Advanced liver fibrosis is currently the best predictor of liver-related mortality in patients with NASH, while patients with early disease and concomitant risk factors such as diabetes, obesity or elevated ALT are also at risk of rapid progression to cirrhosis. The efficacy of OCA was evaluated in a high-risk subgroup of NASH patients in the FLINT trial considered more likely to experience liver-related clinical outcomes, defined as patients with a NAFLD activity score (NAS) of at least 4 and either (i) advanced fibrosis (stage 2 or 3), or (ii) early fibrosis (stage 1) together with concomitant diabetes, obesity or elevated ALT. Approximately 80% of the FLINT patients met these high-risk criteria.
In this post-hoc analysis of the high-risk subgroup after 72 weeks of treatment (n=160; OCA=84; placebo=76), a significant percentage of OCA-treated patients experienced complete resolution of their fibrosis (15% OCA vs. 4% placebo, p=0.006). Improvements in fibrosis resolution were observed in OCA-treated patients across all baseline fibrosis stages (stage 1: 31% OCA vs. 11% placebo, stage 2: 16% OCA vs. 3% placebo, stage 3: 3% OCA vs. 0% placebo). Additionally, OCA treatment prevented progression to cirrhosis (2% OCA vs. 7% placebo), but this finding did not achieve statistical significance in this small number of patients. Improvements in cirrhosis prevention were also observed in patients with stage 3 bridging fibrosis (6% OCA vs. 14% placebo) and stage 2 fibrosis (0% OCA vs. 3% placebo).
The results reported today build on previously reported data from post-hoc analyses showing that OCA-treated patients experienced significant improvements in key histologic features of steatohepatitis, including NAS reduction by at least two points (60% OCA vs. 30% placebo, p=0.0004), NASH resolution (18% OCA vs. 5% placebo, p=0.014), and liver fibrosis improvement by at least one stage (39% OCA vs. 21% placebo, p=0.007). These histologic benefits were observed in OCA-treated patients in all subgroups and regardless of baseline fibrosis stage.
The impact of statin use on LDL cholesterol was also evaluated in the FLINT trial population (n=283). In this post-hoc analysis, OCA-treated patients who initiated statins during the FLINT trial (n=26) experienced a rapid reversal of their observed mean LDL increase to below baseline levels, with a mean decrease after 72 weeks of treatment of -18.9 mg/dL. In contrast, other OCA-treated patients with no reported initiation or change in statin therapy experienced an increase in LDL that peaked at week 12 and was sustained over the 72 week treatment period. Patients treated with statins at baseline who maintained statin treatment over the duration of the study (n=50) experienced a mean LDL increase of 8.7 mg/dL at 72 weeks. Patients not treated with statins during the study (n=65) experienced a mean LDL increase of 16.0 mg/dL. Treatment related LDL increases in all groups reversed with treatment discontinuation. This post-hoc analysis suggests that the OCA associated LDL increase appears to reach a maximum peak and plateaus soon after initiation of therapy and that concomitant statin use in NASH patients receiving OCA may ameliorate any treatment-related LDL increases.
"These data add to our understanding of the potential for OCA treatment to reverse fibrosis and prevent progression to cirrhosis, a pharmacologic benefit not previously confirmed in NASH patients," said Dr. Brent Neuschwander-Tetri, the principal investigator of the trial. "Furthermore, the data support the potential for statins to effectively manage LDL in NASH patients, as currently recommended in the AASLD and EASL practice guidelines."
As previously reported in the primary analysis of FLINT, OCA was generally well tolerated. Adverse events were mild to moderate in severity and the incidence in the OCA and placebo treatment groups was similar for all symptoms except pruritus. Compared with placebo, pruritus in OCA-treated patients occurred more frequently (23% vs 6%, p < 0.0001). Typically, the pruritus was of moderate intensity and resulted in one patient discontinuation. The incidence of severe or life threatening events was not different between the two treatment groups and most of the events in both groups were deemed to be unrelated to treatment, including all severe or life threatening cardiovascular events. Two deaths occurred in the OCA treatment group; neither was considered related to OCA treatment.
The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial was sponsored by the
About Nonalcoholic Steatohepatitis
NASH is a serious chronic liver disease caused by excessive fat accumulation in the liver that induces chronic inflammation which leads to progressive fibrosis (scarring) that can lead to cirrhosis, eventual liver failure and death. There are currently no drugs approved for the treatment of NASH. Studies have shown that 21-26% of NASH patients will develop cirrhosis over 8.2 years of follow-up and that liver-related mortality due to this disease is ten-fold that of the general population. According to recent epidemiological studies, it is estimated that more than 10% of the U.S. adult population has NASH with more than 60% of patients (potentially more than 14 million in total) believed to have liver fibrosis or cirrhosis due to progression of the disease. The proportion of liver transplants attributable to NASH has increased rapidly in past years and by 2020 the disease is projected to become the leading indication for liver transplant ahead of chronic hepatitis C and alcoholic liver disease. NASH patients with fibrosis are at greater risk of progressing to cirrhosis, liver failure and cancer.
About Intercept and Obeticholic Acid
Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat neglected chronic liver diseases. The company's lead product candidate, obeticholic acid (OCA), is a first-in-class agonist of the farnesoid X receptor (FXR). OCA is being developed for a variety of chronic liver diseases, including primary biliary cirrhosis (PBC), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC) and biliary atresia. The
Safe Harbor Statements
This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the potential utility of the histological primary and secondary endpoints used in FLINT; the potential acceptance by regulatory authorities of the endpoints and data from FLINT; the potential of OCA to treat patients with NASH; the potential for OCA to improve histological features of NASH, including resolving liver fibrosis and limiting progression to cirrhosis; the potential that statin use may ameliorate LDL increases resulting from OCA treatment; the anticipated clinical, regulatory and commercial milestones for OCA, including the anticipated completion of the NDA for OCA in PBC in 2Q 2015 and the anticipated commercial launch of OCA in PBC in 2016; and our strategic directives under the caption
"About Intercept." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of important risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the initiation, cost, timing, progress and results of our development activities, preclinical studies and clinical trials; the timing of and our ability to obtain and maintain regulatory approval of OCA, INT-767 and any other product candidates we may develop, particularly the possibility that regulatory authorities may require clinical outcomes data (and not just results based on achievement of a surrogate endpoint) as a condition to any marketing approval for OCA, and any related restrictions, limitations,
and/or warnings in the label of any approved product candidates; our plans to research, develop and commercialize our product candidates; the election by our collaborators to pursue research, development and commercialization activities; our ability to attract collaborators with development, regulatory and commercialization expertise; our ability to obtain and maintain intellectual property protection for its product candidates; our ability to successfully commercialize our product candidates; the size and growth of the markets for our product candidates and our ability to serve those markets; the rate and degree of market acceptance of any future products; the success of competing drugs that are or become available; regulatory developments in
This press release contains the results of retrospective analyses presented at a scientific congress. Retrospective analyses after the unblinding of results can potentially introduce bias and regulatory authorities typically give greatest weight to results from pre-specified analyses as compared to retrospective analyses.
CONTACT: For more information about
Intercept Pharmaceuticals, please contact: Intercept Pharmaceuticals: Barbara Duncanor Senthil Sundaram+1-646-747-1000 firstname.lastname@example.org Media inquiries: Chantal Beaudryor Christopher Frates Lazar Partners+ 1-212-867-1762 Intercept@lazarpartners.com
News Provided by Acquire Media