Isis Pharmaceuticals, Inc. announced it has initiated a Phase I study of Isis 301012, a second-generation antisense inhibitor of ApoB-100, for cardiovascular disease. ApoB-100 is the carrier of low-density lipid (LDL) cholesterol, the "bad" lipid involved in heart disease. This target has been of interest to the pharmaceutical industry for many years, but has been considered "undruggable" by traditional approaches.
"We are enthusiastic about the potential of this compound to offer a new treatment option for patients whose cholesterol levels are not safely or effectively managed with current drugs, " said Mark Wedel, MD, vice president, Clinical Research and chief medical officer. "In preclinical studies, Isis 301012 decreased cholesterol safely in numerous well-recognized animal models of cardiovascular disease. Further, ApoB-100 protein and messenger RNA levels decreased in the drug treated animals. These results are consistent with an antisense mechanism of action and provide us with an early read that the drug is performing as we expected."
The double-blind, placebo-controlled, dose-escalation trial will enroll 40 healthy volunteers with elevated cholesterol. The goal of this Phase I study is to assess the safety, tolerability and pharmacokinetic profile of Isis 301012, and its ability to reduce several components of cholesterol that are important in the management and prevention of cardiovascular disease.
Lowering cholesterol levels is a key component in the management of heart disease. After six weeks of treatment in animal models, Isis 301012 produced a dose-dependent reduction in all components of cholesterol commonly used in evaluating heart disease. More specifically, the second-generation antisense drug produced a 50per cent reduction in total cholesterol, a 15per cent reduction in very-low density lipoprotein (VLDL) and an 88per cent decrease in LDL. Significant reductions in triglyceride levels were also observed and no meaningful adverse events were observed.
As part of the company's new cardiovascular drug discovery program, Isis scientists rapidly explored more than 20 cardiovascular gene targets in vitro and evaluated many of these genes in animal models to identify the most attractive candidate to move into development. ISIS 301012 emerged from these studies and is the first drug to enter the clinic from this programme. Isis scientists continue to advance additional potent and highly specific cholesterol-lowering drugs as potential candidates for clinical study.
Antisense drugs, such as Isis 301012, work at the molecular level by binding to messenger RNA to interrupt the process by which disease-related proteins are produced. Antisense drugs are uniquely suited to inhibit ApoB-100 because of the way they work and because the target resides in fat tissue, a tissue which can be more difficult for conventional drugs to access.
Cardiovascular disease is the leading cause of death in the US, according to the National Institutes of Health. Researchers have shown a strong correlation between high cholesterol levels and subsequent cardiovascular diseases. Statistics from the American Heart Association show more than 100 million American adults have high cholesterol levels.