What is the evidence for teplizumab for treating patients with Stage 3 type 1 DM?

Comment by InpharmD Researcher

Teplizumb-mzwv is FDA-approved to delay the onset of stage 3 type 1 diabetes mellitus (T1D) in patients with stage 2 T1D who are ≥1 year old. Teplizumab-mzwv also received accelerated approval for delaying the decline in endogenous insulin production in pediatric patients aged 8-17 years. The most recent 2026 American Diabetes Association guidelines on diabetes treatment do not provide recommendations specific to the treatment of stage 3 T1D given the recent approval of this indication, but the guidelines do acknowledge the role of teplizumab in prevention progression from stage 2 to stage 3 T1D. Available evidence in patients with stage 3 T1D indicates teplizumab’s effectiveness at both 1 and 2 years post-treatment in preventing diabetes progression especially by increasing C-peptide levels and reduced exogenous insulin requirements, considered surrogate markers for improved endogenous insulin production and pancreatic beta islet cell function.

Background

The 2026 American Diabetes Association (ADA) Standards of Care in Diabetes treatment guideline recognizes the evidence-based role of teplizumab-mzwv in delaying progression from stage 2 to stage 3 type 1 diabetes mellitus (T1D). At the time of this guideline’s development and publication, teplizumab-mzwv had not yet received FDA approval for patients with newly established/diagnosed stage 3 T1D. Specifically within the guideline’s section on prevention or delay of diabetes and comorbidities, it is mentioned that teplizumab-mzwv should be discussed with select patients with stage 2 T1D when intended for use to delay the onset to symptomatic stage 3 T1D (level B recommendation). [1], [2]

A 2023 integrated/pooled analysis of clinical trial data from 5 studies representing 609 patients with stage 3 T1D sought to determine whether the efficacy and safety outcomes of teplizumab-mzwv were consistently observed across multiple studies. Across the cohort, 375 patients received the full 14-day regimen of teplizumab-mzwv and 234 received control. The primary metric for pancreatic beta islet cell functionality was the stimulated C-peptide area under the curve (AUC). The trials revealed that teplizumab significantly preserved C-peptide levels at both 1-year and 2-year intervals (change of 0.08 nmol/L at 1 year, p<0.0001; change of 0.12 nmol/L at 2 years, p<0.0001) suggesting that teplizumab can effectively delay the progression of stage 3 T1D, as indicated by the significantly reduced need for exogenous insulin at both 1 and 2 years. Adverse events associated with teplizumab were largely mild to moderate, typically resolving without intervention. Lymphopenia, a common side effect, was transient, resolving even with continued dosing. The study noted a slight increase in serious infection rates among teplizumab-treated patients, but the overall infection rates were comparable between treatment and control groups. These comprehensive findings strengthen the rationale for teplizumab-mzwv as a disease-modifying therapy capable of preserving beta islet cell function and delaying the onset of stage 3 T1D in a broader clinical context. [3]

Background References: [1] American Diabetes Association Professional Practice Committee for Diabetes*. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2026. Diabetes Care. 2026 Jan 1;49(Suppl 1):S183-S215. doi:10.2337/dc26-S009
[2] American Diabetes Association Professional Practice Committee for Diabetes*; 3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes—2026. Diabetes Care 1 January 2026; 49 (Supplement_1): S50–S60. doi:10.2337/dc26-S003
[3] Herold KC, Gitelman SE, Gottlieb PA, et al. Teplizumab: A Disease-Modifying Therapy for Type 1 Diabetes That Preserves β-Cell Function. Diabetes Care. 2023 Oct 1;46(10):1848-1856. doi:10.2337/dc23-0675
Relevant Prescribing Information

INDICATIONS AND USAGE [4]

TZIELD is indicated to:
-Delay the onset of Stage 3 type 1 diabetes (T1D) in adult and pediatric patients 1 year of age and older with Stage 2 T1D.
-Delay the decline in endogenous insulin production in pediatric patients aged 8 to 17 years recently diagnosed with Stage 3 T1D. This indication is approved under accelerated approval based on evidence of reduced C-peptide decline. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Limitations of Use:
There is limited evidence of safety and effectiveness in patients aged 45 years and older with Stage 2 T1D. TZIELD is not effective as a disease modifying therapy in non-autoimmune dysglycemic conditions.

Relevant Prescribing Information References: [4] Tzield (teplizumab-mzwv injection). Prescribing information. Provention Bio, Inc.; 2026.
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the evidence for teplizumab for treating patients with Stage 3 type 1 DM?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-5 for your response.

