The actual state of P32/98 drug development

During a presentation at the IBC-conference on Obesity & Non-Insulin Dependent Diabetes Mellitus held at the Royal College of Pathologists, Dr. H.-U. Demuth, CRO of probiodrug Gesellschaft für Arzneimittelforschung GmbH announced the actual state of P32/98 drug development.

Halle (Saale), Germany //
P32/98 is a novel insulin secretagogue being developed by probiodrug for the management of type 2 (insulin independent) diabetes mellitus. The compound is a DPIV-inhibitor and acts through enhancing the stability of the DPIV-processed insulinotropic peptide hormones (incretins: GIP and GLP-1). Because some evidence exists that GLP-1 improves insulin sensitivity, it might also be useful for the management of glucose control in type 1 (insulin dependent) diabetes mellitus.
GMP conform drug substance synthesis has been performed by a FDA-inspected custom manufacturer, kg-amounts are available for preclinical and clinical trials. A galenic formulated drug product has been developed. Stability tests and the production of the clinical trial medication is presently being conducted by a recognized contract drug manufacturer. Blistered pills will be available in summer this year.

Performing oral glucose tolerance tests (OGTT), the glucose-lowering action of P32/98 has been demonstrated in Wistar rats and in lean and obese Zucker rats. The compound is able to normalize blood glucose concentrations post-prandially with a positive effect on fasting glucose levels. No hypoglycemia was observed. Measurements of plasma insulin levels revealed enhancement of first phase insulin liberation. Several studies are under way to learn more about the action of P32/98 during subchronic and chronic application in diabetic animal models (body weight, post-prandial and fasting blood glucose levels, insulin liberation, secretion and metabolism of incretins, fatty acid metabolism, comparison to other oral antidiabetic compounds, etc.). During all animal studies performed so far, neither undesired side effects nor toxicity was observed.

Toxicological studies were designed to match the requirements of a number of planned phase I and phase II clinical trials including a chronic 3 months administration to NIDDM-patients as a proof of concept. Toxicological studies, which are in progress, include acute and repeated i.v. and p.o. applications to different animal species, a package of genotoxic and safety pharmacological studies and experiments on metabolism and ADE. First results show, that the compound is well tolerated, even at highest applicable doses. It is readily absorbed orally. High dose p.o. and i.v. applications combined with quantitative determinations of P32/98 in blood plasma probes revealed a maximal bioavailability of the orally given compound and efficient clearing from blood plasma.

A clinical phase I trial with human volunteers is planned to be conducted in the second half of 1999. probiodrug has a CRO under contract, acting globally (US – headquarter). The clinical phase I study will be performed at its German phase I unit.