To date, emricasan has been studied in over 600 subjects in eight Phase 1 clinical trials and seven 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 and Portal Hypertension (PH)
We announced top-line results from the Phase 2 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.
Phase 2b Pharmacokinetic (PK) and Pharmacodynamic (PD) Clinical Trial in ACLF Patients
In 2015, we announced results from a Phase 2b dose ranging clinical trial in ACLF patients. The ACLF clinical trial was designed to assess the PK and PD of emricasan, as well as biomarker and clinical responses, following twice daily, or BID, oral dosing of emricasan or placebo for 28 days. Patients were randomized to receive either placebo, 5 mg, 25 mg or 50 mg emricasan BID. The primary objective in this 28-day dosing trial was to evaluate the PK and PD together with the safety of emricasan to determine whether any dosing adjustments are needed in this critically ill patient population. We measured changes in liver function (creatinine, bilirubin and International Normalized Ratio), changes in biomarkers (ALT, cCK18, Caspase 3/7 and Interleukin 18), time to clinical worsening, or TTCW, which is defined as the first occurrence of liver transplant, progression to next organ failure or death and changes in extra-hepatic organ function. Twenty of 21 patients enrolled in the ACLF clinical trial had alcohol-associated liver disease, consistent with alcoholic liver disease being a major contributor to the ACLF patient population.
Emricasan exposure after the first dose was more than twice the exposure in patients with stable severe hepatic impairment. Emricasan was well-tolerated and there were no drug-related serious adverse events or dose-limiting toxicities. Adverse events observed were reflective of the patient populations being studied.
ALT levels were not increased in the ACLF patient population. By contrast, levels of mechanism-specific biomarkers of caspase activity and inflammation – cCK18, Caspase 3/7, and IL-18 – and a biomarker of more generalized cell death – full-length cytokeratin 18, or flCK18 – were all elevated at baseline, demonstrating their important role in the ACLF disease process. Dose-related responses to emricasan in elevated biomarkers were apparent with no response noted in the placebo cohort, limited or no response in the 5 mg BID cohort, an initial rapid but transitory response in the 25 mg BID cohort, and a rapid and sustained response in almost all of the 50 mg BID cohort. Emricasan 25 mg and 50 mg BID oral dosing reduced cCK18, flCK18 and Caspase 3/7 levels within 24 hours post administration (Study Day 2) by at least 30%. More modest ~20% reductions in elevated IL-18 levels were also observed in the 25 mg and 50 mg BID cohorts by Day 7. Only the emricasan 50 mg dose resulted in sustained reductions in cCK18 over the entire dosing period in the majority of patients. The median reduction in the 50 mg BID cohort on Day 2 was 54% compared with a median reduction of 7%, 13% and 44% in the placebo, 5 mg and 25 mg cohorts, respectively. The observed reduction in cCK18 was maintained in the 50 mg BID cohort (median reduction of 56% and 50% on Day 4 and Day 7, respectively) but not maintained in the other cohorts.
Phase 2b Dose Response Trial in HCV Patients (Study A8491003)
Study A8491003, or the 003 trial, was a Phase 2b, randomized, multicenter, double-blind, placebo-controlled, parallel group, dose response clinical trial. The trial was designed to evaluate the safety and efficacy of emricasan in patients with chronic HCV infection who were unresponsive to antiviral therapy and who had compensated liver disease with or without fibrosis. Patients with cirrhosis or hepatocellular carcinoma were excluded from the clinical trial. The clinical trial enrolled 204 HCV patients across three oral emricasan dose arms of BID 5 mg, 25 mg and 50 mg and one placebo arm. The primary endpoint in the trial was changes from baseline in ALT and AST levels over a period of 12 weeks. This trial also measured cCK18 levels and caspase 3 and 7 activity as exploratory biomarkers. In this clinical trial, emricasan treatment resulted in statistically significant reductions in the primary endpoints of ALT and AST levels as well as statistically significant reductions in cCK18 levels and caspase 3 and 7 activity.
