To date, emricasan has been studied in over 650 subjects in eight Phase 1 clinical trials and eight Phase 2 clinical trials. This includes healthy volunteers, subjects with elevated liver biomarker levels, subjects with liver cirrhosis, and liver transplant subjects receiving single or multiple doses of emricasan ranging from 1 to 500 mg per day orally or 0.1 to 10 mg/kg per day intravenously for up to 12 weeks. Emricasan has demonstrated evidence of a beneficial effect on serological biomarkers in patients with chronic liver disease independent of the cause of disease. Favorable changes have been observed in functional biomarkers of liver damage and inflammation, such as ALT and AST, and mechanistic biomarkers, such as cCK18 and caspase activity, indicating that emricasan works by the presumed mechanism of action of inhibiting apoptosis of liver cells. Importantly, clinical trials have also demonstrated that emricasan does not inhibit normal levels of caspase activity in healthy individuals. Emricasan has been generally well-tolerated in clinical trials completed to date.
Phase 2 Clinical Trial in Patients with Liver Cirrhosis
We announced top-line results from the first stage of the Liver Cirrhosis (LC) Phase 2 trial in January 2016. The three-month, double-blind, placebo-controlled stage of our multicenter Phase 2 Liver Cirrhosis clinical trial showed a statistically significant reduction in caspase-cleaved cytokeratin 18 (cCK18) vs. placebo (p=0.04) in the overall patient population when adjusted for differences between treatment and placebo groups in baseline Model for End-stage Liver Disease (MELD)1 score and disease etiology as specified in the trial statistical analysis plan. cCK18 is a mechanism-specific biomarker of caspase-driven cell death. Multiple additional liver disease biomarkers achieved statistically significant reductions vs. placebo in the overall patient population after three months of treatment, while others achieved positive trends. The company believes that the consistent pattern of improvement across these biomarkers in the overall patient population provides strong evidence of a favorable treatment effect with emricasan, the company’s first-in-class, orally-active pan-caspase inhibitor.
Collectively, two key secondary endpoints and clinically relevant measures of liver function, MELD score and Child-Pugh-Turcotte (Child-Pugh)2 score, along with other key liver function parameters, demonstrated favorable trends vs. placebo in the overall patient population after three months of treatment.
Exploratory Subgroup Analyses Yield Clinically Meaningful Results
Importantly, the trends in the overall patient population were driven by statistically significant improvements in a subgroup of patients with baseline MELD scores ≥15, the established prerequisite for listing a patient for liver transplant. This pattern of greatest responses in highest need patients is consistent with the results from the company’s Phase 2 Portal Hypertension clinical trial announced in the third quarter of 2015.
Additional analyses of the three-month data showed the following broadly evident treatment effects in this subgroup:
- 1.6 reduction in mean MELD score with emricasan vs. 0.6 increase with placebo (p=0.003)
- Patients achieving at least 2-point reductions in MELD score
- 6 of 9 with emricasan vs. 2 of 10 with placebo
- Patients achieving reductions in MELD score to ≤14
- 4 of 9 with emricasan vs. 1 of 10 with placebo
- Patients achieving at least 2-point reductions in MELD score
- 0.6 reduction in mean Child-Pugh score with emricasan vs. 0.6 increase with placebo (p=0.003)
- Patients achieving at least 1-point changes in Child-Pugh score
- 4 of 9 had decreases with emricasan vs. 2 of 10 with placebo
- 0 of 9 had increases with emricasan vs. 4 of 10 with placebo
- Patients achieving at least 1-point changes in Child-Pugh score
Two clinically relevant measures of liver function and prognosis, MELD score and Child-Pugh-Turcotte (Child-Pugh)score, along with other key liver function parameters which demonstrated favorable trends in emricasan treatment effects vs. placebo (improvement in the emricasan group vs. progression in the placebo group) in the overall patient population after three months of treatment showed continued directional improvement after six months of treatment.
