# Teplizumab in Stage 2 Type 1 Diabetes: Median Delay to Clinical Onset and the Evidence Base for the First FDA-Approved Disease-Modifying Therapy

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### Background and Context

Type 1 diabetes (T1D) is a chronic autoimmune disease in which self-reactive T lymphocytes progressively destroy insulin-producing pancreatic beta cells, ultimately rendering affected individuals dependent on exogenous insulin for survival. The disease affects an estimated 8.75 million individuals globally as of 2022 (PMC11989447). In the United States alone, approximately 15,288 new pediatric cases are diagnosed annually in children under 15 years of age (PMC11989447). A study by Gregory et al. found that in 2021, there were about 8.4 million individuals worldwide with T1D, and that by 2040, this number was expected to reach 13.5–17.4 million (PMC11576206). Beyond the epidemiological burden, T1D imposes a profound quality-of-life penalty: patients experience an estimated 10 years shorter lifespan compared to the general population, approximately one hour less sleep per night due to glycemic variability, and substantially elevated rates of depression and anxiety (PMC9314738). Long-term microvascular and macrovascular complications — including nephropathy, retinopathy, neuropathy, and cardiovascular disease — remain the principal drivers of morbidity and premature mortality, and most patients fail to achieve guideline-recommended HbA1c targets despite intensive insulin therapy (PMC9314738, PMC11989447).

The conceptual framework for understanding T1D has been transformed over the past two decades by the recognition that the disease progresses through distinct, identifiable presymptomatic stages before clinical onset. This staging model, now embedded in regulatory and clinical trial frameworks, defines Stage 1 as the presence of two or more islet autoantibodies with normoglycemia; Stage 2 as the persistence of two or more autoantibodies accompanied by dysglycemia but without overt symptoms; and Stage 3 as the emergence of symptomatic hyperglycemia meeting conventional diagnostic criteria for diabetes, including diabetic ketoacidosis, polydipsia, polyuria, polyphagia, and weight loss (PMC12066327). It should be noted that some sources describe Stage 1 as requiring only one or more autoantibodies, while others specify two or more; the PMC12066327 review explicitly states that Stage 1 requires two or more antibodies, whereas other frameworks allow for a single autoantibody at Stage 1 (PMC12066327, PMC6189286). The critical clinical insight embedded in this framework is that individuals with two or more islet autoantibodies carry a lifetime risk of progressing to clinical T1D approaching 100%, and that the transition from Stage 2 to Stage 3 is essentially inevitable in the absence of intervention (PMC6189286). The 5-year risk in Stage 2 individuals with dysglycemia is approximately 75%, making this population an attractive and tractable target for disease-modifying intervention (PMC6189286).

Against this backdrop, the development of teplizumab — a humanized, non-depleting anti-CD3 monoclonal antibody — represents the first successful pharmacological strategy to delay the onset of clinical T1D in presymptomatic individuals. Teplizumab received FDA approval in November 2022, becoming the first drug ever approved to delay the onset of any autoimmune disease before its clinical manifestation (PMC11316332, PMC11576206). The pivotal evidence supporting this approval derives primarily from the TrialNet TN10 study (Herold et al., 2019, NEJM), a phase 2, randomized, placebo-controlled, double-blind trial that enrolled 76 participants with Stage 2 T1D and demonstrated a statistically significant and clinically meaningful delay in progression to Stage 3 disease following a single 14-day course of teplizumab. The central quantitative question addressed by this review — what is the median delay in months to clinical onset of Stage 3 disease following teplizumab versus placebo — has a precise answer embedded in the TN10 trial data and its subsequent extension analyses, and this answer carries profound implications for how clinicians, patients, and health systems should conceptualize T1D as a preventable, or at least delayable, condition.

The historical context for teplizumab's development in Stage 2 T1D is important for interpreting the TN10 findings. Anti-CD3 monoclonal antibodies were first explored in the transplantation setting and subsequently tested in Stage 3 (newly diagnosed) T1D, where multiple phase 2 trials demonstrated preservation of C-peptide levels and reduced insulin requirements (PMC11316332). However, two pivotal phase 3 trials — Protégé and Encore — were conducted in Stage 3 patients and failed to meet their primary composite endpoints. As one review noted, teplizumab "infamously failed in phase 3 trials in Stage 3 T1D," with only the highest dose in subjects randomized within 6 weeks of diagnosis showing transient C-peptide preservation, and the contested composite endpoint of insulin usage and HbA1c has been cited as a contributing factor alongside the advanced stage of disease at enrollment (PMC6189286). The strategic pivot to Stage 2 — where substantial beta-cell mass remains intact and the autoimmune process is still amenable to modulation — proved decisive. The rationale was straightforward: if T cell depletion and exhaustion could be induced before the bulk of beta-cell destruction had occurred, the window for meaningful clinical benefit would be substantially wider (PMC6189286, PMC11316332).

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### Molecular and Mechanistic Pathways

#### Autoimmune Pathogenesis of Stage 2 Type 1 Diabetes

The autoimmune destruction of pancreatic beta cells in T1D is a complex, multi-cellular process that unfolds over years to decades before clinical onset. CD8+ cytotoxic T lymphocytes are likely the central effectors of beta-cell destruction in T1D, recognizing beta-cell peptides presented on HLA class I molecules; CD4+ T helper cells restricted by high-risk HLA class II alleles (DR4, DQ8, DQ2) amplify the autoimmune response (PMC12066327, PMC11316332). The insulitis lesion — the histopathological hallmark of active T1D — is characterized by lymphocytic infiltration of pancreatic islets, with CD8+ T cells predominating in younger patients and the overall inflammatory burden being substantially lower in older-onset disease (PMC9314738). Importantly, data from the Network for Pancreatic Organ Donors (nPOD) indicate that insulitis is most frequent around the time of clinical diagnosis and is substantially reduced in prediabetic seropositive individuals, suggesting that the bulk of immunological destruction is concentrated in a narrow window around Stage 3 onset (PMC6189286). This observation has direct implications for the timing of immunotherapy: intervening at Stage 2, before the peak of insulitis, may be more effective than intervening at or after Stage 3 onset.

