Intercept Pharmaceuticals, Inc. (Intercept) has announced the availability of additional post-hoc analyses from the Phase 2b FLINT trial of obeticholic acid (OCA) in patients with nonalcoholic steatohepatitis (NASH) at the International Liver Congress 2015, the 50th Annual Meeting of the European Association for the Study of the Liver (EASL), being held in Vienna, Austria, from April 22-26, 2015.
The poster entitled “Obeticholic Acid for NASH: Benefits in a High-Risk Subgroup and the Effects of Concomitant Stain Use” (late-breaker ePoster LP18) is currently available for viewing and will be presented in Room A-09 at 3:30 p.m. CET on Saturday April 25, 2015.
The senior authors include Dr. Brent Neuschwander-Tetri, of St Louis University and Dr. Arun Sanyal, former President of the American Association of the Study of Liver Disease, from the NASH Clinical Research Network that conducted the trial.
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 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.