Objective
1. We seek to determine if fully human anti-thymocyte globulins (hATG) can delay loss of beta cell function on patients with established T1D.
2. We seek to apply a baseline immunologically derived definition of responders and non-responders to the study group to confirm responder/non-responder predictions
Background Rationale
Efforts to delay or prevent loss of beta cell function in T1D have seen increased success over the last decade with now more than 10 therapies showing the capacity to delay beta cell loss in new onset T1D. Amongst those therapies, low dose rabbit anti-thymocyte globulin (rATG) has been shown to me amongst the most potent in terms of absolute beta cell function preserved when compared to placebo. However, the therapy is associated with a side effect called serum sickness that limits is use. The development of a fully human anti-thymocyte globulin (hATG) now provides for the potential to treat patient with an ATG product that does not induce serum sickness and affords the possibility to re-treat patients with good clinical responses. In addition, we have now developed baseline immunologic signatures for patients who appear to be more likely to respond well to rATG as well as those who are less likely to respond well. We seek to apply those baseline definitions to a new study population to confirm the accuracy of those predictions and to move the field closer the goal of developing personalized approaches to beta cell preservation.
Description of Project
Low-dose rabbit anti-thymocyte globulin (rATG) has been shown to preserve beta cell function in three separate studies of patients with new onset and established T1D. However, because it is developed by immunizing rabbits with human thymocytes it causes a side effect known as serum sickness in 2/3 of recipients and limits our ability to give it multiple times. A novel approach to developing ATG has emerged in which a cow has been genetically modified to produce fully human anti-thymocyte globulin (hATG) in response to human antigens. This product, developed by SAB BIO, has been successfully tested in Phase 1 studies with no evidence of serum sickness and immunologic responses that compliment those seen with rATG. As such, a phase 2b study will be initiated in the fall of 2025 to determine the efficacy of hATG in new onset, Stage 3, T1D (SAFEGUARD-hATG). We propose a complimentary trial, PRISE-hATG, using placebo treated subjects from SAFEGUARD to explore the efficacy of hATG in participants with established T1D (more than 100 days). Furthermore, our group has identified baseline immunologic characteristics that appear to predict the likelihood of response to rATG in new onset T1D. In order to inform future efforts towards personalized immunotherapy, we seek to apply this responder/non-responder definition to participants in PRISE-hATG.
Anticipated Outcome
We expect to demonstrate that hATG is safe and effective in delaying the loss of remaining beta cell function in patients with new onset and established T1D. We also expect to demonstrate the safety and efficacy of redosing of hATG. Finally, we hope to confirm our ability to predict responders and non-responders to hATG to inform future applications of personalized immunotherapy for patients with T1D
Relevance to T1D
Patients and families affected by T1D urgently needs better therapies seeking to interdict the disease and preserve beta cell function in order to reduce the burdens of living with T1D. Should low-dose hATG be successful in preserving beta cell function it could provide another option for patients seeking immune therapies and would support efforts to test hATG in Stage 2 T1D allowing for the potential delay/prevention of Stage 3 T1D in patients with early stage disease. In addition, our efforts to better understand baseline immunologic characteristics of patients with T1D will help us to inform personalized approaches to immunotherapy so that we maximize the potential for benefit in patients who should receive ATG and direct us towards the use of alternative therapies in patients who are unlikely to respond to ATG.