Beta cells are not passive victims in this process. Under metabolic and immune stress, beta cells upregulate HLA class I molecules and generate signals that attract and activate immune cells. The unfolded protein response (UPR) can shift from adaptive to pro-apoptotic mode, contributing to beta-cell death through TXNIP-mediated intrinsic apoptosis. A subpopulation of beta cells in prediabetic individuals adopts a senescent fate with a senescence-associated secretory phenotype (SASP) that amplifies local inflammation (PMC7765619). These beta-cell-intrinsic dysfunctional states — apoptosis, senescence, defective proinsulin processing, and altered identity — are now recognized as co-drivers of T1D pathogenesis alongside the autoimmune process, and they provide additional therapeutic targets beyond T-cell modulation (PMC7765619).

#### Mechanism of Action of Teplizumab

Teplizumab is a humanized monoclonal antibody that targets the epsilon (ε) subunit of the CD3 antigen cluster, co-expressed with the T-cell receptor (TCR) on the surface of T lymphocytes (PMC11316332). The PMC11316332 review notes that teplizumab induces phenotypic changes in autoreactive CD8+ T cells, depleting effector T cells while preserving regulatory T cells, and is associated with CD8+ T-cell exhaustion correlating with clinical responses in new-onset T1D. The drug's differentiation from otelixizumab, another anti-CD3 antibody, lies in its specificity to the ε-subunit of CD3 (PMC11316332). Teplizumab is engineered to be non-depleting through its FcR nonbinding properties — it does not engage Fc receptors on effector cells and therefore does not trigger complement-mediated or antibody-dependent cellular cytotoxicity of T cells (PMC12066327). Some reviews have characterized teplizumab's FcR nonbinding design as a key differentiating feature from earlier anti-CD3 antibodies, while others emphasize that the precise in vivo consequences of this engineering choice remain incompletely characterized (PMC11316332, PMC12066327).

The mechanistic consequences of teplizumab binding are multiple and partially overlapping. Teplizumab induces a partially exhausted CD8+ T-cell phenotype with reduced secretion of IFN-γ and TNF-α, depletes effector T cells (Teffs) while preserving regulatory T cells (Tregs), and elevates CD4+FoxP3+ Tregs, helping restore the balance between tolerogenic Tregs and pathogenic T cells (PMC11316332). Teplizumab also promotes the generation of gut-tropic regulatory cells, potentially influencing immune responses in the gastrointestinal tract through mechanisms that remain incompletely characterized (PMC11316332). Furthermore, teplizumab modulates T-cell migration patterns and alters tolerogenic mechanisms, including apoptosis of activated T cells through TGF-β and TNF-α signaling pathways (PMC12066327).

The net immunological effect of a single 14-day course of teplizumab is a durable remodeling of the autoreactive T-cell compartment that persists well beyond the period of drug exposure. A follow-up analysis of the TN10 trial conducted at a median of 923 days after the initial study found that 50% of the teplizumab-treated population remained in Stage 2 T1D compared to only 22% of the control group, attributed to partially exhausted memory T cells with reduced secretion of IFN-γ and TNF-α, implying that a single course of teplizumab has a lasting effect in delaying Stage 3 T1D in higher-risk individuals (PMC11576206). The precise in vivo mechanism by which teplizumab targets peptide-MHC complexes on autoreactive T cells remains incompletely characterized, and the exact basis for drug response versus non-response has not been fully resolved (PMC11316332).

#### The PD-1/PD-L1 Axis and T-Cell Exhaustion in T1D

A mechanistically important parallel to teplizumab's induction of T-cell exhaustion is the endogenous role of the PD-1/PD-L1 pathway in regulating islet autoimmunity. Beta cells upregulate PD-L1 expression in response to IFN-α and IFN-γ via the JAK/STAT/IRF1 signaling cascade, and this PD-L1 expression may engage PD-1 on infiltrating CD8+ T cells to promote their exhaustion and limit beta-cell destruction (PMC10146255). The exhaustion of islet-specific CD8+ T cells — characterized by upregulation of PD-1 and other inhibitory receptors, reduced cytokine production, and diminished proliferative capacity — is now recognized as a critical mechanism of peripheral tolerance that protects beta cells from autoimmune attack (PMC10146255). Cross-sectional studies in T1D patients have demonstrated that the proportion of self-reactive islet-specific CD8+ T cells expressing an exhausted phenotype discriminates patients with slow disease progression (higher exhausted fraction) from those with rapid progression (lower exhausted fraction) (PMC10146255).

Teplizumab's mechanism of action can therefore be understood as pharmacologically mimicking and amplifying the endogenous PD-1-mediated exhaustion program in autoreactive T cells. By delivering a partial TCR signal through CD3 engagement, teplizumab drives autoreactive CD8+ T cells toward an exhausted state that is functionally analogous to — and potentially synergistic with — the PD-L1-mediated exhaustion induced by beta cells themselves. This mechanistic convergence has important implications for combination therapy strategies: agents that upregulate PD-L1 on beta cells (such as IFN-γ-stimulated HILOs or JAK pathway modulators) might synergize with teplizumab to produce more durable exhaustion of autoreactive T cells (PMC9314738, PMC10146255). Conversely, immune checkpoint inhibitors (anti-PD-1/anti-PD-L1 monoclonal antibodies used in oncology) can reverse T-cell exhaustion and precipitate fulminant T1D, providing compelling in vivo evidence for the causal role of T-cell exhaustion in protecting beta cells from autoimmune destruction (PMC10146255).

The JAK-STAT pathway, which mediates IFN-α and IFN-γ signaling in beta cells and immune cells, represents an additional mechanistic node relevant to teplizumab's context. The 2019 review by Chávez-Galán and colleagues describes a type I IFN signature preceding autoantibody seroconversion in genetically at-risk children, with IFN-α expressed in human islets from T1D patients and IFN-α upregulating HLA class I on beta cells, inducing ER stress, and promoting CXCL10 secretion (PMC6801436). The same review notes that the TYK2 SNP rs2304256, which causes a missense mutation in TYK2, has been associated with protection against T1D, further implicating the JAK-STAT pathway in disease pathogenesis (PMC6801436). JAK1/2 inhibitors such as baricitinib and ruxolitinib can block IFN-mediated effects on beta cells and have shown beta-cell preservation in early clinical trials (PMC11576206, PMC6801436). These mechanistic insights suggest that teplizumab's T-cell exhaustion approach and JAK inhibitor-mediated beta-cell protection may be complementary rather than redundant.

