Isis Pharmaceuticals, Inc. has reported new results from its phase II study of ISIS-APOCIIIRx as a monotherapy in patients with very high to severely high triglycerides. These new data and an overall summary of the phase II programme for ISIS-APOCIIIRx were presented at the American Heart Association Scientific Sessions in Dallas.
These results were presented by Dr Rosanne Crooke.
In the phase II study, patients with very high to severely high triglyceride levels were treated with ISIS-APOCIIIRx as a monotherapy and achieved statistically significant mean reductions of up to 80 per cent in apolipoprotein C-III (apoC-III) and up to 71 per cent in triglycerides. In addition, patients treated with ISIS-APOCIIIRx achieved statistically significant mean increases of up to 46 per cent in high-density lipoprotein cholesterol (HDL-C). These data are consistent with the interim analysis reported in August of this year. These new data also demonstrated that the favorable changes in lipid parameters were sustained for three months after the last dose.
"Patients with extremely high levels of triglycerides are at significant risk of many serious health conditions, including frequent episodes of pancreatitis, which can be life-threatening and require hospitalization. Although the benefits of lowering triglycerides in these patients are well established, many of these patients are unable to reduce their triglycerides to acceptable levels. ApoC-III is an important regulator of triglycerides in the blood. As such, a drug targeted to reduce ApoC-III should have a profound and positive effect on triglyceride levels," said John Kastelein, MD, Ph.D., professor of medicine, chairman of the department of vascular medicine, Academic Medical Centre, University of Amsterdam.
"ISIS-APOCIIIRx has been shown to be a robust triglyceride-lowering agent in patients with moderately high to severely high triglycerides in multiple phase II settings. Based on the comprehensive phase II data for ISIS-APOCIIIRx, I am very encouraged about the therapeutic potential for ISIS-APOCIIIRx in patients with severely high triglycerides, especially for use in FCS patients who have extremely high triglyceride levels and very limited therapeutic options."
The monotherapy portion of the phase II study of ISIS-APOCIIIRx is a double-blind, randomized, placebo-controlled 13-week study designed to assess the safety and activity of ISIS-APOCIIIRx in patients with very high to severely high triglyceride levels (between 440 and 2,000 mg/dL). In this study, patients received 100 mg, 200 mg or 300 mg dose of ISIS-APOCIIIRx, or placebo via weekly subcutaneous injections for 13 weeks. Patients treated with 300 mg ISIS-APOCIIIRx experienced dose-dependent, robust, prolonged and statistically significant mean reductions in apoC-III, triglycerides and apoC-III-associated VLDL particles of 80, 71 and 88 percent from baseline, respectively. Furthermore, these patients demonstrated a statistically significant mean increase of 46 percent from baseline in HDL-C. In this study ISIS-APOCIIIRx was found to be generally safe and well tolerated.
"We have now demonstrated that ISIS-APOCIIIRx has the ability to lower triglycerides equally well in patients with high to severely high triglycerides as well as in patients with high triglycerides and type 2 diabetes. We have demonstrated that ISIS-APOCIIIRx can work equally well as a single agent and in combination with fibrates to produce significant reductions in apoC-III and triglycerides, and increases in HDL-C. In addition, the observed positive effect of ISIS-APOCIIIRx treatment on lipid parameters, improvements in glucose control and trends toward improvements in insulin sensitivity, suggest that ISIS-APOCIIIRx could have a very attractive therapeutic profile for patients with severely high triglycerides, who often also have diabetes or metabolic syndrome," said Richard Geary, Ph.D., senior vice president of development at Isis.
ISIS-APOCIIIRx is an antisense drug intended to treat patients with severely high triglycerides either as a single agent or in combination with other triglyceride-lowering agents. ISIS-APOCIIIRx targets apoC-III, a protein produced in the liver that plays a central role in the regulation of serum triglycerides. Humans who do not produce apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. In clinical studies, patients with lower levels of apoC-III and triglycerides exhibit lower cardiovascular event rates. Humans with elevated levels of apoC-III have increased dyslipidemia associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In addition, the prevalence of type 2 diabetes is increased in patients with elevated triglycerides.