emricasan (IDN 6556) / Amerimmune - LARVOL DELTA

Therapeutic Potential of Emricasan, a Pan-Caspase Inhibitor, in Reducing Cell Death and Extracellular Matrix Accumulation in Fuchs Endothelial Corneal Dystrophy. (PubMed, Cells) - "Transcriptome analysis revealed distinct gene expression changes in the corneal endothelium following emricasan treatment. These findings suggest that emricasan exerts dual protective effects by inhibiting caspase-7-mediated ECM accumulation and broadly suppressing apoptosis, highlighting its potential as a pharmacological therapy for FECD."

Journal • Ophthalmology • Transplantation • CASP7 • COL8A2 • TGFB1

Vascular Organoid Generation from Human-Induced Pluripotent Stem Cells. (PubMed, J Vis Exp) - "The modified protocol incorporates the use of microwells and the CEPT cocktail (chroman 1, emricasan, polyamines, and the integrated stress response inhibitor, trans-ISRIB) to improve embryoid body formation and cell survival. Differentiated, mature vascular organoids generated using this protocol are characterized by whole-mount 3D immunofluorescence microscopy to analyze their morphology and complex vasculature. This protocol enables the production of high-quality vascular organoids in a scalable manner, potentially facilitating their use in disease modeling and drug screening applications."

Journal

Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease. (PubMed, J Clin Transl Hepatol) - "Agents in this group include peroxisome proliferator-activated receptor agonists (e.g., pioglitazone, elafibranor, saroglitazar), bile acid-farnesoid X receptor axis regulators (obeticholic acid), de novo lipogenesis inhibitors (aramchol, NDI-010976), and fibroblast growth factor 21/19 analogs...Agents in this group include antioxidants (vitamin E), tumor necrosis factor α pathway regulators (emricasan, pentoxifylline, ZSP1601), and immune modulators (cenicriviroc, belapectin). The final group targets the gut (IMM-124e, solithromycin). Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects. This review aimed to provide an update on these medications."

Journal • Review • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Type 2 Diabetes Mellitus • FGF21 • TNFA

Necroptosis-like cell death of infected DC contributes to protection against cutaneous leishmaniasis (ESDR 2024) - "C57BL/6 DC were infected with L. major w/ or w/o Emricasan (inhibits Caspase-8), Birinapant (inhibiting cIAP1/2), or Necrostatin-1 (blocks RIPK1). In contrast, IL-12p40 release is regulated independently of this cell death pathway. Our data shows that myeloid cell death, most likely DC necroptosis, is critical for the generation of protective immunity against L. major."

Dermatology • Infectious Disease • CASP8 • IL1A • IL1B • MYD88 • RIPK1

The caspase-inhibitor Emricasan efficiently counteracts cisplatin- and neomycin-induced cytotoxicity in cochlear cells. (PubMed, J Mol Med (Berl)) - "Sodium thiosulfate and Emricasan provide similar protective effects to cisplatin-treated cells. Emricasan is more potent than sodium thiosulfate in reducing neomycin-induced cytotoxicity."

Journal • Oncology • Otorhinolaryngology • Solid Tumor

Necroptosis in recurrent implantation failure: A bioinformatics analysis of key genes and therapeutic targets. (PubMed, Medicine (Baltimore)) - "Several drugs targeting CASP1, such as nivocasan and emricasan, were identified as potential treatments. The study sheds light on the role of necroptosis in RIF, identifying key genes and immune alterations that could serve as biomarkers and therapeutic targets. These findings pave the way for future experimental research and clinical applications targeting necroptosis in RIF treatment."

