Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis
Catherine Frenette, Zeid Kayali, Edward Mena, Parvez S. Mantry, Kathryn J. Lucas, Guy Neff, Miguel Rodriguez, Paul J. Thuluvath, Ethan Weinberg, Bal R. Bhandari, James Robinson, Nicole Wedick, Jean L. Chan, David T. Hagerty, Kris V. Kowdley, for the IDN-6556-17 Study Investigators
PII: S0168-8278(20)33673-4
DOI: https://doi.org/10.1016/j.jhep.2020.09.029 Reference: JHEPAT 7961
To appear in: Journal of Hepatology
Received Date: 20 February 2020
Revised Date: 6 September 2020
Accepted Date: 22 September 2020
Please cite this article as: Frenette C, Kayali Z, Mena E, Mantry PS, Lucas KJ, Neff G, Rodriguez M, Thuluvath PJ, Weinberg E, Bhandari BR, Robinson J, Wedick N, Chan JL, Hagerty DT, Kowdley KV, for the IDN-6556-17 Study Investigators, Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis, Journal of Hepatology (2020), doi: https://doi.org/10.1016/ j.jhep.2020.09.029.
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© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Primary Efficacy Analysis using interim database Emricasan 5 mg
(N=73) Emricasan 25 mg
(N=71) Placebo
(N=70)
First Primary Event (interim database)
Total # of events 26 (35.6) 29 (40.8) 25 (35.7)
Variceal Hemorrhage 0 5 (7.0) 1 (1.4)
New Onset Ascites 0 1 (1.4) 1 (1.4)
Spontaneous Bacterial Peritonitis 0 0 1 (1.4)
4-point MELD-Na Score Progression 25 (34.2) 22 (31.0) 20 (28.6)
Death 1 (1.4) 1 (1.4) 2 (2.9)
Neither active treatment was superior to placebo treatment
Title: Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis
Authors: Catherine Frenette1, Zeid Kayali2, Edward Mena3, Parvez S. Mantry4, Kathryn J. Lucas5, Guy Neff6, Miguel Rodriguez7, Paul J. Thuluvath8, Ethan Weinberg9, Bal R. Bhandari10, James Robinson11, Nicole Wedick12, Jean L. Chan11, David T. Hagerty11, and Kris V. Kowdley13 for the IDN-6556-17 Study Investigators.
1Department of Organ Transplant, Scripps Clinic, La Jolla, CA. [email protected]
2Inland Empire Liver Foundation, Rialto, CA. [email protected]
3California Liver Research Institute, Pasadena, CA. [email protected]
4Methodist Health System Clinical Research Institute, Dallas, TX. [email protected] 5Diabetes & Endocrinology Consultants, PC, Moorhead City, NC. [email protected] 6Covenant Research, Lakewood Ranch, FL. [email protected]
7IMIC Inc, Palmetto Bay, FL. [email protected]
8Mercy Medical Center, Baltimore, MD. [email protected]
9University of Pennsylvania Medical Center, Philadelphia, PA. [email protected]
10 Delta Research Partners, Bastrop, LA. [email protected]
11Conatus Pharmaceuticals, Inc., San Diego, CA. [email protected]
12SimulStat, Inc., Solana Beach, CA. [email protected] 12Conatus Pharmaceuticals, Inc., San Diego, CA. [email protected] 12Conatus Pharmaceuticals, Inc., San Diego, CA. [email protected] 13Liver Institute Northwest, Seattle, WA. [email protected]
Word count: 6663
Number of tables: 3 (main body); 7 (supplemental)
Number of figures: 2
Correspondence: Kris V. Kowdley MD, Liver Institute Northwest, 3216 NE 45th Place, Suite 212, Seattle, WA 98105 [email protected]
Abbreviations: alanine aminotransferase (ALT), aspartate aminotransferase (AST), Child-Turcotte-Pugh (CTP), cleaved keratin-18 (cCK18), confidence interval (CI), emricasan 5 mg (EMR5), emricasan 25 mg (EMR25), full-length keratin-18 (flCK18), hepatic encephalopathy (HE), hepatorenal syndrome (HRS), non-alcoholic steatohepatitis (NASH), least square means (LSM), Model for End-stage Liver Disease- Sodium (MELD-Na), relative light units (RLU), spontaneous bacterial peritonitis (SBP), treatment- emergent adverse event (TEAE), twice-daily (BID), variceal hemorrhage (VH)
Financial support: The study was funded by Conatus Pharmaceuticals, Inc and Novartis.
Keywords: NASH, MELD-Na, ascites, hepatic encephalopathy, variceal hemorrhage
Disclosures: James Robinson, Jean L. Chan and David Hagerty were employees of Conatus Pharmaceuticals, Inc and Nicole Wedick was a consultant employed by Conatus Pharmaceuticals, Inc.
Author contributions: Kris Kowdley, Catherine Frenette, James Robinson, Jean L. Chan, and David T. Hagerty designed the study, analyzed the results and participated in writing the manuscript. Kris Kowdley and Catherine Frenette were the lead study investigators and participated in the analysis and writing of the manuscript. Nicole Wedick analyzed the results and participated in writing the manuscript. Zachary Goodman read all study liver biopsies and participated in writing the manuscript. Zeid Kayali, Edward Mena, Parvez S. Mantry, Kathryn J. Lucas, Guy Neff, Miguel Rodriguez, Paul J.
Thuluvath, Ethan Weinberg, Bal R. Bhandari were study investigators and participated in writing the manuscript.
Data availability statement: Data were collected by investigators and analyzed by the Sponsor. Authors
had access to the data after unblinding, participated in data analysis and interpretation, and vouch for the accuracy of the results.
Abstract:
Background and aims: Nonalcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity result in chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation, and decreased portal pressures and improved synthetic function in mice with CCl4-induced cirrhosis.
Methods: This double-blind, placebo-controlled study randomized 217 subjects with decompensated NASH cirrhosis 1:1:1 to emricasan (5 or 25 mg) or placebo. Patients were stratified by decompensation status and baseline MELD-Na score. The primary endpoint was comprised of any subject who died, had a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥ grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points.
Results: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (5 mg; 95% confidence interval 0.59, 1.77; p=0.94) and 1.28 (25 mg; 95% confidence interval 0.75, 2.21; p=0.37). MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, INR, total serum bilirubin albumin level or Child-Turcotte-Pugh score. Emricasan was generally safe and well-tolerated.
Conclusions: Emricasan was safe but ineffective in treatment of decompensated NASH cirrhosis with regard to MELD-Na score improvement, reducing new decompensation events, improving liver function or mortality. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis.
Lay summary: Patients with decompensated NASH cirrhosis are at high risk of additional decompensation events and death. Post-hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated NASH cirrhosis.
ClinicalTrials.gov Identifier: NCT03205345
Introduction
Non-alcoholic steatohepatitis (NASH) is the most rapidly growing indication for liver transplantation[1] and the second most common cause of chronic liver disease in patients listed for transplant in the United States[2]. Excessive accumulation of lipids in the liver leads to lipotoxicity, chronic inflammation and hepatocellular damage through oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and activation of death receptors[3]. Caspases are intracellular proteases that activate pro- inflammatory cytokines such as IL-1 and mediate apoptotic cell death by cleaving cytoskeletal proteins such as cytokeratin-18[4]. Levels of cleaved cytokeratin-18 (cCK18) are elevated in patients with NASH[5] and the degree of apoptosis correlated with fibrosis and inflammation[6], suggesting that excessive apoptosis may contribute to developing NASH.
Emricasan is an oral pan-caspase inhibitor that inhibits excessive apoptosis and inflammation in NASH. In addition to decreasing liver injury and fibrosis in a mouse model of NASH[7], emricasan decreased portal pressure and/or improved survival in rodent models of cirrhosis[8]. In rats with CCl4-induced cirrhosis and ascites, emricasan tab liver and microcirculatory function (increase in bile production) and reduced hepatic inflammation with improvement in sinusoidal endothelial cell and hepatic stellate cell phenotypes[9]. In an exploratory 3-month placebo-controlled study of 86 patients with Child-Turcotte- Pugh (CTP) class A or B cirrhosis and elevated Model for End-stage Liver Disease (MELD-Na) score of 11 to 18, emricasan reduced MELD-Na and CTP scores, especially those with MELD-Na ≥15 and NASH cirrhosis[10].
We therefore conducted a randomized, double-blind, placebo-controlled multicenter trial of emricasan in patients with decompensated NASH cirrhosis who had ascites requiring diuretics and/or a history of
variceal hemorrhage to determine if emricasan treatment could improve all-cause mortality, new decompensation events, and MELD-Na progression.
Materials and Methods
Study Design
The study was conducted in outpatients at 91 sites in the U.S. The first subject was enrolled on 13April2017 and the last visit was 23July2019. Eligible subjects were randomized 1:1:1 using a validated program to twice-daily emricasan (5 or 25 mg) or placebo, stratified by baseline decompensation status (variceal hemorrhage [VH] alone, ascites alone, or both VH and ascites) and MELD-Na category (<15 or
≥15). Treatment was intended to be until the last subject in the study reached 48 weeks of treatment. A follow-up visit off study drug was done approximately 2 weeks after the final on-treatment visit. The Sponsor, investigational staff and subjects were blinded until the primary efficacy analysis was conducted.
