Chronic Liver Disease Development Plans
In September 2014, we initiated a Phase 2 liver cirrhosis (LC) clinical trial in subjects with clinical, radiological, or biochemical evidence of liver cirrhosis, mild to moderate hepatic impairment and a Model for End-Stage Liver Disease, or MELD, score of 11 to 18 during the screening period and a Phase 2 PH clinical trial in subjects with clinical, radiological, or biochemical evidence of liver cirrhosis, mild to moderate hepatic impairment and portal hypertension (PH) confirmed by measurement of the hepatic venous pressure gradient, or HVPG, prior to enrollment.
Our ongoing LC clinical trial is assessing validated surrogate endpoints linked to the progression of liver disease and assessing whether emricasan can reduce or prevent progression in these endpoints, which are predictive of symptoms associated with liver decompensation. The Phase 2 LC clinical trial is expected to enroll approximately 80 subjects and consists of two stages. In the first stage, which is double-blind and placebo-controlled, subjects will be randomized 1:1 to receive either 25 mg of emricasan or placebo orally BID for three months. In the second stage, which will be open-label, subjects who complete the first phase of the trial, either on treatment or placebo, may receive emricasan for up to an additional three months. The primary endpoint is change from baseline in cCK18. Secondary endpoints include change from baseline in MELD score and change from baseline in Child-Pugh score, along with other biomarkers, as well as safety and tolerability.
The exploratory, open-label Phase 2 PH clinical trial is designed to enroll approximately 20 subjects. Subjects will receive 25 mg of emricasan orally BID for 28 days. The co-primary endpoints are the changes from baseline in cCK18 and HVPG. Secondary endpoints include the change from baseline in MELD score and the change from baseline in Child-Pugh score. Additional endpoints include other biomarkers as well as safety and tolerability.
POLT-HCV-SVR Development Plans
We were granted orphan drug designation in late 2013 by the FDA for the treatment of POLT patients with reestablished fibrosis to delay the progression to cirrhosis and end-stage liver disease. Our clinical development strategy in the POLT patient population is to conduct a Phase 2b clinical trial tracking biomarkers and histology in POLT-HCV-SVR patients. Only approximately 30% of non-transplant HCV patients with fibrosis and SVR show histological signs of fibrosis improvement two years after virus clearance. Our clinical trial is designed to significantly expand the safety database on emricasan while gaining insight as to the ability of emricasan treatment to improve the liver recovery process in POLT-HCV-SVR patients. We initiated the Phase 2b clinical trial in POLT-HCV-SVR subjects with fibrosis in May 2014 and modified the inclusion criteria in February 2015 to allow subjects with incomplete cirrhosis as well. The double-blind, placebo-controlled clinical trial is designed to enroll approximately 60 subjects. Subjects will be randomized 2:1 to receive either 25 mg of emricasan or placebo orally BID for 24 months. The primary endpoint in this exploratory proof-of-concept clinical trial is the change in the Ishak Fibrosis Score compared to placebo. The trial will also evaluate other histological markers and biomarkers as well as safety and tolerability.
NASH Development Plans
Emricasan has demonstrated activity in preclinical models of both nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In a preclinical model of NAFLD, emricasan reduced inflammation of adipose tissue, resolved hepatic steatosis and improved metabolic parameters by reducing fasting glucose and insulin levels. In preclinical models of NASH, emricasan inhibited apoptosis, fibrosis and inflammation associated with experimental NASH. We believed that these preclinical data provided support for evaluating emricasan in patients with NASH. In order to provide emricasan dosing data specific to patients whose liver disease is due to excess fat, we conducted a double-blind, placebo-controlled Phase 2 clinical trial in 38 patients with NAFLD, including the subset of NAFLD patients with NASH.
We announced top-line results from the Phase 2 trial in March 2015. The trial met its primary endpoint, showing a statistically significant (p<0.05) reduction in alanine amino transferase (ALT) in patients treated for 28 days with emricasan at 25 mg twice per day dosing compared to patients in the placebo control group. Reductions from baseline in ALT at Day 28 of approximately 39% in the emricasan treatment arm and approximately 14% in the placebo arm were similar to results observed in previous trials. Elevated baseline levels of three key serum biomarkers – caspase-cleaved cytokeratin 18 (cCK18), full length cytokeratin 18, and caspase 3/7 – also showed statistically significant reductions from baseline in emricasan-treated patients at Day 28. The baseline elevation in cCK18 confirmed that the underlying targets of emricasan’s mechanism, apoptosis and inflammation, which are believed to drive liver disease progression, were engaged in the NAFLD/NASH patients in this trial. A reduction from baseline in cCK18 at Day 28 of approximately 30% in the emricasan treatment arm and an increase from baseline of approximately 4% in the placebo arm were similar to results observed in previous trials. The reduction in serum cCK18 levels demonstrated that emricasan can effectively reduce inflammation and elevated levels of apoptosis in NAFLD/NASH patients. These results were consistent with data obtained from the company’s previous clinical trials in other liver disease patient populations.
Emricasan was safe and well tolerated in the NAFLD/NASH trial, with no dose-limiting toxicities and no drug-related serious adverse events. Treatment with emricasan also had no adverse effects on lipid levels or insulin sensitivity, important safety assessments in NAFLD/NASH patients who are at risk for cardiovascular disease.
We believe the results from the NAFLD/NASH trial have confirmed that the optimal dose of emricasan is consistent across different etiologies, and strengthened our belief that inhibiting excessive apoptosis and inflammation will be therapeutic in patients whose liver damage is associated with NASH. We further believe that the data from the NAFLD/NASH trial, along with the data from our three organ impairment dosing trials, support the conduct of efficacy trials in patients with liver cirrhosis due to NASH.
Information regarding potential validated surrogate endpoints in patients with cirrhosis was recently made available in a manuscript on findings and recommendations from the September 2013 workshop jointly sponsored by the American Association for the Study of Liver Diseases and the FDA on challenges and opportunities in drug and biomarker development for NASH. We believe that information from this workshop coupled with data from our ongoing Phase 2 NAFLD/NASH clinical trial will provide support for future development of emricasan in patients whose liver disease etiology is NASH.
We recently met with the FDA to discuss our proposed initial registration pathway for emricasan in patients with liver cirrhosis due to NASH. In the meeting, the FDA provided feedback on our proposed patient populations and methods of measuring and analyzing published validated surrogate endpoints of Model for End-stage Liver Disease, or MELD, score, Child Pugh Turcotte, or CPT, score, and hepatic venous pressure gradient, or HVPG, in patients with NASH cirrhosis. Specific design details for registration trials are expected to be finalized based on results expected in the second half of 2015 from our two ongoing cirrhosis clinical trials and additional feedback from regulatory agencies. We also discussed the use of histology-based endpoints for future clinical trials in the FDA meeting, and we are evaluating the potential to include a clinical trial in patients with NASH-driven fibrosis as a component of our overall emricasan registration strategy. We believe a clinical trial in NASH fibrosis could also provide additional safety data supportive of an initial registration in NASH cirrhosis.
Future Indications
Due to its mechanism of action and the presence of apoptosis and inflammation in many liver diseases, we believe there may be several patient populations that could potentially benefit from emricasan, including those that have previously failed HCV treatment and those with alcoholic liver disease, early-stage NAFLD, viral hepatitis and other chronic liver diseases. At this time, we do not plan to explore these indications; however, we may seek partners to pursue the evaluation of these potential indications.