Journal • BIRC3 • CASP1 • FASLG • TLR3 • XIAP

Multisite studies for optimization of a highly efficient culture assay used for in vitro detection of residual undifferentiated human pluripotent stem cells intermingled in cell therapy products. (PubMed, Regen Ther) - "The efficiency of colony formation was significantly higher under culture conditions with the combination of Chroman 1, Emricasan, Polyamines, and Trans-ISRIB (CEPT) than with Y-27632, which is widely used for the survival of hPSCs...The sorting efficiency of microbeads conjugated with the anti-Tra-1-60 antibody was sufficiently higher (>80%) than those of the other various microbeads investigated. Results of these multisite studies are expected to contribute to improvements in the sensitivity and robustness of the HEC assay, as well as to the future standardization of the tumorigenicity risk assessment of hPSC-derived CTPs."

Journal • Preclinical • Oncology

Polyethylene Glycol and Caspase Inhibitor Emricasan Alleviates Cold Injury in Primary Rat Hepatocytes. (PubMed, Cryobiology) - "We show the addition of 5% PEG to the storage medium significantly reduced the release of lactate dehydrogenase (LDH) in plated rat hepatocytes and a combinatorial treatment with emricasan maintains hepatocyte viability and morphology following recovery from cold storage. These results show that cold-stored hepatocytes undergo multiple mechanisms of cold-induced injury and that PEG and emricasan treatment in combination with supercooling may improve cell and organ preservation."

Journal • Preclinical • Transplantation

The positive feedback loop of the NAT10/Mybbp1a/p53 axis promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury. (PubMed, Redox Biol) - "The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan...Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R."

Journal • Cardiovascular • Coronary Artery Disease • Myocardial Ischemia • Reperfusion Injury • NAT10 • SLC7A11

Small Molecules for the Treatment of Long-COVID-Related Vascular Damage and Abnormal Blood Clotting: A Patent-Based Appraisal. (PubMed, Viruses) - "Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium-hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds."

Adverse events • Journal • Cardiovascular • CNS Disorders • Coronary Artery Disease • Heart Failure • Hematological Disorders • Infectious Disease • Ischemic stroke • Novel Coronavirus Disease • Thrombosis • Vascular Neurology • Venous Thromboembolism

A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis. (PubMed, J Hepatol) - "Emricasan treatment did not improve liver histology in subjects with NASH fibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum ALT in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning."

Clinical • Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Biomaterials Functionalized with Inflammasome Inhibitors-Premises and Perspectives. (PubMed, J Funct Biomater) - "Pharmaceutical substances can control the inflammasomes by three mechanisms: inhibiting the intracellular signaling pathways (Allopurinol and SS-31), blocking inflammasome components (VX-765, Emricasan and VX-740), and inhibiting cytokines mediated by the inflammasomes (Canakinumab, Anakinra and Rilonacept). Moreover, phytochemicals inhibit the inflammasomes by neutralizing reactive oxygen species. Biomaterials functionalized by the adsorption of therapeutic agents onto different nanomaterials could represent future research directions to facilitate multimodal and sequential treatment in oral pathologies."

Journal • Review • Dental Disorders • Immunology • Inflammation • Periodontitis

Identification of apoptosis-related gene signatures as potential biomarkers for differentiating active from latent tuberculosis via bioinformatics analysis. (PubMed, Front Cell Infect Microbiol) - "Furthermore, 24 drugs, including progesterone and emricasan, were predicted. The correlation analysis revealed that biomarkers were positively correlated with most m6A or m5C regulators. The six ARGs can serve as effective biomarkers differentiating ATB from LTBI and provide insight into the pathogenesis of Mycobacterium tuberculosis infection."

Biomarker • Gene Signature • Journal • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Tuberculosis • ATF3 • CASP1 • CASP4 • CASP5 • IFI16 • TNFSF10

Emricasan for the treatment of liver cirrhosis: a meta-analysis of randomized controlled trials. (PubMed, Afr Health Sci) - "Overall, compared with control group for liver cirrhosis, emricasan treatment had no substantial impact on MELD (SMD=-0.19; 95% CI=-0.44 to 0.06; P=0.14), INR (SMD=0.12; 95% CI=-0.13 to 0.37; P=0.36), total bilirubin (SMD=-0.27; 95% CI=-0.56 to 0.01; P=0.06), serum albumin (SMD=0; 95% CI=-0.25 to 0.25; P=1.00) or adverse events (OR=1.35; 95% CI=0.56 to 3.24; P=0.50). Emricasan treatment provided no benefit for the treatment of liver cirrhosis."

