Antidiabetic — P32/98
According to the WHO, the number of diabetes sufferers will double from around 150 million in 2000 to 300 million in 2005. Two major forms of the condition exist. Those with Type I, also known as insulin-dependent diabetes or juvenile-onset diabetes, are unable to produce their own insulin in the pancreas. Patients with Type II diabetes — adult-onset or non-insulin dependent diabetes — however, generally do produce enough insulin, but their bodies are incapable of using it effectively.
Numerous different forms of drug therapy are available for the treatment of Type II diabetes, including, sulphonylureas, biguanides, and a range of insulin sensitisers like the glitazone drugs. A further compound under development is P32/98, initially developed by German company Probiodrug, and licensed to Merck & Co. It works by a novel mechanism, as it is an inhibitor of the regulatory enzyme dipeptidyl peptidase. This enzyme is part of the signal transduction processes implicated in the immune responses that are the initial cause of Type II diabetes. As the enzyme inactivates glucose-dependent insulinotropic polypeptide and the truncated form of glucagon-like peptide 1, which are both involved in the secretion of insulin in response to food consumption, the theory is that if the activity of this enzyme could be reduced, it would result in better glucose tolerance. P32/98 is a highly specific transition state analogue inhibitor of the enzyme, which is both competitive and reversible.
The drug's safety and tolerability were shown by a randomised double blind placebo-controlled trial in 36 healthy male volunteers, who were given two single ascending doses of between 7.5 and 240mg before a standard oral glucose tolerance test. The highest dose gave a glucose tolerance improvement of more than 50%, as well as drug dependent reductions in the activity of the enzyme within the plasma 1.
It has also been tested in 24 patients suffering from Type II diabetes. After a wash-out procedure to remove the effects of previous medication, one 60mg tablet was given, and an oral glucose tolerance test taken 15 minutes afterwards. The scale of improvement depended on the previous drug regime the patient was following, with the biggest changes being seen in patients treated with a controlled diet, acarbose or glibenclamide2. The drug is now in Phase II trials, and could ultimately be another step forward in the treatment of this growing therapeutic problem.