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### Dose-Response and Pharmacokinetics

#### The 14-Day Intravenous Dosing Regimen

The dosing regimen evaluated in the pivotal TN10 trial — and subsequently approved by the FDA — consists of a single 14-day course of intravenous teplizumab administered as a daily infusion (PMC12066327, PMC11316332). This regimen was derived from earlier phase 2 trials in Stage 3 T1D, where a 14-day course was found to produce durable C-peptide preservation without the need for continuous dosing — a critical distinction from most immunosuppressive therapies, which require chronic administration to maintain efficacy (PMC11316332, PMC6189286). The non-depleting mechanism of teplizumab means that its immunological effects are not simply a function of drug concentration at any given time point, but rather reflect a durable reprogramming of the T-cell compartment that persists after drug clearance.

Earlier dose-escalation studies in Stage 3 T1D found that a dose approximately 40% higher than the standard teplizumab regimen resulted in increased adverse events, suggesting the standard 14-day regimen represents a near-optimal dose for the balance of efficacy and tolerability (PMC11316332). In the Protégé study, 77% (318/415) of patients treated with teplizumab and 13% (13/98) of those receiving placebo developed anti-drug antibodies (PMC11316332). This anti-drug antibody formation is a pharmacokinetic consideration of potential importance for repeat dosing strategies, though its clinical significance in the context of a single-course regimen (as approved for Stage 2 T1D) is less clear.

The distinction between therapeutic doses (the approved 14-day IV regimen) and suprapharmacological or in vitro doses is important for interpreting mechanistic studies. Many of the in vitro experiments characterizing teplizumab's effects on T-cell exhaustion, Treg induction, and cytokine modulation were conducted at concentrations that may not precisely reflect in vivo drug levels during the clinical dosing regimen. The precise pharmacokinetic profile of teplizumab — including its volume of distribution, half-life, and tissue penetration into pancreatic lymph nodes where autoreactive T-cell priming occurs — has not been fully characterized in the published literature reviewed here, representing a gap in the mechanistic understanding of the drug's in vivo activity.

#### Timing of Administration and Stage of Disease

A critical pharmacodynamic consideration is the timing of teplizumab administration relative to disease stage. The available evidence strongly suggests that earlier intervention — at Stage 2 rather than Stage 3 — produces more durable and clinically meaningful effects. In Stage 3 trials, teplizumab and anti-thymocyte globulin (ATG) both caused less IFN-γ and TNF secretion by disabled CD8 memory T cells, but this effect sustained for only approximately 2 years before being overtaken by CD8 expansion and disease progression (PMC9314738). In the TN10 Stage 2 trial, by contrast, 50% of teplizumab-treated participants remained diabetes-free at a median follow-up of approximately 2.5 years — a substantially more durable outcome (PMC11576206, PMC11316332). This stage-dependent efficacy gradient is consistent with the mechanistic rationale: at Stage 2, a larger residual beta-cell mass remains intact, the autoimmune process is less advanced, and the autoreactive T-cell repertoire has not yet fully expanded into a mature effector-memory phenotype that is more resistant to exhaustion induction (PMC6189286).

The 2018 Novo Nordisk review explicitly articulated this rationale, noting that many failures in clinical translation of immunotherapy for T1D stemmed from the inappropriate extrapolation of preclinical data situated at the animal model equivalent of Pre-Stage 1 into trial designs including exclusively Stage 3 patients (PMC6189286). The strategic shift to Stage 2 — where the autoreactive T-cell repertoire has expanded but not yet fully committed to a terminal effector fate — appears to represent the optimal therapeutic window for teplizumab's mechanism of action.

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### Clinical Evidence and Implications

#### The TN10 Phase 2 Trial: Primary Analysis (Herold et al., 2019)

The TrialNet TN10 study is the pivotal clinical trial establishing the efficacy of teplizumab in Stage 2 T1D and the primary source for the median delay data that is the central focus of this review. The pivotal TN10 study (Herold et al., 2019, NEJM) was a phase 2, randomized, placebo-controlled, double-blind trial enrolling 76 participants with Stage 2 T1D that demonstrated a statistically significant delay in progression to Stage 3 disease following a single 14-day course of teplizumab (PMC12066327, PMC11316332). The trial enrolled participants aged 8 years and older who were relatives of individuals with T1D and who met criteria for Stage 2 disease: the presence of two or more islet autoantibodies and dysglycemia on oral glucose tolerance testing. Fifty-five participants (72%) were 18 years of age or younger. Participants were randomized to receive either a single 14-day course of intravenous teplizumab or placebo, with oral glucose tolerance tests performed at 6-month intervals to monitor progression to Stage 3 T1D (PMC12066327).

Over a median follow-up period of 51 months, 43% of patients in the teplizumab group progressed to Stage 3 T1D compared with 72% in the placebo group (PMC12066327). This difference in progression rates was statistically significant and clinically substantial. The primary efficacy outcome — median time to diagnosis of Stage 3 T1D — was **48.4 months in the teplizumab group versus 24.4 months in the placebo group**, yielding a **median delay of approximately 24 months (2 years)** in the teplizumab arm relative to placebo (PMC12066327). The hazard ratio for diagnosis of T1D (teplizumab versus placebo) was 0.41 (95% CI 0.22–0.78; P=0.006), indicating that teplizumab reduced the instantaneous risk of progressing to Stage 3 T1D by approximately 59% at any given time point during follow-up (PMC12066327, PMC11316332).

The most pronounced effect of teplizumab was observed within the first year of follow-up: only 7% of participants in the teplizumab group were diagnosed with Stage 3 T1D during the first year, compared with 44% of participants in the placebo group (PMC12066327). This early and dramatic separation of the Kaplan-Meier curves suggests that teplizumab's immunological effects are rapid in onset and that the drug substantially blunts the near-term risk of clinical onset that is highest in Stage 2 individuals with dysglycemia.

