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March 15, 2009 (Vol. 29, No. 6)

Honing In On Fatty Liver Disease Treatment

Galmed Medical Research Bets on Aramchol to Treat NAFLD and Steatohepatitis

  • Prevention and Treatment

    The corporation’s top clinical compound, called Aramchol (arachidyl amido cholanoic acid), recently completed the first, single-dose part of a Phase I study. The second part, to be carried out in hypercholesterolemic, mildly obese volunteers, has just started. Aramchol is being developed to treat nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH).

    Galmed is also developing a secondary compound called Steamchol, but Dr. Angel explains that Steamchol is currently in preclinical studies as a back-up of Aramchol, though it will eventually be used for additional indications.

    So what exactly is distinctive about this product? Dr. Angel says that the compound’s effect on lipid metabolism is the key. It is an inhibitor of an important enzyme in the regulation of lipids, prevents and treats Stearoyl Co A Desaturase 1, and thereby, is capable of both preventing and treating fatty liver conditions in experimental animals. In addition, it reduces cholesterol level and also reverses cholesterol gallstones, he says.

    During several strings of experiments in various strains of mice, or in hamsters in which hypercholesterolemia was induced either by excessive dietary intake or by increased synthesis, oral Aramchol significantly reduced plasma cholesterol as compared to saline-treated controls. In some of the studies the reduction was to levels lower than those found in comparable animals on a regular diet.

    The effects on plasma cholesterol levels were observed both in animals that have received Aramchol with the high-fat diets, as well as in animals that were initially primed to have hypercholesterolemia and later treated with Aramchol.

    The effects of Aramchol in mice were confirmed via experiments in hamsters. In those experiments, hypercholesterolemia was induced by diet or by stimulation of endogenous synthesis. Aramchol reduced the high cholesterol levels more than simvastatin and was comparable to or reduced it more than atorvastatin.

    Dr. Gilat believes that the fact that the compound is a conjugate of two natural components is critical. The compound is made up of cholic acid and arachidic acid. “They are conjugated by a solid bond, not broken down during absorption and, subsequently, little metabolized. The two components do not have any of the effects of the whole conjugate,” he clarifies.

    According to the company, the major effects of the conjugate are: reduction and prevention of liver fat in NAFLD, preventsion or dissolution of cholesterol gallstones, and major effects on cholesterol metabolism.

    The compound enhances fecal sterol losses, enhances cholesterol catabolism to bile acids (via the CYP7A1 enzyme), and stimulates reverse-cholesterol transport from cells to liver via HDL and through bile to feces via the ABCA1 transporter. Those effects on cholesterol are additive, resulting in up to a 50% reduction in blood cholesterol levels.

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