What is the evidence for use of teplizumab for adult patients to delay onset of insulin dependence?

Comment by InpharmD Researcher

The evidence from the TN-10 phase 2 trial shows that teplizumab delays the onset of insulin dependence (stage 3 type 1 diabetes) in high-risk adults and children by approximately two years (48.4 vs. 24.4 months; HR 0.41, p=0.006), with lower progression rates (43% vs. 72%) and preserved beta-cell function via T-cell modulation. However, critical appraisals, such as Canada's Drug Agency, have deemed this evidence insufficient for widespread use due to significant trial limitations and a complete lack of data demonstrating long-term benefits like reduced complications or improved quality of life. Consequently, while the short-term efficacy in delaying insulin dependence is clear, substantial evidence gaps, high costs, and uncertain safety profiles mean teplizumab's clinical value remains unproven in many health-system evaluations.

Background

A 2024 overview provided an in-depth analysis of teplizumab for the delay in the onset of type 1 diabetes mellitus (T1DM). This approval followed the TrialNet TN-10 phase 2 clinical trial, which assessed teplizumab’s efficacy, safety, and tolerability in high-risk, nondiabetic individuals with stage 2 T1DM. In this randomized trial involving 76 participants, a 14-day course of teplizumab was shown to extend the median time to a clinical diagnosis of stage 3 T1DM to 48.4 months, compared to 24.4 months in the placebo group, with a significant hazard ratio of 0.41 (p= 0.006). Notably, the teplizumab group exhibited a 43% progression rate to stage 3 T1DM, a contrast to the 72% observed in the placebo group. The trial highlighted that the effect of teplizumab was most pronounced within the first treatment year, during which the onset of T1DM was substantially reduced in the treatment cohort compared to the control. The study elucidated teplizumab’s mechanism, which involves inducing T cell exhaustion, thereby promoting immune tolerance and preserving pancreatic beta-cell function, as evidenced by a favorable C-peptide response. Additionally, the article discussed the drug's adverse effect profile, noting occurrences of transient lymphopenia and rash among other side effects, yet these did not significantly differ from those occurring in the placebo group. While the promising results underscore teplizumab’s potential as a groundbreaking disease-modifying therapy for T1DM, the authors noted limitations such as the trial’s relatively small sample size and homogenous participant demographics, which could constrain its broader applicability. The report calls for further research to explore the therapy's generalizability across diverse populations and to optimize the economic feasibility and strategic implementation of teplizumab in clinical practice. [1]

Based on the comprehensive review Canada's Drug Agency (CDA-AMC) issued a final recommendation not to reimburse teplizumab for delaying insulin-dependent stage 3 type 1 diabetes in patients aged 8 and older with stage 2 disease. While the pivotal TN-10 trial showed a median delay of approximately two years, the committee deemed the evidence insufficient for public funding. Key limitations included the small trial (N= 76), baseline imbalances, and poor generalizability, as participants were overwhelmingly white, exclusively had a family history of type 1 diabetes (excluding ~85% of those who develop the disease), and excluded common comorbidities. Crucially, the trial did not demonstrate that this delay translates into long-term benefits such as reduced macrovascular or microvascular complications, improved glycemic control after progression, or better health-related quality of life. Short-term safety data showed increased adverse events, and long-term safety data are absent. With a cost of ~$258,000 per course, a cost-effectiveness ratio of $747,542 per QALY gained, and a projected 3-year budget impact of $485 million, the therapy far exceeds typical thresholds. Implementation challenges further compound the decision, including Canada's lack of population-based screening for asymptomatic stage 2 patients, inequitable access to autoantibody testing and infusion infrastructure, and the ethical concern of funding an expensive, unproven therapy for an inevitable chronic condition. Despite strong patient and clinician testimonials about diabetes burden, the committee concluded the uncertain benefits do not outweigh the risks, costs, and evidence gaps, and thus recommended against reimbursement. [2]

Background References: [1] Novograd J, Frishman WH. Teplizumab Therapy to Delay the Onset of Type 1 Diabetes. Cardiol Rev. 2024;32(6):572-576. doi:10.1097/CRD.0000000000000563[2] Teplizumab (Tzield): Indication: To delay the onset of stage 3 type 1 diabetes in adult and pediatric patients 8 years of age and older with stage 2 type 1 diabetes. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; January 2026.
[2] Teplizumab (Tzield): Indication: To delay the onset of stage 3 type 1 diabetes in adult and pediatric patients 8 years of age and older with stage 2 type 1 diabetes. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; January 2026.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence for use of teplizumab for adult patients to delay onset of insulin dependence?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
Design

Phase 2, randomized, placebo-controlled, double-blind trial

N= 76
Objective To test whether teplizumab treatment would prevent or delay the onset of clinical type 1 diabetes in high-risk persons
Study Groups

Teplizumab group (n= 44)

Placebo group (n= 32)
Inclusion Criteria Nondiabetic relatives of patients with type 1 diabetes, at least 8 years of age, high risk for development of clinical diabetes, two or more diabetes-related autoantibodies, evidence of dysglycemia during an oral glucose-tolerance test
Exclusion Criteria Clinically important medical histories, abnormal laboratory chemical values, or abnormal blood counts
Methods