A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes
Design

Phase I/II randomized, controlled, open-label study

N= 42
Objective To study the safety and efficacy of a single course of treatment with hOKT3γ1(Ala-Ala) on the loss of insulin production over 2 years in patients with new onset type 1 diabetes
Study Groups

Drug treated (n= 21)

Control (n= 21)
Inclusion Criteria Individuals with type 1 diabetes between the ages of 7.5 and 30 years and within 6 weeks of hospital discharge or diagnosis
Exclusion Criteria Not specified
Methods

Patients received a 12-day or 14-day course of hOKT3γ1(Ala-Ala) with incremental dose escalation. C-peptide levels were measured using a mixed-meal tolerance test (MMTT). After drawing samples for baseline C-peptide and glucose, the patients drank a liquid meal (6 mL/kg) over 5 min. The C-peptide levels were measured in samples drawn after 15, 30, 60, 90, 120, 150, 180, 210, and 240 min. Glycated hemoglobin (HbA1c) levels and insulin dosage were monitored. Adverse events were scored using the National Cancer Institute common toxicity criteria. An increase or decrease in the response was designated if the change in the response was greater or less than 7.5% (one-half of the interassay coefficient of variation of the C-peptide assay) of the response at study entry.
Duration

2 years
Outcome Measures

Primary: Preservation of C-peptide responses

Secondary: Improvement in HbA1c levels, reduction in insulin requirements
Baseline Characteristics  

Drug treated (n= 21)

Control (n= 21)
Sex (male/female) 14/7 12/9
Mean age, years 13.9 ± 1.17 14.9 ± 1.31
History of diabetic ketoacidosis (DKA), n (%) 20 (95.2%) 21 (100%)
Mean HbA1c at entry, % 8.98 ± 0.38 7.97 ± 0.24
Mean fasting C-peptide 0.207 ± 0.026 0.210 ± 0.015
GAD, % 81 74
ICA512, % 71 74
IAA, % 62 74
Results  

Drug treated (n= 21)

Control (n= 21)

 p-value
C-peptide response at 1 year (% of entry) 97.1 ± 9.6% 53.1 ± 7.6% <0.001

C-peptide response at 2 years (% of entry) significantly improved (p< 0.02).

HbA1c levels over 2 years significantly improved (p< 0.004).

Insulin dosage over 2 years significantly improved (p< 0.001).
Adverse Events Common adverse events included fever (36.4%), headache (72.7%), myalgia (22.7%), arthralgia (13.6%), rash (90.9%), and a single case of grade 3 thrombocytopenia.
Study Author Conclusions Treatment with the anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.
Critique The study demonstrated significant preservation of C-peptide responses and improved clinical parameters without continuous immunosuppression. However, the open-label design and small sample size may limit the generalizability of the findings. The lack of a placebo group and potential bias in treatment assignment could also affect the results.
Table 1 References:
[5] Herold KC, Gitelman SE, Masharani U, et al. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005 Jun;54(6):1763-9. doi:10.2337/diabetes.54.6.1763

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial
Design

Phase 3, multicentre, randomized, placebo-controlled trial

N= 516
Objective To assess the safety and efficacy of teplizumab in preserving β-cell function and reducing insulin needs in patients with recent-onset type 1 diabetes
Study Groups

14-day full-dose teplizumab (n=209)

14-day low-dose teplizumab (n=102)

6-day full-dose teplizumab (n=106)

Placebo (n=99)
Inclusion Criteria Aged 8–35 years; diagnosed with type 1 diabetes for 12 weeks or fewer; body mass of at least 36 kg; detectable fasting or stimulated C-peptide; positive autoantibody titre against an islet-cell antigen, glutamic acid decarboxylase, or insulin
Exclusion Criteria Serious cardiovascular disorders, active infections, recent participation in a clinical trial, vaccination, or pregnancy
Methods Patients were randomly assigned to receive one of three regimens of teplizumab infusions or placebo at baseline and at 26 weeks. The primary composite outcome was the percentage of patients with insulin use of less than 0.5 U/kg per day and HbA1C of less than 6.5% at 1 year. Analyses included all patients who received at least one dose of study drug
Duration 2-year trial with 1-year results reported
Outcome Measures

Primary: Percentage of patients with insulin use <0.5 U/kg per day and HbA1C <6.5% at 1 year
Baseline Characteristics  

14-day full-dose (n=209)

14-day low-dose (n=102)

6-day full-dose (n=106)

