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Emerging diabetes drugs in
early development
Barcelona, January 30, 2006:
The complexity of glucose metabolism and the number of cellular processes
affected by diabetes provides ample space for new drug targets and for
first-in-class molecules. Some of them have reached or are close to early
clinical development in type 2 diabetes. Roche pioneered and leads the field of
glucokinase activators with a phase I compound. Karo Bio has a first-in-class
hepatic glucocorticoid receptor antagonist which is in preclinical development.
Bayer is about to enter phase I in the first half of this year with Bay 76-7171
which has an undisclosed novel mechanism of action. Sankyo and Metabasis reached
clinical proof of concept with its first-in-class fructose 1,6-bisphosphatase
inhibitor. Leaders in the arena of glycogen phsophorylase inhibitors are Pfizer
and Sanofi-Aventis with clinical stage projects. Isis is ahead in the field of
protein tyrosine phosphatase 1B inhibitors with its 2nd generation antisense
project. These results were found in a search conducted by La Merie Business
Intelligence. The results were published in the January 30 issue of R&D Pipeline
News, edited by La Merie Business Intelligence.
Glucokinase activators (GKA) enhance glucose-stimulated insulin release from
pancreatic islet cells and glucose disposition by the liver, thus reducing blood
glucose and reducing weight as shown by Innodia’s ID1101 in phase I. The
compound had an excellent safety profile and now serves as an anti-obesity drug
candidate. The stimulation of insulin secretion by GKAs is glucose-dependent
which should make it less likely that GKAs cause hypoglycemia. Inhibition of
glycogenolysis by glycogen phosphorylase inhibitors (GPI) is another strategy to
reduce blood glucose and has attracted the interest of many companies with drug
discovery activities. The opposite approach is to inhibit gluconeogenesis by
antagonizing the activity of fructose 1,6-bisphosphatase. Sankyo’s and Metabasis’
CS-917 was shown to cause a clinically significant reduction in blood glucose.
Protein tyrosine phosphatase 1B (PTP-1B) downregulates the insulin receptor.
Inhibition of PTP-1B should prevent downregulation of the insulin receptor, thus
improving insulin action. Isis showed clinically that its antisense compound
could induce insulin sensitizing activity in healthy volunteers. Results of
12-weeks treatment of diabetes patients with ISIS 113715 are expected this year.
Small molecule PTP-1B inhibitors are in the pipeline, but do not lead the field
after failure of Wyeth’s phase II compound. Further novel approaches include a
beta3 adrenergic agonist in phase II, a phosphodiesterease 11A inhibitor and a
dually acting small molecule in preparation for phase I which increases insulin
secretion and peripheral insulin sensitivity.
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