Isis Reports Reduction Of ApoB-100 Levels In Atherosclerosis
Isis Pharmaceuticals presented the results of two studies designed to assess the impact of lowering apoB-100 on atherosclerosis at the 2008 Annual Atherosclerosis, Thrombosis and Vascular Biology (ATVB) Conference in Atlanta, Georgia. The data were presented in a poster entitled "Antisense Inhibition of Apolipoprotein B Ameliorated Diet-Induced Hypercholesterolemia and Reduced Atherosclerosis in LDL Receptor-Deficient Mice" by Adam E. Mullick, Ph.D. of Isis yesterday at ATVB.
Both studies were performed in a murine model in which the LDL receptor, which is responsible for the maintenance of normal serum cholesterol levels, has been genetically eliminated. These animals have very high cholesterol levels (1,000 - 2,000 mg/dL on a high fat diet) and develop severe atherosclerosis. In the first study, the impact of treatment with an antisense drug was evaluated in the context of two atherogenic high fat diets. Animals on these diets had elevated total cholesterol and LDL-cholesterol levels that increased during the two weeks of high fat diet prior to drug treatment. These cholesterol levels dramatically decreased during the 10 week treatment period. At a dose of 50 mg/kg twice weekly, the murine apoB-100 antisense drug reduced total cholesterol and LDL-cholesterol by 87% and 93%, respectively. These reductions in cholesterol directly correlated with reduction in liver and plasma apoB-100 levels. Aortic atherosclerotic lesions were reduced by 78% - 92% in the same animals.
The second study, which evaluated the effects of increasing doses of drug on lipid levels, confirms and extends the results of the previous study, and showed that the effects of the apoB-100 antisense drug were linearly dose-dependent with regard to reductions on apoB-100 and atherogenic lipid levels, triglycerides, and atherosclerotic plaques. The maximum reduction of atherosclerotic plaques was 89% in this study.
"These studies add to a growing body of data showing that reducing apoB-100 results in substantial reductions in atherosclerosis," said Rosanne Crooke, Ph.D., Executive Director of Cardiovascular Research of Isis. "We have now shown that mipomersen or species-specific analogs reduce atherosclerosis in several animal models and that the effects on atherosclerosis correlate with reductions in apoB-100 and atherogenic lipids, including LDL-cholesterol and triglycerides."
Early 2008, Isis announced the licensing of mipomersen to Genzyme as the preferred partner to continue development, commercialize and market the drug.
Mipomersen is a second-generation antisense drug that reduces the production of apoB-100, a protein critical to the synthesis and transport of "bad" cholesterol. Cholesterol can be carried in the bloodstream in a variety of forms, with high-density lipoprotein, or HDL-C, being the good form, and low-density lipoproteins, or LDL-C, and very low-density lipoproteins, or VLDL-C, being bad forms directly involved in heart disease. Collectively lowering LDL-C, VLDL-C, and other bad forms of cholesterol are a key component in the prevention and management of cardiovascular disease.
Currently in Phase 3 development, mipomersen has been shown in Phase 2 trials to reduce cholesterol and other atherogenic lipids more than 40 percent beyond reductions achieved with standard lipid-lowering drugs, enabling more patients to achieve LDL-C targets. These trials have shown that treatment with mipomersen is well-tolerated, and that mipomersen has an attractive safety profile, and works equally well in the presence and absence of other lipid-lowering therapies including statins. A weekly injectable therapeutic, mipomersen is being developed primarily for patients at high cardiovascular risk who are unable to achieve target cholesterol levels with statins alone or who are intolerant of statins.
Mipomersen's initial indication will be for patients with familial hypercholesterolemia (FH). There are approximately 1.5 million people in the United States and Europe with FH, an inherited disorder that causes exceptionally high levels of LDL-cholesterol. After appropriate clinical development, the next indication pursued for mipomersen will be for other patients with high cholesterol at high risk of cardiovascular events.