Placebo (n=99)
Age, years 18.9 ± 7.6 17.9 ± 6.1 18.1 ± 6.9 18.2 ± 7.3
HbA1C, % 8.3 ± 2.0   8.4 ± 2.1 8.1 ± 1.8 8.2 ± 2.0
Insulin use, U/kg per day 0.63 ± 0.42 0.68 ± 0.41 0.63 ± 0.39 0.65 ± 0.32
Results   14-day full-dose (n= 209) 14-day low-dose (n= 102) 6-day full-dose (n= 106) Placebo (n= 99)
Primary outcome met 19.8% 13.7% 20.8% 20.4%
Patients not taking insulin at 1 year 5% - - 0%
Adverse events 99% 99% 99% 99%
Serious adverse events 10% - - 9%
Adverse Events The most common clinical adverse event in the teplizumab groups was rash (53% vs 20% in the placebo group). Mild cytokine release syndrome was infrequent in the teplizumab groups (5%) and was not recorded in the placebo group.
Study Author Conclusions Findings suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.
Critique The study was well-designed with a large sample size and multinational scope, but it failed to achieve the primary outcome, necessitating post-hoc analyses. The lack of extensive data for hypoglycaemia and the need for additional follow-up to examine long-term safety and efficacy are limitations. The study identified subgroups that might be more likely to respond to treatment, highlighting the heterogeneity in type 1 diabetes.
Table 2 References:
[6] Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (Protg study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011;378(9790):487-497. doi:10.1016/S0140-6736(11)60931-8
Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial
Design

Randomized, double-blind, placebo-controlled trial

N= 58
Objective To test whether treatment with teplizumab affects the decline in C-peptide production in individuals with type 1 diabetes after the new-onset period
Study Groups

Teplizumab group (n= 31)

Placebo group (n= 27)
Inclusion Criteria Participants aged 8-30 years, diagnosed with type 1 diabetes 4-12 months before enrolment, with at least one autoantibody and a stimulated C-peptide level of at least 0.2 nmol/L
Exclusion Criteria Not meeting inclusion criteria, declined to participate, or laboratory abnormalities meeting exclusion criteria
Methods

Participants received a 14-day course of intravenous teplizumab or saline. C-peptide responses were measured using a mixed meal tolerance test (MMTT) at 6 and 12 months. Insulin use and hemoglobin A1c (HbA1c) levels were monitored.
Duration 12 months
Outcome Measures

Primary: C-peptide response to a mixed meal after 1 year

Secondary: Percentage change in C-peptide response, insulin dose, HbA1c levels
Baseline Characteristics   Teplizumab group (n= 31) Placebo group (n= 27)  
Age, years 12.9 ± 4.18 12.0 ± 5.2  
Male 52% 63%  
Baseline C-peptide AUC, nmol/L  0.618 ± 0.302 0.6 ± 0.43  
Baseline insulin use, U/kg/day 0.405 ± 0.141 0.386 ± 0.197  
Duration of diabetes, months  7.09 ± 2.45 7.14 ± 2.44  
Baseline HbA1c, % 6.37 ± 0.787  7.14 ± 1.21  
Positive for anti-GAD65 antibody  74% 55%  
Positive for anti-IA-2 antibody  87% 73%  
Results   Teplizumab (n= 31) Placebo (n= 27) p-value
C-peptide response, nmol/L 0.45 0.37 0.03
Percentage change in C-peptide -20.6% -36.8% 0.04
Insulin use U/kg/day 0.38 0.43 0.01

The teplizumab group required less exogenous insulin (p<0.001) but treatment differences in HbA1c levels were not observed.
Adverse Events

Teplizumab was well tolerated. Common adverse events included rash, lymphopenia, and nausea. Serious adverse events were rare, with one allergic reaction related to injection in the teplizumab group and four serious events in the placebo group. 
Study Author Conclusions Teplizumab may modulate the course and reduce the decline of C-peptide in patients with type 1 diabetes of up to 1 year duration. Younger age and near normal blood glucose control may improve responses to teplizumab.
Critique The study was well-designed as a double-blind placebo-controlled trial, providing robust data on teplizumab's effects. However, the small sample size and baseline imbalances in HbA1c levels may limit the generalizability of the findings. The study's exploratory nature in subgroup analyses suggests the need for further research to confirm these results. 
Table 3 References:
[7] Herold KC, Gitelman SE, Willi SM, et al. Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial. Diabetologia. 2013;56(2):391-400. doi:10.1007/s00125-012-2753-4
Teplizumab Preserves C-Peptide in Recent-Onset Type 1 Diabetes: Two-Year Results From the Randomized, Placebo-Controlled Protégé Trial
Design

Phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study

N= 516
Objective To determine the efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response
Study Groups

14-day full-dose teplizumab (n= 209)

14-day low-dose teplizumab (n= 102)

6-day full-dose teplizumab (n= 106)

