Clinical Trials

Date: 2017-05-12

Type of information: Presentation of results at a congress

phase: 2b

Announcement: presentation of results at the American Diabetes Association's 77th Scientific Sessions

Company: Intercept Pharmaceuticals (USA - NY)

Product: obeticholic acid (OCA)

Action mechanism:

• farnesoid X receptor agonist. Obeticholic acid (OCA) is a bile acid analog and a first-in-class farnesoid X receptor (FXR) agonist being developed for primary biliary cirrhosis (PBC), NASH and other chronic liver indications. Intercept has initiated a rolling New Drug Application with the FDA for PBC, and expects to complete the NDA and MAA submission in 2Q 2015. The commercial launch of OCA in the U.S. and Europe is planned in 2016. OCA was also recently granted breakthrough therapy designation by FDA for the treatment of NASH with liver fibrosis.

 

Disease: NASH (non-alcoholic steatohepatitis)

Therapeutic area: Liver diseases - Hepatic diseases

Country: USA

Trial details:

• The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial was sponsored by the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK). FLINT enrolled 283 adult NASH patients at eight U.S. centers comprising the NIDDK's NASH clinical research network (CRN). Patients were randomized to receive either a 25-mg dose of OCA or placebo for 72 weeks. Patients enrolled in the trial were qualified based on a diagnosis determined by liver biopsy at the start of the trial with a NAFLD Activity Score (NAS) of four or greater and with a score of at least one in each component of the NAS eight point scale (steatosis 0-3, lobular inflammation 0-3, ballooning 0-2). End of trial biopsies were conducted in patients after the 72-week treatment period, with all biopsies centrally scored in a blinded fashion. (NCT01265498)
• The results from the FLINT trial were published online in The Lancet in November 2014.

 

Latest news:

