To date, emricasan has been studied in approximately 700 subjects in eight Phase 1 clinical trials and nine Phase 2 clinical trials. This includes approximately 500 subjects with liver disease, 50 liver transplant subjects and 150 healthy volunteers 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. Recent emricasan clinical trial results have demonstrated emricasan's ability to provide significant improvements in validated functional surrogate endpoints of portal hypertension and liver function across a variety of etiologies in the subgroups of liver cirrhosis patients with high medical need. Emricasan has been generally well-tolerated in clinical trials completed to date.
Phase 2 Clinical Trial in Liver Transplant Recipients with Residual Fibrosis or Cirrhosis
We announced top-line results from the company’s exploratory Phase 2b POLT-HCV-SVR proof-of-concept clinical trial in liver transplant patients with fibrosis or cirrhosis in April 2018. The POLT-HCV-SVR trial, initiated in the second quarter of 2014, enrolled post-orthotopic liver transplant (POLT) recipients whose transplanted livers were damaged by recurrent HCV infection. They subsequently achieved a sustained viral response (SVR) following HCV antiviral therapy, but their transplanted livers had residual fibrosis or cirrhosis (baseline Ishak Fibrosis Score of F2 to F6). Patients were randomized 2:1 to receive 25 mg of emricasan, the company’s first-in-class, orally active pan-caspase inhibitor, or placebo, twice daily for two years. Biopsies were taken at baseline, after one year of treatment, and after two years of treatment.
The primary endpoint was defined as the difference in percentage of responders between the treatment and placebo arms at the two-year biopsy compared with the baseline biopsy. A response was defined as improvement or stability in Ishak Fibrosis Score for patients with baseline scores of F2 to F5 or improvement in Ishak Fibrosis Score for patients with baseline scores of F6. The prespecified goal was a difference of 15 percentage points or more in response rates between the treatment and placebo arms.Although the trial did not meet its primary endpoint in the heterogeneous overall trial population, the emricasan treatment effect in the subgroup of patients where the histology endpoint is most relevant, patients with advanced fibrosis and early cirrhosis, supports further evaluation. POLT-HCV-SVR has a separate patient population versus the other three Phase 2b clinical trials in the company’s collaboration with Novartis, which are in non-viral indications in patient populations with nonalcoholic steatohepatitis (NASH) fibrosis or cirrhosis.
Patients were stable transplant recipients who were an average of seven years post-transplant on chronic immunosuppression. Hepatitis C virus (HCV), the initial cause of the inflammatory insult to the transplanted liver, was eliminated by antiviral therapies prior to the study.
This is the first demonstration of the anti-fibrotic efficacy with emricasan using a histology endpoint in patients with fibrosis. Consistent with the previous 16 clinical trials, emricasan was generally well-tolerated in the POLT-HCV-SVR clinical trial, and the overall safety profile was similar in the emricasan and placebo groups.
A descriptive summary of the observed response rates (patients with both a baseline and two-year biopsy) after two years of dosing for different stages of fibrosis is provided below. All p values noted are ad hoc, as prospective statistical powering was not feasible in this previously unstudied patient population.
Emricasan provided evidence of an anti-fibrotic treatment effect in the prespecified subgroup of patients with advanced fibrosis or early cirrhosis (F3-F5 at baseline), with 95.0% of patients (19/20) in the emricasan arm achieving responses in Ishak Fibrosis Score after two years of treatment, compared with 58.3% (7/12) in the placebo arm, a 36.7 percentage point difference in response rate (p<0.02). Inflammatory activity markers (ALT, cCK18, flCK18, Knodell activity index components) were either normal or only slightly elevated at baseline in both the emricasan and placebo groups.
Key takeaways from the POLT-HCV-SVR clinical trial are summarized below.
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.