As shown below, the changes in ALT demonstrated in the 003 trial were statistically significant in each of the emricasan treatment groups compared with the placebo group. The decreases in ALT were seen by day seven, the first time post-dosing that ALT was measured, and the decreases were maintained throughout the treatment period (up to 12 weeks) in all emricasan treatment groups. Discontinuation of emricasan at the end of the treatment period was followed by a gradual return of ALT towards baseline levels.
Change in ALT (Mean ± SEM(1)) from Baseline Following BID Dosing in Subjects with HCV
(1) Standard Error of the Mean.
(2) Upper limit of normal for males.
In addition to ALT levels, the 003 trial also examined changes in AST levels. As shown below, the reductions in AST levels demonstrated in the 003 trial were also statistically significant in each of the emricasan treatment groups compared with the placebo group. Consistent with the ALT results, reductions in AST levels were seen as early as seven days and were maintained throughout the treatment period. At the end of treatment, AST levels gradually returned to baseline levels. During the 003 trial, biochemical flare, which is defined as ALT or AST values twice as high as the baseline value while on emricasan treatment, or overshoot, which is defined as ALT or AST values twice as high as the baseline value after stopping emricasan treatment, occurred in patients randomized to both placebo and emricasan. Twenty-one patients in the clinical trial experienced flare and/or overshoot; six of these patients had both flare and overshoot; six of these patients had flare only; and nine of these patients had overshoot only. Of the six patients with flare and overshoot, four were in the placebo group, one was in the 5 mg group and one was in the 25 mg group. Of the six patients with flare only, two were in the placebo group, one was in the 5 mg group and three were in the 50 mg group. Of the nine patients with overshoot only, one was in the placebo group, five were in the 5 mg group, two were in the 25 mg group and one was in the 50 mg group. These data suggest that the occurrence may be part of the natural variability of ALT or AST levels in the patient population under study. All subjects were followed up until levels had returned to baseline levels and there were no reports by the investigator of any clinical concern.
Change in AST (Mean ± SEM(1)) from Baseline Following BID Dosing in Subjects with HCV
(1) Standard Error of the Mean.
(2) Upper limit of normal for males.
The 003 trial data also provide evidence that emricasan reduces cCK18 levels from baseline in patients with elevated cCK18 levels, as shown 5 below. Statistically significant reductions in cCK18 levels were reported as early as three hours after dosing and were still evident following ten weeks of treatment, within each of the 5 mg, 25 mg and 50 mg dose arms compared to baseline values in the relevant dose group. Importantly, in the 003 trial, after ten weeks of dosing, cCK18 levels in all emricasan treatment groups were similar to the baseline level of cCK18 in healthy volunteers as established in our Phase 1 clinical trial (see the description of trial IDN-6556-03 below) and as generally reported from independent trials. We believe this observation suggests that normal levels of caspase activity remain intact. We also believe that by returning apoptosis to normalized levels, emricasan may enable the balance between apoptosis and the body’s normal clearance mechanism for apoptosis to be restored.
Change in cCK18 from Baseline Following BID Dosing in Subjects with HCV
The 003 trial also included measurements of caspase 3 and 7 enzymatic activity. As shown below, emricasan significantly reduced caspase 3 and 7 activity in a pattern similar to its effect on cCK18. We believe these data demonstrate that emricasan rapidly reduces elevated levels of caspase enzymatic activity and, as a consequence, excessive apoptosis in these patients. Since caspase 3 and 7 are known to be involved in the cleavage of CK18, which produces cCK18, we also believe these data suggest that the effect of emricasan on cCK18 is a result of inhibiting caspase activity. In addition, consistent with the cCK18 data, emricasan did not eliminate all caspase 3 and 7 activity in these patients. We believe this suggests that emricasan does not interfere with normal base levels of caspase activity or apoptosis, which is important in establishing the overall safety profile of emricasan.