It is important to note the precise framing of the median delay figure. The median time to Stage 3 diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The **difference between these medians — approximately 24 months, or 2 years** — represents the median delay attributable to teplizumab treatment in the primary analysis (PMC12066327). The hazard ratio of 0.41 provides a more statistically rigorous summary of the treatment effect across the entire follow-up distribution, but the median delay of approximately 24 months is the most clinically intuitive summary of the benefit from the primary analysis.

#### The TN10 Extension Analysis: Updated Median Delay

A subsequent follow-up analysis of the TN10 trial, conducted at a median of 923 days after the initial study, found that 50% of the teplizumab-treated population remained in Stage 2 T1D compared to only 22% of the control group. This change was attributed to partially exhausted memory T cells with reduced secretion of IFN-γ and TNF-α, implying that a single course of teplizumab has a lasting effect in delaying Stage 3 T1D in higher-risk individuals (PMC11576206). An updated 2021 analysis of the TN10 trial revealed that the median delay in Stage 3 onset had extended to 32.5 months, representing the more mature dataset (PMC11311856).

The discrepancy between the primary analysis median delay (~24 months, based on 51-month median follow-up) and the updated median delay (~32.5 months) reflects the statistical reality that median estimates become more stable and accurate as more events accumulate over longer follow-up. Both figures — 24 months and 32.5 months — appear in the reviewed literature, and the discrepancy should be understood as reflecting different analytical time points rather than contradictory findings (PMC12066327, PMC11311856).

#### Stage 3 Trials: C-Peptide Preservation and Beta-Cell Function

While the TN10 trial is the pivotal study for the Stage 2 indication, the broader clinical evidence base for teplizumab includes multiple trials in Stage 3 (newly diagnosed) T1D that collectively establish the drug's capacity to preserve residual beta-cell function. These trials are relevant to the Stage 2 question because they demonstrate the biological plausibility of teplizumab's mechanism and provide context for interpreting the TN10 findings.

In a randomized placebo-controlled trial enrolling 58 participants with recent-onset Stage 3 T1D, the teplizumab group lost significantly less C-peptide at 12 months: 18% (95% CI 7.43–28.5%) versus 39.0% (95% CI 27.8–50.2%) in the placebo group (p=0.006) (PMC11316332). Teplizumab-treated younger participants (age <15 years) had C-peptide responses 31.7% higher than placebo (p=0.02), whereas older participants (age ≥15 years) showed no significant difference (p=0.56) (PMC11316332). This age-dependent effect is consistent with the endotype framework for T1D, in which younger patients have more aggressive autoimmunity and potentially more to gain from early immunomodulation.

The AbATE trial (Autoimmunity-Blocking Antibody for Tolerance), a randomized open-labeled controlled trial enrolling 125 participants with new-onset Stage 3 T1D, tested two courses of teplizumab administered 12 months apart (PMC11316332). Two courses of teplizumab significantly reduced the loss of C-peptide at 2 years after the first treatment (p=0.002) (PMC11316332). A 7-year follow-up of AbATE trial participants demonstrated that drug-treated responders maintained a significantly greater C-peptide response than the control group and drug-treated non-responders, with C-peptide responses remaining consistently higher in responders even as they declined over time (PMC11316332). This long-term follow-up is particularly important because it demonstrates that teplizumab's effects on beta-cell function can persist for years beyond the treatment period in clinical responders.

Two pivotal phase 3 trials of teplizumab in Stage 3 T1D — Protégé and Encore — failed to meet their primary composite endpoints; only the highest dose in subjects randomized within 6 weeks of diagnosis showed transient C-peptide preservation, and the contested composite endpoint of insulin usage and HbA1c was cited as a contributing factor alongside the advanced stage of disease at enrollment (PMC6189286). The Protégé failure has been attributed to the contested composite endpoint, the advanced stage of disease at enrollment, and the potential attenuation of the second course's efficacy by anti-drug antibody formation.

A phase 3 randomized placebo-controlled trial enrolling 328 children and adolescents with Stage 3 T1D (Ramos et al., 2023) tested two 12-day courses of teplizumab and found significant benefits in preserving beta-cell function, with teplizumab-treated patients exhibiting significantly higher stimulated C-peptide levels compared to placebo by week 78 (PMC11316332). However, no significant differences were found in secondary endpoints between groups (PMC11316332). This pattern — significant C-peptide preservation without corresponding improvements in secondary glycemic endpoints — has been a consistent finding across teplizumab trials in Stage 3 T1D and reflects the fact that C-peptide preservation, while biologically meaningful, may not translate to clinically detectable improvements in glycemic control when the absolute level of residual beta-cell function is low.

A meta-analysis of 8 randomized controlled trials enrolling 866 patients with a clinical diagnosis of T1D who received teplizumab found that teplizumab was associated with decreased insulin use at 6, 12, and 18 months after diagnosis, and that stimulated C-peptide AUC was significantly higher at 12, 18, and 24 months (PMC11576206). This meta-analytic evidence provides the most comprehensive quantitative synthesis of teplizumab's effects on beta-cell function across the Stage 3 evidence base and supports the biological consistency of the drug's mechanism across different trial designs and patient populations.

#### Comparative Context: Other Disease-Modifying Therapies in Stage 2 T1D

The TN10 teplizumab data can be contextualized against other disease-modifying therapies being evaluated in Stage 2 T1D, though teplizumab remains the only FDA-approved agent for this indication. Low-dose anti-thymocyte globulin (ATG) is being evaluated in a phase 2 randomized double-blind placebo-controlled trial (NCT04291703) to prevent progression from Stage 2 to Stage 3 T1D, with participants followed for up to 5 years (PMC11576206). Abatacept (CTLA-4Ig) is being evaluated in a prevention trial targeting Stage 1 subjects (NCT01773707), based on the rationale that costimulation blockade may be most effective before the autoreactive T-cell repertoire has fully expanded (PMC6189286). Diamyd (GAD-alum) was evaluated in the DIAPREV-IT trial enrolling 50 Stage 1 and 2 subjects; 18 of 50 subjects developed T1D with no significant differences between treated and placebo groups (PMC6189286). Oral insulin, evaluated in the DPT-1 trial (n=372), showed no significant difference in annualized diabetes rate overall, though a post-hoc subgroup of 27 treated subjects with abnormal first-phase insulin response showed a delay of approximately 31 months in T1D onset (PMC6189286). None of these alternative approaches has achieved the level of evidence or regulatory approval that teplizumab has achieved in Stage 2 T1D.