The Sponsor and clinicians experienced in NASH cirrhosis designed the study. The protocol was approved by institutional review boards prior to study-related procedures and conducted according to the 1975 Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines. Subjects provided written informed consent prior to study-related procedures. An independent Data Monitoring Committee reviewed unblinded safety and efficacy data every 3 months. External experts not involved in the study performed blinded adjudication for all subjects that may have met the primary endpoint for clinical events of hepatic encephalopathy (HE) and hepatorenal syndrome (HRS). Decompensation events of new or recurrent VH and new ascites requiring diuretic treatment
were captured as adverse events and not adjudicated. Data were collected by investigators and analyzed by the Sponsor. Authors had access to the data after unblinding, participated in data analysis and interpretation, and vouch for the accuracy of the results. All authors reviewed the manuscript and approved submission.
Patient Population
Subject were 18 years or older, willing to comply with study requirements and to use effective contraception. They had NASH cirrhosis with exclusion of other causes of cirrhosis and had at least 1 decompensation event of VH or a history of at least moderate ascites currently requiring diuretic treatment. The cirrhosis diagnosis was based on either biopsy or clinical criteria (platelet <150K, AST>ALT, and either nodular liver surface on imaging or splenomegaly) or evidence of significant portal hypertension (gastroesophageal varices or ascites). The diagnosis of NASH as the etiology required one of the following: a prior or current biopsy showing NASH; ≥2 metabolic risk factors (diabetes mellitus, impaired fasting glucose, obesity, hypertension, high triglycerides, low high-density lipoprotein) for ≥5 years prior to cirrhosis; or fatty liver disease on prior imaging and at least 1 metabolic risk factor for at least 5 years prior to cirrhosis. Subjects with a history of VH had the event ≥3 months prior to randomization. Subjects treated with vitamin E were on a stable dose at least 6 months. Previous transient ascites or ascites that was not clinically evident or requiring treatment were not sufficient for meeting the ascites inclusion criteria. Subjects were required to have MELD-Na score ≤20, albumin ≥2.5 g/dL, and serum creatinine ≤1.4 mg/dL during screening.
Exclusion criteria included ascites requiring regular therapeutic paracenteses; ascites complicated by hyponatremia within 3 months; prior spontaneous bacterial peritonitis (SBP); acute kidney injury within
3 months; history of HRS; >1 episode of VH within 12 months; >2 episodes of HE requiring hospitalization within 6 months; or CTP score ≥10.
Complete inclusion/exclusion criteria are in Supplemental Table 1.
Dose selection
Emricasan doses were selected based on biomarker dose-response modelling using ALT, AST, cCK18, and caspase 3/7 in earlier studies that were conducted primarily in patients with chronic liver disease due to HCV infection, as well as based on the dose (25 mg) used in a previous placebo-controlled study evaluating the 25 mg dose of emricasan in cirrhosis patients (majority decompensated) with elevated MELD-Na scores[10].
Study Endpoints
The primary efficacy measure included all-cause mortality; new decompensation events (any VH documented by endoscopy and requiring hospitalization; new ascites requiring diuretics in a subject without prior history of ascites requiring diuretics; new onset unprecipitated HE ≥grade 2 requiring hospitalization in a subject without prior history of HE ≥grade 2; HRS requiring hospitalization; spontaneous bacterial peritonitis [SBP] requiring hospitalization); or MELD-Na score increase ≥4 points from baseline. An independent adjudication committee evaluated HE and HRS events to determine if they met criteria of the primary endpoint. SBP was defined based on ascitic fluid polymorphonuclear leukocyte count >250 cells/mm3. MELD-Na score progression excluded subjects who were treated with anticoagulants during the study. Subjects met the primary endpoint if they experienced any of the
events, with the first event being counted. Subjects with MELD-Na score progression alone remained on study medication and continued in the study. Subjects who underwent liver transplant were withdrawn from the study.
Other efficacy endpoints included: composite clinical endpoint without MELD-Na progression, changes in biomarkers (including caspase 3/7, cCK18, flCK18, ALT, AST) and clinical labs/scores (MELD-Na, CTP, total bilirubin, INR, serum albumin).
Clinical laboratory tests and biomarker measurements were performed by PPD Labs (Highland Heights, KY, USA; Zaventem, Belgium). Full-length keratin-18 (flCK18) and caspase-cleaved keratin-18 (cCK18) were quantified in sera using enzyme-linked immunosorbent assays detecting the M65 epitopes (VLVbio, Sundbyberg, Sweden; measures both full-length and cleaved keratin-18, reference range: 115- 413 U/L) and the M30 epitope (VLVbio, Sundbyberg, Sweden; measures cleaved keratin-18 only, reference range: <260 U/L), respectively. Executioner caspase-3/7 activity (Caspase-Glo 3/7, Promega, Madison, WI, USA; reference range: 1429-3908 relative light units or RLU) was measured in sera.
Statistical Analyses
The primary efficacy analysis was planned when at least 72 subjects met the primary endpoint. All subjects with a primary event at the interim database lock were included in the analysis. The primary analysis used a Cox proportional hazards regression model with treatment group, baseline decompensation status (VH alone, ascites alone, or both), and baseline MELD-Na (<15 or ≥15) as factors. Subjects not experiencing an event at the time of the primary analysis were censored on the date of their last study visit. A multiplicity adjustment for the 2 primary efficacy comparisons (of each emricasan
dose vs. placebo) was made according to the Holm’s testing procedure to protect the overall type 1 error rate at the 20% (1-sided) level.
All secondary efficacy and safety analyses were conducted on randomized and treated subjects using the final database. No adjustments were made for multiplicity and 2-sided p-values were reported for all comparisons between emricasan and placebo for descriptive purposes. Treatment comparisons were performed at weeks 24 and 48 unless otherwise specified. Confidence intervals were presented as 2- sided at the 95% level.
A key secondary endpoint included only all-cause mortality and new decompensation events (without MELD-Na progression events). This endpoint was analyzed using the same statistical procedures as the primary endpoint.
Treatment comparisons for the change from baseline in MELD-Na score, CTP score and biomarkers used a linear mixed-effects model with treatment, visit, treatment-by-visit interaction, baseline decompensation status and baseline MELD-Na score as fixed effects. Least-square adjusted means (LSMeans), along with the estimated difference in adjusted means between each emricasan dose versus placebo, were calculated with their corresponding 95% CIs.
With ≥72 subjects with events, the study had at least 70% power to detect a relative reduction of ≥30% in the primary endpoint of all-cause mortality; new decompensation events (VH, including recurrent VH documented by endoscopy and requiring hospitalization; new ascites requiring diuretics in a subject
without prior history of ascites requiring diuretics; new onset unprecipitated HE ≥grade 2 requiring hospitalization in a subject without prior history of HE ≥grade 2; HRS requiring hospitalization; spontaneous bacterial peritonitis [SBP] requiring hospitalization); or MELD-Na score progression (any increase ≥4 points from baseline) for at least one of the emricasan dose groups (i.e. a hazard ratio of 0.7 or lower) while controlling the false-positive risk within an acceptable level in the null case (i.e. 0% reduction). A 30% reduction was considered to be clinically meaningful. Approximately 210 randomized subjects were expected to allow at least 72 events to be observed during the study.
Results
Disposition and participant flow diagram
Subject disposition is shown in Figure 1. A total of 399 subjects were screened, 217 randomized and 214 treated. Forty-eight subjects (22.1%) discontinued the study at the time of the primary efficacy analysis, although 23/48 had experienced a primary endpoint event before discontinuation, thus limiting the missing data for the primary analysis to 25/214 subjects (11.7%). Eight subjects were transplanted during the study (n=4 in placebo, n=2 in emricasan 5 mg [EMR5], n=2 in emricasan 25 mg [EMR25]) and 8 subjects died (n=4 in placebo, n=1 in EMR5, n=3 in EMR25). Causes of death in the placebo group included hypertensive cardiovascular disease (n=1), HRS (n=1), pulmonary edema (n=1) and “unknown” (n=1). Causes of death in the EMR25 group were cardiogenic shock (n=1), HE (n=1) and pneumonia (n=1). The cause of death in the EMR5 group was adenocarcinoma of the small intestine.
Baseline demographics and clinical characteristics
Baseline characteristics are shown in Table 1 and Supplemental Table 2. Treatment groups were generally well-balanced with regard to demographics and baseline clinical characteristics. Placebo subjects had a small increase in history of HE (50% compared to 43.8% in EMR5 and 39.4% in EMR25) although the proportion of placebo subjects with a history of HE ≥grade 2 were similar in the placebo and EMR25 groups (27.1% and 28.2%, respectively compared to 21.9% EMR5). The proportion of subjects with a history of hospitalization for HE was also similar (placebo 14.3%; EMR5 16.4%; and EMR25 14.1%). The proportion of subjects with a MELD-Na score ≥15 was also higher in placebo subjects (14.3% compared to EMR (9.6% and EMR25 4.2%). Total bilirubin and INR values were similar in all 3 groups. Baseline CTP scores and the proportions of subjects who were CTP class A and B were also similar in all 3 groups. Current use of NSBB for prophylaxis of variceal bleeding was similar in the placebo and EMR5 groups (41.4% and 43.8%, respectively) compared to EMR25 subjects (35.2%).