Change in Caspase 3 and 7 Enzymatic Activity from Baseline Following BID Dosing in Subjects with HCV
In the 003 trial, emricasan was generally observed to be well-tolerated. The most commonly reported adverse events in emricasan-treated subjects were headache, fatigue, nausea and diarrhea, most of which were mild to moderate in severity. Thirteen subjects withdrew from the trial including seven in the placebo group, three from the 5 mg, two from the 50 mg and one from the 25 mg emricasan groups. Nineteen adverse events reported by 14 subjects were considered severe with the greatest incidence in the placebo and 5 mg emricasan-treated groups (seven events each) and the lowest incidence in the 25 mg treatment group (one event). Severe adverse events were varied and showed no pattern across the treatment groups. The majority of adverse events had been resolved by the end of the trial, and the numbers of continuing events were similar for each of the patient cohorts. In addition, no concerning changes in any of the laboratory parameters and no clinically relevant changes in vital signs, electrocardiograms, physical examinations or liver ultrasound scans could be attributed to emricasan
Phase 2 Ascending Dose Trial in Patients with Hepatic Impairment (Study A8491004)
Study A8491004, or the 004 trial, was a Phase 2, randomized, multicenter, double-blind, placebo-controlled, ascending dose clinical trial in 105 patients with mild to moderate hepatic impairment. The trial was designed to evaluate the safety, tolerability and PK of several dosing regimens of orally administered emricasan in these patients. The secondary objective of the clinical trial was to evaluate the effects of emricasan on ALT and AST, as markers of efficacy. The clinical trial was conducted at seven trial sites, and emricasan was administered orally for up to three times daily for 14 days. The trial predominantly included patients with HCV liver disease and also included limited numbers of patients with liver disease attributed to other causes, including HBV, NASH and primary biliary cirrhosis/primary sclerosing cholangitis. While once-daily, or QD, and BID dosing in the HCV patients demonstrated significant reductions in ALT from baseline, the BID dosing cohorts demonstrated greater percentage decreases of ALT levels than QD dosing.
In the 004 trial, 25 HCV patients were administered emricasan once per day for 14 days. As shown below, ALT reductions were rapid and sustained during the 14-day dosing period with a 30% to 40% reduction from baseline. While ALT decreases were statistically significantly different than placebo for QD dosing at 25 mg, 100 mg and 200 mg (p-values ranging from 0.0041 to <0.0001), those seen at a QD dose of 5 mg were less dramatic. After treatment with emricasan was completed, ALT levels returned to pre-treatment levels.
Percentage Change in ALT from Baseline Following QD Dosing in Subjects with HCV
The 004 trial also examined BID and three times daily, or TID, dosing of emricasan. In the clinical trial, 30 patients received BID dosing at different dose levels and six patients were treated TID. As shown below, ALT reductions were rapid and sustained during the 14-day dosing period. In general, decreases in ALT were more pronounced than with QD dosing, with ALT reductions from baseline ranging from 39% to 56%. One cohort of patients was treated with 5 mg TID dosing. The results from this dosing group were similar to the BID dosing groups. Patients with liver disease from causes other than HCV were dosed at 100 mg BID. Most of these patients had reductions in ALT similar to those observed in the HCV patients. All dosing groups were statistically significantly different than placebo (p-values ranging from 0.0041 to <0.0001).
Percentage Change in ALT from Baseline Following BID and TID Dosing in Subjects with HCV
In all of the patient populations in this trial, emricasan was generally well-tolerated. The most commonly reported adverse events related to emricasan were upper abdominal pain, dyspepsia, fatigue, dizziness and headache. No subject was discontinued due to an adverse event. Importantly, in both the HCV and HBV infected patients studied, no increases in viral load parameters were observed.