Key Exploratory Subgroup Results
Statistically significant emricasan treatment effects vs. placebo (improvement in the emricasan group vs. progression in the placebo group) after the first three months in a subgroup of patients with baseline MELD scores ≥15 showed continued directional improvements after the second three months.
In patients whose liver cirrhosis was caused by NASH, statistically significant emricasan treatment effects vs. placebo (slower progression in the emricasan group than in the placebo group) on measures of liver function after the first three months showed continued directional improvement after the second three months.
Consistent with the company’s previous 15 clinical trials, emricasan was generally well-tolerated in the Liver Cirrhosis clinical trial, and the overall safety profile was similar in the emricasan and placebo groups with regard to both serious and other adverse events.
Phase 2 Clinical Trial in Patients with Liver Cirrhosis and Portal Hypertension
We announced top-line results from the Phase 2 Portal Hypertension (PH) trial in September 2015. The trial met its primary endpoints, a) a clinically meaningful and statistically significant change from baseline in hepatic venous pressure gradient (HVPG), a measurement of pressure in the portal vein, in patients with liver cirrhosis and severe portal hypertension (HVPG ≥12 mmHg); and b) a statistically significant change from baseline in cleaved Cytokeratin 18 (cCK18), a mechanism-specific biomarker of excessive cell death that contributes to chronic inflammation, in the total evaluable liver cirrhosis patient population.
The open-label PH trial was conducted at nine U.S. sites and enrolled 23 patients (22 evaluable) with portal hypertension and compensated liver cirrhosis that was predominantly due to nonalcoholic steatohepatitis (NASH) or hepatitis C virus (HCV), including patients with active HCV infection and patients who had a sustained viral response (SVR) to antiviral therapy. Portal hypertension, or elevated blood pressure in the major vein feeding into the liver, was confirmed by HVPG measurement >5 mmHg at baseline and measured again after treatment with 25 mg of emricasan orally twice daily for 28 days. Patients were divided according to the HVPG therapeutic threshold of 12 mmHg, which indicates more severe portal hypertension. Reducing the HVPG to below 12 mmHg or reducing HVPG by ≥10% or ≥20% has been strongly associated with clinical benefit in this patient population.
The HVPG endpoint was analyzed in: a) patients with baseline HVPG values ≥12 mmHg (N=12); b) patients with baseline HVPG values <12 mmHg (N=10); and c) all evaluable patients (N=22). HVPG measurement was standardized, and tracings were evaluated by a single expert reader not otherwise involved in the PH trial. HVPG decreased by a mean of 3.7 mmHg from the mean baseline of 20.6 mmHg in the higher baseline HVPG group (p<0.003), with 8 of 12 achieving a ≥10% decrease, 4 of 12 achieving a ≥20% decrease, and 2 of 12 achieving reductions below 12 mmHg. The changes from baseline HVPG were not statistically significant in the lower baseline HVPG group (+1.9 mmHg mean increase from mean baseline of 8.1 mmHg; p=0.12) or the total evaluable patient population (–1.1 mmHg from mean baseline of 15.2 mmHg; p=0.26). The cCK18 endpoint, analyzed in the total evaluable patient population, showed a statistically significant reduction (p<0.03) from baseline. Consistent with results from prior trials, emricasan was safe and well tolerated in the PH trial, with no dose-limiting toxicities and no drug-related serious adverse events. Detailed results are expected to be presented in a future scientific forum.
We believe the results from the PH trial demonstrate that emricasan can cause a clinically meaningful improvement in portal hypertension in the liver cirrhosis patients who need it most. Specifically, patients with therapeutically relevant baseline portal hypertension showed meaningful decreases in HVPG. We believe the results from this trial establish the near-term effects of emricasan on portal hypertension.
Phase 2 Clinical Trial in Patients with Nonalcoholic Fatty Liver Disease (NAFLD), Including Patients with Nonalcoholic Steatohepatitis (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.