Date: 2012-10-04
Type of information: Initiation of preclinical development
phase: preclinical
Announcement: results
Company: Zealand Pharma (Denmark)
Product: ZP3022
Action
mechanism: ZP3022 is a novel GLP-1-gastrin dual agonist showing significant improvement of glycemic control and increased beta-cell mass. GLP-1 (glucagon-like peptide-1) is a naturally occurring peptide hormone that is released from the intestinal L-cells within minutes of food ingestion. The main physiological actions of GLP-1 are glucose-dependent stimulation of insulin secretion from pancreatic beta-cells and suppression of glucagon secretion from pancreatic alpha-cell secretion of glucagon. ZP3022 is a GLP-1 receptor agonist.
Disease: diabetes
Therapeutic area: Metabolic diseases
Country:
Trial
details: In a first study, daily doses of ZP3022, liraglutide, or vehicle (passive control) were administered to db/db mice for 2, 4 or 8 weeks. HbA1c and fasting blood glucose levels were determined at start and at end of treatment. Beta-cell mass was determined at end of treatment.
In another study, 84 diabetic Zucker Diabetic Fatty (fa/fa) rats (11 weeks of age) were stratified into seven treatment groups of n=12 with matching HbA1c and blood glucose (BG) levels. 12 lean ZDF (fa/+) rats were used as lean controls. The ZDF (fa/fa) rats were dosed subcutaneously twice daily (BID) for eight weeks with vehicle, ZP3022 (10, 40 nmol/kg), liraglutide (40 nmol/kg), exendin-4 (30 nmol/kg), gastrin17 (80 nmol/kg) or exendin-4 plus gastrin 17 (30 + 80 nmol/kg). Lean rats were dosed with vehicle.
HbA1c was measured at the start and end of treatment and an oral glucose tolerance test was performed after five weeks of treatment. Fed blood glucose was measured every other week and beta-and alpha-cell mass was determined at the end of the study.
Latest
news: * On October 4, 2012, Zealand Pharma has reported that new data from preclinical studies with a novel peptide agonist, ZP3022, from the company’s GLP-1-gastrin dual agonist program, demonstrate a significant increase in pancreatic beta-cell mass associated with a significant improvement in glycemic control. The data were revealed by the company in a poster presentation at the European Association for the Study of Diabetes (EASD) 48th Annual Meeting in Berlin, Germany. The poster presentation is titled: “The Novel GLP-1-Gastrin Dual Agonist ZP3022 Improves Glycemic Control in ZDF Rats” (J. Skarbaliene et al, Zealand Pharma A/S)
Treatment with ZP3022 significantly enhanced beta-cell mass (per BW) and improved glycemic control in diabetic Zucker Diabetic Fatty rats, as evidenced by a significant decrease in HbA1c levels and blood glucose concentrations as well as improvements in glucose tolerance and increased insulin levels after an oral glucose tolerance test. Notably, ZP3022 had a significantly better effect on beta-cell mass and glycemic control than liraglutide at equimolar dose. The anti-diabetic effects of ZP3022 make this compound a promising therapeutic candidate for the treatment of type 2 diabetes.
* Zealand Pharma has presented new preclinical data on ZP3022 at the American Diabetes Association's 72nd Annual Scientific Sessions. In this study, both ZP3022 and liraglutide caused a significant increase in beta-cell mass compared to vehicle following 4 weeks of treatment. However, after 8 weeks of treatment only ZP3022 resulted in a significant increase in beta-cell mass, compared to both vehicle and liraglutide. Both ZP3022 and liraglutide caused a significant improvement in glycemic control as measured by HbA1c.
In this study, treatment of db/db mice with the GLP-1-gastrin dual agonist ZP3022 caused a sustained increase in beta-cell mass accompanied by an improvement in glycemic control. In comparison, liraglutide also caused improved glycemic control, but displayed only a transient effect on beta-cell mass.
In another study, Zucker Diabetic Fatty (ZDF) rats were dosed for 8 weeks with two different doses of ZP3022, liraglutide, exendin-4, h[Leu15]gastrin17, or exendin-4 + h[Leu15]gastrin17. ZP3022 clearly improved glycemic control as did all treatments, except h[Leu15]gastrin17. Notably, ZP3022 caused a significantly greater reduction in HbA1c levels than liraglutide at comparable dose levels.
The highest dose of ZP3022 (p< 0.001), exendin-4 (p< 0.05) and exendin-4 + h[Leu15]gastrin17 (p< 0.001) significantly improved glucose tolerance vs. vehicle after an OGTT. Moreover, the effect of ZP3022 on lowering non-fasting blood glucose levels was present already after 2 weeks of treatment and persisted throughout the study (p< 0.001 vs. vehicle). Other treatments, except h[Leu15]gastrin17, also had a significant blood glucose lowering effect. However, the effect of liraglutide tended to be transient.
Treatment with ZP3022 markedly improved glycemic control in diabetic ZDF rats, indicating that GLP-1-gastrin dual agonists have potential as a novel treatment approach in diabetes.