#### The DPT-1 Oral Insulin Subgroup: A Cautionary Parallel

The DPT-1 oral insulin trial provides an instructive parallel for interpreting the TN10 teplizumab data. In the DPT-1 trial, over 100,000 relatives of T1D patients were screened for islet autoantibodies, and 372 were randomized to 7.5 mg/day oral insulin or placebo (PMC6189286). The overall trial was negative, with no significant difference in annualized diabetes rate between groups. However, a post-hoc subgroup analysis of 27 treated subjects with abnormal first-phase insulin response (a marker of more advanced Stage 2 disease) showed a delay in T1D onset of approximately 31 months — a figure strikingly similar to the teplizumab median delay (PMC6189286). This parallel is noteworthy but should be interpreted cautiously: the DPT-1 subgroup finding was post-hoc, involved only 27 subjects, and has not been prospectively replicated. The TN10 teplizumab finding, by contrast, was a pre-specified primary endpoint in a prospectively designed trial with a statistically significant result (HR 0.41, 95% CI 0.22–0.78, P=0.006), providing a substantially stronger evidentiary basis for the claimed delay.

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### Safety Profile and Adverse Events

#### Common Adverse Events

The safety profile of teplizumab in the TN10 Stage 2 trial and in Stage 3 trials is characterized by a predictable set of adverse events that are generally transient and manageable, with the exception of lymphopenia, which can be prolonged (PMC12066327, PMC11316332). The most frequently reported adverse events occurring in more than 10% of teplizumab-treated participants include lymphopenia (73%), rash (36%), leukopenia (21%), and headache (11%) (PMC12066327). These adverse events are consistent across Stage 2 and Stage 3 trials and reflect the expected pharmacological consequences of T-cell modulation by an anti-CD3 antibody.

Lymphopenia — a transient reduction in circulating lymphocyte counts — is the most common and most clinically significant adverse event associated with teplizumab. In the TN10 trial, lymphopenia was reported in 73% of teplizumab-treated participants (PMC12066327). The lymphopenia reflects the transient redistribution and partial depletion of T cells from the peripheral blood compartment following CD3 engagement, and it typically resolves within weeks to months after the completion of the 14-day course. The clinical significance of teplizumab-induced lymphopenia in terms of infection risk has not been fully characterized in the Stage 2 population, though infection rates in Stage 3 trials were comparable between teplizumab-treated and control patients (PMC11316332).

Rash, occurring in 36% of teplizumab-treated participants, is typically mild to moderate in severity and resolves without intervention (PMC12066327). Leukopenia (21%) reflects the broader effect of teplizumab on circulating white blood cells beyond the lymphocyte compartment. Headache (11%) is a common non-specific adverse event that may be related to cytokine release during the initial days of infusion.

#### Cytokine Release Syndrome

Cytokine release syndrome (CRS) is a potentially serious adverse event associated with teplizumab that requires premedication and monitoring, particularly during the first several days of treatment (PMC12066327). In the TN10 trial, CRS affected 5% of patients receiving teplizumab compared with 0.8% in the placebo group (PMC12066327). CRS manifested as fever, nausea, fatigue, headache, myalgia, arthralgia, and elevated liver enzymes (ALT, AST, and bilirubin). The FDA label for teplizumab requires premedication with antihistamines, antipyretics, and antiemetics before each infusion, specifies discontinuation if ALT or AST exceeds five times the upper limit of normal, and contraindicates use in individuals with active serious infections (PMC12066327). The CRS risk with teplizumab is substantially lower than that associated with earlier anti-CD3 antibodies (such as OKT3, which caused severe CRS in virtually all treated patients due to its Fc receptor-engaging properties) and is also lower than that associated with conventional immunosuppressive therapies such as azathioprine, cyclosporine, and prednisone, which were used in early T1D trials and caused serious long-term adverse effects (PMC12066327). The overall safety profile of teplizumab compares favorably with these historical comparators, supporting its use in the presymptomatic Stage 2 population where the risk-benefit calculus is particularly sensitive to safety considerations.

#### Anti-Drug Antibody Formation

Anti-drug antibody (ADA) formation is a pharmacokinetic and immunological concern with teplizumab, particularly in the context of repeat dosing. In the Protégé study, 77% (318/415) of patients treated with teplizumab and 13% (13/98) of those receiving placebo developed anti-drug antibodies (PMC11316332). ADA formation was associated with reduced drug exposure and potentially attenuated efficacy of the second treatment course. In the AbATE trial, the observed phenotypic changes across cell types were associated with favorable responses to treatment specifically in the subgroup of study participants who did not develop anti-drug antibodies after the first course of therapy (PMC11316332). For the single-course regimen approved for Stage 2 T1D, ADA formation after the first course may be less clinically relevant, but it could become important if repeat dosing is considered in the future.

#### Epstein-Barr Virus

New Epstein-Barr virus (EBV) infection emerged in teplizumab-treated patients in clinical trials, while overall infection rates were comparable between teplizumab-treated and control patients (PMC11316332). The clinical significance of this finding — in terms of risk of EBV-associated lymphoproliferative disease or other EBV-related complications — has not been fully characterized in the available literature, and long-term monitoring for EBV-related adverse events is warranted in teplizumab-treated individuals.

#### Hypersensitivity Reactions

Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and peripheral edema have been observed in teplizumab-treated patients (PMC11316332). These reactions are uncommon but potentially serious, and they underscore the importance of administering teplizumab in a clinical setting with appropriate monitoring and resuscitation capabilities. The frequency of these reactions in the Stage 2 population has not been separately reported from the Stage 3 data, and the overall incidence appears to be low based on the available trial data.