Participants received a 14-day outpatient course of teplizumab or saline intravenously. Teplizumab was administered at increasing doses from 51 μg/m² to 826 μg/m² over 14 days. Follow-up for progression to clinical type 1 diabetes was performed using oral glucose-tolerance tests at 6-month intervals.
Duration July 2011 through November 2018
Outcome Measures

Primary: Time from randomization to clinical diagnosis of diabetes

Secondary: Frequency of KLRG1+TIGIT+CD8+ T cells, adverse events
Baseline Characteristics   Teplizumab group (n= 44) Placebo group (n= 32)
Age ≤18 years 72% 72%
Positive for ≥3 autoantibodies 71% 71%
Siblings of patients with type 1 diabetes More than half More than half
Results   Teplizumab group (n= 44) Placebo group (n= 32) p-value
Median time to diagnosis, months 48.4 24.4 0.006
Annualized rate of diagnosis, % per year 14.9% 35.9% --
Participants diagnosed with diabetes 19 (43%) 23 (72%) --
Adverse Events Expected adverse events of rash and transient lymphopenia. EBV reactivation observed in some participants in the teplizumab group
Study Author Conclusions

Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. The findings support the notion that type 1 diabetes is a chronic T-cell–mediated disease and suggest that immunomodulation before the development of clinical disease can be useful.
Critique

The study demonstrated a significant delay in the progression to type 1 diabetes with teplizumab treatment. However, the cohort was relatively small, and the participants were primarily non-Hispanic white relatives of patients with type 1 diabetes, which may limit generalizability. The trial population was also overwhelmingly made up of children, and the effects of repeated dosing were not tested.

 

Table 1 References:
[3] 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
Safety and pharmacokinetics of teplizumab in children less than 8 years of age with stage 2 type 1 diabetes
Design

Single-arm, open-label, multicentre study

N= 23
Objective To evaluate the safety, tolerability, and pharmacokinetics of teplizumab in children aged <8 years with stage 2 type 1 diabetes
Study Groups All participants (N= 23)
Inclusion Criteria Children aged <8 years with stage 2 type 1 diabetes, defined as positivity for two or more islet autoantibodies and presence of dysglycaemia without overt hyperglycaemia
Exclusion Criteria Clinically significant alterations in haematological parameters, liver function test abnormalities, active infections, recent or planned live vaccinations within specified timeframes
Methods Participants received a 14 day course of teplizumab via i.v. infusion. Premedication included NSAIDs or acetaminophen, antihistamines, and antiemetics as needed. Safety and pharmacokinetics were assessed through TEAEs, serum concentrations, and CD3 receptor occupancy
Duration 2 years, with interim analysis after 1 year
Outcome Measures

Primary: Treatment-emergent adverse events (TEAEs), TEAEs causing treatment discontinuation, serious adverse events (SAEs)

Secondary: Immunogenicity, pharmacokinetics, pharmacodynamics, progression to stage 3 type 1 diabetes
Baseline Characteristics   Teplizumab (N= 23)
Age at day 1, years - Mean (SD) 4.8 (1.2)
Age group at day 1 - <2 years 1 (4.3%)
Age group at day 1 - 2 to <5 years 12 (52.2%)
Age group at day 1 - 5 to <8 years 10 (43.5%)
Sex - Female 12 (52.2%)
Sex - Male 11 (47.8%)
Race - White 22 (95.7%)
Ethnicity - Hispanic or Latino 3 (13.0%)
HbA1c at baseline, mmol/mol - Mean (SD) 37 (5.5)
Type of T1D-related autoantibody - ICA 11/13 (84.6%)
Type of T1D-related autoantibody - GADA 19/23 (82.6%)
Type of T1D-related autoantibody - IAA 20/23 (87.0%)
Type of T1D-related autoantibody - IA-2A 15/22 (68.2%)
Type of T1D-related autoantibody - ZnT8A 17/23 (73.9%)
Results   Teplizumab (N= 23)
Any TEAE 23 (100%)
Grade 1 TEAE 22 (95.7%)
Grade 2 TEAE 17 (73.9%)
Grade 3 TEAE 6 (26.1%)
Serious TEAE 2 (8.7%)
TEAE leading to study drug discontinuation 3 (13.0%)
Serious TEAE related to study drug 2 (8.7%)
Patients that progressed to stage 3 2 (8.7%)
Estimated probability lack of progression to stage 3 (95% confidence interval [CI]) 89.6% (64.3% to 97.3%)
Adverse Events All participants experienced one or more TEAE, with most being mild to moderate. No grade 4 or 5 TEAEs were reported. Three participants had TEAEs leading to teplizumab discontinuation: anaemia, elevated liver enzymes, and maculo-papular rash. Two participants had serious adverse events
Study Author Conclusions Teplizumab was safe and well tolerated in children <8 years of age with stage 2 type 1 diabetes. Adverse events were consistent with those seen in previous studies, with no new safety risks identified. Surveillance is ongoing.
Critique The study provides valuable insights into the safety of teplizumab in a younger population, but the small sample size and lack of a control group limit the ability to draw definitive conclusions about efficacy. The study population was predominantly White, which may affect the generalizability of the findings. Additionally, the study did not include formal statistical inference or powered subgroup comparisons.

 

Table 2 References:
[4] Gitelman SE, Simmons K, Sherr JL, et al. Safety and pharmacokinetics of teplizumab in children less than 8 years of age with stage 2 type 1 diabetes. Diabetologia. 2026;69(2):330-342. doi:10.1007/s00125-025-06586-1