Current use of diuretics to treat ascites was similar in the placebo and EMR25 subjects (71.4% and 70.4%, respectively compared to EMR5 subjects (79.5%). To be eligible for the study, subjects without a history of VH were required to have a history of at least moderate ascites currently requiring diuretic treatment. Approximately half of the subjects in this study were recompensated on diuretics, with 46.6%, 58.9% and 44.3% of subjects in the EMR25, EMR5, and placebo groups having detectable ascites on an imaging study at baseline, respectively. One subject randomized to EMR5 did not qualify for the study based upon baseline decompensation status but was included in the efficacy and safety analyses.
Primary endpoint: time to first event
The primary endpoint was a time-to-first-event analysis for the subjects with an event, defined as all- cause mortality; new decompensation event, or ≥4 point MELD-Na score progression. Overall, 37.4% of subjects experienced 80 first events at the time of the primary analysis (EMR5: 35.6%; EMR25: 40.8%;
placebo: 35.7%) (Table 2). A Kaplan-Meier plot of the time-to-first event analysis is shown in Figure 2A. There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (EMR5; 95% CI 0.59, 1.77; p=0.94) and 1.28 (EMR25; 95% CI 0.75, 2.21;
p=0.37). The median times to first event were 43 weeks (EMR5), 42 weeks (EMR25) and 40 weeks (placebo). Table 2 shows the events included in the primary analysis. In the EMR5 group, 25/26 events were MELD-Na score progressions; in the EMR25 group, 22/29 events were MELD-Na score progressions; and in the placebo group, 20/25 events were MELD-Na score progressions. Baseline MELD-Na scores were similar in subjects with and without a primary event (10.3 ±3.2 and 10.3 ±2.9, respectively).
The primary analysis was repeated on the final database for informational purposes in which there were an additional 8 events (Supplemental Table 3) and showed similar results.
Clinical event rates excluding MELD-Na score progression
A secondary analysis evaluated subjects with the same clinical events included in the primary analysis but excluded those whose first event was MELD-Na score progression. Overall, 10.3% of subjects experienced 22 first clinical events excluding MELD-Na score progression at the time of the final database lock (EMR5: n=4 [5.5%]; EMR25: n=9 [12.7%]; placebo: n=9 [12.9%]) (Supplemental Table 3). A Kaplan-Meier plot of the time-to-first clinical event analysis is shown in Figure 2B. There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 0.45 (EMR5; 95% CI 0.14, 1.47; p=0.09) and 1.29 (EMR25; 95% CI 0.48, 3.46; p=0.69). The
median times to first clinical event for this analysis were 42 weeks (EMR5), 39 weeks (EMR25) and 40 weeks (placebo). Baseline MELD-Na scores were similar in subjects with and without clinical events
(11.2 ±3.9 and 10.2 ±2.9, respectively). The clinical events at the time of the primary analysis and final database lock are shown in Supplemental Table 3. Although there were numerical differences in the types of events between the treatment groups, the small number of clinical events in each group precludes making definitive conclusions.
Given the low number of clinical events in the secondary analysis that excluded MELD-Na score progression, an ad hoc analysis that included new and worsening decompensation events was performed where a worsening event was based on an adverse event of ascites or HE reported in a subject with a pre-existing history of that same condition. Overall, 66/214 (30.8%) experienced a new or worsening decompensation event or death (EMR5: 22/73 [30.1%]; EMR25: 25/71 [35.2%]; placebo: 19/70 [27.1%]) (Supplemental Table 4). The most common new or worsening decompensating event was HE (42/214 [19.6%]) followed by ascites (27/214 [12.6%]) and VH (7/214 [3.3%]). New adverse HE events were reported in 18/119 (15.1%) of subjects without a history of HE, but only 3/119 (2.5%) were not precipitated and required hospitalization according to the independent adjudication committee. The median times to the first new HE event were 43 weeks (EMR5), 39 weeks (EMR25) and 39 weeks (placebo). Worsening HE was more common at 25.3% (24/95) of all subjects with a history of HE. Similarly, new adverse events of ascites were reported in 5/60 (8.3%) of all subjects without ascites requiring treatment, with 4/60 (6.7%) meeting the primary endpoint criteria of requiring diuretics.
Worsening ascites was more common at 14.3% (22/154) in subjects with a history of ascites requiring treatment. The median times to a new ascites event were 41 weeks (EMR5), 39 weeks (EMR25) and 39 weeks (placebo). The incidences of new and recurrent VH events were similar at 2.8% (3/109) and 3.8% (4/105) overall, respectively. Spontaneous bacterial peritonitis was infrequent (2/214 [0.9%]). There were no adjudicated cases of HRS, although there were two adverse events of HRS, as assessed by the investigator. The subject incidence of death over the follow-up period (median duration of follow-up 36
weeks) was 3.7% (8/214). A similar number of subjects who died had a prior history of VH, ascites, HE, or ≥2 of these conditions.
Ability of MELD-Na progression to predict subsequent clinical events
To assess whether ≥4-point increases in MELD-Na score predicted subsequent clinical events (i.e., new decompensation event or death), MELD-Na score was assessed as a time-dependent variable. MELD-Na score increases were not a significant predictor of subsequent events in this patient population, with the number of clinical events observed, either modeled continuously (p=0.37) or as a binary variable (p=0.41).
Baseline characteristics of the subjects with and without clinical events
The baseline clinical characteristics of those subjects who did, or did not, have a new clinical decompensation event are in Supplemental Table 5. Compared to subjects without an event, more subjects with a clinical event had a baseline MELD-Na score ≥15 (22.7% vs. 7.8%). There were few other differences with baseline total bilirubin, INR, serum creatinine, serum sodium, CTP score, CTP class, non- selective beta-blocker use, and use of medications for prophylaxis/treatment of HE was similar.
Decompensation status at baseline was also similar between those with and without a clinical event, with a similar proportion of subjects with prior VH (54.5% vs. 48.4%), HE (40.9% vs. 44.8%), history of HE
≥grade 2 (22.7% vs. 26.0%), ascites (72.7% vs. 84.9%), ascites not requiring diuretic treatment (13.6% vs. 11.5%), moderate ascites treated with diuretics (59.1% vs. 75.0%), and ascites treated with paracentesis
≥5L in the previous 3 months (18.2% vs. 12.5%).
Changes in MELD-Na and CTP scores, INR, total bilirubin and serum albumin
Supplemental Table 6 shows the average change from baseline in MELD-Na score, INR, direct bilirubin, total bilirubin, serum albumin, CTP score at weeks 24 and 48. There was no consistent treatment effect of emricasan upon these parameters.
Changes in caspase-related biomarkers
In order to interpret the lack of clinical efficacy, it was important to make sure that at least 1 of the emricasan doses was pharmacodynamically active in this decompensated patient population. Caspase 3/7 activity, a direct measure of the pharmacologic target, was measured at baseline, week 24 and week
48. Average baseline levels were at or just above the upper end of the reference range (1429-3908 relative light units) with mean values of 3872 RLU (EMR5), 4046 RLU (EMR25) and 4562 (placebo) (Supplemental Table 2). Emricasan decreased caspase 3/7 activity at weeks 24 and 48, with EMR25 being more active than EMR5, decreasing median week 24 and 48 values to 2734 and 1977 relative light units, respectively (Supplemental Table 6). The decrease in caspase 3/7 activity in the emricasan groups compared to placebo was statistically significant at weeks 24 and 48 in the EMR25 group (p=0.005 and p=0.017, respectively), but not in the EMR5 group (p=0.097, p=0.664; respectively).
We performed a post-hoc analysis of clinical events in subjects who were “sustained responders” (defined as at least a 20% decrease from the baseline value for at least 75% of post-baseline visits) compared to subjects who were not (“non-responders”). In all subjects, there were 85 events, with 21 events in 59 “sustained responders” and 64 events in 148 “non-responders” (p=0.390). A similar analysis was performed by treatment group. In the placebo group there were 67 events with 2 events in the 5 “sustained responders” and 23 events in the 62 “non-responders” (p=0.609). In the EMR25 group there were 34 events with 13 events in the 34 “sustained responders” and 21 events in the 36 “non-
responders” (p=0.096). In the EMR5 group there were 26 events with 6 events in the 20 “sustained responders” and 20 events in the 50 “non-responders” (p=0.609).
The effect of emricasan on other biomarkers is also shown in Supplemental Table 6. Average levels of cCK18 and flCK18 were slightly elevated above the upper end of the reference ranges at baseline, and there was no significant effect of emricasan upon cCK18 or flCK18 levels at weeks 24 or 48. ALT and AST values were well within the reference range at baseline. The change from baseline in ALT relative to placebo at weeks 24 and 48 was not significant in either the EMR25 or the EMR5 groups. The change from baseline in AST relative to placebo was not significant in either emricasan group at week 24 but was significant in the EMR25 group-only at week 48 (p=0.031).
