MON-562 A New Drug, Opt101, Reduced Inflammatory Biomarkers In Type 1 Diabetes Type 1a And Stimulated C-peptide In 2 Undetectable Subjects

Abstract Disclosure: D.H. Wagner: Op-T, LLC. G. Vaitaitis: Op-T, LLC. D. Waid: Op-T, LLC. R. Brazg: Op-T, LLC. Introduction: The American Diabetes Association has proposed that Type 1 Diabetes (T1D) can be designated as Type 1A, immune-mediated, or Type 1B, idiopathic. We performed a Phase 1b clinical trial in T1D subjects developing a novel drug that targets CD40. CD40 interaction with CD154 constitutes a prominent inflammatory autoimmune axis. Previous work showed Th40 cells, helper T cells that express CD40, are autoimmune effector cells that attack islet beta cells. We hypothesize that elevated Th40 levels (>35% of total T helper cells compared to a level of 22.5% in healthy controls) better define Type 1A and lower Th40 level corresponds to Type 1B. We further hypothesize that regulating CD40-mediated inflammation, specifically in Th40 cells, improves beta cell function. Methods: Rather than a monoclonal antibody, we developed a drug product that is a 15-amino acid peptide (OPT101) that targets CD40 and conducted a Phase 1b clinical trial in 18 diagnosed T1D subjects. T1D duration was from 2 to 19 years (avg.12.8 years, 50% female). In a double-blind study, 12 T1D subjects were randomly assigned to 1.1 mg/kg cohort (n = 6) or 2.8 mg/kg cohort (n = 6) with 3 additional placebo treated subjects (n = 6) in each cohort. Subjects were dosed by IV infusion on days 1, 4, 7, and weekly thereafter for 8 doses. A mixed meal tolerance test (MMTT) with C-peptide determination was performed at screening and within 2 weeks after the final dose. Th40 and other inflammatory biomarkers were measured; adverse events were recorded. Results: OPT101 proved safe and well tolerated. Using Th40 level criteria, 12 subjects identified as Type 1A and 6 as Type 1B. Residual C-peptide was detected in 8 subjects, 4 of whom were Type 1A. Residual C-peptide correlated with lower Th40, TNFα, and IFNγ levels. In the 1.1 mg/kg treatment cohort inflammatory biomarkers Th40 and IFNγ reduced significantly by visit 8 while in the 2.8 mg/kg cohort significant reduction in Th40, IFNγ and TNFα occurred by visit 4. In placebo, there was no change in Th40 or cytokines over the study. In two Type 1A subjects, one in 1.1 mg/kg and the other in 2.8 mg/kg cohort, at screening, C-peptide was at the detection limit (0.1 ng/L) but increased to detectable after final treatment. In Type 1A residual C-peptide subjects, treatment preserved C-peptide in one of the 1.1 mg/kg cohort and increased C-peptide in two of the 2.8 mg/kg cohort. Conclusion: The data support that elevated Th40 levels, IFNγ, and TNFα differentiate Type 1A and 1B diabetes and that regulating CD40 - CD154 interaction protects and possibly restores, beta cell function. An increase in C-peptide in people with T1D at baseline C-peptide (0.1 ng/L, no residual C-peptide) has not been reported previously and was only achieved with OPT101 treatment. Presentation: Monday, July 14, 2025