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Emricasan Fails To Meet Primary Endpoint In ENCORE-PH Study But Shows Potential Benefits In High-risk Individuals

ILC 2019: ENCORE-PH study of emricasan in nonalcoholic steatohepatitis (NASH)-related cirrhosis and severe portal hypertension (PH) fails to meet primary endpoint, but benefits reported in individuals at high risk of decompensation

13 April 2019, Vienna, Austria

EASL (EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER)

The ENCORE-PH study of emricasan in the treatment of nonalcoholic steatohepatitis (NASH)-related cirrhosis with severe portal hypertension (PH), has failed to meet its primary endpoint, but meaningful reductions in portal pressure were observed in a subgroup of individuals with high-risk disease. The first results of the Phase 2b study, which were presented today at The International Liver Congress™ 2019 in Vienna, Austria, demonstrated that, although emricasan did not reduce the hepatic venous pressure gradient (HVPG) across the entire cohort of study participants, meaningful reductions were reported in those with compensated cirrhosis and a high baseline HVPG of ≥16 mmHg.

Portal hypertension is a frequent complication of liver cirrhosis and is characterized by an increased pressure gradient between the portal vein and the hepatic vein – the so-called portal pressure gradient or HVPG.1 An HVPG >10 mmHg defines clinically-significant PH and, in those with cirrhosis, predicts the development of decompensated disease and severe clinical complications.1 An HVPG >12 mmHg is defined as severe PH,1 with pressures >16 mmHg associated with a very high risk of major clinical events and death.2,3 Studies have demonstrated that if portal pressure of high-risk patients can be reduced sufficiently (e.g. by ≥20%), the risk of development or progression of decompensation and death can be greatly reduced in individuals with PH.4

Emricasan is an oral pan-caspase inhibitor that ameliorated portal hypertension and improved survival in animal models of cirrhosis5–8 and reduced HVPG among individuals with compensated cirrhosis and severe PH in a previously-reported open-label study.7 The aim of the ENCORE-PH study reported today was to confirm the results reported in this open-label study.

The randomized, double-blind, placebo-controlled ENCORE-PH study enrolled 263 subjects with NASH cirrhosis and a baseline HVPG ≥12 mmHg (severe PH). All subjects were randomized to receive oral emricasan 5 mg, 25 mg, 50 mg or placebo twice-daily (bid) for 48 weeks. Most study participants (201/263, 76%) had compensated cirrhosis at the time of enrollment, while a smaller proportion (62/263, 24%) had early decompensated disease. The primary endpoint of the study was the mean change in HVPG from baseline to Week 24 across the entire study cohort.

‘In the overall primary endpoint analysis, which included patients with compensated and early decompensated cirrhosis, although reductions in HVPG were seen in all emricasan treatment groups, the differences compared with placebo were not statistically significant’, said investigator, Professor Guadalupe Garcia-Tsao from Yale University in Connecticut, USA. Relative reductions of 3 to 5 U/L in ALT and 2 to 6 U/L in AST were also observed in the emricasan treatment groups compared with placebo (p<0.05 in all but one group).

A post hoc analysis of data from the ENCORE-PH study demonstrated that, for participants with compensated cirrhosis and an HVPG ≥16 mmHg, emricasan resulted in meaningful reductions in HVPG compared with placebo. The mean changes from baseline at Week 24 with emricasan were –1.6 mmHg (5 mg bid), –1.7 mmHg (25 mg bid), –1.5 mmHg (50 mg bid) compared with an increase of 0.5 mmHg with placebo (p<0.05 vs placebo for all comparisons).

Emricasan was generally well tolerated with an overall safety profile similar to that of placebo.

‘Although the primary endpoint was not met in this study, the reductions in HVPG observed in patients with compensated NASH cirrhosis and very severe PH are encouraging and support additional exploration in these patients’, said Prof. Garcia-Tsao. ‘This group of patients is at greatest risk of progressing to decompensation and there are currently no approved treatments available to them’.

’There is a significant unmet need for new therapies in patients with cirrhosis due to NAFLD,’ said Professor Philip Newsome, Vice-Secretary of EASL, ‘and this study shows that emricasan may be of potential value in this setting. Further studies are required to confirm the effectiveness of emricasan in patients with more advanced portal hypertension.’

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About The International Liver Congress™

This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2019 will take place from 10­–14 April 2019 at the Reed Messe Wien Congress and Exhibition Center, Vienna, Austria.

About The European Association for the Study of the Liver (EASL)

Since its foundation in 1966, this not-for-profit organization has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Contact

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Onsite location reference

Session title: ‘Late breaker’

Time, date and location of session: 16:00–16:15, 13 April 2019, Main plenary

Presenter: Guadalupe Garcia-Tsao, USA

Abstract:  Double-blind, placebo-controlled, randomized trial of emricasan in subjects

with NASH cirrhosis and severe portal hypertension (PH) (LB-01)

Author disclosures

Gudalupe Garcia-Tsao is a consultant for Biovie, Conatus, Enterome, Galectin, Genfit, Intercept and has received research grant funding from Intercept. Conatus funded the present study.

References

  1. Bosch J, Iwakiri Y. The portal hypertension syndrome: etiology, classification, relevance, and animal models. Hepatol Int. 2018;12(Suppl 1):1–10.
  2. Silva-Junior G, et al. The prognostic value of hepatic venous pressure gradient in patients with cirrhosis is highly dependent on the accuracy of the technique. 2015;62(5):1584–92.
  3. Berzigotti A, et al. Prognostic value of a single HVPG measurement and Doppler-ultrasound evaluation in patients with cirrhosis and portal hypertension. J Gastroenterol. 2011;46(5):687–95.
  4. Berzigotti A. Advances and challenges in cirrhosis and portal hypertension. BMC Med. 2017;15(1):200.
  5. Barreyro FJ, et al. The pan-caspase inhibitor emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35(3):953–66.
  6. Gracia-Sancho J, et al. The pan caspase inhibitor emricasan improves the hepatic microcirculatory dysfunction of CCl4-cirrhotic rats leading to portal hypertension amelioration and cirrhosis regression. Hepatology. 2016;64:1043A.
  7. Eguchi A, et al. Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation. J Mol Med (Berl). 2018;96(6):575–83.
  8. Garcia-Tsao G, et al. Emricasan (IDN-6556) lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension. 2019;69(2):717–28.