Safety
The proportion of subjects in each group experiencing TEAEs (Table 3) was slightly higher in the emricasan groups although the number of TEAEs in the emricasan groups was similar to placebo. A similar proportion of emricasan-treated subjects experienced serious TEAEs compared with placebo and a slightly lower proportion of emricasan-treated subject experienced severe TEAEs compared with placebo. A higher proportion of emricasan-treated subjects experienced moderate TEAEs. TEAEs leading to study discontinuation occurred in a slightly higher proportion of emricasan-treated subjects than placebo-treated subjects. Eight subjects died during the study (4 emricasan, 4 placebo). Two of the 8 subjects had liver-related deaths, including a placebo subject who died of liver failure and one subject treated with EMR25 who died of HE.
The most frequent (≥5% of subjects) TEAEs by system organ class and preferred term in any treatment group are in Supplemental Table 7. There were small numerical differences with some events more
common in emricasan subjects and others in placebo subjects. Constipation, cellulitis and pruritus were numerically more common in placebo subjects while urinary tract infection, headache and insomnia were more common in emricasan subjects. There were no TEAEs for which causality could clearly be attributed to the randomized treatment. Similarly, while there were occasional small numerical differences in serious TEAEs between treatment groups (Supplemental Table 7), none were clearly attributable to emricasan.
Discussion
This study of emricasan is the largest trial of its sort in decompensated NASH cirrhosis. To our knowledge, it is also the only Phase 2 or Phase 3 study specifically designed to evaluate liver-related outcomes, such as decompensation events and MELD-Na score progression in patients with decompensated NASH cirrhosis[11]. This study enrolled subjects with decompensated NASH cirrhosis in order to evaluate whether emricasan could potentially decrease new decompensation events. A previous 3-month placebo-controlled study (followed by 3-month open-label treatment) in patients with decompensated cirrhosis from any cause had suggested that EMR25 could improve MELD-Na score progression and liver synthetic function in the small subgroup of subjects with cirrhosis due to NASH or the subgroup with elevated MELD scores[10]. Those preliminary results were not replicated in this larger, longer study performed only in subjects with decompensated NASH cirrhosis. Emricasan did not affect MELD-Na score progression, clinical decompensation events, or liver synthetic function at either dose.
One potential limitation of this study is that the dosage of emricasan may not have been sufficient in this patient population. While EMR25 had some effect upon caspase 3/7 activity, the magnitude and
consistency of caspase 3/7 reduction in this study did not appear to be maximal. A major challenge in the design and conduct of clinical trials among patients with cirrhosis is determining the appropriate dose of a therapeutic agent. Emricasan is well-absorbed following oral administration and it is estimated that in healthy adults, over 90% of the administered emricasan dose is taken up by hepatocytes on the first-pass through the liver via organic anion transporter polypeptides (OATP1B1 and 1B3). However, cirrhosis can lead to a number of pathologic changes such as decreased functional hepatocyte mass, decreased hepatic blood flow, porto-systemic shunting and decreased hepatocyte transporter expression which can increase systemic drug levels, and decrease hepatocyte drug levels. A single-dose hepatic impairment study previously assessed emricasan systemic drug concentrations in patients with Child-Turcotte-Pugh (CTP) class A, B and C cirrhosis and showed that while CTP class A subjects had serum emricasan concentrations similar to healthy adults, subjects with CTP class B cirrhosis had serum emricasan concentrations 3- to 5-fold greater and subjects with CTP class C cirrhosis had concentrations 8- to 12-fold greater than healthy adults. The maximum dose in this study was limited to 25 mg twice-daily, and the patient population restricted to those with CTP class A and B cirrhosis, due to health authority concerns about high serum emricasan concentrations, and thus the potential for unintended toxicity, in this patient population. While it is possible that a higher dose may have had a beneficial effect, this seems unlikely given that there was no indication that EMR25 affected liver function in this study. In addition, a recently completed study that examined emricasan doses of 5, 25 and 50 mg twice-daily in subjects with severe portal hypertension due to NASH cirrhosis also failed to demonstrate therapeutic benefit upon either portal hypertension or liver function despite showing inhibition of caspase activity[12].
A second potential limitation of this study is that despite randomization that was stratified by baseline decompensation status (variceal hemorrhage [VH] alone, ascites alone, or both VH and ascites) and
MELD-Na category (<15 or ≥15) there were some baseline differences in clinical characteristics that could potentially have affected study interpretation although given the totality and consistency of the results across efficacy measures this seems unlikely. There were no imbalances in both the EMR5 and EMR25 groups that might have resulted in more severe disease in those groups relative to the placebo group. More placebo subjects had a history of HE compared to the EMR groups. This difference could have resulted in a bias for more severe disease at baseline and more subsequent clinical events in placebo subjects, although that was not observed. In addition, other assessments of HE severity such as the proportion of subjects with HE ≥grade 2 and history of hospitalizations for HE were similar in all 3 groups. Thus, it seems unlikely that the baseline differences in HE obscured a potential EMR treatment effect. There were also more placebo subjects with a baseline MELD-Na score ≥15 compared to both EMR groups. This bias also could have favored the EMR groups if it resulted in more clinical events in the placebo subjects, but this was also not observed. Other important baseline measures of disease severity such as total bilirubin, INR, CTP score and CTP class were similar in all 3 treatment groups. We are therefore confident that a clinically significant potential treatment effect was not obscured by differences in baseline clinical characteristics.
This study also highlights a number of issues related to clinical trial design, including the choice of primary endpoint in a decompensated patient population. Although patients with compensated cirrhosis may remain relatively asymptomatic with well-preserved liver function for a long period of time, the development of a decompensating event such as VH, ascites, or HE is associated with a markedly worse prognosis and median survival time that decreases to less than 2 years[13-15]. In addition, development of additional decompensation events further increases the risk of death[13]. In a decompensated patient population, preventing further worsening decompensation, death or need for liver transplant are the goals of treatment. A recent workshop on clinical trial endpoints in NAFLD listed
hepatic decompensation, progression to MELD-Na ≥15, death or liver transplantation as “hard outcomes” that were likely to be meaningful in NASH cirrhosis trials[15].
One important design element of the study was that subjects who met the primary endpoint did not discontinue from the study if the primary event was only a MELD-Na score progression. This provided an opportunity for those subjects to have a clinical event and to assess whether MELD-Na score progression might predict the development of clinical events. This element of study design allows us to also gain important data about the natural history of decompensated NASH cirrhosis, for which there is currently a paucity of data in the literature. The patient population enrolled, although intermediate between early and severely decompensated, had relatively few clinical events over the period of follow- up (median 56 weeks). Only 10.3% of subjects had a clinical event excluding MELD-Na score progression over the follow-up period. In addition, there were too few subjects with clinical events to determine whether a ≥4-point MELD-Na score progression identified subjects who would subsequently have a clinical event. This is a much lower rate of further decompensating events than what has been reported in the literature for other etiologies of cirrhosis such as hepatitis C or alcohol. Baseline MELD>15 predicted clinical outcomes in this patient population, but a ≥4-point MELD-Na score progression did not; this is supported by the baseline MELD scores of 10.3 in the overall patient population, so a MELD score increase of 4 points would still result in a MELD<15 with associated low rate of clinical events. A recent publication by Sanyal et al analyzed the simtuzumab trials to evaluate the natural history of advanced fibrosis in patients with NASH. In this patient cohort, liver-related events occurred in 19% of patients with cirrhosis over a 2 year time period[16]. In the PRELHIN study, Angulo et al reported 24% of patients developed liver-related events over a median follow up of 12.6 years[17]. Loomba and Adams proposed the 20% rule of NASH progression, where 20% of patients progress from bridging fibrosis to cirrhosis in 2 years, and 20% of patients with NASH cirrhosis develop hepatic decompensations in 2
years[18]. A systematic review of 118 studies by D’Amico et al reported overall survival in patients with cirrhosis of any etiology as 75% at 2 years, although the range was very broad at 44-100%[13]. Possible explanations for the lower rate of clinical outcome events in our study include different natural history in patients with NASH related decompensated liver disease than in other etiologies or the selection criteria may have identified patients with less severe liver disease. Our goal was to identify patients with evidence of decompensation but at a stage where recovery and reduction in clinical outcome events was possible with treatment, but this may have excluded patients most likely to have clinical events. Nevertheless, this study provides a novel element in trial design in that we examined the relationship between MELD-Na progression and clinical events in an advanced NASH cirrhosis population.
All subjects (except 1) in this study had either a history of VH or at least moderate ascites requiring diuretics at baseline. The 2015 Baveno Consensus Workshop recommended that in patients after VH but without additional decompensation, a composite endpoint that included new decompensation events and variceal rebleeding was appropriate[19]. Thus, the composite endpoint chosen for this study assessed the recommended clinical events. In patients with VH and other decompensation events, mortality was selected as the appropriate endpoint. However, the results from our randomized, controlled study suggest that new decompensation events are infrequent and that new decompensation events and mortality may develop infrequently enough to use these criteria as a primary endpoint in a pragmatically-sized study. It will be challenging to develop new drugs for patients with early or intermediate decompensated NASH cirrhosis unless a validated surrogate endpoint that reliably identifies patients who will have a new clinical event is developed.
