Emricasan is a member of a new class of drugs to modulate caspases (cell death proteases) involved in the apoptosis and inflammation pathways. Caspases are a family of cysteine proteases that become activated by apoptotic and pro-inflammatory stimuli. Emricasan (IDN-6556) is a novel and proprietary small molecule, orally active caspase inhibitor designed to block apoptosis of cells in a variety of organ systems. Emricasan has been evaluated in clinical trials to determine its usefulness as an anti-fibrotic drug to delay the progression of hepatitis and prevent the development of cirrhosis.
Caspase Inhibitors in Chronic HCV
Caspases are an attractive target mechanism in the setting of HCV:
- Caspase inhibitors protect hepatocytes from death signals during HCV infection and organ stress.
- Apoptotic markers are decreased in HCV patients after treatment with caspase inhibitors.
- Caspases are activated in human biopsy specimens of chronic HCV patients.
- Activation precedes morphological evidence of cell death.
- Levels of caspase activation in hepatocytes correlate with histological grade of disease.
- ~4X more apoptotic cells are detected in HCV-infected liver tissue compared to control.
In the clinic, the ultimate result of caspase inhibition could be an overall reduction in the negative consequences of the host response to the virus infection (i.e., reduction in inflammation, apoptosis and fibrosis). In HCV infected patients, emricasan treatment could lead to rapid and sustained reduction in biochemical markers of liver disease (aminotransferases) with a corresponding reduction in liver damage (improvement in liver histology) as cell death mechanisms are controlled.
The mechanism of action of emricasan involves selective irreversible inhibition of activated caspases, which are cysteine proteases mediating apoptosis. In vitro, emricasan potently and irreversibly inhibits caspases 1, 2, 3, 6, 7, 8, and 9. Other cysteine and serine proteases, including those in the coagulation cascade, are inhibited only at much higher concentrations. Emricasan inhibits apoptosis of diverse cell types challenged with nerve growth factor deprivation, concanavalin A, Fas, dexamethasone, doxorubicin, or adrenergic overstimulation.
Emricasan was studied in models of liver disease that demonstrate apoptotic hepatocyte cell death mediated directly by Fas receptor ligation, by inflammatory liver damage using the LPS/Gln model, or liver fibrosis using the bile duct ligation model. In the Fas and LPS/Gln models, the ED50 when administered orally was < 0.05 mg/kg. In the bile duct ligation model, treatment with 10 mg/kg BID reduced markers of hepatocyte apoptosis and liver injury, inflammation, and fibrogenesis, and decreased liver collagen deposition. The efficacy of emricasan in all of these models support its therapeutic potential to decrease liver inflammation and apoptosis, with an impact on fibrogenesis. Refer to Publications section for further details.
To date, nine clinical studies were completed by Idun and Pfizer (with over 600 people receiving one or more doses of the drug), and there are currently no studies ongoing. In seven of these studies emricasan was orally administered to healthy male and female subjects and subjects with liver disease of a variety of etiologies. The maximum tolerated dose has not been reached. Single oral doses of emricasan were studied in the range 1 to 500 mg in healthy subjects. All dose levels were well tolerated. Subjects with liver disease have received multiple oral doses up to 200 mg BID for 14 days and 50 mg BID for 12 weeks. No safety signals of concern were seen in these studies and the adverse events reported were generally reflective of the patient population under study.
A Phase 1 safety trial of an intravenous formulation of emricasan was completed in 2002. The single-blind, placebo-controlled study was designed to test the safety and tolerability of single and multiple rising doses in 60 normal volunteers. Pharmacokinetics and metabolism were also studied in these subjects. The test group also included 16 individuals with stable liver impairment, including individuals infected with HCV. Results from the normal volunteer group and the liver impaired groups show that the drug was well tolerated. Emricasan did not reduce liver enzyme levels in normal volunteers. However, emricasan administration in liver impaired patients resulted in statistically significant reductions in liver enzyme levels (ALT & AST). Ten out of 11 patients in the drug treatment groups had enzyme levels reduced to the normal range during drug treatment, which returned to previous levels after the drug treatment ended.
Cold ischemia/warm reperfusion (CI/WR) injury remains a problem in liver transplantation. A Phase 2 trial was conducted to assess the utility of emricasan on CI/WR injury during human liver transplantation. Emricasan, when administered in cold storage and flush solutions during liver transplantation, offered local therapeutic protection against CI/WR-mediated apoptosis and injury, but this was not observed when emricasan was administered to the patient. No safety signals of concern were seen in the study and the adverse events were generally reflective of the patient population under study.
Two Phase 2a clinical trials of an oral formulation of emricasan were carried out in patients infected with HCV, most of whom had failed existing approved treatments. In a 14-day dosing study, various doses and dose regimens of emricasan were tested in groups of eight patients where six patients received the drug and two patients were given a placebo. Dosages ranging from 25 milligrams to 200 milligrams once a day (QD), and 50 to 100 milligrams twice a day (BID) were examined during a two-week dosing period. Emricasan was well tolerated and a maximum tolerated dose was not identified. All doses of the drug significantly lowered ALT and AST by the end of the treatment period and were well tolerated. Comparable results were obtained in a follow-up trial which dosed patients for 3 months.
A small group of patients with fatty liver disease, and a group with HBV were evaluated as supplemental cohorts of the Phase 2a HCV clinical trial. Aminotransferase reductions were readily observed during treatment with emricasan in both groups.