In like FLINT

NEW YORK—Intercept Pharmaceuticals Inc. has taken difficult-to-treat liver disease to a promising outcome, as seen in the results of a clinical trial called FLINT that were recently reported in The Lancet. The FLINT trial, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), evaluated obeticholic acid (OCA) made by Intercept for the treatment of nonalcoholic steatohepatitis (NASH).

NASH is a chronic, progressive form of fatty liver disease, marked by inflammation and scarring (fibrosis) of the liver. NASH is the most prevalent chronic liver disease, affecting more than 10 percent of the adult population of the United States, greater than chronic hepatitis C viral infection and alcoholic liver disease. Obesity and type 2 diabetes, which afflict a large percentage of NASH patients, are important clinical risk factors associated with more progressive NASH-associated liver disease.

In the FLINT trial, OCA showed a significant improvement in all histologic features of NASH as well as a significant improvement in fibrosis (the scarring of the liver that leads to negative patient outcomes). This was the first time that a pharmaceutical therapy has been shown to improve both liver fibrosis and other important histologic features of NASH in a significant proportion of patients.

These results were observed in a difficult-to-treat patient population, which included a large proportion of vitamin E nonresponders and patients with type 2 diabetes. A number of other observations were made in FLINT regarding OCA in NASH, including those related to the safety and tolerability of OCA.

“The readout from FLINT marks the first time that a therapy has been shown to meaningfully improve both liver fibrosis and other important histologic features of NASH in a significant proportion of patients,” said Dr. Mark Pruzanski, CEO of Intercept. “After more detailed review of the data provided in the publication, we are pleased to see that the benefits observed with OCA therapy are consistent across key subpopulations of NASH patients, including those at most risk of progression to liver failure. FLINT provides us with a rich set of results in a ‘real-world’ NASH population that will inform the design of our upcoming pivotal Phase 3 program that we plan to initiate in the first half of 2015.”

Intercept’s focus on bile acid chemistry and farnesoid X receptor (FXR) agonism has been the driving force in the development of OCA, according to Pruzanski. FXR is a nuclear receptor that has been shown in animal disease models to regulate bile acid synthesis and clearance from the liver, thereby preventing excessive bile acid buildup in the liver, which may be toxic. Additionally, animal disease models have shown that bile acid activation of FXR induces antifibrotic, anti-inflammatory, antisteatotic and other mechanisms that are associated with the normal regeneration of the liver. As a result, FXR appears to be a potential target for the treatment of multiple liver diseases, such as NASH and primary biliary cirrhosis (PBC).

Intercept intends to seek initial regulatory approval for OCA in PBC (a rare autoimmune liver disease) as a second-line treatment for patients who fail to respond adequately to the current standard of care. Earlier this year, Intercept announced that OCA met the primary endpoint of its pivotal Phase 3 trial in PBC patients (known as POISE) with high statistical significance.

Based on the positive results from the FLINT trial, Intercept plans to initiate its Phase 3 program for NASH during the first half of 2015. Intercept plans to initiate a Phase 2 trial investigating the use of OCA for the treatment of primary sclerosing cholangitis, a rare liver disease with no approved treatments.

No new treatments have been introduced for PBC in more than 20 years, and recent studies have shown that up to 50 percent of PBC patients fail to respond adequately to the current standard of care, representing an addressable market of up to 30,000 patients in developed markets. NASH is the most prevalent chronic liver disease, but a narrower focus on those NASH patients with advanced fibrosis and cirrhosis, thought to be irreversible stages in the natural history of the disease, still amounts to an estimated prevalence of more than 2.5 percent of the general adult population, potentially afflicting approximately six million adult patients in the United States.

By 2020, NASH is expected to be the leading indication for liver transplant in the United States. If approved, OCA could potentially help address the unmet needs in these patients.