• • On June 12, 2017, Intercept Pharmaceuticals announced a retrospective analysis of the Phase 2 FLINT trial in patients who had a diagnosis of nonalcoholic steatohepatitis and type 2 diabetes. These data have been prestented presented at the American Diabetes Association's 77th Scientific Sessions in San Diego ("Improvements in Liver Histology with Obeticholic Acid in Patients with Nonalcoholic Steatohepatitis and Type 2 Diabetes Mellitus" was , California).
• Both type 2 diabetes and advanced fibrosis are associated with lower transplant-free survival in patients with NASH. In the FLINT trial, 149 NASH patients (53%) had type 2 diabetes and, within this population, 45% (67/149) had advanced bridging fibrosis (?F3). In a retrospective analysis of FLINT patients with a diagnosis of NASH and type 2 diabetes at baseline, a greater percentage of OCA-treated patients achieved the primary endpoint of the trial, a?2-point improvement in NAFLD activity score (NAS) without worsening of fibrosis, at week 72 as compared to placebo (57% vs. 21%, p<0.01). More than twice as many OCA-treated patients with fibrosis (F1-F3) experienced ?1 stage of fibrosis improvement as compared to patients in the placebo group (41% vs. 19%, p<0.05). This benefit was observed for every fibrosis stage.
• OCA treatment resulted in a mean 3.3 kg reduction in body weight from baseline compared to a 0.3 kg increase in the placebo group (p<0.01). Most patients (83-89%) were taking concomitant anti-diabetic medications and were generally well controlled at baseline (HbA1c of 7.0-7.2%). OCA administration did not impact glycemic control over the 72-week treatment period (HbA1c unchanged). Changes in liver and lipid biochemistry were similar to findings previously reported in FLINT.
• In FLINT the incidence of adverse events in the OCA and placebo arms were similar except for pruritus (23% vs. 6%, p< 0.0001). OCA-associated pruritus was mostly mild or moderate and resulted in only one patient discontinuation. The incidence of severe or life-threatening events was not different between the two treatment groups.
• • On November 14, 2015, Intercept Pharmaceuticals announced new results from the first non-invasive evaluation of liver fibrosis in patients from the FLINT trial of obeticholic acid for the treatment of nonalcoholic steatohepatitis (NASH). The data will be presented on November 17 at the American Academy for the Study of Liver Diseases (AASLD) Annual Meeting (The Liver Meeting®) in an oral presentation entitled, "Longitudinal changes in FIB-4 and improvement in fibrosis stage with obeticholic acid: A secondary analysis of FLINT Trial" . In the FLINT trial, treatment with once daily 25 mg obeticholic acid was shown to reverse fibrosis in a significant proportion of biopsy-proven NASH patients, as observed by repeat liver biopsy at the end of the double-blind treatment phase (week 72). The post-hoc analysis to be presented at AASLD evaluated the early predictive value of three known non-invasive fibrosis tests in identifying patients who experienced improvement in fibrosis: FIB-4, APRI and NFS. Each was assessed at baseline and over the course of treatment in the study population and then correlated with histologic changes observed in the 200 OCA and placebo patients who completed the trial with a repeat liver biopsy. The analysis demonstrated that OCA treatment of NASH patients in FLINT led to a statistically significant decrease in FIB-4 from baseline as compared to placebo (-0.246 OCA vs -0.047 placebo; p=0.0076). Further, a decline in FIB-4 of 10% after 24 weeks of treatment predicted improvement in fibrosis by at least one stage as assessed by biopsy at 72 weeks (p=0.0448). Similarly, OCA-treated patients experienced a significant decrease in APRI as compared to placebo (-0.243 OCA vs. -0.082 placebo; p=0.0009) and a 34% reduction in APRI at 24 weeks predicted improvement in fibrosis by at least one stage at 72 weeks (p=0.0346). On average, OCA treatment reduced the FIB-4 score to < 1.3 and the APRI score to < 0.5, the respective cut-off values associated with advanced fibrosis, while placebo patients remained above these cut-offs. While NFS declined in the OCA-treated patients and increased in the placebo patients, it did not appear to be sensitive to changes in fibrosis. Advanced liver fibrosis has been shown to be the best predictor of liver-related mortality in patients with NASH, and the current standard for staging fibrosis is liver biopsy. The FLINT results provide support for the use of both the FIB-4 and APRI scores as potential non-invasive alternative means for monitoring fibrosis changes in response to treatment through simple blood tests. FIB-4 is calculated using an algorithm based on aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count and age, while APRI is based on AST and platelet count alone.
• • On April 23, 2015, Intercept Pharmaceuticals 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.
• 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.
• • On March 20, 2015, Intercept Pharmaceuticals announced new subgroup analyses from the Phase 2b FLINT trial of obeticholic acid (OCA) in patients with nonalcoholic steatohepatitis (NASH). Intercept is presenting the data in two posters during poster session at the American Association for the Study of Liver Disease (AASLD) and Industry Colloquium: Novel Targets and Therapies in Liver Disease.
• OCA Histological Effects in High-Risk NASH Patients: Established fibrosis is currently the best predictor of liver-related mortality in patients with NASH (Younossi, Hepatology 2011), and patients with early disease but with risk factors such as diabetes, obesity or elevated ALT are at risk of rapid progression to cirrhosis (Adams, J Hepatology 2005; Ekstedt, Hepatology 2006). The efficacy of OCA was evaluated in a high-risk subset of NASH patients in the FLINT trial more likely to experience liver-related clinical outcomes, defined as patients with a NAFLD activity score (NAS) of 4 or more and (i) advanced fibrosis (stage 2 or 3), or (ii) those with both early fibrosis (stage 1) and concomitant diabetes, obesity or elevated ALT. In this post hoc analysis of the high-risk subgroup (n=160; OCA=84; placebo=76), OCA-treated patients experienced improvements in NASH resolution (18% OCA vs 5% placebo, p=0.014), NAS by ?2 points (60% OCA vs 30% placebo, p=0.0004), and liver fibrosis by at least one stage (39% OCA vs 21% placebo, p=0.007). Further analysis of the observed fibrosis improvement in NASH patient subgroups with the greatest risk of progression demonstrated that OCA treatment resulted in at least one stage fibrosis improvement in obese patients (39% OCA vs 18% placebo, p=0.003) and patients with diabetes (43% OCA vs 18% placebo, p=0.009). In addition, fewer OCA-treated patients experienced fibrosis progression (17% OCA vs 29% placebo, p=0.047). The histologic benefits observed in OCA-treated patients occurred across all baseline fibrosis stages, supporting the potential for long-term OCA treatment to prevent progression to cirrhosis.
• OCA Effects on Cardiometabolic Parameters: Patients with NASH generally experience cardiometabolic abnormalities that correspond to a relatively high cardiovascular disease risk and mortality. In the FLINT trial, OCA treatment for 72 weeks resulted in improvements in liver fibrosis (the hepatic feature most correlated with both cardiovascular and liver-related mortality) and other markers of cardiovascular risk, such as body weight (median: -1.7 kg OCA vs +0.6 kg placebo, p=0.001) systolic blood pressure (mean: -4.0 mmHg OCA vs -0.8 mmHg placebo, p=0.0331) and triglyceride/HDL ratio, a marker of cardiovascular risk and mortality (mean: -0.6 OCA vs 0.1 placebo, not significant). OCA treatment was not associated with changes in the Framingham Risk Score, a long-term measure of cardiovascular risk.
• This post hoc analysis also evaluated the effect of statin use during FLINT. 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 reaches 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.
• Further, another new finding in this analysis was that statin use appeared to have an additive effect to OCA-related improvements in liver biochemistry parameters, while not impacting liver histology.
• Previously Reported Safety and Tolerability Information: As previously reported in the primary analysis of FLINT, OCA was generally well tolerated. Adverse events were generally mild to moderate in severity and the incidence in the OCA and placebo treatment groups was similar for all symptoms except pruritus. Pruritus in the OCA treatment group occurred more frequently (23% vs 6%, p < 0.0001), at a higher grade (predominantly moderate pruritus) 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. As previously disclosed, two deaths occurred in the OCA treatment group, but neither was considered related to OCA treatment.

Is general: Yes