A Pangenotypic Hepatitis E Virus Replication Inhibitor With High Potency in a Rat Infection Model

Background & aims: Hepatitis E virus (HEV) constitutes a substantial public health burden with ∼20 million human infections annually, including 3.3 million symptomatic cases. Appropriate treatment options for, in particular, immunocompromised patients with HEV infection and pregnant women are lacking, underscoring the urgent need for potent and safe antiviral drugs.

Methods: HEV subgenomic replicon systems were used to screen a small library of preselected nucleoside analogues, originally developed in a hepatitis C virus (HCV) antiviral program. Antiviral activity of the selected hit on HEV infection was evaluated in a variety of cell culture systems, and the efficacy of the compound was assessed in the athymic nude rat HEV infection model.

Results: Compound JNJ-9117 exerts pangenotype antiviral activity against HEV in different cell types as well as in primary human hepatocytes. A high level of conservation is observed between 3 crucial motifs in the catalytic domain of the HCV and HEV polymerases. This suggests a mechanism of action that is identical to that of the molecule against HCV, whereby the 5'-triphosphate of JNJ-9117 acts as a chain terminator during viral RNA synthesis. JNJ-9117 has a favorable pharmacokinetic and safety profile in rats and results in a pronounced antiviral effect in a chronic rat HEV infection model, both in a prophylactic and therapeutic setting. The combination of JNJ-9117 and ribavirin (each at an intentionally selected suboptimal/inactive dose) was highly effective in infected rats in lowering the viral RNA load in liver and feces to (almost) undetectable levels.

Conclusions: JNJ-9117 has a profile that holds promise for the treatment of life-threatening HEV infections in humans. Phase I studies with JNJ-9117 have been initiated in healthy human volunteers.