2131-LB: A New Drug That Targets CD40 Induced Two Long-Term Stage 3 T1DM Subjects from Undetectable C-Peptide to Detectable in a Phase 1b Human Clinical Trial

by sugaradmin



Introduction and Objective: CD40 promotes autoimmune inflammation. Current therapeutic approaches are monoclonal antibodies. We designed a 15-amino acid peptide targeting the CD40 receptor.Methods: We treated autoimmune canine diabetes mellitus (CDM) and human T1DM subjects with the peptide. CDM were treated with 2 mg/kg by IV or subcutaneous injection (Sub-Q) for up to 18 months. A phase 1a, human healthy controls, then phase 1b multiple ascending doses in eighteen diagnosed T1D subjects were conducted. T1D duration was 2 to 19 years (avg.12.8 years). In a double-blind study, 6 T1D subjects were randomly assigned to 1.1 mg/kg cohort or 2.8 mg/kg cohort; in each cohort 3 placebo subjects were included. A mixed meal tolerance test (MMTT) was performed prior to enrollment and after the 8th dose on day 42.Results: In CDM biomarkers of chronic inflammation including Th40 cells, glycated fructosamine, blood glucose, and insulin requirement were significantly reduced. In all dogs examined C-peptide increases were seen. In human T1D subjects OPT101 resulted in dramatic improvements. At baseline in Cohort 1, two subjects had detectable (> 0.1 ng/ml) C-peptide post MMTT and 4 did not; in Cohort 2 and placebo three subjects had detectable C-peptide and three did not. In subjects with detectable C-peptide there was a slight increase after OPT101 treatment. In 1 subject in Cohort1 and 1 in Cohort 2 with undetectable C-peptide OPT101 treatment resulted in detectable C-peptide, which has never been reported. In placebos C-peptide remained undetectable at study termination. In drug recipients limited adverse events and no immune suppression were recorded. Biomarkers of chronic inflammation including Th40 cell numbers, production of inflammatory cytokines IFNg and TNFa were reduced in a dose dependent manner when compared to placeboConclusion: The data suggest that regulating CD40 – CD154 interaction is beneficial in T1D, protecting, possibly restoring, islet beta cell functions.

Disclosure

D.H. Wagner: Stock/Shareholder; Op-T, LLC. Advisory Panel; Sanofi. G.M. Vaitaitis: Stock/Shareholder; Op-T-Mune Inc. / Op-T LLC. Consultant; Op-T-Mune Inc. / Op-T LLC. R.L. Brazg: Research Support; Pfizer Inc, Moderna, Inc, Lilly Diabetes, Novo Nordisk, Senseonics, Abbott, Medtronic, OP-T-MUNE, INC.

Funding

NIH (R01DK131196)



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