While this study did not meet the primary endpoint, it did provide important information on the rate of clinical events in patients with decompensated NASH cirrhosis that will be valuable for designing future clinical studies in this patient population.
Acknowledgements: The authors would like to acknowledge the expert assistance of Dr. Paul Kwo in the design of the study and the help of Dr. Joanne Imperial in helping to provide medical oversight for the conduct of the study.
We would also like to thank the patients and investigators who participated in our study:
Kathleen Corey, David Bernstein, Mazen Noureddin, Nyingi Kemmer, Andrew DeLemos, Nikolaos Pyrsopoulos, William Lee, Marwan Ghabril, Andrew Scanga, Mark McKenzie, Eric Lawitz, Viviana Figueroa-Diaz, Douglas Simonetto, Richard Frederick, Kimberly Brown, George Therapondos, Aasim Sheikh, Danielle Brandman, Lance Stein, Victor Ankoma-Sey, Kalyan Bhamidimarri, Charles Landis, Brett Fortune, Hugo Vargas, Manal Abdelmalek, Bradley Freilich, Don Rockey, John Vierling, Harvey Tatum, Michael Curry, Mitchell Shiffman, Kiran Bambha, Reem Ghalib, Amy Stratton, Nadeem Anwar, Stephen Caldwell, Ayman Koteish, Mohammad Siddiqui, Sammy Saab, Nikunj Shah, Anita Kohli, Mary Rinella, Souvik Sarkar, Dawn Torres, Elizabeth Verna, Ravi Ravendhran, Justin Reynolds, Ray Thomason, Ray Kim, Fernando Membreno, Sofia Jakab, Stevan Gonzalez, Andrew Keaveny, Jen-Jung Pan, Satinder Gill, Jonathan Huang, James Strobel, Amanda Wieland, Giuseppe Morelli, Thomas Amankonah, Marina Roytman, Warren Schmidt, Gary Abrams, Bhaktasharan Patel.
Table 1. Baseline clinical characteristics
Emricasan 5 mg
(N=73) Emricasan 25 mg
(N=71) Placebo
(N=70)
History of Decompensation
Prior variceal hemorrhage—n(%) 34 (46.6) 36 (50.7) 35 (50.0)
Hepatic encephalopathy—n(%) 32 (43.8) 28 (39.4) 35 (50.0)
Weeks since diagnosis – mean (SD) 148.8 (109.79) 112.6 (113.04) 130.1 (100.08)
Hepatic encephalopathy ≥ grade II—n(%) 16 (21.9) 20 (28.2) 19 (27.1)
Weeks since diagnosis – mean (SD) 125.1 (96.05) 125.1 (128.01) 83.2 (63.23)
Hospitalization for hepatic encephalopathy 12 (16.4) 10 (14.1) 10 (14.3)
Ascites—n(%) 63 (86.3) 57 (80.3) 59 (84.3)
Weeks since diagnosis – mean (SD) 131.1 (119.57) 122.1 (99.57) 174.4 (274.85)
Ascites not requiring diuretics—n(%) 8 (11.0) 8 (11.3) 9 (12.9)
Weeks since diagnosis – mean (SD) 154.1 (147.63) 205.9 (140.84) 118.8 (137.08)
Moderate ascites treated with diuretics—n(%) 57 (78.1) 50 (70.4) 50 (71.4)
Weeks since diagnosis – mean (SD) 129.5 (125.35) 118.6 (179.60) 176.9 (292.32)
Stratification Decompensation Status—n(%)
Variceal hemorrhage alone 15 (20.5) 21 (29.6) 20 (28.6)
Moderate ascites alone 38 (52.1) 35 (49.3) 35 (50.0)
Variceal hemorrhage and moderate ascites 19 (26.0) 15 (21.1) 15 (21.4)
MELD-Na Classification
MELD-Na Score < 15 66 (90.4) 68 (95.8) 60 (85.7)
MELD-Na Score ≥ 15 7 (9.6) 3 (4.2) 10 (14.3)
MELD-Na Score—Mean (SD) 10.4 (3.04) 9.8 (2.71) 10.8 (3.26)
Table 2. Primary efficacy analysis.
Primary Efficacy Analysis using interim database Emricasan
5 mg (N=73) Emricasan
25 mg (N=71) Placebo
(N=70) All Subjects
(N=214)
First Primary Event (interim database)
Total # of events 26 (35.6) 29 (40.8) 25 (35.7) 80 (37.4)
Variceal Hemorrhage 0 5 (7.0) 1 (1.4) 6 (2.8)
New Onset Ascites 0 1 (1.4) 1 (1.4) 2 (0.9)
Spontaneous Bacterial Peritonitis 0 0 1 (1.4) 1 (0.5)
≥4-point MELD-Na Score Increase 25 (34.2) 22 (31.0) 20 (28.6) 67 (31.3)
Death 1 (1.4) 1 (1.4) 2 (2.9) 4 (1.9)
Table 3. Overview of Safety Experience.
Emricasan
5 mg (N=73) Emricasan
25 mg (N=71) Placebo
(N=70)
Safety summary
Subjects with TEAE - n (%) 70 (95.9) 63 (88.7) 61 (87.1)
Number of TEAE events - n 354 367 370
Subjects with serious TEAEs - n (%) 22 (30.1) 25 (35.2) 23 (32.9)
Subjects with moderate TEAEs - n (%) 27 (37.0) 31 (43.7) 22 (31.4)
Subjects with severe TEAEs - n (%) 22 (30.1) 18 (25.4) 22 (31.4)
Subjects with TEAEs related to study drug - n (%) 20 (27.4) 17 (23.9) 20 (28.6)
Subjects with TEAEs leading to study discontinuation-n (%) 3 (4.1) 7 (9.9) 4 (5.7)
Subjects with TEAEs leading to study drug discontinuation-n (%) 4 (5.5) 11 (15.5) 5 (7.1)
Figure legends
Figure 1. Disposition of all subjects who provided informed consent. Reasons for early discontinuation and number of subjects contributing to the primary endpoint by treatment group are shown.
Figure 2. Kaplan-Meier plots of the time-to-first event analysis. (A) The primary endpoint was a time to first event analysis for the subjects who had an event, defined as all-cause mortality; new decompensation event (VH including recurrent VH documented by endoscopy and requiring hospitalization, new onset ascites requiring diuretics in a subject without prior history of ascites requiring diuretics, new onset HE ≥ grade 2 requiring hospitalization in the absence of alternative causes in a subject without prior history of HE ≥ grade 2, HRS requiring hospitalization, SBP requiring hospitalization), or MELD-Na score progression (any increase ≥4 points from baseline). (B) A Kaplan- Meier plot of the time-to-first event analysis including only all-cause mortality and new decompensation events (without MELD-Na progression events). This endpoint was analyzed using the same procedures as described for the primary endpoint.
Figure 1: Disposition of all enrolled subjects.
Assessed for eligibility (n= 399)
Excluded (n= 182)
⦁ Not meet inclusion/exclusion criteria (n= 165)
⦁ Declined to participate (n= 7)
⦁ Other reasons (n= 10)
Randomized (n= 217)
Allocated to placebo (n=71)
⦁ Received allocated intervention (n=70)
⦁ Did not receive allocated intervention Withdrew consent (n=1)
Allocation
Allocated to emricasan (n=146)
⦁ Received allocated intervention (n=144)
⦁ Did not receive allocated intervention (n=2)
⦁ Completed study (n=49)
⦁ Withdrew early and with primary event prior to withdrawal (n=11)
⦁ Withdrew early without a primary event prior to withdrawal (n=10)
Reasons for withdrawal: Adverse event (n=3) Withdrew consent (n=6) Liver transplant (n=4) Death (n=4)
Investigator decision (n=4)
Disposition
⦁ Completed study (n=117)
⦁ Withdrew early and with primary event prior to withdrawal (n=12)
⦁ Withdrew early without a primary event prior to withdrawal (n=16)
Reasons for withdrawal: Adverse event (n=10) Withdrew consent (n=5) Liver transplant (n=4) Death (n=4)
Investigator decision (n=2) Lost to follow up (n=3)
Analysis
Analysed in primary endpoint (n=144)
Figure 2. Kaplan-Meier plot of time to first event.
Supplemental Table 1. Complete inclusion and exclusion criteria. INCLUSION CRITERIA
To participate in this study, subjects must meet all of the following criteria:
⦁ Male or female subjects 18 years or older, able to provide written informed consent and able to understand and willing to comply with the requirements of the study.
⦁ Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.)
