Multicenter, Double‐Blind, Randomized Trial of Emricasan in Hepatitis C–Treated Liver Transplant Recipients With Residual Fibrosis or Cirrhosis

Abstract

Despite achieving sustained virologic response (SVR) to hepatitis C virus (HCV) therapy, there remains a post liver transplantation population with advanced fibrosis/cirrhosis. Emricasan is an orally active, pan-caspase inhibitor that suppresses apoptosis and inflammation, potentially decreasing hepatic inflammation and fibrosis. We aimed to determine the safety and efficacy of emricasan (IDN-6556-07) in a double-blind, randomized, placebo-controlled, multicenter study in reducing or preventing the progression of hepatic fibrosis in HCV liver transplant recipients with residual fibrosis or cirrhosis after achieving SVR. A total of 64 participants were randomly assigned to receive 25 mg twice daily of emricasan or placebo in a 2:1 ratio for 24 months. 41 participants were randomly assigned to emricasan and 23 to placebo; 32 participants in the emricasan group (78.0%) and 19 who took a placebo (82.6%) completed the study. There was no difference in the primary endpoint (Ishak fibrosis stages F2-F5, improvement in fibrosis or stability; Ishak fibrosis stage F6, improvement) between the emricasan (77.1%) and placebo groups (74.1%); P = NS. There was no difference between the emricasan (54.5%) and placebo (60.7%) arms in the rate of fibrosis improvement alone. However, those in the prespecified F3 to F5 subgroup had higher rates of stability or improvement in fibrosis in the emricasan group (95.2%) compared with placebo (54.6%) (P = 0.01). The tolerability and safety profiles were similar in both groups. In conclusion, overall stability in the Ishak fibrosis stage was similar between emricasan and placebo groups at 24 months. However, there was improvement and/or stability in fibrosis stage in the prespecified F3 to F5 subgroup with emricasan versus placebo, suggesting that patients with moderate fibrosis may benefit with emricasan.

Natural killer cells induce HIV-1 latency reversal after treatment with pan-caspase inhibitors

“…In another study, a pan-caspase inhibitor was shown to inhibit death of T cells from SIV-infected rhesus macaques and was suggested to represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS ( 48 ). Although Z-VAD-FMK itself will not be useful as drug treatment, the pan-caspase inhibitor drug emricasan is currently in clinical trials for treatment of liver diseases ( 49 – 55 ) and could be repurposed without lengthy preclinical development. However, since the main function of pan-caspase inhibitors is inhibiting all caspases and consequently inhibiting caspase-induced cell death, we also inhibit cytotoxic lymphocyte-mediated target cell death of the HIV-1 reactivated cells.…”

Clinical Pharmacology Applications of Real‐World Data and Real‐World Evidence in Drug Development and Approval–An Industry Perspective

“…In a few cases, dedicated efficacy and safety studies in patients with organ impairment are conducted. [22][23][24][25][26] In general, enrolling participants with organ impairment is challenging irrespective of the study type, especially for those with moderate and severe organ impairment. RWD/RWE can be used in this space in multiple ways: (i) informing the need for organ impairment studies, (ii) evaluating the feasibility of characterizing exposure changes of the investigational drug in target patient populations with organ impairment, (iii) generating post-approval efficacy and safety data to guide dosing in patients with organ impairment, and (iv) assessing the time course of organ impairment progression.…”

“…It is a typical practice in drug development to explicitly exclude participants with advanced organ impairment from phase II and phase III trials. In a few cases, dedicated efficacy and safety studies in patients with organ impairment are conducted 22–26 . In general, enrolling participants with organ impairment is challenging irrespective of the study type, especially for those with moderate and severe organ impairment.…”

Caspase-2 in liver disease and hepatocellular carcinoma

“…Emricasan has been also investigated in other etiologies of liver disease. Chronic hepatitis C patients with residual fibrosis or cirrhosis treated with Emricasan for 24 months achieved an improvement and/or stabilization in the fibrosis stage [99]. Emricasan administration over 3 months improved hepatic function in patients with decompensated cirrhosis and more severe end-stage liver disease (including NASH patients) [100].…”