Placebo (n= 99)
Inclusion Criteria Patients with type 1 diabetes diagnosed within the prior 12 weeks, requiring injected insulin therapy, with detectable levels of fasting or stimulated C-peptide and autoantibodies to one or more standard islet autoantigens
Exclusion Criteria Medical disorders such as active infections that might confound results or interfere with safe trial completion
Methods Patients were randomly assigned to one of four treatment groups, receiving daily intravenous treatment starting at baseline and another course at week 26. The 14-day full-dose group received a total cumulative teplizumab dose of ~9,034 mg/m2. Intensive diabetes care was provided, aiming for HbA1c ≤6.5% and insulin dose ≥0.25 units/kg/day. HbA1c and AUC mean C-peptide were measured at specified intervals.
Duration 2 years
Outcome Measures Primary: Composite of insulin <0.5 units/kg/day and HbA1c <6.5% at year 1 Secondary: AUC mean C-peptide, HbA1c, insulin use
Baseline Characteristics   14-day full-dose (n= 209) Placebo (n= 99)  
Age, years 8-35 8-35  
HbA1c, % 7.6 7.6  
Insulin use, units/kg/day 0.47 0.47  
AUC mean C-peptide, nmol/L 0.77 0.77  
Results   14-day full-dose (n= 209) Placebo (n= 99) p-value
Adjusted mean change in AUC of C-peptide from baseline -0.136 -0.191 0.027
Composite of insulin dose <0.5 units/kg/day and HbA1c <6.5% 17 (8.2%) 9 (9.2%) 0.775
Adjusted mean change in HbA1c from baseline, % 0.233 0.135 0.706
Adverse Events No differences in adverse events or serious adverse events among groups at year 2. Grade 3 adverse events were increased in teplizumab groups, primarily due to lymphopenia. No differences in infection incidence, except possible increase in herpes zoster in teplizumab patients
Study Author Conclusions Teplizumab treatment showed significant improvement in stimulated C-peptide responses compared with placebo, especially in children, those treated sooner after diagnosis, and U.S. participants. No new safety or tolerability issues emerged
Critique Limitations include heterogeneous baseline disease status, post hoc analyses without adjustment for multiple comparisons, and discontinuation of some measurements after year 1, potentially reducing statistical power.
Table 4 References:
[8] 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 Protg trial. Diabetes. 2013;62(11):3901-3908. doi:10.2337/db13-0236
Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes
Design

Phase 3, randomized, placebo-controlled trial

N= 328
Objective To assess beta-cell preservation, clinical end points, and safety in children and adolescents with newly diagnosed type 1 diabetes receiving teplizumab or placebo
Study Groups

Teplizumab (n= 217)

Placebo (n= 111)
Inclusion Criteria Male and female patients 8 to 17 years of age with stage 3 type 1 diabetes diagnosed within 6 weeks before randomization, at least one autoantibody associated with type 1 diabetes, and a peak stimulated C-peptide level of 0.2 pmol per milliliter or greater
Exclusion Criteria Major systemic illnesses, active infection, or a history of chronic infection
Methods Patients received teplizumab or placebo intravenously for two 12-day courses, 26 weeks apart. Teplizumab was administered at 106 mcg/m² on day 1, 425 mcg/m² on day 2, and 850 mcg/m² on days 3-12. Patients received premedication with ibuprofen or acetaminophen, an antihistamine, and an antiemetic for at least the first 5 days of each course. Continuous glucose monitoring was used, and insulin doses were recorded in an electronic diary.
Duration March 2019 to May 2023
Outcome Measures

Primary: Change from baseline in beta-cell function (stimulated C-peptide levels) at week 78

Secondary: Insulin doses required to meet glycemic goals, glycated hemoglobin levels, time in target glucose range, clinically important hypoglycemic events
Baseline Characteristics   Teplizumab (n= 217) Placebo (n= 111)
Mean age, years 12.0 ± 2.5 12.3 ± 2.6
Male sex, % 54.8% 62.2%
White, % 87.1% 84.7%
Body weight, kg 46.7 ± 15.0 49.2 ± 15.9
Glycated hemoglobin level, % 8.90 ± 1.73 9.18 ± 1.92
Results   Teplizumab (n= 217) Placebo (n= 111)
C-peptide level at week 78, pmol/ml 0.46 ± 0.20 0.34 ± 0.21
Glycated hemoglobin level at week 78, % 6.97 ± 1.26 7.07 ± 1.45
Percentage of time in target glucose range at week 78 68.7 ± 19.6 64.6 ± 22.4
Insulin dose at week 78, units/kg/day 0.45 ± 0.27 0.60 ± 0.33
Adverse Events Adverse events included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. Severe hypoglycemia occurred in 13.4% of teplizumab patients and 16.2% of placebo patients. Transient lymphopenia and Epstein-Barr virus reactivation were observed in the teplizumab group
Study Author Conclusions Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of beta-cell function, but no significant differences between the groups were observed with respect to the secondary end points
Critique The lack of significant differences in secondary outcomes suggests limited clinical impact. Limitations include potential bias due to the Covid-19 pandemic, underrepresentation of non-White populations, and the trial being underpowered for secondary outcomes. Study funded by Provention Bio and Sanofi.
Table 5 References:
[9] 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