A new family of small, synthetic, orally active molecules with potential breakthrough therapies for major Metabolic Diseases
These are recently synthesized, patent protected molecules. They are composed of a bile acid conjugated with a fatty acid using a bonding molecule. The first series of patents relates to composition as well as use in cholesterol gallstone disease and atherosclerosis. The patents have been granted in the USA (6,589,946 B2 until 2019) and in Europe (1071702 B1 until 2019) and have been granted or submitted in about 43 countries. The second series PCT/IL02/00303 is in the national phase in the same countries, as use patents for: treatment and prevention of fatty liver, reduction of blood and body cholesterol and treatment and prevention of hyperglycemia and diabetes,valid until 2022.
These completely synthetic molecules to which the body has never been exposed were found to have many metabolic effects and to affect specific transporters and enzymes. A central regulatory gene(s) has not been definitely excluded.
The effects were proven in animals or in cells (mostly human cells) in several major fields.
Cholesterol Metabolism In more than 15 different series of experiments in various strains of mice in whom hypercholesterolemia was induced by excessive dietary intake oral FABACs reduced plasma cholesterol by about 50%(with high statistical significance) as compared to saline treated controls. In some of the cases the reduction was to levels lower than those found in these animals on a regular diet. The oral doses shown to be effective in animals were equivalent to human doses in the range of less than 1 mg/kg/day.We have now identified four mechanisms of hypocholesterolemic activity for the FABACs (which does not exclude additional ones): 1) Moderate reduction (about 50%) of synthesis via HMGCoA Reductase; 2) Considerable (2-3 fold) increase in catabolism to bile acids via CYP7A1(Hypocholesterolemic effects of FABACS in mice, Archives of Biochemistry and Biophysics 2007 accepted); 3) Efflux from human cells ex vivo via ABCA1 (Biochem. J. 2006, 396:529). There was a 2-3 fold increase in cholesterol efflux which is the first step in reverse cholesterol transport. Efflux from macrophages is particularly effective and important in the context of Atherosclerosis while efflux from the liver is particularly important for reduction of body cholesterol stores. Both were proven in human cells. 4) Increase in fecal sterol excretion (bile acids + neutral sterols) of about 2 fold. (Biochem. Soc. Trans. 2004:32:131). This represents the final step in reverse cholesterol transport.
These effects of FABACs in mice were confirmed in 3 series of experiments in hamsters. In these experiments hypercholesterolemia was induced by diet or by stimulation of endogenous synthesis. FABACs reduced the high cholesterol levels more than simvastatin and similar or more than atorvastatin. A FABAC-Atorvastatin combination was the most potent compound (Unpublished).
Fatty Liver (NAFLD) FABACs, given orally, were proven to prevent diet induced fatty liver in several animal species, using different diets (Hepatology 2003; 38:346). More recently we have proven (unpublished) that they also reduce preexisting fat induced fatty liver; i.e. they are effective in a therapeutic setting. The rapidity of the effect (weeks or months) is inversely proportional to the fat concentration in the maintenance diet during the treatment period. Two mechanisms for this effect were identified. Fatty liver affects over 20% of the general population in most westernized countries and its prevalence is rising rapidly in parallel with the prevalence of obesity. Some 25% of patients with fatty liver progress to inflammation (NASH) and cirrhosis. FABAC treatment reduces mostly triglycerides in the liver. The molecular mechanism of this effect has been elucidated. Neither fatty liver nor gallstones have currently an accepted medical treatment.
Cholesterol Gallstones Gallstones affect about 15% of the general population in industrialized countries. Close to 80% of them are cholesterol gallstones. Some 20-25% of patients with gallstones develop pain and complications and are referred to surgery. FABACs were shown to prevent and dissolve preformed gallstones in numerous in vivo experiments. These results were published (Gut 2001; 48:75, Lipids 2001; 36:1135, Hepatology 2002; 35:597). Our current calculations indicate that dissolution using oral FABACs will cost only a fraction of the price of surgery. It eliminates the small mortality and moderate morbidity associated with surgery (laparoscopic or open). Previous experience and current surveys indicate that most patients and general physicians favor a trial of medical dissolution prior to surgery. Intermittent maintenance therapy may or may not be needed following dissolution. The molecular mechanism of gallstone dissolution by Fabacs has been elucidated.