Phase 2 Ascending Dose Crossover Trial in Patients with HCV and Liver Fibrosis (Study A8491010)
Study A8491010 was a Phase 2, randomized, double-blind, placebo-controlled crossover dose response clinical trial of emricasan in 24 patients with chronic HCV infection and liver fibrosis conducted by Pfizer. This trial assessed the effects of BID dosing of emricasan on ALT and AST levels in these patients. For each patient, the trial consisted of a screening visit, a two-week baseline period, three 14-day trial periods separated by a minimum washout period of two weeks and a two-week follow-up period after the last treatment period. Each patient was to receive three of five possible treatments (emricasan 0.5, 1, 2.5, 5 mg or placebo) BID for 13 days and QD on the final day of each trial period. This clinical trial was voluntarily discontinued early due to an unanticipated finding of inflammatory infiltrates in mice in a preclinical study that was ongoing concurrently with the clinical trial and was unrelated to this Phase 2 clinical trial. Pfizer notified the FDA of the findings in mice and the discontinuation of the clinical trial, which resulted in the agency placing a clinical hold on the study of emricasan in 2007. At the time the clinical hold was imposed, 18 of 24 subjects had completed study A8491010. Because the trial was discontinued prematurely, formal statistical tests were not performed. However, reductions in ALT in the 5 mg BID dose group were similar to the results of the 5 mg BID dose groups in the 003 and 004 trials. As described in the Emricasan History section below, the clinical hold was lifted in January 2013.
Phase 2 Trial of IDN-6556 in Patients with Severe Alcoholic Hepatitis and Contradictions to Steroid Therapy
We were previously supporting a pilot clinical trial funded by the National Institute on Alcohol Abuse and Alcoholism in patients with alcoholic hepatitis. This exploratory trial was a placebo-controlled trial that was being conducted at three centers in the United States to assess patient survival as the primary endpoint. In November 2014, we notified the FDA, the National Institute on Alcohol Abuse and Alcoholism and the clinical sites involved in the trial that we were terminating the clinical trial prematurely. This decision was based on data from our PK clinical trials in hepatic impairment subjects, which showed higher than expected exposure of emricasan in blood levels in patients with severe hepatic impairment. Trial closure activities are now occurring at the clinical sites.
Clinical Studies in Organ Preservation in Transplant Patients
Preclinical studies demonstrated that emricasan is effective in protecting organs from damage that can occur during transplantation due to ischemia or reduced oxygen during isolation of donor organs and reperfusion injury resulting from rapid exposure to oxygen following transplantation.
Phase 2 Efficacy and Safety in Patients Undergoing Liver Transplantation (Study A8491002)
Study A8491002 was a Phase 2 randomized, double-blind, placebo-controlled, parallel group clinical trial to evaluate the effects of emricasan when administered in liver transplantation storage and flush solutions used in the preparation of the donated liver and when administered to the recipient via IV during the first 24 hours after liver transplantation. Ninety-nine patients were randomized into one of four groups. In the first group, the liver was treated with placebo in the storage and flush solution and the patient was given placebo following transplantation. In the second group the liver was treated with 15 µg/mL emricasan in the storage and flush solution, but the patient received placebo following transplantation. The third group was treated with a lower concentration of emricasan, 5 µg/mL, in the storage and flush solution, and the patient received 0.5 mg/kg emricasan for 24 hours by IV administration following transplantation. The fourth group was treated with 15 µg/mL emricasan in the storage, and flush solution and the patient received 0.5 mg/kg emricasan for 24 hours by IV administration following transplantation.
The co-primary endpoints were peak absolute change from baseline in ALT and AST measured up to three days post-transplantation. Large increases in both ALT and AST occurred in all groups reflecting liver injury typically occurring after liver transplantation. The outcome on the co-primary endpoints was not different between the placebo and the treatment groups possibly due to the short duration of drug treatment (24 hours) following transplantation. A serum marker of liver cell apoptosis, cCK18, was reduced in all groups receiving drug as compared to placebo. In addition, the level of liver cell apoptosis in liver tissue as determined by quantitation of cells with caspase 3 and 7 activity was reduced in all groups receiving emricasan, suggesting that the drug has activity through the anticipated mechanism of action.
