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Introduction: MALT1 is the only human paracaspase, a protease with unique cleavage activity and substrate specificity. As a key regulator of immune responses, MALT1 has attracted attention as an immune modulatory target for the treatment of autoimmune/inflammatory diseases. Further, chronic MALT1 protease activation drives survival of lymphomas, suggesting that MALT1 is a suitable drug target for lymphoid malignancies. Recent studies have indicated that MALT1 inhibition impairs immune suppressive function of regulatory T cells in the tumor microenvironment, suggesting that MALT1 inhibitors may boost anti-tumor immunity in the treatment of solid cancers., Areas Covered: This review summarizes the literature on MALT1 patents and applications. We discuss the potential therapeutic uses for MALT1 inhibitors based on patents and scientific literature., Expert Opinion: There has been a steep increase in MALT1 inhibitor patents. Compounds with high selectivity and good bioavailability have been developed. An allosteric binding pocket is the preferred site for potent and selective MALT1 targeting. MALT1 inhibitors have moved to early clinical trials, but toxicological studies indicate that long-term MALT1 inhibition can disrupt immune homeostasis and lead to autoimmunity. Even though this poses risks, preventing immune suppression may favor the use of MALT1 inhibitors in cancer immunotherapies.

Background & Aims: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause 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; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis., Methods: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, 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 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated., Conclusions: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis., Lay Summary: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis 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 cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS., Gov Identifier: NCT03205345., Competing Interests: Conflict of interest James Robinson, Jean L. Chan and David Hagerty were employees of Conatus Pharmaceuticals, Inc., during the conduct of the study. Nicole Wedick was a consultant employed by Conatus Pharmaceuticals, Inc., and reports personal fees from SimulStat, Inc., during the conduct of the study. Catherine Frenette reports research funding from Conatus Pharmaceuticals, Inc., during the conduct of this study and personal fees from Conatus Pharmaceuticals, Inc., outside of the submitted work. Kris Kowdley reports grants from Conatus Pharmaceuticals, Inc., during the conduct of the study; personal fees from Abbvie, Gilead and Intercept, outside of the submitted work; grants from Enanta, Genfit, Gilead, CymaBay, HighTide, Intercept, Allergan and LaJolla, outside of the submitted work; royalties from UpToDate, outside of the submitted work. Kris Kowdley was on the Advisory Board of Assembly Biosciences, Blade, Enanta, Genefit, Gillead, CymaBay and Merck and was a consultant for HighTide and Intercept, outside of the submitted work. Guy Neff reports grants from Echosens and personal fees from Intercept, outside the submitted work. Parvez Mantry reports personal fees from Gilead, Intercept, Salix, Eisai, Abbvie and grants from Allergan, Genfit, Bristol-Myers, Galmed, Viking, Pfizer, Merck, outside the submitted work. Ethan Weinberg reports personal fees from Mallinckrodt Pharmaceuticals and from Sequana, outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis., Methods: We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes., Results: There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21, -0.45, -0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups., Conclusions: Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated., Lay Summary: Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients., Clinical Trial Number: Clinical Trials.gov #NCT02960204., Competing Interests: Conflict of interest Jean L. Chan, James Robinson, and David T. Hagerty are employees of Conatus Pharmaceuticals. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile., Areas Covered: In this article, we review patents (2013-2015) for peptide and non-peptide caspase inhibitors and their compositions., Expert Opinion: Noteworthy patents include a peptidic caspase-2 inhibitor for nasal administration and a peptidomimetic caspase-6 inhibitor that can be administered via several routes for the treatment of neurodegenerative diseases. Furthermore, caspase-1 inhibitors for contact dermatitis and inflammation, cardiovascular diseases, and liver diseases and a caspase-3 inhibitor for cerebral stroke have been patented. Of particular interest is the novel use of tyrosine kinase inhibitors (sunitinib and its derivatives) for the prevention and treatment of age-related ocular diseases via inhibition of the caspase-3, dual-leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) pathways. However, for effective clinical application of caspase inhibitors, novel peptidic and nonpeptidic caspase inhibitors with lower toxicity and improved efficacy should be developed via structural modifications, and further animal studies and preclinical and clinical trials are needed. In addition, the poor pharmacokinetic properties of classic caspase inhibitors may be improved by using advanced drug delivery systems that employ liposomes, polymers, and nanoparticles through effective administration routes.