1D Ab+ and dysglycemia) with a 14-day course of therapy. (Adapted from Herold KC et al. NEJM 2019)(1)
Teplizumab-mzwv was approved for treatment of Stage 2 T1D based on results of a study performed by the TrialNet consortium (TN10) (Figure 1). The trial participants were relatives of people with type 1 diabetes who had two or more islet autoantibodies and an abnormal oral glucose tolerance test (see Module 8). Of the 76 high-risk individuals who participated in the study, the majority (72%) were under the age of 18 and the oldest individual was 49 years old. 93% of participants in the treatment group and 88% of participants in the placebo group completed the 14-day course of the assigned trial agent. At the end of the study at a median follow-up of 2 years, individuals who received teplizumab had an average of more than two additional years without needing insulin therapy when compared to the placebo group.(1) In an extended follow-up analysis of this trial (median 2.5 years), 78% of the control group had progressed to Stage 3 T1D compared to 50% of the intervention group.(2) There was a suggestion that teplizumab therapy relative placebo was beneficial in a variety of subgroups, including those whose C-peptide level was below the median, those who were negative for ZnT8 antibody, negative for IA-2 antibody, positive for HLA-D4 haplotype, or negative for HLA-D3 haplotype. It should be noted that this type of post-hoc subgroup analysis must be interpreted with caution.(2) Work is ongoing to better identify which patients are more likely to respond to teplizumab therapy. The subsequent PETITE T1D enrolled 23 pediatric patients aged 1 to less than 8 years with stage 2 T1D to assess safety and pharmacokinetics and dynamics of teplizumab in young children.(3) Adverse reactions in this younger population were consistent with those reported in adults and older children.
Identifying Patients with Islet Autoimmunity is the First Step to Immunotherapy
FIGURE 2 Identifying patients eligible for immunotherapy
Early T1D Clinic at the Barbara Davis Center for Diabetes (BDC)
Eligibility for Immunotherapy
To assess eligibility for immunotherapy (Figure 1), patients need to have evidence of islet autoimmunity and undergo a full metabolic evaluation in a clinical setting (see Table 1, Figure 2).
1) Within the last 6 months: Antibody testing must indicate that the patient is positive for two or more
islet autoantibodies.
2) Within the last 2 months: Metabolic testing (oral glucose tolerance test including fasting glucose
and/or A1c) must indicate that a patient has dysglycemia. Per prescribing information, this
includes(4): (A) 2-hour OGTT glucose 140-199 mg/dL; OR (B) HbA1c 5.7-6.4%
Consistent with ADA criteria for Stage 2 T1D, an OGTT 30- 60- or 90-minute glucose greater than 200 mg/dL may also be used to support approval for immunotherapy.
Further, while CGM and home glucose testing are helpful modalities for monitoring the evolution of hyperglycemia, they are NOT currently considered eligibilty criteria for teplizumab therapy.
Patients must be assessed for current symptoms of hyperglycemia to rule out Stage 3 T1D and clinical history should be reviewed to rule out individuals with presentation more consistent with type 2 diabetes and to identify other medical comorbidities that could complicate treatment.
Finally, in order to ensure patient safety, it is strongly recommended that patients are up-to-date on all vaccines, including influenza and COVID-19 vaccines, prior to initiation of immunotherapy. Last inactivated or mRNA vaccines should have been administrated at least 2 weeks and live-attenuated vaccines at least 8 weeks prior to initiation of treatment.
Patients with Stage 2 Type 1 Diabetes
Should Be Offered Immunotherapy
FIGURE 3 Staging for immunotherapy eligibility
If a patient is determined to be eligible for teplizumab and wishes to proceed with treatment, there are financial assistance programs through the drug manufacturer as well as programs to help the patient navigate the treatment process. The pharmacy and/or the clinic billing the insurance for the drug and/or the drug administration will need to obtain prior authorization for the medication before it can be administered. Once authorization is obtained, laboratory tests and a clinical history need to be completed to make sure that the patient is a healthy candidate for the infusion, is not currently pregnant, and does not have an active infection (see Table 1). Recommended laboratory assessment before and during therapy are available (see references 6 and 7). Alternately, patients who wish to pursue participation in a clinical trial can be referred to relevant options (see Module 10).
Table 1: Eligibility for teplizumab-mzvw therapy
Patient Counseling
During a clinic appointment where eligibility for immunotherapy is being assessed, patients and their families should be advised of risks and benefits as well as additional options for care. This should include information about current clinical trials (see Module 10) for which the patient may be eligible, and it is recommended that clinical staff be able to provide basic information on all current options. Patient expectations must be established by clarifying that teplizumab-mzwv therapy is not a “cure” for T1D and that the evidence supports delay, rather than prevention of future insulin requirement. Potential side-effects should be reviewed (see below and Table 2 for detail) including severity and relative frequency of their occurrence. Social and economic barriers to engaging in 14 consecutive days of IV therapy should be discussed. Counseling should also include education on symptoms of hyperglycemia and targeted behavioral health support. In addition, education and instructions for home blood glucose monitoring with a glucose monitor or continuous glucose monitor wear should be completed (see Module 8).