⦁ Diagnosis of cirrhosis is based on at least one of the following:
⦁ Biopsy (documented by pathology review)
AND/OR
⦁ Clinical evidence: platelet count <150,000, AST > ALT, and either nodular liver surface (on computed tomography [CT] or magnetic resonance imaging [MRI]) or splenomegaly (longitudinal dimension >13 cm on CT or MRI) (the latter in the absence of portal vein thrombosis)
AND/OR
⦁ Clinical evidence of significant portal hypertension based on: current or history of gastroesophageal varices on endoscopy AND/OR evidence of portosystemic collaterals (on contrast CT or MRI with contrast) AND/OR presence or history of ascites
⦁ NASH as the etiology of cirrhosis is based on at least one of the following:
⦁ Prior or current biopsy showing steatohepatitis (fat, ballooning degeneration, inflammation) consistent with NASH
⦁ At least 2 metabolic risk factors for at least 5 years preceding the diagnosis of cirrhosis: diabetes mellitus, impaired fasting glucose, obesity (body mass index [BMI] ≥30 kg/m2 or central obesity), hypertension, dyslipidemia (see Appendix II)
⦁ At least 1 metabolic risk factor (as above) for at least 5 years preceding the diagnosis of cirrhosis and fatty liver on prior imaging
Note: Previous viral hepatitis that was curatively treated (with sustained viral response) is not an exclusion as long as: 1) viral eradication was achieved at least 3 years prior to the diagnosis of cirrhosis and 2) all other criteria are met for NASH as the etiology of cirrhosis
⦁ At least one of the following: a) history of variceal hemorrhage (more than 3 months prior to day 1) documented on endoscopy, b) history of at least moderate ascites (on physical exam or imaging) currently treated with diuretics.
Note: Previous transient ascites or ascites only detectable on imaging in a subject who is currently not on diuretics for ascites does not meet inclusion criteria
⦁ MELD score ≤20 during screening
Note: Subjects with baseline MELD scores of ≥15 and ≤20 will be at least 30% of study subjects.
⦁ Albumin ≥2.5 g/dL during screening 6. Serum creatinine within the normal range for PPD central laboratory (≤1.4 mg/dL; 124 μmol/L) during screening
⦁ Willingness to utilize effective contraception (for both males and females of reproductive potential) from Screening to 4 weeks after the last dose of study drug
⦁ If on therapeutic doses of vitamin E, must be stable for 6 months prior to Day 1
7.2 EXCLUSION CRITERIA
Subjects who meet any of the following criteria will be excluded from the study:
⦁ Evidence of severe decompensation, defined as:
⦁ Ascites requiring concurrent diuretic therapy and regular therapeutic paracenteses
⦁ Ascites complicated by hyponatremia (serum sodium <130 mEq/L) within 3 months of screening unless precipitated by a transient, reversible cause (e.g. over-diuresis)
⦁ History of SBP
⦁ Acute kidney injury within 3 months of screening
Note: Elevation in serum creatinine due to reversible cause (i.e. overdiuresis) and that subsequently resolved does not meet criteria for AKI
⦁ History of hepatorenal syndrome (type 1 or type 2)
⦁ Hepatopulmonary syndrome with resting O2 saturation by pulse oximetry <90%
⦁ Variceal hemorrhage or bleeding from a portal hypertensive source (e.g. portal hypertensive gastropathy) within 3 months of screening, or more than 1 such episode within 12 months of screening
⦁ More than 2 hospitalizations for HE within 6 months of screening
⦁ Non-cirrhotic portal hypertension
⦁ Child-Pugh score ≥10
⦁ Current use of anticoagulants that affect prothrombin time (PT) or INR
⦁ ALT >3 times upper limit of normal (ULN) or AST >5 times ULN during screening
⦁ Initiation or discontinuation of NSBB (e.g. propranolol, nadolol, carvedilol), rifaximin, or statin within 1 month of screening
⦁ Placement or revision of transjugular intrahepatic portosystemic shunt or other porto-systemic bypass procedure within 6 months of screening
⦁ Alpha-fetoprotein >50 ng/mL in the last year
⦁ History of HCC or evidence of HCC (intermediate, probable, or definite) on CT or MRI performed within 3 months of screening
⦁ History of malignancies other than HCC, unless successfully treated with curative intent and believed to be cured
⦁ Prior liver transplant
⦁ Uncontrolled diabetes mellitus (glycated hemoglobin [HbA1c] >9%)
⦁ Change in diabetes medications within 3 months of screening, including initiation, discontinuation, or change in dose except for medications titrated according to blood glucose 14. Restrictive bariatric surgery or bariatric device within 1 year of screening or prior malabsorptive bariatric surgery unless reversed or failed based upon weight regain
⦁ Symptoms of biliary colic, e.g. due to symptomatic gallstones, within the last 6 months, unless resolved following cholecystectomy, other definitive treatment (e.g. sphincterotomy) or medical management (e.g. ursodeoxycholic acid)
⦁ History of significant alcohol consumption (>20 g/day for females and >30 g/day for males on average) within the past 5 years
⦁ Current use of medications that are considered inhibitors of organic anion transporting polypeptide OATP1B1 and OATP1B3 transporters: atazanavir, cyclosporine, eltrombopag, gemfibrozil, indinavir,
lopinavir, ritonavir, rifampin, saquinavir, simeprevir, telaprevir, tipranovir, or some combination of these medications
⦁ Prolongation of screening (pre-treatment) QT Interval Corrected by the Fridericia Correction Formula (QTcF) interval of >500 msecs, or history or presence of clinically concerning cardiac arrhythmias
⦁ Significant systemic or major illness other than liver disease that in the opinion of the investigator would preclude the subject from participating in and completing the study, including but not limited to acute coronary syndrome or stroke within 6 months of screening or major surgery within 3 months of screening
⦁ Known human immunodeficiency virus infection
⦁ Use of alcohol, controlled substances (including inhaled or injected drugs), or non-prescribed use of prescription drugs within 1 year of screening to the point of interfering with the subject’s ability to comply with study procedures and study drug administration in the investigator’s judgement
⦁ If female: planned or known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding
⦁ Previous treatment with emricasan or active investigational medication (except methacetin) in a clinical trial within 3 months prior to Day 1
Supplemental Table 2. Baseline characteristics.
Emricasan
5 mg (N=73) Emricasan
25 mg (N=71) Placebo
(N=70)
Age (yrs)
n 73 71 70
Mean (SD) 62.6 (8.77) 60.2 (9.80) 62.8 (6.83)
Age group – n (%)
≥ 18 – ≤ 40 0 2 (2.8) 1 (1.4)
≥ 41-≤ 64 41 (56.2) 43 (60.6) 40 (57.1)
≥ 65 32 (43.8) 26 (36.6) 29 (41.4)
Gender – n (%)
Female 34 (46.6) 37 (52.1) 40 (57.1)
Male 39 (53.4) 34 (47.9) 30 (42.9)
Race – n (%)
American Indian / Alaska
Native 0 (0.0) 0 (0.0) 0 (0.0)
Asian 1 (1.4) 1 (1.4) 2 (2.9)
Native Hawaiian / Other
Pacific Islander 0 (0.0) 0 (0.0) 0 (0.0)
Black / African American 2 (2.7) 0 (0.0) 1 (1.4)
White 67 (91.8) 68 (95.8) 65 (92.9)
More than one race 2 (2.7) 1 (1.4) 2 (2.9)
Unknown or Not Reported 1 (1.4) 1 (1.4) 0 (0.0)
Ethnicity – n (%)
Hispanic or Latino 16 (21.9) 19 (26.8) 16 (22.9)
Non Hispanic or Latino 56 (76.7) 52 (73.2) 54 (77.1)
Unknown (individuals not
reporting ethnicity) 1 (1.4) 0 0
Height (cm)
Mean (SD) 169.0 (10.81) 168.9 (11.76) 167.7 (10.75)
Weight (kg)
Mean (SD) 95.5 (24.47) 98.1 (23.20) 95.7 (23.95)
BMI (kg/m2)
Mean (SD) 33.2 (6.51) 34.3 (6.49) 33.9 (6.95)
Total Bilirubin—Mean (SD) 1.4 (1.00) 1.3 (0.71) 1.5 (0.86)
Serum Creatinine—Mean (SD) 0.9 (0.28) 0.8 (0.24) 0.8 (0.28)
INR—Mean (SD) 1.2 (0.16) 1.2 (0.17) 1.2 (0.18)
CTP Score—Mean (SD) 6.8 (1.25) 6.6 (1.22) 6.7 (1.23)
CTP Score Classification—
n(%)
Class A: 5-6 34 (46.6) 36 (50.7) 34 (48.6)
Class B: 7-9 36 (49.3) 34 (47.9) 35 (50.0)
Class C: 10-15 3 (4.1) 1 (1.4) 1 (1.4)
Caspase 3/7—Mean (SD) 3872 (1988.36) 4046 (2916.69) 4562 (3316.08)
Concomitant Medications of
Interest—n(%)
NSBB for prophylaxis of
variceal bleeding 32 (43.8) 25 (35.2) 29 (41.4)
Nitrate prophylaxis of
variceal bleeding 1 (1.4) 0 0
Diuretics for ascites 58 (79.5) 50 (70.4) 50 (71.4)
Lactulose for hepatic
encephalopathy 13 (17.8) 15 (21.1) 16 (22.9)
Rifaximin for hepatic
encephalopathy 11 (15.1) 15 (21.1) 12 (17.1)
Supplemental Table 3. Additional efficacy analyses.
