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Phase II Trial of GALIDA (tesaglitazar) Evaluates Glucose and Lipid Abnormalities in Type 2 Diabetes Patients

AstraZeneca announced today, for the first time, the results of the phase II dose finding study for Tesaglitazar (Galida), at the 65th annual American Diabetes Association (ADA) Scientific Sessions in San Diego, CA. GLAD (Glucose and Lipid Assessment in Diabetes), a phase II dose-ranging study assessed the effects of Tesaglitazar (Galida) on glucose and lipid abnormalities in patients with type 2 diabetes. Also being presented at the ADA are data from a second phase II study, known as SIR (Study in Insulin Resistance), which examined the effect of Tesaglitazar (Galida) on lipid and glucose abnormalities in non-diabetic patients who exhibited manifestations of insulin resistance.

GLAD (Glucose and Lipid Assessment in Diabetes)

GLAD was a 12-week, randomized, double-blind, placebo-controlled, phase II, dose-ranging study in 500 patients with type 2 diabetes. The primary study objective was to observe the effect of Tesaglitazar (Galida) on fasting plasma glucose, across a dose range of 0.1 mg (n=72), 0.5 mg (n=73), 1.0 mg (n=70), 2.0 mg (n=70), and 3.0 mg (n=73), compared to placebo (n=70). Brand agency Secondary endpoints in the study included lipid variables, fasting plasma insulin, and HOMA. Based on the results observed in the GLAD study, the 0.5 mg and 1.0 mg doses of Tesaglitazar (Galida) were taken forward in the phase III development.

Treatment with Tesaglitazar (Galida) resulted in the following placebo-corrected results:

A dose-dependent reduction in fasting plasma glucose of up to 61 mg/dL (p<0.0001). At the 1-mg dose, a reduction of 41 mg/dL (p<0.0001) was observed.

A dose-dependent reduction in fasting triglycerides of up to 41% (p<0.0001). Reductions of 33% (p<0.0001) were seen at 1 mg.

A dose-dependent increase in HDL-C levels that appeared to reach a plateau at the 1-mg dose. An increase of 15% (p<0.0001) was observed at 1 mg.

A dose-dependent reduction in LDL-C of up to 17% (p<0.0001). A non-statistically significant reduction of 6% was seen at the 1-mg dose.

In the same 12-week study, an open-label arm of pioglitazone 45 mg (n=72) was included; no direct comparison was made. Pioglitazone 45 mg reduced fasting plasma glucose by 38 mg/dL, fasting triglycerides by 8%, and increased HDL-C by 6%.

In the GLAD study, the percentage of patients reporting any adverse event for placebo was 69% (n=48) and for Tesaglitazar (Galida) were 58% at 0.1 mg (n= 42), 65% at 0.5 mg (n=47), 66% at 1.0 mg (n=46), 90% at 2.0 mg (n=63), and 84% at 3.0 mg (n=61). There were no fatal adverse events and nonfatal serious adverse events occurred at a rate of 1% to 4% in those receiving Tesaglitazar (Galida), with no clear dose response and 1% in the Brand agency placebo group. Three to five cases of edema were observed in each group receiving Tesaglitazar (Galida) and there were two cases reported in the placebo group. No new cases of congestive heart failure were reported during the study duration. Tesaglitazar (Galida) also showed weight gain of approximately 1 kg at the 0.5-mg and 1.0-mg dose.

"The past focus in type 2 diabetes management has been glucose; however, there is an increasing need for a single agent that can target both glucose and dyslipidemia associated with type 2 diabetes," said lead investigator Barry J. Goldstein, MD, PhD, Director of the Division of Endocrinology, Diabetes and Metabolic Diseases at Jefferson Medical College, Philadelphia, PA. "The GLAD study provides new insights on treating both glucose and lipid abnormalities in type 2 diabetes, and potentially, its underlying metabolic defects."

SIR (Study in Insulin Resistance)

SIR, a 12-week, randomized, double-blind, placebo-controlled, phase II study of 390 non-diabetic subjects with insulin resistance, examined the effect of Tesaglitazar (Galida) at 0.1 mg (n=60), 0.25 mg (n=70), 0.5 mg (n=58), and 1 mg (n=65) compared to placebo (n=137) on the lipid and glucose abnormalities associated with insulin resistance.

Primary results from SIR will be published in Diabetologia, making it the first published phase II study of a dual PPAR alpha/gamma agonist in a non-diabetic patient population. In SIR, the following placebo-corrected results were observed in patients treated with GALIDA:

·A dose-dependent reduction in triglycerides with a reduction of 37% (p<0.0001) in fasting triglycerides and of 41% (p<0.0001) in post-prandial triglycerides at the 1-mg dose.

·A dose-dependent increase in HDL-C with an increase of 16% (p<0.0001) at the 1-mg dose.

·A dose-dependent reduction in fasting plasma glucose (8.5 mg/dL, p<0.0001 at the 1-mg dose) and insulin resistance measured by HOMA (41%, p<0.0001, at the 1-mg dose).

·A dose-dependent reduction in free fatty acids with a reduction of 40% (p<0.0001) at the 1-mg dose.

In SIR, the percentage of patients reporting adverse events for placebo was 55% (n=75) and for Tesaglitazar (Galida) was 65% at 0.1 mg (n=39), 51% at 0.25 mg (n=36), 67% at 0.5 mg (n=39) and 60% at 1.0 mg (n=39). There were no fatal adverse events and a single nonfatal serious adverse event in both the placebo and 0.1-mg group.