Type 1 diabetes (T1D) is increasingly being treated as a condition requiring early intervention to slow progression, with numerous agents under investigation. The first disease-modifying drug—the Fc receptor-nonbinding anti-CD3 monoclonal antibody teplizumab—was approved by the Food and Drug Administration (FDA) in 2022. Teplizumab is approved for the delay of the onset of clinical T1D in patients 8 years of age and older with stage 2 T1D, and is administered as a 14-day outpatient course delivered intravenously with dosing based on body surface area.1
The FDA approved teplizumab based on the phase 2 double-blind AT-Risk (TN-10) clinical study of relatives of patients with T1D at high risk for developing clinical disease. In this study, patients received a 14-day course of teplizumab or placebo, with monitoring for progression every 4 months using an oral glucose tolerance test. At 6 years of follow-up, 50% of patients receiving teplizumab were diabetes free vs 22% of those receiving placebo (Figure 1). The most common adverse events were rash and transient lymphopenia.2,3 Treatment with teplizumab delayed progression to stage 3 T1D by 32.5 additional months compared with placebo. The median time to diagnosis with teplizumab was 59.6 months vs 27.1 months with placebo, with certain individuals having even longer delays with teplizumab. Additionally, treatment with teplizumab was associated with reversal of C-peptide decline and improved beta cell function compared with placebo.3
In addition, recent results from the phase 3 PROTECT study, published in the New England Journal of Medicine in late 2023, demonstrated the potential utility of teplizumab in newly diagnosed T1D.4
The PROTECT trial enrolled 328 children and adolescents with stage 3 T1D who had been diagnosed within 6 weeks of randomization and assigned them to receive either teplizumab or placebo for two 12-day courses. The primary endpoint was β-cell preservation as measured by stimulated C-peptide levels at week 78. Key secondary endpoints were insulin doses required to meet glycemic goals, glycated hemoglobin (HbA1c) levels, time in the target glucose range, and clinically important hypoglycemic events.4
Patients treated with teplizumab (217) had significantly higher stimulated C-peptide levels than patients receiving placebo (111) at week 78 (95% confidence interval [CI], 0.09–0.17; P < .001); 94.9% of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of ≥0.2 mmol/mL (95% CI, 89.5–97.6) compared with 79.2% of those receiving placebo (95% CI, 67.7–87.4) (Figure 2). The groups did not differ significantly in the key secondary endpoints. Adverse events occurred primarily during drug or placebo administration and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome (CRS).4
If an individual is confirmed to have stage 2 T1D, and upon appropriate education and shared decision-making about treatment goals with patients and their caregivers, clinicians should consider starting teplizumab to delay progression to stage 3 T1D, or refer eligible patients to specialty care based on the criteria shown below (Table 1).1 Teplizumab is given as a daily infusion over 14 days. Clinicians should obtain a complete blood count and liver enzyme tests prior to the first infusion. Patients should be premedicated with a nonsteroidal anti-inflammatory drug or acetaminophen, an antihistamine, and/or an antiemetic before each dose for at least the first 5 days of the 14-day treatment course.1
Consider temporarily pausing teplizumab if severe CRS develops. It should be discontinued in patients who develop CRS with alanine transaminase (ALT) or aspartate transaminase (AST) levels elevated to more than 5 times the upper limit of normal. Patients also need to be monitored for signs of infection before and after infusions and for lymphopenia.1
Teplizumab is also being investigated in the Phase 4 PETITE-T1D trial in pediatric patients with stage 2 T1D (NCT05757713) and in a Phase 2 extension (NCT04270942) of the AT-Risk (TN-10) trial.
Several other investigational agents are in development. To date, most have been tested in new-onset T1D, some with mixed results; additional studies are ongoing. These studies include additional approaches to modulating or depleting effector T-cells, decreasing B cells and antigen presentation, as well as anti-inflammatory and beta cell protective agents. Some of the key investigational agents are discussed below.
Otelixizumab. Clinical trials investigating this anti CD-3 monoclonal antibody in T1D failed to meet their primary or secondary endpoints.5 Its use is also limited by the dose-dependent reactivation of the Epstein-Barr virus.
Rituximab. This anti-CD20 monoclonal antibody targets B-lymphocytes and is approved for the treatment of several oncologic and autoimmune conditions. In the Diabetes TrialNet Anti-CD20 Study, rituximab infusion at week 0, 1, 2, and 3 after T1D diagnosis delayed beta-cell function decline at 12 and 24 months, reduced HbA1c levels over 12 months, and led to less need for insulin. However, no difference was shown after 30 months with rituximab. Primary adverse events occurred with infusion, with no increased rate of neutropenia or infection.6
Imatinib. This tyrosine kinase inhibitor approved for the treatment of chronic leukemia, was assessed in a phase 1 trial in 67 adult patients with recent onset T1D. Results suggested some benefit on beta-cell function up to 12 months, which faded by 24 months. Infection and infestation and gastrointestinal adverse events were more common in the imatinib group.7
Abatacept. This CTLA4-Ig is approved for use in psoriatic arthritis and other autoimmune conditions. A study in 112 participants (age 6–36 years) with recently diagnosed T1D demonstrated beta-cell preservation in the intervention group at 2 years and an estimated 9.6-month delay in decline of beta-cell function throughout the study. There was no increase in infections or neutropenia.8 Abatacept is also under investigation as a preventive therapy in at-risk children and adults.9
Verapamil. This antihypertensive medication downregulates a thioredoxin-interacting protein (TXNIP), the overexpression of which induces beta-cell apoptosis. A double-blind randomized clinical trial in 88 children and adolescents aged 7 to 17 years with newly diagnosed T1D found greater B cell preservation at 1 year in the verapamil group vs placebo, as well as a slightly lower HbA1c.10 It is also being investigated in adults newly diagnosed with T1D for beta cell preservation.9
Golimumab. This human monoclonal antibody specific for tumor necrosis factor-alpha is approved for the treatment of rheumatoid arthritis, ulcerative colitis, and other autoimmune conditions in pediatric and adult settings. A phase 2 study found higher C-peptide levels and less insulin use in children and young adults with T1D receiving golimumab versus placebo, with 43% of those in the golimumab group achieving a partial remission. There were no significant differences in safety between the two groups other than a slightly higher rate of mild infections with golimumab.11
Antithymocyte globulin (ATG). This antirejection drug depletes T-cells through apoptosis, antibody-dependent cell-mediated cytotoxicity, and complement-dependent cytotoxicity. A clinical trial in 89 people with T1D randomized to ATG alone, ATG with granulocyte-colony stimulating factor (GCSF), or placebo demonstrated significant beta-cell preservation in those treated with ATG alone vs placebo but not in the ATG/GCSF group vs placebo. However, both ATG groups demonstrated HbA1c reductions at 2 years. Immune reactions were higher in the treatment groups but there were no differences in infection, neoplasm, or lymphatic cancers.12 Low-dose ATG is currently being investigated for delaying or preventing T1D in individuals aged 12–35 years with a 50% risk of clinical diagnosis of T1D within 2 years.9