Journal • Retrospective data • Review • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis

Caspase cleavage of RIPK3 after Asp is dispensable for mouse embryogenesis. (PubMed, Cell Death Differ) - "Ripk3 macrophages died at the same rate as wild-type (WT) macrophages in response to TNF plus cycloheximide, TNF plus emricasan, or infection with murine cytomegalovirus (MCMV) lacking M36 and M45 to inhibit caspase-8 and RIPK3 activation, respectively. We conclude that caspase cleavage of RIPK3 is dispensable for mouse development, and that cleavage of caspase-8 substrates, including RIPK1, is sufficient to prevent necroptosis."

Journal • Preclinical • Cytomegalovirus Infection • Infectious Disease • Oncology • CASP3 • CASP8 • RIPK1 • TNFA

Stress-free cell aggregation by using the CEPT cocktail enhances embryoid body and organoid fitness. (PubMed, Biofabrication) - "Application of CEPT (chroman 1, emricasan, polyamine, trans-ISRIB) for just 24 hours during cell aggregation has long-lasting consequences affecting morphogenesis, gene expression, cellular differentiation, and function. Various qualification methods confirmed that CEPT treatment enhanced experimental reproducibility and consistently improved EB and organoid fitness as compared to the widely used ROCK inhibitor Y-27632. Collectively, we discovered that stress-free cell aggregation and superior cell survival in the presence of CEPT are critical quality control determinants that establish a robust foundation for bioengineering complex tissue and organ models.&#xD."

Journal • Developmental Disorders

THREE-DIMENSIONAL PRIMARY CELL BASED LIVER MODEL PREDICTS CLINICAL OUTCOMES OF NASH IN VITRO (AASLD 2023) - "Using the diseased 3D liver tissues, we were then able to accurately predict the response of Elafibranor (PPAR inhibitor, Genfit), Emricasan (pan-caspase inhibitor, Conatus/Novartis), Selonsertib (ASK1 inhibitor, Gilead) and OCA (FXR agonist, Intercept) in vitro using fibrosis as the primary endpoint. Our results demonstrate the advanced potential of our 3D liver tissues as a reliable preclinical screening tool for NASH drug discovery. These models offer a more physiologically relevant platform than traditional 2D cell culture systems or animal models for the evaluation of efficacy of clinical compounds and may accelerate the development of effective therapies for NASH and reduce clinical failures."

Clinical data • Preclinical • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis

Calpain Activation in Early Reperfusion Triggers Pyroptosis Resulting in Myocardial Ischemia/Reperfusion Injury (AHA 2022) - "This result was amplified by lack of added protection when mice received combined CPT and emricasan (EMRI), a pan-cas blocker. In contrast, EMRI plus preconditioning does give additive protection. Hence calpain activity in the initial minutes of reperfusion is also involved in injurious pyroptosis and may be a viable target in treatment of acute MI."

Cardiovascular • Inflammation • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury

An oral caspase inhibitor as monotherapy or with antibiotics eradicates MRSA skin infections in mice. (PubMed, Drug Dev Res) - "Importantly, the efficacy of emricasan against S. aureus was not due to direct antibacterial activity. Collectively, pan-caspase inhibitor emricasan and emricasan plus doxycycline reduced both the lesion size and bacterial burden in vivo, and emricasan is a potential host-directed immunotherapy against MRSA skin infections in a preclinical mouse model."

Journal • Monotherapy • Preclinical • Dermatology • Infectious Disease

Z-DNA BINDING PROTEIN 1 AGGRAVATED THE SEPSIS-INDUCED ACUTE KIDNEY INJURY VIA PANOPTOSIS (ERA-EDTA 2023) - "ZBP1 exacerbated SI-AKI via activating PANoptosis with the potencial PANoptosome of ZBP1, caspase 8, pglyrp1, and RIPK1."

