Teplizumab Has Competition: A Head-to-Head Trial Could Reshape Type 1 Diabetes Prevention

Type 1 diabetes prevention has entered a new phase. Instead of asking whether immune therapy can delay clinical disease, researchers can now ask which approach works best. TrialNet's newly launched ASCEND T1D study is directly comparing low-dose anti-thymocyte globulin (ATG) with teplizumab in people with Stage 2 type 1 diabetes. This head-to-head study could provide important evidence about the next generation of immunotherapy for type 1 diabetes and whether patients may eventually have more than one disease-modifying treatment option.

Table of Contents

• Why the ASCEND T1D Trial Matters
• Teplizumab and Type 1 Diabetes Prevention
• Why Researchers Are Studying ATG
• What Another Disease-Modifying Option Could Mean
• Conclusion
• Frequently Asked Questions

Why the ASCEND T1D Trial Matters

Stage 2 type 1 diabetes is no longer viewed simply as a risk state. People at this stage have multiple diabetes-related autoantibodies and abnormal glucose tolerance but have not yet developed clinical, or Stage 3, disease. Without intervention, however, the risk of eventually progressing to Stage 3 type 1 diabetes is high.

ASCEND T1D is designed to enroll 60 participants ages 4 to 34 with confirmed Stage 2 disease. Rather than comparing an experimental treatment with placebo, all participants will receive an active immune therapy. Forty participants will be randomly assigned to low-dose ATG, while 20 will receive teplizumab.

The treatment schedules are also notably different. Participants assigned to ATG receive two infusions over two to three days. In contrast, those receiving teplizumab undergo 14 daily infusions over two weeks. Researchers will then monitor participants with laboratory testing, including oral glucose tolerance tests, to track disease progression.

Importantly, ASCEND T1D is not designed as a definitive superiority trial between two established prevention treatments. ATG has evidence in newly diagnosed type 1 diabetes, but its ability to delay progression from Stage 2 disease remains under investigation. Instead, TrialNet says early results will help determine whether a larger extension study of ATG is warranted.

More information about the study and eligibility is available from TrialNet's ASCEND T1D study.

Teplizumab Changed the Landscape of Type 1 Diabetes Prevention

Teplizumab, marketed as Tzield, changed expectations for type 1 diabetes prevention when it became the first FDA-approved therapy capable of delaying progression from Stage 2 to Stage 3 disease in eligible patients.

The landmark TrialNet prevention study included 76 people with Stage 2 type 1 diabetes. Participants received either a 14-day course of teplizumab or placebo. According to the FDA's review, the median time to Stage 3 diagnosis was approximately 49.5 months with teplizumab compared with 24.9 months with placebo. The estimated hazard ratio was 0.41.

That finding represented a major shift. Immune therapy for type 1 diabetes was no longer limited to experimental strategies aimed at preserving beta-cell function after diagnosis. Instead, researchers had evidence that modifying the immune response before clinical diagnosis could meaningfully delay disease progression.

However, delaying diabetes is not the same as permanently preventing it. Moreover, one approved therapy may not meet every patient's clinical or practical needs. Therefore, researchers continue to investigate other immune approaches that could potentially preserve beta-cell function or delay progression.

That is where ATG becomes particularly interesting.

Why Researchers Are Putting ATG Against Teplizumab

ATG is not new to medicine or type 1 diabetes research. The therapy affects several immune-cell populations and temporarily reduces immune activity. Researchers hope this immune modulation may help protect insulin-producing beta cells from continued autoimmune destruction.

Previous TrialNet research provides the rationale for testing low-dose ATG earlier in the disease process. In a randomized study involving people with recently diagnosed type 1 diabetes, low-dose ATG slowed the decline in C-peptide, a marker of the body's own insulin production. Participants receiving ATG also had lower HbA1c levels at one year compared with placebo.

Follow-up results remained encouraging. At two years, participants treated with low-dose ATG continued to demonstrate significantly greater stimulated C-peptide levels than those receiving placebo.

