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

Abstract

The nonclinical safety profile of GS-8873, an HBV RNA transcript inhibitor was evaluated in rat and monkey 13-week toxicity studies with 8-week recovery phases. Vehicle or GS-8873 was dosed orally for 13 weeks at 2, 6, 20, and 60 mg/kg/day to Wistar Han rats and at 0.5, 1.5, 3 and 6 mg/kg/day to cynomolgus monkeys. In vitro and in vivo screening results from an analog discovered prior to GS-8873 informed the 13-week toxicology study designs. Neuroelectrophysiology and neurobehavioral evaluations were included at week 4 and 13 of the dosing and recovery phases for GS-8873. No adverse neurobehavioral effects were observed. Significant nerve conduction velocity (NCV) decreases and latency increases occurred at the high doses after 4 weeks of dosing. By week 13, dose responsive NCV reductions and latency increases worsened across all dose groups compared to controls. Some reversal occurred 8 weeks after the last dose administered, but not to vehicle control levels. A minimal, axonal degeneration was observed in rat spinal and peripheral nerves across dose groups compared to controls. No monkey nervous system microscopic findings were observed. NOAELs could not be determined for either species due to the neuroelectrophysiology findings and development was halted in the interest of safety. A retrospective risk assessment approach utilizing benchmark dose (BMD) modeling contributed 13-week NCV BMDL estimates (lower limits of the 95% confidence interval) in lieu of NOAELs. The best fitted models extrapolated NCV BMDLs for the rat caudal and monkey sural nerve at 0.3 mg/kg/day and 0.1 mg/kg/day, respectively.

Structure–Activity Relationships and Discovery of (S)-6-Isopropyl-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic Acid (AB-452), a Novel Orally Available HBV RNA Destabilizer

“…At doses ≤5 mg/kg/day, no test article related pathology or adverse behavior issues were observed during the 90-day dosing period. Similar to our findings, significant nerve conduction velocity (NCV) decreases and latency increases were observed with the structurally related GS-8873 after dosing in rats and monkeys for 4 weeks . More recently, polyneuropathy after repeat dosing in monkeys was also reported for RG7834 .…”

“…Using a procedure analogous to that which was used to prepare 23, 58c (9 mg, 0. Ethyl 6-(2-(Benzyloxy)-5-chloro-4-methoxyphenyl)-4-oxo-4Hpyran-3-carboxylate (31). To a cooled (−78 °C) mixture of LiHMDS (1 M solution in THF, 34 mL, 34 mmol) in THF (50 mL) was added a solution of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (2.8 g, 15 mmol) and 2-(benzyloxy)-5chloro-4-methoxybenzoyl chloride 30 (4.7 g, 15 mmol) in THF (50 mL) dropwise over 10 min while keeping the temperature at −78 °C.…”

“…The intriguing in vitro and in vivo properties of (S)-20 or AB-452 supported our decision for advancement of this novel HBV therapeutic agent into preclinical safety evaluation. Despite a NOAEL of 150 mg/kg/day and 30 mg/kg/day in 28-day rat and dog toxicity studies, respectively, further progression was halted after the observation of 31 More recently, polyneuropathy after repeat dosing in monkeys was also reported for RG7834. 32 The optimization of our series of analogues to address the peripheral neuropathy adverse events will be reported in due course.…”

Preclinical Antiviral and Safety Profiling of the HBV RNA Destabilizer AB-161

“…Multiple HBV RNA destabilizers have progressed into late-stage preclinical development (RG7834, AB-452, GS-8873), and some compounds were assessed in Phase 1 clinical studies including GST-HG131 [ 22 ], EDP-721 (NCT04971512), and GSK3965193 (NCT05330455). A number of these compounds have been discontinued due to undisclosed safety concerns during Phase 1a clinical studies (EDP-721) or observations of neurotoxicity during long-term preclinical tolerability studies (RG7834, GS-8873) [ 23 , 24 , 25 ]. Peripheral neurotoxicity (splayed limbs or decreased activity starting at 15 mg per kg) was also observed for AB-452, our first-generation HBV RNA destabilizer, during a 13-week repeat-dose safety study in dogs, which ultimately led to termination of AB-452 [ 25 ].…”

Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873

“…Our work culminated in the identification of development candidate GS-8873 (46), a DPP demonstrating cellular activity and preclinical pharmacokinetic parameters superior to RG7834. In the early stages of development, GS-8873 was shown to cause neuroelectrophysiology deficits in rats and monkeys, 27 leading to its discontinuation.…”