This site complies with the HONcode standard for trustworthy health information:
verify here.

Rewarding for
you and us
Defeat Diabetes Foundation

Defeat Diabetes
Foundation
150 153rd Ave,
Suite 300
Madeira Beach, FL 33708

EASD: New Drug Classes Entering Type 2 Pipeline

Posted: Sunday, October 03, 2010

Farnesoid X receptor agonists, 11-â-HSD1 inhibitors, and glucokinase activators are some of the new approaches to treating Type 2 diabetes described in research presented, but some senior researchers expressed doubts about the clinical need for them.

Early-stage clinical data was reported for a new drug in the diabetes pipeline called INCB13738. Reid Huber, PhD, of Incyte Corp., said that A1c levels dropped about 0.5% after 12 weeks of treatment with an 11-â-HSD1 inhibitor called INCB13739 in a placebo-controlled, 159-patient phase II trial. Insulin resistance, as measured by the HOMA-IR scale, was reduced by a full point at the highest dosage of the drug, whereas it increased 0.25 points in the placebo group. Blood lipid levels -- particularly low-density lipoprotein cholesterol -- also declined by a clinically significant degree, Huber said.

The 11-â-HSD1 target is an enzyme that catalyzes the conversion of cortisone to cortisol in vivo. Huber explained that that attracted drug-development interest in Type 2 diabetes because of evidence that it is up-regulated in obese patients and those with insulin resistance.

Also, Cushing syndrome, which results from defective cortisol metabolism, shares features with Type 2 diabetes including insulin insensitivity, obesity, and hypertension.

INT-747: David Shapiro, MD, of Intercept Pharmaceuticals, said an agent that activates farnesoid X receptors showed promising signs of activity in patients with Type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) in a brief, placebo-controlled pilot study.

Farnesoid X intracellular receptors regulate lipid metabolism and also appear to control insulin sensitivity and body fat mass, Shapiro said.

The company's drug, INT-747, is an analogue of the receptors' natural ligand, chenodeoxycholic acid.

Two doses were tested against placebo in 64 patients in a six-week, double-blind trial. Duration was too short to use HbA1c as an endpoint, so Shapiro and colleagues instead measured glucose disposal rates under euglycemic clamp conditions.

Both with low- and high-dose insulin, glucose disposal rates increased from baseline to the end of treatment, whereas they declined in patients receiving placebo.

Patients taking a 25-mg daily dose of INT-747 had a mean 1% loss of body weight, while a 50-mg dose was associated with a 2% loss, Shapiro reported. No change was seen in the placebo group (not significant).

Data on two glucokinase activators were presented as well.

Glucokinase is a glucose-sensing enzyme that is critical in the homeostatic system by which insulin secretion is matched to blood glucose levels. Activating this pathway is expected to lead to increased insulin secretion whenever blood glucose is elevated, such as after meals.

Agents developed by Merck and Array BioPharma were described in separate poster presentations.

Elizabeth Migoya, PharmD, of Merck, reported that a glucokinase activator called MK-0599 reduced plasma glucose levels relative to placebo in healthy, nondiabetic volunteers.

Similar phase I results were also reported for the Array product, ARRY-403, except that its study involved patients with Type 2 diabetes.

James Trevillyan, PhD, said that daytime glucose concentrations, both postprandial and at other times, were reduced following administration of the drug after acute dosing. Fasting plasma glucose levels were reduced as well, compared with placebo.

Insulin and C-peptide levels were increased "consistent with the mechanism of action," Trevillyan reported.

Source: http://www.diabetesincontrol.com/index.php?option=com_content&view=article&id=9869&catid=53&Itemid=8, Huber R, et al "Efficacy and safety of the 11-beta-HSD1 inhibitor, INCB13739, added to metformin therapy in patients with Type 2 diabetes" Diabetologia 2009; 52: S77. Mudaliar S, et al "Farnesoid-X receptor agonists -- a new therapeutic class for diabetes and NAFLD -- First clinical data" Diabetologia 2009; 52: S78.