Isis Reports Preclinical Data Supporting Liver Safety of ISIS301012- Results of animal studies distinguish liver effects of apoB inhibition from MTP inhibition and support liver safety of ISIS 301012
CARLSBAD, Calif., October 06, 2007 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. announced new results of preclinical studies reaffirming the safety profile of ISIS 301012 and enhancing the understanding of its activity in the liver presented by Richard Lee, Ph.D. of Isis in a 3:45 p.m. oral session today at the Drugs Affecting Lipid Metabolism (DALM) XVI International Symposium in New York City. Isis will host a conference call Monday morning at 8:00 a.m. E.T. to discuss these results along with results of Phase 2 studies of ISIS 301012 presented at DALM.
The preclinical data presented provide a mechanistic explanation for Isis' previous observations that, in mice and monkeys, treatment with antisense inhibitors of apolipoprotein B-100 (apoB) is associated with reduced liver fat content. This observation is in contrast to the effects of either small molecule or antisense inhibitors of microsomal triglyceride transfer protein (MTP), another component of the cholesterol export pathway, which cause severe liver fat accumulation in the same animal models.
In the study reported today at DALM, Isis demonstrated that apoB inhibition led to compensatory changes in liver fat metabolism including reduced fat production and increased fat breakdown. These changes were documented in metabolic indicators measured in the blood serum and were accompanied by consistent changes in liver gene expression profiles. Having now developed the appropriate tests and demonstrated that serum metabolites are relevant indicators of liver fat metabolism in preclinical studies, Isis plans to incorporate similar measurements in its future clinical trials of ISIS 301012.
ABOUT ISIS 301012 AND CHOLESTEROL
ISIS 301012 is a second-generation antisense drug that reduces the production of apoB-100, a protein critical to the synthesis and transport of "bad" cholesterol and a target that has proved to be undruggable using traditional, small-molecule approaches. 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, LDL-C, VLDL-C, and other bad forms of cholesterol are referred to as "non-HDL-C." The lowering of non-HDL-C is a key component in the prevention and management of cardiovascular disease. Isis plans to develop ISIS 301012 as the drug of choice for patients who are unable to achieve target cholesterol levels with statins alone or who are intolerant of statins. Isis has selected 200 mg/week as its development dose for future studies, including the registration studies for FH and the long-term coadministration study planned for patients with routine high cholesterol, both expected to begin this year.
Posted: October 2007