Isis: Oral form of ISIS 301012 reduces cholesterol in humans

By E. Janene Geiss

Philadelphia, Feb. 7 - Isis Pharmaceuticals, Inc. said Tuesday that it has completed a phase 1 study of an oral formulation of ISIS 301012 and has demonstrated oral bioavailability and pharmacological activity of the drug in this study.

ISIS 301012, a second-generation antisense drug, targets apoB-100, a protein critical to the synthesis and transport of the "bad" cholesterol involved in heart disease - low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein (VLDL), according to a company news release.

One month of dosing in healthy volunteers with an oral capsule formulation of ISIS 301012 resulted in an average of 6% bioavailability and a statistically significant average reduction of about 13% in apoB-100 and commensurate reductions in LDL-C as compared to a placebo, officials said.

Lowering cholesterol levels is a key component in the prevention and management of cardiovascular disease.

In the trial, healthy volunteers received either oral ISIS 301012 or a placebo over a one-month period.

The formulation in the oral capsules used in the study contained a penetration enhancer that was previously shown to increase the oral bioavailability of second-generation antisense drugs, officials said.

Treatment with ISIS 301012 resulted in a statistically significant average reduction in apoB-100 of about 13% as compared to a placebo, officials said.

Reductions in LDL-C also were statistically significant, officials said.

Pharmacological effects were correlated with maximum plasma concentration with healthy volunteers who absorbed more drug demonstrating greater pharmacological effects, officials said.

The oral form of ISIS 301012 was generally well-tolerated. Only mild intermittent gastrointestinal symptoms were observed.

No healthy volunteers withdrew from the study because of side effects.

"We are continuing to make progress in the oral delivery of second-generation antisense drugs," said Mark Wedel, senior vice president of development and chief medical officer at Isis, in the release.

"Achieving oral bioavailability and statistically significant pharmacological activity in humans with oral ISIS 301012 is a significant step for the technology. We intend to report these data at an appropriate scientific meeting later this year," Wedel added.

According to the American Heart Association, an estimated 106.9 million American adults have total blood cholesterol values of 200 mg and higher and of these about 37.7 million American adults have levels of 240 or above.

Isis is a Carlsbad, Calif., biopharmaceutical company using its expertise in RNA to develop novel drugs for its product pipeline and for its partners. The company has successfully commercialized the world's first antisense drug and has 12 antisense drugs in development to treat metabolic, cardiovascular, ocular and inflammatory diseases and cancer.

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