Acute Kidney Injury • Infectious Disease • Nephrology • Renal Disease • Septic Shock • CASP3 • CASP8 • FADD • IGF2BP1 • IL6 • KIM1 • RIPK1 • TNFA

Utilization of CEPT Polypharmacological Cocktail in Machine Perfusion Promotes Whole-Organ Resuscitation from Warm Ischemic Damage [Board No. DLB009] (ATC 2023) - "CEPT is a polypharmacological cocktail (Chroman-1, Emricasan, Polyamine, and Trans-ISRIB) that targets several pathways to inhibit apoptosis... CEPT treatment protects against warm ischemia at room temperature. Further experiments with the addition of CEPT to individual Flush, Storage, and Perfusate solutions are needed to stratify its protective effect."

Late-breaking abstract • Cardiovascular • Hepatology • Solid Organ Transplantation • Transplantation

Celastrol inhibits necroptosis by attenuating the RIPK1/RIPK3/MLKL pathway and confers protection against acute pancreatitis in mice. (PubMed, Int Immunopharmacol) - "Here we showed that celastrol significantly suppressed necroptosis induced by lipopolysaccharide (LPS) plus pan-caspase inhibitor (IDN-6556) or by tumor-necrosis factor-α in combination with LCL-161 (Smac mimetic) and IDN-6556 (TSI). Moreover, in a mouse model of acute pancreatitis that is associated with necroptosis, celastrol administration significantly reduced the severity of caerulein-induced acute pancreatitis accompanied by decreased phosphorylation of MLKL in pancreatic tissues. Collectively, celastrol can attenuate the activation of RIPK1/RIPK3/MLKL signaling likely by attenuating mtROS production, thereby inhibiting necroptosis and conferring protection against caerulein-induced pancreatitis in mice."

Journal • Preclinical • Metabolic Disorders • Oncology • Ophthalmology • Pancreatitis • RIPK1 • TNFA

The irreversible pan-caspase inhibitor emricasan is a potential host-directed immunotherapy against methicillin-resistant S. aureus (MRSA) skin infections in mice (ISID 2023) - "When compared to placebo, all three groups, placebo plus doxycycline, emricasan plus doxycycline, and emricasan treated group, exhibited biological effect, with reduction of both the lesion size (*p=0.0277, ****p<0.0001, ****p<0.0001, respectively) and bacterial burden (***p=0.003, ****p<0.0001, ****p<0.0001, respectively). Collectively, pan-caspase inhibitor emricasan and emricasan plus doxycycline reduced both the lesion size and bacterial burden in vivo, and emricasan is a potential host-directed immunotherapy against MRSA skin infections in a preclinical mouse model."

Preclinical • Dermatology • Infectious Disease

Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity. (PubMed, Int J Mol Sci) - "The calpain inhibitor calpeptin duplicated emricasan's protection. Unlike IPC, adding calpain to emricasan offered no additional protection, suggesting that caspase-1/4 and calpain may share the same protective target."

Journal • Cardiovascular • Reperfusion Injury

DIACC2010, Sole-in-Class Selective Inhibitor of Kinesin KIF20A, Has Potent Preclinical Efficacy in Acute Myeloid Leukemia (ASH 2022) - "In the same experimental conditions, cytarabine (CYTA) had median IC50 of 207 nM (range 4-1580 nM)...Nevertheless, caspase inhibitors ZVAD-fmk and Emricasan partially rescued DIACC2010 cell death, although these inhibitors significantly rescued caspase activation induced by Venetoclax, a BCL-2 inhibitor triggering intrinsic apoptosis commonly used in AML treatment... Altogether, these results confirm the relevance of KIF20A-directed therapeutic approaches and support the development of DIACC2010 for the treatment of AML."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • ANXA5 • GLI2 • KIF20A • PRKDC