Neurotoxicity of an Hepatitis B Virus (HBV) Transcript Inhibitor in 13-Week Rat and Monkey Studies

Area of Science:

• Pharmacology
• Toxicology
• Hepatitis B Virus Research

Background:

• GS-8873 is an investigational RNA transcript inhibitor for Hepatitis B virus (HBV).
• Nonclinical safety evaluations are crucial for drug development, especially for novel mechanisms targeting viral replication.

Purpose of the Study:

• To evaluate the 13-week nonclinical safety profile of GS-8873 in rats and monkeys.
• To assess neurotoxicity, including neuroelectrophysiology and neurobehavioral effects, of GS-8873.
• To determine a no-observed-adverse-effect-level (NOAEL) for GS-8873.

Main Methods:

• 13-week oral toxicity studies in Wistar Han rats and cynomolgus monkeys with 8-week recovery phases.
• Dose escalation from sub-therapeutic to high doses (rats: 2-60 mg/kg/day; monkeys: 0.5-6 mg/kg/day).
• Inclusion of neuroelectrophysiology (nerve conduction velocity, latency) and neurobehavioral assessments.
• Retrospective risk assessment using benchmark dose (BMD) modeling.

Main Results:

• GS-8873 induced dose-responsive decreases in nerve conduction velocity and increases in nerve signal latency in both species.
• Neurotoxicity effects worsened by week 13 and showed incomplete reversal during the recovery phase.
• Minimal axonal degeneration observed in rat nerves; no microscopic nervous system findings in monkeys.
• NOAEL could not be established due to observed neurotoxicity; development was halted.

Conclusions:

• GS-8873 exhibits dose-dependent neurotoxicity in rats and monkeys, impacting nerve conduction.
• Development of GS-8873 was discontinued due to safety concerns.
• Benchmark dose modeling provided estimated nerve conduction velocity BMDL values (rat: 0.3 mg/kg/day; monkey: 0.1 mg/kg/day) for risk assessment.