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### Unresolved Controversies and Disagreements

#### The Precise Median Delay: 24 Months Versus 32.5 Months

A notable source of apparent inconsistency in the reviewed literature concerns the precise figure cited for the median delay in Stage 3 onset attributable to teplizumab. The primary TN10 analysis (median follow-up 51 months) reported median times to diagnosis of 48.4 months (teplizumab) versus 24.4 months (placebo), yielding a difference of approximately 24 months (PMC12066327). An updated 2021 analysis of the TN10 trial revealed that the median delay in Stage 3 onset had extended to 32.5 months, representing the more mature dataset (PMC11311856). Some secondary sources in the reviewed literature cite "approximately 24 months" as the median delay, while others cite "approximately 3 years" or "32.5 months" (PMC11311856). This discrepancy is not a contradiction but rather reflects the maturation of the trial data over time: as more participants progressed to Stage 3 T1D during extended follow-up, the Kaplan-Meier estimates of median time to diagnosis became more stable and shifted upward for both groups. The extension analysis figure of approximately 32.5 months is the more mature and reliable estimate, but both figures are defensible depending on which analytical time point is referenced.

One secondary source (PMC7765619) describes the teplizumab effect as "a ~three year median delay in the progression to T1D onset when compared to a placebo," which is consistent with the extension analysis figure of approximately 32.5 months but slightly overstates the primary analysis figure of approximately 24 months. This imprecision in secondary reporting underscores the importance of returning to the primary trial data for quantitative claims.

#### Efficacy in Non-Responders and Predictors of Response

A significant unresolved controversy in the teplizumab literature concerns the identification of clinical and immunological predictors of treatment response. In Stage 3 trials, a substantial proportion of teplizumab-treated patients are "non-responders" who show no meaningful preservation of C-peptide relative to placebo (PMC11316332). In the AbATE trial, clinical responders showed a significant reduction in circulating CD4+ effector memory T cells and an increase in CD8+ central memory T cells, while non-responders did not show these immunological changes (PMC11316332). Drug-treated responders also showed significantly lower HbA1c levels and reduced insulin use compared to non-responders during the first 2 years of follow-up (PMC11316332). However, no prospectively validated biomarker has been identified that can reliably predict response before treatment initiation, which is a major limitation for patient selection and clinical decision-making (PMC6189286, PMC11316332).

Trials reveal teplizumab's positive outcomes, justifying its use especially in individuals with specific HLA genotypes and serological markers (PMC11316332), but prospective validation of these subgroup findings is needed. The 2018 Novo Nordisk review explicitly noted that "we are not aware of studies that managed to identify solid response biomarkers that would support use as an inclusion criterion for further studies" (PMC6189286), and this gap remains unresolved in the current literature. The identification of predictive biomarkers — whether immunological (T-cell exhaustion markers, Treg frequency), genetic (HLA genotype, non-HLA risk loci), or metabolic (C-peptide level, OGTT parameters) — is a critical priority for optimizing the clinical use of teplizumab and for designing future combination trials.

#### The Role of Age and Disease Heterogeneity

The age-dependent efficacy of teplizumab — more pronounced in younger patients in Stage 3 trials — raises important questions about whether the TN10 Stage 2 findings are generalizable across the full age range of Stage 2 individuals. In the randomized placebo-controlled trial of 58 Stage 3 participants, teplizumab-treated younger participants (age <15 years) had C-peptide responses 31.7% higher than placebo (p=0.02), whereas teplizumab-treated older participants (age ≥15 years) showed no significant difference (p=0.56) (PMC11316332). This age-dependent effect is consistent with the T1D endotype framework, in which younger patients have more aggressive, CD8-dominated autoimmunity and potentially more residual beta-cell mass at the time of intervention (PMC9314738). In the TN10 Stage 2 trial, 72% of participants were 18 years of age or younger, so the trial population was predominantly pediatric and adolescent, and the generalizability of the findings to adults with Stage 2 T1D is uncertain (PMC12066327).

The broader issue of T1D disease heterogeneity — encompassing differences in HLA genotype, autoantibody profile, age of onset, rate of progression, and immune cell composition — is a fundamental challenge for interpreting teplizumab trial results and for designing future trials (PMC9314738, PMC6189286). The precision medicine framework for T1D, which advocates stratifying patients by disease endotype to optimize treatment selection, has not yet been systematically applied to teplizumab trials, and it remains unknown whether specific endotypes are more or less likely to benefit from teplizumab (PMC9314738). Most immunotherapy trials in T1D, including TN10, have been conducted predominantly in populations of European ancestry; the precision medicine literature has explicitly noted that genetic risk scores and some therapies perform differently across patient populations, and that disease was accelerated by abatacept in patients of color, underscoring the importance of diverse enrollment and endotype-stratified analyses for all immunotherapies in T1D (PMC9314738).

#### Failure of Phase 3 Trials in Stage 3 T1D

The failure of the Protégé and Encore phase 3 trials in Stage 3 T1D — despite promising phase 2 data — represents a significant unresolved controversy in the teplizumab literature. As one review noted, teplizumab "infamously failed in phase 3 trials in Stage 3 T1D," with only the highest dose in subjects randomized within 6 weeks of diagnosis showing transient C-peptide preservation (PMC6189286). The 2018 Novo Nordisk review noted that "the somewhat contested composite endpoint of insulin usage and HbA1c illustrates the issue raised above on attaining clinically relevant value, namely that an attractive and commercially viable product needs to offer more than C-peptide preservation" (PMC6189286). This controversy highlights the broader challenge of defining clinically meaningful endpoints for immunotherapy trials in T1D: C-peptide preservation is biologically meaningful but may not translate to detectable improvements in HbA1c or insulin use when residual beta-cell function is already severely depleted at Stage 3 onset. The Stage 2 indication sidesteps this problem by using time to Stage 3 diagnosis as the primary endpoint — a hard clinical outcome that is unambiguous and clinically meaningful.

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### Limitations of the Evidence Base

The TN10 trial, while pivotal and statistically significant, enrolled only 76 participants — a relatively small sample size that limits the precision of the median delay estimates and the power to detect subgroup effects (PMC12066327). The 95% confidence interval for the hazard ratio (0.22–0.78) is wide, reflecting the limited sample size and the relatively small number of events in the teplizumab group during the primary analysis period (PMC12066327). Larger confirmatory trials would be needed to narrow these confidence intervals and to provide more precise estimates of the treatment effect in specific subgroups.

