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

Galmed Medical Research Bets on Aramchol to Treat NAFLD and Steatohepatitis

In early January 2008, the National Center for Health Statistics released updated cardiovascular disease (CVD) mortality statistics based on data through 2005, the most recent year accurately completed.

Though death rates from CVD declined 24.7% from 1994–2004, and actual deaths declined 8% within that same time frame, fully 80,700,000 people in the U.S. still suffer from one or more forms of CVD. And coronary heart disease, the claimed single leading cause of death in the U.S. today, caused 451,326 deaths in 2004 alone.

While those were U.S. statistics, cardiovascular disease is clearly an enormous worldwide health issue and is associated with many other lipid-related diseases, one of which is fatty liver disease.

According to Galmed Medical Research, at present, no established medicines exist to treat either fatty liver disease (FLD) or gallstones. That set of circumstances is something that the company—and in particular Itzchak Angel, Ph.D., vp, business development, and Tuvia Gilat, M.D., CEO—is working to rectify.

Within the field, there is an increasing awareness of FLD, and more studies are demonstrating its link to cardiovascular and metabolic disorders. The industry is looking for effective drugs for gallstones and FLD, and for a  patented therapy following statins, says Dr. Gilat. Galmed Medical Research claims to be well positioned in this regard because the company’s expertise is in liver diseases in general, and FLDs in particular.

The company, established in September  2000, develops drugs for the treatment of chronic lipid-related diseases, and has created a series of fatty acid bile acid conjugates (FABACs) that selectively affect several pathways in lipid metabolism, as demonstrated in several species in vivo and in human cells and tissues in vitro. The FABACs, conjugates of cholic acid with long-chain fatty acids using a solid bond that is not broken down during absorption, are taken up intact and are only minimally metabolized in the body, explains Dr. Gilat.

FABACs normalize fat deposition in the liver of hamsters fed a high-fat diet.

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.

Potential Patients

Dr. Gilat says the company initially chose to develop Aramchol because of the large potential market size. He reports that 30% of the general population above age 20 has NAFLD. Complications of NAFLD include inflammation, cirrhosis, liver cancer, and cardiovascular disease.

“Gallstones are also devoid of medical therapy at present, though there is surgery. Statins depress body cholesterol synthesis, they do not actively remove cholesterol from the body. We found a statin-Aramchol combination particularly effective. Possibly due to its two natural components, Aramchol has been found to be unusually safe to date,” adds Dr. Gilat.

An international consortium coordinated by Galmed Medical Research has been established for a Phase IIa study of the effectiveness of Aramchol in patients with NAFLD and NASH, and to investigate basic aspects of these diseases. The consortium is composed of six leading liver centers, located in London, Barcelona, Paris, Frankfurt, Prague, and Tel Aviv, as well as five other leading research institutes.

When asked about the advantage Aramchol has over competition in the field, Dr. Gilat replied “The combination of the effects on triglyceride and cholesterol metabolism is, to the best of my knowledge, unmatched by any medicine existing today. Nor is there a single medicine having major beneficial effects on three such frequent and important diseases.”

Fatty liver, cholesterol deposits, and gallstones before and after Aramchol therapy.

Future Tactics

Moving ahead, the company plans to develop alliances as one of its strategies for success. It is looking to partner with biotechnology and pharmaceutical companies in collaborations that would enhance the growth and market opportunity for both companies. “We hope to be positioned as a key player in the field of treatment of fatty liver diseases, subsequent to demonstration of efficacy in Phase II studies,” says Dr. Angel.

Discussion of licensing and codevelopment opportunities related to Aramchol or development of new or improved drugs based on FABAC technology will also be a focus, as the company continues to build its pipeline and advance existing drugs that can deliver successful therapeutics in the field of liver and cholesterol metabolism to patients. Five to ten years down the road, Dr. Gilat sees the company having licensed or brought to market one to two compounds and developing others.

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