Precision administration of anti-thymocyte globulin with or without verapamil in adolescents and young adults with type 1 diabetes

University Of Florida, Gainesville FL

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Insulin is a replacement, not a curative, therapy in the management of type 1 diabetes (T1D) which is caused by loss of immune tolerance and destruction of pancreatic beta cells. More recently, beta cell stress has also been found to contribute to T1D pathogenesis. Despite this knowledge, no disease-modifying therapies (DMTs) have been approved for the treatment of symptomatic T1D. A T cell specific immune therapy, anti- thymocyte globulin (ATG), in low doses, has been shown to lower HbA1c and preserve endogenous insulin production (measured by C-peptide) in individuals with recently diagnosed T1D. However, not all individuals who received ATG responded to the therapy. A portion who received drug had a similar decline in C-peptide as the placebo-treated individuals. Another monotherapy in T1D shown to preserve C-peptide, Verapamil, is a calcium channel blocker and is proposed to reduce beta cell stress. To advance our long-term goal, to directly inform the development and translation of DMTs in those with T1D in a precision-directed manner, this proposal seeks to address three gaps in the field: (1) identification of who is most likely to “respond” to ATG prior to drug administration, (2) use of sequential therapies to increase efficacy using both immunomodulatory and beta cell protective therapies, and (3) clinical trial design to assess efficacy earlier than the standard endpoint at 1 year allowing for shorter trials. This proposal includes a randomized, placebo-controlled, and blinded trial. Using a predictive biomarker of response to ATG we developed, participants with T1D will be stratified as “responders” and “non- responders.” This study will be powered to detect a difference at the standard 12-month time point and a novel 6-month endpoint to allow for validation of both an adaptive trial design and responder signature. Such a signature was developed by our group using data from a large ATG in T1D clinical trial. To address the beta cell-specific disease mechanism, at 1-year participants will be re-randomized to take verapamil or not for an additional year. To understand the driving mechanisms of each therapy and their potential synergy, we will perform in depth immunophenotyping and quantify biomarkers of beta cell stress and abnormal prohormone processing, as verapamil has been shown by us and others to not only affect beta cell stress but also T cell subsets. Our central hypothesis is that population enrichment via our novel ATG responder prediction tool will dramatically enhance C-peptide preservation following ATG which will be prolonged with verapamil via immune-specific mechanisms. Completion of these aims will prospectively validate the utility of responder immune profiling, alternative trial designs, and synergies emanating from the use of unique and potentially complimentary therapies in T1D. Ultimately, these efforts seek to accelerate approval of repurposed disease-modifying precision-directed therapies for T1D.