The TN10 trial enrolled exclusively relatives of individuals with T1D who had two or more islet autoantibodies and dysglycemia, which is a highly selected population. As noted in the broader screening literature, most programs targeting relatives of T1D patients contradict the epidemiological reality that the majority of future T1D cases arise in individuals without a family history of the disease (PMC11576206). The efficacy of teplizumab in sporadic T1D cases — who may have different genetic backgrounds, autoantibody profiles, and rates of progression — has not been established, limiting the generalizability of the TN10 findings to the broader at-risk population.

The TN10 trial did not include children younger than 8 years of age, leaving a significant gap in the pediatric evidence base for teplizumab (PMC12066327). This is particularly important because T1D incidence is rising most rapidly in young children, and the disease in this age group is characterized by more aggressive autoimmunity and faster progression (PMC9314738). Ongoing trials are evaluating teplizumab in younger children, but results are not yet available (PMC11576206).

The follow-up duration of the TN10 trial, while extended in subsequent analyses, is still insufficient to determine whether teplizumab permanently prevents Stage 3 T1D in any participants or merely delays it (PMC12066327). The observation that 50% of teplizumab-treated participants remained diabetes-free at approximately 2.5 years of follow-up is encouraging, but the long-term trajectory of these individuals — whether they will eventually progress to Stage 3 T1D, remain in Stage 2 indefinitely, or revert to Stage 1 — is unknown. The lifetime risk of Stage 3 T1D in Stage 2 individuals approaches 100%, and it is possible that teplizumab delays but does not prevent clinical onset in most treated individuals.

The optimal dosing regimen, treatment duration, and timing of teplizumab administration in Stage 2 T1D have not been fully established (PMC12066327). The approved regimen (single 14-day course) was derived from Stage 3 trial experience and may not be optimal for Stage 2 disease. Whether repeat courses of teplizumab would provide additional benefit — and whether the anti-drug antibody formation observed in Stage 3 trials would attenuate the efficacy of repeat courses in Stage 2 — are open questions that require prospective investigation.

The long-term safety profile of teplizumab in Stage 2 individuals — who are treated before the onset of clinical disease and may be followed for decades — has not been fully characterized (PMC12066327). The risks of prolonged lymphopenia, EBV-related adverse events, and other immune-related complications over a lifetime of follow-up are unknown, and the benefit-risk calculus for treating presymptomatic individuals requires careful ongoing assessment.

The narrative review methodology employed by most of the secondary sources in the reviewed literature is subject to selection bias and does not provide quantitative pooling of results across trials (PMC11316332, PMC11311856). The meta-analysis of 8 RCTs (n=866) cited in PMC11576206 provides the most rigorous quantitative synthesis of teplizumab's effects on C-peptide in Stage 3 T1D, but a comparable meta-analysis specifically addressing the Stage 2 indication is not available in the reviewed literature, given that TN10 is currently the only completed randomized trial in Stage 2 T1D.

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### Special Populations

#### Pediatric and Adolescent Patients

The TN10 trial enrolled a predominantly pediatric and adolescent population (72% aged ≤18 years), making it the most relevant evidence base for this age group (PMC12066327). The efficacy findings — median time to Stage 3 diagnosis of 48.4 months (teplizumab) versus 24.4 months (placebo) in the primary analysis — are therefore most directly applicable to children and adolescents with Stage 2 T1D (PMC12066327, PMC11316332). The safety profile in this age group appears consistent with that observed in adults, with lymphopenia, rash, and leukopenia being the most common adverse events (PMC12066327).

However, as noted above, children younger than 8 years of age were excluded from the TN10 trial, and the safety and efficacy of teplizumab in this youngest age group — who may have the most aggressive autoimmunity and the most to gain from early intervention — remain unknown (PMC12066327). Ongoing trials will be critical for extending the evidence base to this population (PMC11576206). Additionally, the age-dependent efficacy observed in Stage 3 trials (more pronounced benefit in patients <15 years) suggests that younger Stage 2 patients may derive greater benefit from teplizumab than older patients, though this hypothesis has not been formally tested in the Stage 2 setting.

A parent-survey study (n=95) assessing awareness and attitudes toward teplizumab among parents of children with T1D who also had at least one other child without the condition found that only 6.3% of participants had a detailed understanding of teplizumab, yet 52.6% were willing to approve its use if their child met the eligibility criteria (PMC12066327). When asked about the benefits of teplizumab for delaying disease progression, 62.1% reported reduced stress for families, 40% noted prevention of DKA, and 27.4% reported increased readiness to manage diabetes (PMC12066327). Emotional responses were mixed, with 53.7% of parents expressing hope about the treatment and 52.6% expressing concern about potential negative emotional impacts during its administration (PMC12066327). These findings highlight the importance of patient and family education in the context of teplizumab deployment for Stage 2 T1D.

#### Adults with Stage 2 T1D

The TN10 trial enrolled participants aged 8 years and older, and the adult subgroup (28% of participants, aged >18 years) was too small to permit reliable subgroup analyses of efficacy by age (PMC12066327). The generalizability of the TN10 findings to adults with Stage 2 T1D is therefore uncertain. In Stage 3 trials, teplizumab showed no significant benefit in older participants (age ≥15 years) in one trial (PMC11316332), though other Stage 3 trials did not report consistent age-dependent effects. The FDA approval of teplizumab for Stage 2 T1D covers adults and adolescents aged 8 years and older, but the evidence base is substantially stronger for the pediatric and adolescent subgroup that comprised the majority of TN10 participants.

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### Conclusions and Future Directions

#### What the Evidence Supports

The evidence from the TN10 trial and its follow-up analyses provides robust, statistically significant support for the conclusion that a single 14-day course of intravenous teplizumab delays the onset of Stage 3 T1D in non-diabetic individuals with Stage 2 disease by a median of approximately 24 months in the primary analysis (median follow-up 51 months; median time to diagnosis 48.4 months teplizumab vs. 24.4 months placebo; HR 0.41, 95% CI 0.22–0.78, P=0.006) and approximately 32.5 months in the more mature follow-up analysis (PMC12066327, PMC11316332, PMC11311856). The extension analysis figure of approximately 32.5 months represents the more mature and reliable estimate of the median delay. The evidence also supports the conclusion that teplizumab reduces the instantaneous risk of Stage 3 onset by approximately 59% at any given time point (HR 0.41), reduces the first-year diagnosis rate from 44% to 7%, and results in 50% of treated participants remaining diabetes-free at a median follow-up of approximately 2.5 years (PMC12066327, PMC11576206).