Generally, the adverse events reported in the trial were reflective of the severity of disease in the patient population. There were 1,240 adverse events reported in the 99 subjects, with similar numbers reported across the four trial groups, as discussed above. There were 79 serious adverse events (6.4%) reported by 32 patients in this trial. Of all the adverse events, 15 events were reported as possibly treatment-related but none were reported as probably or definitely treatment-related. The type and frequency of adverse events were similar across all groups, including placebo. There were deaths reported in all treatment groups (two in the placebo treatment group and one in each of the emricasan treatment groups). These data in total support the conclusion that treatment with emricasan in this trial has been generally well-tolerated.
Phase 2 Safety and Efficacy in Clinical Islet Transplantation
Health Canada clinical trial PRO00024049, an investigator sponsored clinical trial, was initiated in 2012 at the University of Alberta to evaluate the safety and efficacy of islet cell culture and short-term (14 days) oral administration of emricasan in patients with established Type 1 diabetes mellitus with unstable glycemic control. This clinical trial was an open-label pilot trial conducted in two parts, Pilot 1 (low dose) and Pilot 2 (high dose), and funded by a grant from the Juvenile Diabetes Research Foundation. Patients enrolled in this clinical trial were not able to adequately regulate their blood glucose levels with insulin. The patients underwent pancreatic islet cell transplantation, a procedure referred to as the Edmonton procedure, with the goal of eliminating their need for insulin. One objective of this clinical trial was to determine whether emricasan can improve upon the success rate of the Edmonton procedure by reducing the amount of islet cell death after transplantation. Patients were dosed orally for 14 days following islet transplantation and then monitored for their ability to control blood glucose without the need for insulin. In both Pilots of the trial, the proportion of patients who became insulin independent will be assessed at 90 days, six months, 12 months and yearly thereafter to three years. Enrollment and treatment is complete for all patients in Pilot 1 and Pilot 2, and patients are being observed for the scheduled assessments.
Phase 1 Clinical Trials
We have conducted eight Phase 1 clinical trials in subjects with both single and multiple-dose administration of emricasan. The objective of these trials was to examine the safety, tolerability, PK and, in some trials, the mechanistic PD of emricasan. As shown below, emricasan was generally well-tolerated in all eight Phase 1 clinical trials.
Emricasan Phase 1 Clinical Trial Summary
A Phase 1 clinical trial was conducted in subjects with hepatic impairment to evaluate the PK and PD of a single 50 mg oral dose of emricasan. This clinical trial included subjects with mild, moderate and severe hepatic impairment (corresponding to Child-Pugh A, B and C, respectively). A control group was matched to the severe hepatic impairment group. Emricasan rapidly reduced the PD and mechanism specific biomarker of apoptosis, cCK18, as shown below. Emricasan also reduced a generic biomarker of cell death, flCK18, as well as caspase enzymatic activity, shown in the figures below, respectively.
Absolute Change from Baseline of cCK18 in the Hepatic Impairment Clinical Trial
Absolute Change from Baseline of flCK18 in the Hepatic Impairment Clinical Trial
Absolute Change from Baseline of Caspase 3/7 in the Hepatic Impairment Clinical Trial
To understand the activity of emricasan on caspase activity in healthy subjects, a Phase 1 clinical trial (trial IDN-6556-03) in 15 subjects was conducted. In the clinical trial, the levels of cCK18 in healthy human subjects was measured pre-dosing and then after dosing at different time intervals up to 12 hours post dosing. In this trial, patients were administered 25 mg of emricasan BID as part of a drug-drug interaction trial for 24 days with blood levels of cCK18 measured serially on days one, 17 and 24. As shown below, dosing with emricasan did not cause meaningful decreases in cCK18 from predose levels in healthy subjects. We believe this demonstrates that emricasan does not interfere with the normal level of caspase activity and apoptosis in humans.