Atherosclerosis We have previously shown that FABACs reduce experimental atherosclerosis in mice (Pathobiology 2003; 70:215.) This has been reconfirmed. Lately we are concentrating on cholesterol metabolism on the premise that reduction of blood and body cholesterol has been amply proven to have a beneficial effect on also on mortality from non vascular causes and also on total mortality as compared to cardiovascular mortality.
General FABACs are absorbed following oral administration and exercise their biologic effects at the doses indicated. Enhancement of absorption has been recently achieved. There are several thousand molecules covered by the patents. We have already chosen the lead molecule and an alternative one. The synthesis is not problematic and an optimal, economic, synthetic process has been developed by an international firm. More than 7.5 kg of GMP material have been synthetized. A MS based analytical procedure has been developed and validated. Incubation of Aramchol with human, dog and pig liver microsomes for 15 hours demonstrated 83% of the intact compound. This indicates very slow metabolism and degradation and suggests that the effects are due to the intact molecule (performed at a CRO).
No Toxicity Found No toxicity whatsoever has been noted in studies conducted over 6-7 years in more than 2,000 experimental animals of various species, mostly rodents. Biochemical and histological studies were negative (Europ. J. Gastroent. Hepatol. 2003; 15:1).
On LD50 and MTD testing, starting from the therapeutic dose of 8 mg/kg, there was no mortality and no evidence of toxicity up to a dose of 2,000 mg/kg, in 4 series of experiments. This indicates a particularly large therapeutic window with no evidence of toxicity at 250-fold the therapeutic dose. Formal toxicity testing at several international facilities (CROs) has produced the following results: No evidence of Mutagenicity (Ames test); No evidence of Genotoxicity (Human lymphocytes); No deleterious effects on a long series of human receptors (as formally required for regulatory purposes). Chronic toxicity studies in rats, 28 days at doses of 100,500 and 1000 mg/kg/day revealed no drug related toxicity. All 72 rats tested survived. Chronic toxicity studies in dogs, 28 days at doses of 100-1000mg/kg/day showed no toxicity whatsoever. The No Observed Adverse Effects Level, NOAEL, has been determined to be above 1000 mg/kg/day. ADME and Safety Pharmacology studies are ogoing and will complete our preclinical regulatory package.
FABAC Effects proven in HUMAN cells and fluids Effects in human material obviate all the potential problems associated with species differences. The proven effects are: Cholesterol efflux (Reverse Cholesterol Transport) from human fibroblasts. All the mechanisms of action via the ABCA1 transporter were elucidated in these cells; Efflux from macrophages was demonstrated in human cells, this is particularly relevant to treatment of Atherosclerosis;. Efflux from the liver was shown in a in a human liver cell line. The liver accounts for circa 95% of the total Reverse Cholesterol Transport in the body; Increase in Cholesterol Catabolism to bile acids was demonstrated in fresh human liver cells, this is relevant to reduction of cholesterol body stores. Inhibition of fatty acid synthesis and inhibition of the key enzyme Stearoyl CoA Desaturase, by FABACs, were proven in a Human Liver cell line. This is relevant to reduction of hepatic fat in Fatty Liver Disease; Inhibition of cholesterol crystallization and dissolution of formed cholesterol crystals were demonstrated in human bile. The molecular mechanism of gallstone dissolution was demonstrated in material of human origin.
CLINICAL DEVELOPMENT
The company’s flagship clinical compound Aramchol (arachidyl amido cholanoic acid), is about to start PhaseIIA clinical studies in 60 patients with NAFLD or NASH in the summer of 2010. This follows successful 1 and 3 months formal toxicity studies in rats and dogs in CROs in Holland ,India and Canada, as well as a successful phase I study in 41 healthy volunteers in Israel. .
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