New therapies are desperately needed to relieve patients with Type 1 diabetes from the neuropathy, nephropathy and retinopathy associated with the current standard of treatment, injected insulin. Transplantation of pancreatic islet ?-cells, in combination with immunosuppressant to avoid immune rejection, is restricted to a subgroup of diabetics and is limited by the shortage in availability of donor islets. Combination treatment using Epidermal Growth Factor Receptor Agonist (EGFRA) and Gastrin (G17) results in an increase in ?-cell mass and reverses hyperglycemia in diabetic mice and rats. Because of short half-life (minutes) of both G17 and EGFRA, these were administered by infusion (rats) or frequent daily injection (mice) and a clinical trial of this treatment combination suffered from limited efficacy. Results from Phase 1 SBIR demonstrated the proof of concept that the experimental diabetes treatment using a combination of EGFRA and G17 can be improved significantly by the use of EGFRA with Protected-graft-copolymer (PGC) excipient (PGC-EGFRA). The PGC protects and stabilizes EGFRA in the blood (10- fold stabilization) in combination with Omeprazole (OPZ), an over the counter proton pump inhibitor for the treatment of stomach hyperacidity. The OPZ in this combination provides sustained elevation (up to 1000 fold over the baseline) of blood G17 level (over 24hr versus few minutes from G17 injection) without the associated hyperacidity of the stomach.
The aims of the Phase 2 SBIR are to 1) produce well characterized PGC formulations, 2) find the maximum tolerable dose (MTD) of the formulations and the most effective dosing regimen for the treatment of STZ-diabetic mice, and 3) find the most effective dosing regimen for each formulation with or without Anti-CD3 for the treatment of NOD mice to achieve a cure rate of higher than 60%, and 4) to evaluate stability and safety of each formulation. At the end of Phase 2, we will have a single treatment regimen which we will use to collect data for an IND filing.
This Phase 2 application will be a full pre-clinical development and optimization of the treatment regimen effective in preserving and enhancing islet ?-cell function in diabetic mice. This treatment will alleviate suffering of people with diabetes and will be a cost saving treatment that will reduce the economic burden to society. The eventual goal is the filing of an IND application with the FDA.
