Objective
This study will have 2 main objectives. Objective 1 is to test the clinical efficacy of oral DFMO treatment to improve β cell insulin production in persons recently diagnosed with type 1 diabetes (T1D). This will be defined based on measuring insulin levels in blood at multiple timepoints before and after consumption of a Boost meal and comparing values from individuals treated with DFMO compared to values from individuals treated with placebo. Objective 2 will be to confirm the safety and tolerability of this treatment regimen that we observed in people recently diagnosed with T1D in our 3-month safety study, but in a larger number of individuals over a longer 6-month period. Safety screening will include assessments for any side effects experienced, as well as measurements of blood counts, electrolyte profiles, and hearing assessments.
Background Rationale
Type 1 diabetes (T1D) develops through a cascade of steps leading to autoimmune β cell destruction. Immunomodulation has shown some efficacy to attenuate T1D progression, but effects are often variable with limited long-term effectiveness. One significant barrier for T1D prevention is in part related to insufficient consideration of the insulin producing β cell’s role in T1D development. Research has suggested that molecular signaling pathways within the β cell, which may be initially activated to improve survival and function under circumstances of autoimmunity-induced β cell stress, can also ultimately increase β cell death or exacerbate immune cell presence and effects. Thus, an urgent need is the identification of novel therapies targeting β cell health. Combination approaches using treatments targeting β cell health with other therapies targeting other contributors to T1D could yield more effective and consistent responses to T1D interventions. One pathway that impacts β cell health involves the polycationic aliphatic amine (polyamine) biosynthesis pathway, a molecular pathway that regulates a variety of functions in different cell types, including the β cell’s response to the stress of autoimmunity. Difluoromethylornithine (DFMO) is an existing drug that is FDA-approved for other indications and works by inhibiting the polyamine biosynthesis pathway. We performed a safety study to test if different doses of DFMO given by mouth over a 3-month period would be safe and well tolerated by children and adults with recent onset T1D. We found that DFMO was well tolerated at all doses without safety concerns. We also found that study participants on the highest doses of DFMO had healthier β cells, with better insulin production, compared to study participants taking placebo pills. However this safety study only tested small numbers of individuals. To be sure that this treatment truly improves β cell health in people with T1D, we need to test treatment in a larger number of people.
Description of Project
Combination approaches to type 1 diabetes (T1D) therapy and prevention, using different treatments that target multiple pathologies contributing to T1D could ultimately yield more effective and consistent responses to T1D interventions. One pathologic contributor to T1D development is dysfunctional activation of molecular signaling pathways within insulin-producing β cells. We recently completed a Phase 2 safety study in children and adults that were recently diagnosed with T1D testing different doses of Difluoromethylornithine (DFMO) a drug that studies in the lab suggest works to improve health and function of the β cell. This study suggested that all tested doses of DFMO given by mouth over a 3-month period were safe and well tolerated. We also found that the group of study participants on the highest doses of DFMO had healthier β cells, with better insulin production, compared to study participants taking placebo pills. To be sure that this treatment truly improves β cell health in people with T1D, this project will test DFMO treatment in a larger number of individuals that were recently diagnosed with T1D. We propose to test 68 children and adults treated with either DFMO or placebo pills given by mouth every day for 6 months. Participants will be recruited from 6 clinical centers in the Midwest and Rocky Mountain regions. We will measure β cell insulin production over time for a total of 12 months and compare insulin production between people who took DFMO to people taking placebo pills, before, during, and after treatment. We will also continue to carefully monitor safety and for any side effects of DMFO treatment compared to placebo.
Anticipated Outcome
We anticipate that this work will answer the question of whether treatment with oral DFMO safely improves β cell health and insulin production in individuals that were recently diagnosed with T1D. We also anticipate that studies performed as part of this project will provide better insights into the ways that DFMO has its effects on the β cells. Our long-term goal is to use the results from this study as the basis for testing this treatment’s impact to delay T1D onset in individuals who are at high risk, but have not yet developed T1D.
Relevance to T1D
This study is highly relevant to type 1 diabetes because it is testing a therapy with a goal of improving islet β cell health and insulin production in people with type 1 diabetes.