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Basic Research and Clinical Data

Background Information

In the majority of patients, NAFLD/NASH is associated with the metabolic syndrome, the latter diagnosed as the presence of three or more out of the following features: 1) waist circumference greater than 102cm in men and 88cm in women, 2) triglyceride level of 150 mg/dl or more, 3) high density lipoprotein cholesterol lower than 40 mg/dl in men and 50 mg/dl in women, 4) systolic blood pressure 130 mm Hg or greater and diastolic 85 mm Hg or greater, 5) fasting blood glucose 110 mg/dl or greater1.

The definition of NAFLD requires that there is evidence of hepatic steatosis, either by imaging or by biopsy, in the absence of causes for secondary fat accumulation, such as significant alcohol consumption, use of steatogenic medication or hereditary liver diseases. NAFLD is histologically further characterized as non-alcoholic fatty liver (NAFL) and NASH. NAFL is defined as the presence of fat infiltration of the liver, expressed by ballooning of the hepatocytes, without additional signs of hepatocellular injury. NASH is defined as hepatic steatosis, inflammation and hepatocite injury, with or without liver fibrosis2. The two entities are not always easily discernible by histological features, as they present a spectrum of conditions with different degrees of inflammation.

Due to the uncertainty regarding treatment options, routine screening for NAFLD/NASH of adults attending primary care or diabetic clinics is not recommended2. Nevertheless, the presence of the metabolic syndrome may raise the suspicion of NAFLD in a patient and warrant further work-up to detect NAFLD and NASH. The existing paradigm is that liver biopsy is the most reliable approach for the diagnosis of inflammation and fibrosis associated with liver steatosis. Nevertheless, the procedure-related morbidity, sample errors and costs limit its use to patients with a high index of suspicion of NASH.

Elevated serum aminotransferase levels and imaging tests such as ultrasound, CT and MR are good indicators of the presence of NAFLD/NASH, but not reliable in assessing the degree of inflammation and fibrosis which would distinguish between them. Nuclear Magnetic Resonance Spectroscopy (NMRS) is generally considered a validated noninvasive technique for in-vivo fat and metabolite quantification3. It is routinely used for measuring triglycerides and potentially other liver fat components3, and is increasingly being used as an endpoint in clinical trials and observational studies4,5.

Pathological findings in those non-invasive procedures and markers, in patients with metabolic syndrome, warrant the performance of a liver biopsy, by which the diagnosis and severity of NASH or cirrhosis is diagnosed2.

Although the burden of NAFLD and NASH and the related long term effects is continuously growing, there are very few evidence-based options for the management of the disease, and the efficacy and long term effect of those treatment options are not well established. The 2012 Guidelines recommend weight loss of at least 3-5% and up to 10%, by means of low-calorie diets and exercise, although effective, adherence to life change modifications is difficult to maintain in the long term. Bariatric surgery can be performed in obese patients with NASH, but is not an established procedure to treat NASH. Vitamin E is recommended for non-diabetic patients with biopsy proven NASH, but not for diabetics with NASH, NAFLD and liver cirrhosis, thus limiting its uses. Pioglitazone, although not authorized for the condition, can be used to treat patients with biopsy proven NASH, but its long term safety and efficacy in those patients has not been established. Other pharmacological interventions, including Metformin, Ursodeoxicholic acid, Omega 3 fatty acids and statins are not recommended as specific treatment options for NAFLD/NASH patients2.

Due to its mechanism of action and findings in animal models and human clinical studies, aramchol has the potential to answer the unmet need of a safe and effective pharmaceutical treatment for NAFLD/NASH and some of the related features of metabolic syndrome.

[1] Ratziu V., Bellentani S. et al., “A position statement on NAFLD/NASH based on the EASL 2009 special conference“, J Hepatol. 2010 Aug;53(2):372-84

[2] Chalasani N, Younossi Z et al., “The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology“, Gastroenterology. 2012 Jun;142(7):1592-609

[3] Browning J.D., Szczepaniak L.S. et al., “Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity“, Hepatology. 2004 Dec;40(6):1387-95

[4] Schwimmer J.B., Middleton M.S. et al., “A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis“, Aliment Pharmacol Ther. 2005 Apr 1;21(7):871-9

[5] Szczepaniak L.S., Nurenberg P., et al., “Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population“, Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E462-8

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