Isis Pharmaceuticals, Inc., a leading company in antisense drug discovery and development, exploiting a novel drug discovery platform, announced the publication of new data in the journal Circulation Research demonstrating that antisense targeting of apolipoprotein C-III (apoC-III) resulted in significant reductions in apoC-III and triglycerides, each an independent risk factor for cardiovascular disease.  

Hypertriglyceridemia is a serious medical condition associated with premature coronary artery disease and an increased risk for pancreatitis.  Isis is developing its antisense apoC-III inhibitor, ISIS-APOCIIIRx, for the treatment of patients with severe hypertriglyceridemia and plans to report top-line data in the middle of this year.

"Patients with high triglycerides and high apoC-III levels are at significant risk of developing cardiovascular disease, metabolic syndrome, diabetes and pancreatitis.  Despite currently available triglyceride-lowering agents, many patients cannot reduce their triglycerides to acceptable levels.  Because apoC-III is a key regulator of triglyceride clearance from the blood and itself is an independent risk factor for cardiovascular disease, lowering both apoC-III and triglycerides could provide significant therapeutic benefit," said Richard Geary, senior vice president of development at Isis.  "In this paper, we report consistent activity of antisense inhibition of apoC-III to lower both apoC-III and triglycerides in multiple rodent models of dyslipidemia, in non-human primates and in man.  These data support the potential therapeutic benefit a selective apoC-III inhibitor could offer patients with hypertriglyceridemia and elevated apoC-III.   Following the completion of the Phase 2 study, we plan to move rapidly into a Phase 3 study in the most severe patients with triglyceride levels greater than 880 mg/dL who are unable to reach acceptable triglyceride levels with currently available treatments."

In the published data, treatment with an antisense compound targeting apoC-III produced a variety of potential cardio-protective effects including significant dose-dependent reductions of apoC-III and triglycerides in all models and species, including man.  In addition, treatment with an antisense compound targeting apoC-III resulted in enhanced triglyceride clearance from blood following a high-fat meal, reduction of VLDL particles and a slight increase in HDL-C levels.  In all models and in the Phase 1 study, antisense inhibition of apoC-III was well tolerated.  These data were consistent across multiple preclinical models and species and in a Phase 1 study in healthy volunteers demonstrating that Isis' antisense technology was able to produce predictable and consistent responses among different animal models that translate into corresponding activity in man. In the Phase 1 study, treatment with ISIS-APOCIIIRx was well tolerated and produced rapid, dose-dependent median reductions of up to 44 percent in plasma triglycerides and up to 78 percent in apoC-III protein, with two out of the three subjects in the highest dose group achieving undetectable levels of apoC-III.

ISIS-APOCIIIRx inhibits the production of apoC-III, a traditionally 'undruggable' target that inhibits the clearance of triglycerides from the blood. People who do not produce apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. ApoC-III is elevated in patients with dyslipidemia, or an abnormal concentration of lipids in the blood, and is frequently associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In human population studies, lower levels of apoC-III and triglycerides correlated with a lower rate of cardiovascular events.