Immunotherapy Administration
Management with immunotherapies should be in a specialized setting with appropriately trained personnel.(5) At the BDC, the infusion is given by a trained registered nurse (RN) with Advanced Cardiac Life Support (ACLS) or Pediatric Advanced Life Support (PALS) certification and ready access to evaluation by a healthcare provider familiar with immunotherapy treatment and side effect management. For patients aged 1 to less than 8 years, the infusion is administered over a minimum of 2 hours (compared to 30 minutes for patients ≥8 years).
Side Effects of Therapy
Lymphopenia is reflective of the medication’s mechanism of action and
typically reaches a nadir on day 5 and resolves by day 45 in most.(1)
White blood cell counts should be monitored during treatment period,
as significant decreases in various cell lines are among criteria to hold
or stop infusion therapy.(6,7) Patients should receive counseling for
infection precautions prior to and during treatment. Other common
side effects include rash and headache, which can be managed using
over-the-counter medications (see Table 2). In young children, there is
a slight increase in gastrointestinal side effects.
The most significant side effect, occurring in about 5% of patients (vs 1% of controls), is cytokine release syndrome (CRS).(5) CRS manifestations in patients who received teplizumab therapy included fever, nausea, headache, myalgia, arthralgia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), and increased total bilirubin. Most (88%) CRS events were grade 1 or 2 in severity (with grade 4 being the most severe(8)) and resolved with only non-prescription medication therapy. Severe CRS is rare, but requires pausing or halting of therapy.(6,7) CRS signs/symptoms typically occurred during the first 5 days of treatment and can be mitigated by premedicating with antipyretics and antihistamines and monitoring liver enzymes. A plan for expeditious evaluation, identification, and transfer to an acute care facility must occur in the rare situation of severe CRS.
Patient experiences with teplizumab therapy.
A survey of 47 people ages 8 and older and their families who had received teplizumab therapy in the clinical setting explored their thoughts and feelings before and after receiving treatment. This study found that many (40%) believed that their or their child’s glucose levels had improved after treatment. Most still thought about what they (or their child) were eating (68%), diabetes (62%), and glucose levels (75%) following treatment. More than half of caregivers (53%), but only 20% of adult patients endorsed that they felt more relaxed after the treatment. Finally, most people (83%) were glad that they (or their child) received teplizumab.(9)
The most common side effect during the teplizumab infusion is lymphopenia, observed in about 80% of persons who received treatment in clinical trials (see Table 2).
TABLE 2:
Percent of participants experiencing adverse events (for events affecting 20% of group or more) in six clinical trials of teplizumab.
Total individuals receiving teplizumab (N=791), control/placebo (N=245).
REFERENCES
1. Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J
Med. 2019 Aug 15;381(7):603–13. doi:10.1056/NEJMoa1902226 PubMed PMID: 31180194; PubMed Central PMCID: PMC6776880.
2. Sims EK, Bundy BN, Stier K, Serti E, Lim N, Long SA, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals.
Sci Transl Med. 2021 Mar 3;13(583). doi:10.1126/scitranslmed.abc8980 PubMed PMID: 33658358.
3. doi:10.1007/s00125-025-06586-1 PubMed PMID: 41196293; PubMed Central PMCID: PMC12779737.
4. American Diabetes Association Professional Practice Committee for Diabetes*. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes—2026.
Diabetes Care. 2025 Dec 8;49(Supplement_1):S27–49. doi:10.2337/dc26-S002
5. Thakkar S, Chopra A, Nagendra L, Kalra S, Bhattacharya S. Teplizumab in Type 1 Diabetes Mellitus: An Updated Review. TouchREVIEWS Endocrinol. 2023
Nov;19(2):22–30. doi:10.17925/EE.2023.19.2.7 PubMed PMID: 38187075; PubMed Central PMCID: PMC10769466.
6. AsktheExperts [Internet]. [cited 2023 Dec 9]. Home | Ask the Experts – Early T1D Answers and Guidance. Available from: https://www.asktheexperts.org
7. Mehta S, Ryabets-Lienhard A, Patel N, Breidbart E, Libman I, Haller MJ, et al. Pediatric Endocrine Society Statement on Considerations for Use of Teplizumab
(Tzield®) in Clinical Practice. Horm Res Paediatr. 2024 Apr 30;1. doi:10.1159/000538775
8. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity
Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr 1;25(4):625–38. doi:10.1016/j.bbmt.2018.12.758
9. O’Donnell HK, Simmons KM, Gitelman SE, Dex T, Hill R, Wieloch M, et al. Real-world experience with teplizumab in stage 2 type 1 diabetes: a plain language
summary. Ther Adv Endocrinol Metab. 2026;17:20420188261417154. doi:10.1177/20420188261417154 PubMed PMID: 41694289; PubMed Central PMCID:
PMC12901838.