842-P: A Novel Drug to Modulate Autoinflammation and Promote Glucose Control in Type 1 Diabetes Mellitus

NOD mice are the accepted model for Type 1 Diabetes Mellitus (T1DM) Canine Diabetes (CD) demonstrates clinical outcomes identical to NOD and human T1DM. We described helper T cells that express the CD40 receptor, termed Th40 cells. In human T1DM Th40 cells expand significantly in number in peripheral blood prior to hyperglycemia; and respond to human islets. In NOD mice, Th40 cells increase first in the pancreatic lymph nodes, expand in number in the periphery prior to hyperglycemia, are the prominent T cell type detected in the pancreas during insulitis, and transfer diabetes to SCID recipients. Naturally occurring CD is insulin requiring and demonstrates the same clinical parameters as human disease. In a clinical pilot study using diabetic dogs we discovered significantly elevated Th40 cell numbers in PBMC compared to non-diabetic dogs (p < 0.0001) . Th40 cell numbers may help predict risk of development of T1DM as a subset of “at-risk” pre-T1DM human subjects who developed T1DM showed elevated Th40 numbers. Using a novel approach to target CD40-mediated inflammation we created a series of small peptides. The lead candidate, OPT101, has an approved IND and completed Phase 1a human clinical trials establishing human safety profiles. OPT501, a canine version caused a rapid reduction in Th40 cell numbers in diabetic dogs. Daily insulin requirements were reduced on average by 75% and in 2 cases by 90%. Fructosamine, the canine equivalent of HbA1c, was reduced 40.2% on average with 3 subjects achieving normal range. All participants had significantly reduced daily blood glucose averages, and 3 subjects maintained normal glucose levels and time-in-range (TIR) increased to greater than 50%, and in some cases greater than 90%, from a previous TIR of 10%. All participants demonstrated increased c-peptide levels, a measure of restored beta cell function, after 6 weeks of treatment. Equivalent clinical outcomes have not been reported for any other drug candidate in veterinary or human T1DM trials.