First Clinical Event (excluding ≥4-Point
MELD-Na Progression) using interim database
Total # of events 4 (5.5) 7 (9.9) 7 (10.0) 18 (8.4)
Variceal Hemorrhage 1 (1.4) 5 (7.0) 1 (1.4) 7 (3.3)
New Onset Ascites 0 1 (1.4) 1 (1.4) 2 (0.9)
New Onset Hepatic Encephalopathy 2 (2.7) 0 1 (1.4) 3 (1.4)
Spontaneous Bacterial Peritonitis 0 0 2 (2.9) 2 (0.9)
Death 1 (1.4) 1 (1.4) 4 (5.7) 6 (2.8)
Efficacy Analysis using final database
First Primary Event (final database)
Total # of events 28 (38.4) 34 (47.9) 26 (37.1) 88 (41.1)
Variceal Hemorrhage 0 5 (7.0) 1 (1.4) 6 (2.8)
New Onset Ascites 0 1 (1.4) 1 (1.4) 2 (0.9)
Spontaneous Bacterial Peritonitis 0 0 1 (1.4) 1 (0.5)
4-point MELD-Na Score Progression 27 (37.0) 26 (36.6) 21 (30.0) 74 (34.6)
Death 1 (1.4) 2 (2.8) 2 (2.9) 5 (2.3)
First Clinical Event (excluding ≥4-Point MELD-Na Progression) using final
database
Total # of events 4 (5.5) 9 (12.7) 9 (12.9) 22 (10.3)
Variceal Hemorrhage 1 (1.4) 5 (7.0) 1 (1.4) 7 (3.3)
New Onset Ascites 0 2 (2.8) 1 (1.4) 3 (1.4)
New Onset Hepatic Encephalopathy 2 (2.7) 0 1 (1.4) 3 (1.4)
Spontaneous Bacterial Peritonitis 0 0 2 (2.9) 2 (0.9)
Death 1 (1.4) 2 (2.8) 4 (5.7) 7 (3.3)
Note: the number of clinical events in “First Primary Event” and “First Clinical Event” are different since subjects who had a MELD-Na score increase of ≥4 points and subsequently had a clinical event were counted as a MELD-Na score progression in the “First Primary Event” analysis and as a clinical event in the “First Clinical Event” analysis.
Supplemental Table 4. Analysis of Subjects with New or Worsening Clinical Events
Emricasan 5 mg
(N=73) Emricasan 25 mg
(N=71)
Placebo (N=70) All subjects (N=214)
Subjects with Any Clinical Event 22 (30.1%) 25 (35.2%) 19 (27.1%) 66 (30.8%)
Variceal hemorrhage 1 (1.4%) 5 (7.0%) 1 (1.4%) 7 (3.3%)
N without history of VH N=39 N=35 N=35 N=109
New VH 0 2 (5.7%) 1 (2.9%) 3 (2.8%)
N with history of VH N=34 N=36 N=35 N=105
Recurrent VH 1 (2.9%) 3 (8.3%) 0 4 (3.8%)
Ascites (AE) 11 (15.1%) 9 (12.7%) 7 (10.0%) 27 (12.6%)
N without history of ascites requiring
treatment N=18 N=22 N=20 N=60
New adverse event of Ascites (TEAE) 1 (5.6%) 3 (13.6%) 1 (5.0%) 5 (8.3%)
New ascites (NDE) 0 3 (13.6%) 1 (5.0%) 4 (6.7%)
N with history of ascites requiring
treatment N=55 N=49 N=50 N=154
Worsening ascites 10 (18.2%) 6 (12.2%) 6 (12.0%) 22 (14.3%)
Worsening ascites requiring treatment 6 (10.9%) 6 (12.2%) 5 (10.0%) 17 (11.0%)
Worsening ascites requiring
hospitalization 2 (3.6%) 3 (6.1%) 2 (4.0%) 7 (4.5%)
Hepatic encephalopathy (TEAE) 15 (20.5%) 13 (18.3%) 14 (20.0%) 42 (19.6%)
N without history of HE N=41 N=43 N=35 N=119
New adverse event of HE 8 (19.5%) 5 (11.6%) 5 (14.3%) 18 (15.1%)
New HE event (adjudicated*) 2 (4.9%) 0 1 (2.9%) 3 (2.5%)
N with any history of HE N=32 N=28 N=35 N=95
Adverse event of worsening HE 7 (21.9%) 8 (28.6%) 9 (25.7%) 24 (25.3%)
Worsening HE requiring treatment 6 (18.8%) 5 (17.9%) 8 (22.9%) 19 (20.0%)
Worsening HE requiring hospitalization 5 (15.6%) 5 (17.9%) 7 (20.0%) 17 (17.9%)
Spontaneous bacterial peritonitis 0 (0%) 0 (0%) 2 (2.9%) 2 (0.9%)
Hepatorenal syndrome (adjudicated) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Hepatorenal syndrome (TEAE) 0 0 2 (2.9%) 2 (0.9%)
Death 1 (1.4%) 3 (4.2%) 4 (5.7%) 8 (3.7%)
History of VH 0 3 1 4
History of ascites 1 1 3 5
History of HE 0 1 3 4
History of 2 or more 0 1 3 4
VH=variceal hemorrhage, HE=hepatic encephalopathy, NDE=, TEAE=treatment-emergent adverse event
Supplemental Table 5. Baseline clinical characteristics of the subjects who did, or did not, have a clinical event outcome on study.
Clinical Event
(N=22) No Clinical
Event (N=192) All Subjects
(N=214)
History of Decompensation
Prior variceal hemorrhage
No 10 (45.5) 99 (51.6) 109 (50.9)
Yes 12 (54.5) 93 (48.4) 105 (49.1)
Hepatic encephalopathy
n (%) 9 (40.9) 86 (44.8) 95 (44.4)
Weeks since diagnosis – mean (SD) 100.4 (98.00) 134.5 (108.06) 131.2 (107.13)
Hepatic encephalopathy ≥ grade II
n (%) 5 (22.7) 50 (26.0) 55 (25.7)
Weeks since diagnosis – mean (SD) 49.4 (32.42) 117.1 (103.74) 110.6 (100.97)
Hospitalization for hepatic encephalopathy
n (%) 3 (13.6) 29 (15.1) 32 (15.0)
Months since hospitalization – mean (SD) 6.0 (6.24) 17.0 (17.21) 15.9 (16.73)
Ascites
n (%) 16 (72.7) 163 (84.9) 179 (83.6)
Weeks since diagnosis – mean (SD) 107.3 (79.07) 145.8 (188.54) 142.4 (181.62)
Ascites not requiring diuretics
n (%) 3 (13.6) 22 (11.5) 25 (11.7)
Weeks since diagnosis – mean (SD) 61.3 (58.18) 171.2 (144.77) 160.5 (142.05)
Moderate ascites treated with diuretics
n (%) 13 (59.1) 144 (75.0) 157 (73.4)
Weeks since diagnosis – mean (SD) 89.4 (63.17) 145.6 (215.14) 140.9 (207.25)
Ascites and ≥5L paracentesis
n (%) 2 (9.1) 26 (13.5) 28 (13.1)
Ascites & ≥5L paracentesis in past 3 months
n (%) 4 (18.2) 24 (12.5) 28 (13.1)
Stratification Decompensation Status
Variceal hemorrhage alone 9 (40.9) 47 (24.5) 56 (26.2)
Moderate ascites alone 10 (45.5) 98 (51.0) 108 (50.5)
Variceal hemorrhage and moderate ascites 3 (13.6) 46 (24.0) 49 (22.9)
Concomitant Medications of Interest
NSBB for prophylaxis of variceal bleeding 7 (31.8) 79 (41.1) 86 (40.2)
Nitrate prophylaxis of variceal bleeding 0 1 (0.5) 1 (0.5)
Diuretics for ascites 13 (59.1) 145 (75.5) 158 (73.8)
Lactulose for hepatic encephalopathy 5 (22.7) 39 (20.3) 44 (20.6)
Rifaximin for hepatic encephalopathy 4 (18.2) 34 (17.7) 38 (17.8)
MELD-Na Classification
MELD-Na Score < 15 17 (77.3) 177 (92.2) 194 (90.7)
MELD-Na Score ≥ 15 5 (22.7) 15 (7.8) 20 (9.3)
MELD-Na Score
n 22 192 214
Mean (SD) 11.2 (3.85) 10.2 (2.91) 10.3 (3.02)
Total Bilirubin
n 22 192 214
Mean (SD) 1.4 (0.79) 1.4 (0.88) 1.4 (0.87)
Serum Creatinine
n 22 192 214
Mean (SD) 0.9 (0.28) 0.8 (0.27) 0.8 (0.27)
Sodium
n 22 192 214
Mean (SD) 138.2 (3.04) 139.4 (2.46) 139.3 (2.55)
INR
n 22 192 214
Mean (SD) 1.2 (0.16) 1.2 (0.17) 1.2 (0.17)
CTP Score
n 22 190 212
Mean (SD) 6.7 (1.46) 6.7 (1.21) 6.7 (1.23)
CTP Score Classification
Class A: 5-6 11 (50.0) 93 (48.4) 104 (48.6)
Class B: 7-9 11 (50.0) 94 (49.0) 105 (49.1)
Class C: 10-15 0 5 (2.6) 5 (2.3)
Caspase 3/7
n 22 187 209
Mean (SD) 4526 (3456.26) 4109 (2705.39) 4153 (2787.03)
cCK18/M30
n 21 185 206
Mean (SD) 459.5 (571.25) 324.4 (512.56) 338.1 (518.96)
flCK18/M65
n 22 186 208
Mean (SD) 879.2 (828.20) 676.9 (490.70) 698.3 (537.28)
ALT
n 22 192 214
Mean (SD) 27.8 (11.16) 28.6 (12.02) 28.5 (11.91)
AST
n 22 192 214
Mean (SD) 42.4 (18.26) 42.7 (20.32) 42.7 (20.08)
Supplemental Table 6. Average change from baseline in key liver and biomarker parameters at weeks 24 and 48.
