Vebicorvir plus Nrtl safe, well tolerated in patients with chronic HBV infection

Treatment with vebicorvir (VBR) plus nucleos(t)ide reverse transcriptase inhibitors (NrtIs) among virologically suppressed patients with chronic hepatitis B virus (HBV) is well tolerated and has a favourable safety profile, according to a 24-week study.

“While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pregenomic (pg)RNA with the addition of VBR compared to NrtI alone,” the researchers said.

Seventy-three noncirrhotic, Nrtl-suppressed patients with chronic HBV were randomly assigned to receive VBR 300 mg once daily or matching placebo for 24 weeks. Treatment was stratified according to hepatitis B e antigen (HBeAg) status. Change in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks from baseline was the primary endpoint.

Of the participants, 47 were HBeAg positive and 26 were HBeAg negative. In both cohorts, no differences were observed in the change from baseline at week 24 for either HBsAg or HBeAg. [J Hepatol 2022;77:642-652]

A novel, high-sensitivity assay was used to detect HBV DNA, which showed that a greater proportion of patients with detectable HBV DNA at baseline had undetectable HBV DNA at week 24 in the VBR+Nrtl group relative to the placebo+Nrtl group. In addition, a greater change was seen at week 24 in HBeAg-positive patients on VBR+Nrtl compared with those who received placebo+Nrtl.

“Since reductions in viral antigens through core inhibition can only occur via reduction of cccDNA transcriptional activity, longer-term treatment may be required to induce downstream HBV antigen reductions,” the researchers said.

“The addition of core inhibitors to novel combination regimens with agents directly interfering with HBV antigen production, such as RNA interference, may improve treatment outcomes through complementary mechanisms. Studies are ongoing with VBR to test this hypothesis,” they added.

Safety profile

Of note, treatment-emergent adverse events (TEAEs) occurred in VBR+Nrtl patients, such as respiratory tract infection, nausea, and pruritus. However, no serious adverse events, grade 4 TEAEs, or any deaths were documented.

“Current first-generation core inhibitors have a relatively low barrier to resistance when used as a monotherapy,” the researchers said. “In this study, no patients experienced protocol-specified virologic breakthrough criteria, and therefore, resistance sequencing was not performed.” [J Hepatol 2020;73:S129-S130]

While standard-of-care Nrtls are generally well tolerated, some core inhibitors in clinical development have been discontinued because of emergent safety concerns. [Lancet Gastroenterol Hepatol 2016;1:185-195; Lancet Gastroenterol Hepatol 2016;1:196-206; https://investor.arbutusbio.com/news-releases/news-release-details/arbutus-announces-decision-discontinue-development-ab-506-oral]

“Vebicorvir was well tolerated when administered with NrtI for 24 weeks in virologically suppressed, HBeAg-positive and -negative patients,” the researchers said. “Rashes were observed in several patients taking VBR, which were generally low-grade, self-limiting, or treated with topical agents and did not lead to study drug discontinuation.”

Drug-drug interactions between VBR and Nrtl were not observed at the dose levels, supporting continued assessment of VBR in Nrtl combination regimens.

“These data support further clinical investigation of core inhibitors as potential therapeutic agents in patients with chronic HBV,” the researchers said.