Still, an important question remained: Could the treatment work earlier?

ASCEND T1D moves ATG upstream into Stage 2 disease, before clinical diagnosis. This approach reflects a broader change in type 1 diabetes research. Rather than waiting until substantial beta-cell function has been lost, investigators increasingly aim to intervene while patients still produce meaningful amounts of their own insulin.

The trial also gives researchers an active benchmark. Teplizumab has already demonstrated an ability to delay progression. Consequently, comparing ATG with teplizumab may provide clinically useful information about different approaches to altering the autoimmune process.

What Another Disease-Modifying Option Could Mean

More than one effective type 1 diabetes immunotherapy could eventually give clinicians and patients something they have rarely had in this disease: treatment choice.

For example, infusion schedules differ substantially between the therapies used in ASCEND T1D. Participants receiving ATG undergo two infusions over two to three days, whereas teplizumab requires daily infusions for 14 consecutive days.

However, convenience is only one consideration. Safety, durability of response, patient age, immune characteristics, monitoring requirements, accessibility, and long-term effectiveness could all influence future treatment decisions.

The study may also help researchers understand whether different immune pathways can produce similar clinical benefits. Teplizumab is an anti-CD3 monoclonal antibody that modifies T-cell activity. ATG has broader effects across multiple immune-cell populations. Therefore, studying both approaches could provide valuable clues about different ways to interrupt the autoimmune process driving type 1 diabetes.

Just as importantly, ASCEND could help move the field away from a one-treatment model. Future immune-based treatment for type 1 diabetes may involve multiple therapies, repeat treatment courses, combination approaches, or treatments selected according to disease stage and individual immune characteristics.

For clinicians, that possibility makes early identification increasingly relevant. Detecting Stage 1 or Stage 2 disease through autoantibody screening can create opportunities for monitoring, education, clinical trial participation, and, for eligible patients, discussion of approved disease-modifying therapy.

Conclusion

The ASCEND T1D trial represents an important next step in type 1 diabetes prevention research. Teplizumab established that immune therapy can delay progression from Stage 2 to clinical type 1 diabetes. Now researchers are asking whether low-dose ATG can offer another route toward the same goal.

Results will not arrive immediately. TrialNet estimates that enrollment of all 60 participants could take about three years, with participants followed for at least one year and some for three to four years.

Nevertheless, the study signals where the field is heading. The future of immune-based treatment for type 1 diabetes may not revolve around a single drug. Instead, clinicians could eventually have several disease-modifying approaches for preserving beta-cell function and delaying progression to clinical disease.

Frequently Asked Questions

What is the ASCEND T1D study?

ASCEND T1D is a TrialNet clinical study comparing low-dose anti-thymocyte globulin with teplizumab in people ages 4 to 34 with Stage 2 type 1 diabetes. The study plans to enroll 60 participants.

What is Stage 2 type 1 diabetes?

Stage 2 occurs when a person has multiple type 1 diabetes-related autoantibodies along with abnormal glucose regulation but does not yet meet the criteria for clinical Stage 3 diabetes.

Is ATG approved to delay type 1 diabetes?

No. ATG is being investigated for this purpose. Earlier TrialNet research found that low-dose ATG preserved C-peptide and improved HbA1c in people with recently diagnosed type 1 diabetes, providing a rationale for studying the treatment earlier in the disease process.

How is ATG treatment different from teplizumab in ASCEND?

Participants assigned to ATG receive two infusions over two to three days. Those assigned to teplizumab receive 14 daily infusions over two weeks. Researchers will monitor participants to evaluate disease progression and other outcomes.

Could ATG replace teplizumab?

It is too early to know. ASCEND T1D is intended to generate comparative evidence and help determine whether further study of ATG for delaying Stage 2 disease progression is warranted. Teplizumab remains the FDA-approved treatment for delaying progression to Stage 3 type 1 diabetes in eligible patients.

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