Another Possible Class of Drugs for Diabetes: the GKAs   (April 8, 2011)

The media recently picked up a press release about a "New Drug to Treat Diabetes." Turns out that the FDA has authorized Zydus Cadila, a drug company in India, to start human studies of a drug they call ZYGK1.

ZYGK1 is in a class of diabetes drugs called "glucokinase activators" (GK activators, or GKAs, for short) that has been undergoing studies for a while, but so far no GKA has been approved for sale anywhere, and I can't identify any that have entered Phase III trials based on searches on ClinicalTrials.gov and at Google. Lots of companies have done early human studies (Phase I and II) of various GKAs. Hoffmann-La Roche has one simply called "GK Activator (2)" that completed several Phase II studies. Lilly had a GK activator they had in-licensed from OSI called LY2599506, but its development was halted due to what is described on ClinicalTrials.gov as "nonclinical safety findings" (whatever that means: I can't locate any details while searching on-line). Lilly has at least on other, LY2608204, that is in Phase I. Amgen has one that they in-licensed from Array Biopharma (ARRY-403) that's done some Phase I studies. And TransTech Pharma is apparently developing a GKA from Novo Nordisk.

GKA drugs activate an enzyme called glucokinase, which is found in the beta cells of the pancreas and also in the liver. GK seems to be responsible for the rate of glucose metabolism. Technically, what it does is to "phosphorylate" glucose (change glucose to glucose-6-phosphate). It is anticipated that these drugs may lower blood glucose levels by two mechanisms: by increasing insulin secretion by the beta cells of the pancreas, and by increasing the uptake of glucose in the liver.

Very little human safety information is available about the GKAs. In one report from a phase I study, among 41 patients with type 2 diabetes, there was one case of moderate symptomatic hypoglycemia. The report states that no patients discontinued participation in the study, no patterns of abnormal lab values nor significant changes in EKGs were observed, and there were no serious  adverse events. The worrisome concern I have about the GKAs is whatever happened to cause discontinuation of the studies of LY2599506: whatever happened, it must be assumed that it could be a "class effect," affecting all the GKA drugs, until further evaluation is done in animals and humans. Maybe that's why none of the GKAs can be identified as planning the big, expensive, Phase III trials? 

But hope springs eternal in the marketing departments of the pharmaceutical industry. Press releases make bold claims: "Glucokinase activators... represent a promising new class of drugs for the treatment of Type 2 diabetes" and "The promise of glucokinase activators to transform diabetes therapy is enormous" and "We ... are excited about the potential of this glucokinase activator. Type 2 diabetes has long been an important focus of research for [us], and the addition of [a GKA] clearly strengthens our diabetes pipeline." 

Caution is in order. Lilly should let us all know what happened with LY2599506; until then, the future success of the entire GKA class of drugs is in doubt.