MELD-Na Score Emricasan
5 mg (N=73) Emricasan
25 mg (N=71) Placebo (N=70)
Week 24, n 63 52 59
Mean (SD) 0.7 (2.25) 0.6 (1.83) 1.0 (2.56)
Week 48, n 31 20 25
Mean (SD) 0.8 (2.72) 0.4 (2.58) 1.8 (2.31)
INR
Week 24, n 63 52 60
Mean (SD) 0.0 (0.25) 0.0 (0.10) 0.0 (0.09)
Week 48, n 31 19 26
Mean (SD) -0.0 (0.14) 0.1 (0.45) 0.0 (0.13)
Total bilirubin
Week 24, n 63 52 60
Mean (SD) 0.0 (0.40) -0.0 (0.32) 0.2 (0.55)
Week 48, n 32 20 26
Mean (SD) 0.0 (0.46) 0.0 (0.43) 0.1 (0.95)
Serum Albumin
Week 24, n 63 52 60
Mean (SD) -0.0 (0.28) -0.1 (0.24) -0.1 (0.22)
Week 48, n 32 20 26
Mean (SD) 0.1 (0.25) -0.0 (0.33) -0.0 (0.24)
CTP score
Week 24, n 61 52 56
Mean (SD) 0 (0.75) -0 (0.65) 0 (0.94)
Week 48, n 29 16 22
Mean (SD) 0 (0.81) 0 (1.41) 0 (1.33)
Caspase 3/7
Week 24, n 56 47 52
Median -194 -235 136
Week 48, n 29 17 20
Median -238 -952 167
cCK18
Week 24, n 57 45 49
Median -13.0 -23.0 3.0
Week 48, n 29 16 20
Median -87.0 -26.0 -1.0
flCK18
Week 24, n 57 47 50
Median 39.0 6.0 -21.0
Week 48, n 29 17 19
Median -14.0 -33.0 -9.0
ALT
Week 24, n 63 52 60
Median 0 -2 -1
Week 48, n 32 20 26
Median 3 -2 0
AST
Week 24, n 63 52 60
Median 1 -0 1
Week 48, n 32 20 26
Median 4 -1 -0
Supplemental Table 7. Treatment emergent and serious adverse events.
TEAE in 5% or more of subjects*
Blood and lymphatic system disorders 8 (11.0) 5 (7.0) 8 (11.4)
Anaemia 3 (4.1) 4 (5.6) 5 (7.1)
Gastrointestinal disorders 44 (60.3) 36 (50.7) 42 (60.0)
Abdominal pain 5 (6.8) 4 (5.6) 6 (8.6)
Abdominal pain upper 5 (6.8) 6 (8.5) 10 (14.3)
Ascites 11 (15.1) 9 (12.7) 7 (10.0)
Constipation 1 (1.4) 4 (5.6) 11 (15.7)
Diarrhoea 12 (16.4) 9 (12.7) 13 (18.6)
Nausea 12 (16.4) 13 (18.3) 14 (20.0)
Oesophageal variceal haemorrhage 1 (1.4) 4 (5.6) 1 (1.4)
Vomiting 6 (8.2) 8 (11.3) 8 (11.4)
General disorders and administration site conditions 21 (28.8) 23 (32.4) 23 (32.9)
Fatigue 6 (8.2) 10 (14.1) 8 (11.4)
Oedema peripheral 6 (8.2) 10 (14.1) 9 (12.9)
Pyrexia 5 (6.8) 2 (2.8) 1 (1.4)
Infections and infestations 43 (58.9) 35 (49.3) 30 (42.9)
Cellulitis 3 (4.1) 1 (1.4) 5 (7.1)
Influenza 6 (8.2) 2 (2.8) 3 (4.3)
Nasopharyngitis 6 (8.2) 3 (4.2) 2 (2.9)
Pneumonia 5 (6.8) 1 (1.4) 3 (4.3)
Sinusitis 2 (2.7) 6 (8.5) 5 (7.1)
Upper respiratory tract infection 11 (15.1) 11 (15.5) 7 (10.0)
Urinary tract infection 15 (20.5) 16 (22.5) 7 (10.0)
Injury, poisoning and procedural complications 14 (19.2) 11 (15.5) 7 (10.0)
Contusion 4 (5.5) 3 (4.2) 3 (4.3)
Fall 4 (5.5) 4 (5.6) 3 (4.3)
Musculoskeletal and connective tissue disorders 22 (30.1) 17 (23.9) 19 (27.1)
Back pain 7 (9.6) 4 (5.6) 7 (10.0)
Muscle spasms 10 (13.7) 3 (4.2) 5 (7.1)
Nervous system disorders 29 (39.7) 26 (36.6) 21 (30.0)
Dizziness 6 (8.2) 5 (7.0) 6 (8.6)
Headache 5 (6.8) 8 (11.3) 2 (2.9)
Hepatic encephalopathy 15 (20.5) 13 (18.3) 14 (20.0)
Psychiatric disorders 9 (12.3) 8 (11.3) 4 (5.7)
Insomnia 4 (5.5) 5 (7.0) 1 (1.4)
Respiratory, thoracic and mediastinal disorders 10 (13.7) 13 (18.3) 14 (20.0)
Dyspnoea 1 (1.4) 4 (5.6) 4 (5.7)
Epistaxis 1 (1.4) 4 (5.6) 5 (7.1)
Skin and subcutaneous tissue disorders 11 (15.1) 11 (15.5) 18 (25.7)
Pruritus 4 (5.5) 3 (4.2) 8 (11.4)
Serious TEAE in 2 or more subjects#
Blood and lymphatic system disorders 2 (2.7) 1 (1.4) 1 (1.4)
Cardiac disorders 0 2 (2.8) 1 (1.4)
Gastrointestinal disorders 6 (8.2) 10 (14.1) 5 (7.1)
Ascites 2 (2.7) 3 (4.2) 2 (2.9)
Oesophageal varices haemorrhage 1 (1.4) 4 (5.6) 1 (1.4)
Upper gastrointestinal haemorrhage 0 2 (2.8) 2 (2.9)
General disorders and administration site conditions 2 (2.7) 2 (2.8) 2 (2.9)
Hepatobiliary disorders 2 (2.7) 1 (1.4) 2 (2.9)
Hepatorenal syndrome 0 0 2 (2.9)
Infections and infestations 7 (9.6) 6 (8.5) 8 (11.4)
Cellulitis 2 (2.7) 1 (1.4) 1 (1.4)
Peritonitis bacterial 0 0 2 (2.9)
Sepsis 1 (1.4) 1 (1.4) 2 (2.9)
Metabolism and nutrition disorders 1 (1.4) 1 (1.4) 3 (4.3)
Hyponatraemia 0 1 (1.4) 2 (2.9)
Neoplasms benign, malignant and unspecified 1 (1.4) 2 (2.8) 1 (1.4)
Hepatocellular carcinoma 0 2 (2.8) 0
Nervous system disorders 9 (12.3) 5 (7.0) 11 (15.7)
Hepatic encephalopathy 9 (12.3) 5 (7.0) 10 (14.3)
Renal and urinary disorders 3 (4.1) 1 (1.4) 2 (2.9)
Respiratory, thoracic and mediastinal disorders 3 (4.1) 3 (4.2) 4 (5.7)
Hepatic hydrothorax 2 (2.7) 1 (1.4) 2 (2.9)
Vascular disorders 0 2 (2.8) 1 (1.4)
*Treatment-emergent adverse events (TEAE) are shown by System Organ Class and Preferred Term (PT) for adverse events that occurred in 5% or more subjects in any treatment group.
#Serious TEAE are shown by SOC and PT for serious TEAE that occurred in 2 or more subjects in any treatment group.
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Highlights:
⦁ Pan-caspase inhibition with emricasan did not decrease events in patients with decompensated NASH cirrhosis
⦁ Caspase inhibition did not affect MELD-Na scores, INR, total serum bilirubin or Child-Turcotte- Pugh score
⦁ Emricasan was generally well-tolerated over the duration of treatment