Isis Pharmaceuticals, Inc. announced the initiation of a phase I study of Isis-APOCIIIRx, an anti-sense drug designed to lower triglycerides to treat a variety of diseases associated with elevated triglycerides. Hypertriglyceridemia, a condition characterized by elevated levels of triglycerides, is an independent risk factor for cardiovascular disease and is a component of numerous cardiovascular and metabolic diseases, including metabolic syndrome. Isis-APOCIIIRx inhibits the production of apolipoprotein C-III (apoC-III), a traditionally “undruggable” target that plays a central role in the regulation of triglycerides.

“Humans who cannot produce apoC-III have lower triglycerides and LDL-C levels, increased HDL levels and a lower risk of cardiovascular disease, suggesting that apoC-III inhibition could provide an effective new tool for lipid management. Many of the current therapies designed to lower triglycerides are associated with undesirable side effects, such as flushing, the most common side effect of niacin,” said Rosanne Crooke, PhD, vice president, Cardiovascular Diseases Drug Discovery Research at Isis. “In preclinical studies, anti-sense inhibition of apoC-III reduced the target mRNA and protein, lowered triglyceride levels in plasma, mitigated symptoms of metabolic syndrome and decreased atherosclerosis.”

“ApoC-III is an excellent anti-sense target to reduce triglyceride levels and is another example of the broad applicability of our technology to selectively inhibit targets that could have a profound impact on diseases. ApoC-III inhibits the clearance of triglycerides from the blood. It is produced in the liver, a tissue that anti-sense drugs work very effectively in, and it is a target that has been difficult to inhibit with traditional approaches,” said Stanley Crooke, MD, PhD, chairman and chief executive officer of Isis. “We plan to develop Isis-APOCIIIRx in a staged program similar to mipomersen, in which we will first evaluate the drug in very sick patients who cannot adequately lower their triglyceride levels using available therapies and who, as a result, have few therapeutic options. In this regard, we can exploit the knowledge we have gained from our mipomersen and PCSK9 programs to inform our development plan for Isis-APOCIIIRx.”

Isis-APOCIIIRx targets apoC-III, a gene produced in the liver that plays a central role in the regulation of serum triglycerides. Recent data suggest that loss-of-function mutations within the apoC-III gene lower triglyceride levels and appear to improve health and extend longevity. In clinical studies, patients with lower levels of apoC-III and triglycerides exhibit lower cardiovascular event rates. In addition, apoC-III mediates insulin resistance, leading to worsening of the metabolic syndrome.

Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first anti-sense drug and has 22 drugs in development. Isis' drug development programs are focused on treating cardiovascular, metabolic, and severe neurodegenerative diseases and cancer. Isis' partners are developing anti-sense drugs invented by Isis to treat a wide variety of diseases. Isis and Alnylam Pharmaceuticals are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development and commercialization of microRNA therapeutics. Isis also has made significant innovations beyond human therapeutics resulting in products that other companies, including Abbott, are commercializing. As an innovator in RNA-based drug discovery and development, Isis has designed and executed a patent strategy that has provided the Company with strong and extensive protection for Isis' drugs as well as all aspects of anti-sense drug discovery, development and manufacturing.