Development Programs

Potential Use of OCA to Treat Nonalcoholic Steatohepatitis (NASH)

Potential Use of OCA to Treat Nonalcoholic Steatohepatitis (NASH)

FXR activation has been shown to play a key role in the regulation of the metabolic pathways relevant to NASH, highlighting FXR as a potential drug target for treatment of the disease.

NASH is a common and serious chronic liver disease caused by excessive fat accumulation in the liver, or steatosis, that induces inflammation and may lead to progressive fibrosis and cirrhosis, followed by eventual liver failure and death. NASH is now considered to be the second leading and rapidly increasing cause of hepatocellular carcinoma, or primary liver cancer, which may develop in NASH patients prior to the liver becoming cirrhotic. While the condition of steatosis alone, known as nonalcoholic fatty liver disease, or NAFLD, may not necessarily be harmful to the liver, approximately one-third of NAFLD patients progress to NASH for reasons that are not yet completely understood. Other common co-existing conditions such as obesity and type 2 diabetes, which afflicts up to half of all NASH patients, are important risk factors in NASH, and insulin resistance is believed to promote inflammation and fibrosis in the liver. NASH is believed to be one of the most common chronic liver diseases worldwide, with an estimated prevalence of more than 10% of the general adult population in the United States, with similar prevalence estimated in Europe, Japan and other developed countries. Additionally, NASH has become a highly prevalent liver disease in developing countries such as India and China. A narrower focus on those NASH patients with advanced fibrosis and cirrhosis, thought to be irreversible stages in the natural history of the disease, amounts to an estimated prevalence of more than 2.5% of the general adult population, potentially afflicting approximately 6 million adult patients in the United States. Although the prevalence of NASH is lower in children, it has also become a serious disease burden in the pediatric population.

While NASH is commonly associated with obesity, it also can occur in non-obese patients and has been linked in both developed and developing countries to the adoption of a Western diet, with increased consumption of processed foods containing polyunsaturated fatty acids and fructose. Cardiovascular disease, cancer and liver failure are the most common causes of death in NASH patients. More than 20% of NASH patients progress to cirrhosis within a decade of follow-up and, with the rapidly increasing prevalence of the disease, NASH has become the third most common reason for liver transplant in the United States and is projected to become the leading indication for transplant in the next few years, overtaking both chronic hepatitis C infection and alcoholic liver disease. NASH patients have a 10-fold greater risk of liver-related mortality as compared to the general population and a 6-fold greater risk of liver-related mortality as compared to patients with less severe NAFLD. The presence of type 2 diabetes in the broader NAFLD population is associated with a much greater mortality risk, with a 23-fold higher rate of liver-related mortality as compared to non-diabetic NAFLD patients.

Currently, a definitive diagnosis of NASH is based on a histologic assessment of a liver biopsy for certain key features associated with NASH, including steatosis, lobular inflammation and hepatocyte ballooning. However, non-invasive methods of diagnosis are being explored, including transient elastography (an ultrasound technology approved in Europe and more recently in the United States for the measurement of liver fibrosis), magnetic resonance imaging and serum biomarkers. We believe that further validation and approval of non-invasive diagnostic and disease staging methods, as well as the anticipated future regulatory approval of novel NASH therapies, will lead to a significant increase in diagnosis and treatment of patients with NASH.

Currently Available Treatment Options for NASH

There are currently no drugs approved for the treatment of NAFLD or NASH. However, it has been reported that in 2010 there were approximately $615 million in off-label sales of various therapeutics for the treatment of NASH, such as vitamin E (an antioxidant), insulin sensitizers (e.g., metformin), antihyperlipidemic agents (e.g., gemfibrozil), pentoxifylline and ursodiol. Lifestyle changes, including modification of diet and exercise to reduce body weight, as well as treatment of concomitant diabetes and dyslipidemia, are commonly accepted as the standard of care, but have not conclusively been shown to prevent disease progression.

Phase 2b FLINT Trial for NASH

The FLINT trial is sponsored and conducted by the National Institute of Diabetes and Digestive and Kidney Diseases, or NIDDK, which oversees a clinical research network of 8 leading NASH centers in the United States.

The FLINT trial enrolled 283 NASH patients who were randomized to either a 25 mg single daily dose of OCA or placebo. Of the 283 patients enrolled in FLINT, 187 (66%) were female and 229 (81%) were over 40 years of age. Patients enrolled in FLINT were qualified based on a diagnosis determined by liver biopsy confirming a diagnosis of definite or probable NASH and a NAS of 4 or greater out of a total 8-point scale, and with a score of at least 1 in each component of the NAS (steatosis 0-3, lobular inflammation 0-3, ballooning 0-2). End of study biopsies were conducted in patients who completed the 72-week treatment period, with all biopsies centrally read and scored in a blinded fashion. The primary endpoint of the study was defined as a decrease in the NAFLD Activity Score (NAS) of at least 2 points with no worsening of fibrosis as compared to placebo.

In January 2014, the treatment phase of the Phase 2b FLINT trial of OCA for patients with NASH was stopped early following a planned interim analysis showing that the primary endpoint of the trial exceeded a pre-defined efficacy threshold of p < 0.0031. The decision to stop the treatment phase early was in accordance with the recommendation of the trial’s Data Safety Monitoring Board, or DSMB, and based primarily on achievement of the pre-defined efficacy criterion, while being informed by the risks involved in conducting liver biopsies in the remaining patients and the available safety data. All patients have stopped dosing of OCA and placebo and have entered into a pre-specified 24-week observational follow-up phase, during which blinding is maintained.