The evidence supports the mechanistic conclusion that teplizumab's durable effects are mediated by the induction of a partially exhausted CD8+ T-cell phenotype with reduced IFN-γ and TNF-α secretion, and by the preservation of regulatory T cells, collectively shifting the balance of the autoreactive immune response toward tolerance (PMC11316332, PMC11576206, PMC12066327). The evidence also supports the conclusion that teplizumab's safety profile in Stage 2 T1D is manageable, with the most common adverse events (lymphopenia, rash, leukopenia, headache) being generally transient and reversible, and with CRS occurring in 5% of treated participants (PMC12066327).

#### What the Evidence Does NOT Support

The evidence does not support the conclusion that teplizumab permanently prevents Stage 3 T1D in any treated individuals. The observation that 50% of teplizumab-treated participants remained diabetes-free at approximately 2.5 years of follow-up is encouraging, but the long-term trajectory of these individuals is unknown, and the lifetime risk of Stage 3 T1D in Stage 2 individuals approaches 100% (PMC12066327). The evidence does not support the use of teplizumab in children younger than 8 years of age, or in individuals with Stage 1 T1D (two or more autoantibodies with normoglycemia), as these populations were not enrolled in the TN10 trial (PMC12066327). The evidence does not support the use of repeat courses of teplizumab in Stage 2 T1D, as this regimen has not been evaluated in this population, and anti-drug antibody formation may attenuate the efficacy of subsequent courses (PMC11316332). The evidence does not support the identification of any prospectively validated biomarker that can predict teplizumab response before treatment initiation (PMC6189286, PMC11316332).

#### Future Research Priorities

First, prospective validation of predictive biomarkers for teplizumab response in Stage 2 T1D is urgently needed. Candidate biomarkers include HLA genotype (particularly DR3/DR4 heterozygosity), autoantibody profile (number, type, and titer), baseline C-peptide level, OGTT parameters, and immunological markers (Treg frequency, CD8+ T-cell exhaustion markers, PD-1 expression on islet-specific T cells) (PMC11316332, PMC10146255, PMC6189286). Prospective biomarker studies embedded within ongoing teplizumab trials would be the most efficient approach to this question.

Second, the evaluation of teplizumab in children younger than 8 years of age is a critical priority, given that this age group has the most aggressive autoimmunity and the most to gain from early intervention (PMC12066327, PMC11576206). Ongoing trials will provide initial safety and pharmacokinetic data, but efficacy data will require a larger randomized trial.

Third, combination therapy strategies that pair teplizumab with complementary mechanisms — such as beta-cell stress reduction (GLP-1 receptor agonists, verapamil), JAK inhibition (baricitinib), or antigen-specific tolerance induction — deserve systematic evaluation in Stage 2 T1D (PMC9314738, PMC7765619, PMC11576206). The rationale for combination approaches is compelling: teplizumab addresses the T-cell arm of autoimmunity, while beta-cell-directed therapies could reduce the immunogenic stress signals that perpetuate the autoimmune response, and antigen-specific approaches could reinforce tolerance to specific beta-cell autoantigens. An early-phase 1 crossover trial (NCT06338553) is already evaluating a single GLP-1 receptor agonist dose in combination with teplizumab in Stage 2 T1D (PMC11576206).

Fourth, the evaluation of repeat courses of teplizumab in Stage 2 T1D — potentially timed to coincide with evidence of immunological waning (e.g., rising autoantibody titers, deteriorating OGTT parameters) — is a logical next step that could extend the duration of the delay beyond what a single course achieves (PMC11316332). The anti-drug antibody concern would need to be addressed, potentially through modified dosing regimens or immunological monitoring.

Fifth, population-based screening programs that identify Stage 2 individuals in the general population (not just relatives of T1D patients) are essential for realizing the public health potential of teplizumab (PMC12066327, PMC11576206). Studies show that DKA rates drop to less than 5% in screened populations compared to 15–80% in unscreened individuals, and early identification of Stage 2 disease opens the door to teplizumab treatment before the window of opportunity closes (PMC12066327). The integration of teplizumab therapy with population-based screening programs — analogous to newborn screening for metabolic disorders — represents a transformative public health opportunity that has not yet been systematically studied.

Sixth, long-term safety surveillance of teplizumab-treated Stage 2 individuals is essential, given that these individuals are treated before the onset of clinical disease and may be followed for decades (PMC12066327). Particular attention should be paid to the long-term risks of EBV-related adverse events, lymphoproliferative disease, and other immune-related complications that may emerge only after extended follow-up.

Seventh, the application of the T1D endotype framework — stratifying patients by age of onset, HLA genotype, autoantibody profile, and immune cell composition — to teplizumab trials could identify subpopulations with differential benefit and guide precision medicine approaches to Stage 2 T1D treatment (PMC9314738, PMC6189286). Disease was accelerated by abatacept in patients of color in T1D trials, underscoring the importance of endotype-stratified analyses and diverse enrollment for immunotherapies in T1D (PMC9314738).

In summary, the TN10 trial and its follow-up analyses establish with high confidence that a single 14-day course of teplizumab delays the median time to Stage 3 T1D onset by approximately 24–32.5 months in non-diabetic individuals with Stage 2 disease, with the more mature follow-up figure of approximately 32.5 months representing the updated estimate. This delay — achieved with a manageable safety profile and a durable immunological mechanism — represents a landmark advance in the prevention of T1D and establishes the proof of concept that presymptomatic immunomodulation can meaningfully alter the natural history of this devastating autoimmune disease. The challenge for the field now is to extend this benefit to broader populations, to identify who benefits most, and to develop combination strategies that can convert a delay into a durable prevention.

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*This review synthesizes evidence from the following primary sources: PMC12066327, PMC11316332, PMC11576206, PMC11311856, PMC9314738, PMC7765619, PMC6189286, PMC6801436, PMC10146255, PMC11989447.*

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