Vebicorvir plus entecavir safe, effective in chronic HBV patients

The addition of vebicorvir to entecavir in treatment-naïve patients with chronic hepatitis B virus (HBV) infection provides further antiviral activity, with a positive safety and tolerability profile, results of a phase II trial have shown.

“[O]nce-daily vebicorvir 300 mg plus entecavir 0.5 mg resulted in no deaths or adverse events (AEs) leading to discontinuation,” the researchers said.

“When added to entecavir, interference of the additional steps in HBV replication by vebicorvir resulted in significant additive reductions in HBV DNA and pgRNA and increased rates of ALT normalization over entecavir monotherapy,” they noted.

For 24 weeks, hepatitis B e-antigen (HBeAg)-positive, treatment-naïve patients were randomly assigned to once-daily vebicorvir plus entecavir (n=12) or placebo plus entecavir (n=13). Change in mean log₁₀ HBV DNA from baseline to weeks 12 and 24 was the primary endpoint.

All patients in the two treatment arms completed the study. Those who received vebicorvir plus entecavir had greater mean reduction from baseline in log₁₀ IU/ml HBV DNA than those in the placebo group (‒4.45 vs ‒3.30; p=0.0077) at week 12. [J Hepatol 2022;77:1265-1275]

At week 24, the vebicorvir plus entecavir group also showed a greater decrease in log₁₀ IU/ml HBV DNA than the placebo group from baseline (‒5.33 vs ‒4.20; p=0.0084). In addition, patients on vebicorvir plus entecavir had greater mean reductions in pregenomic RNA at weeks 12 (p<0.0001) and 24 (p<0.0001).

Changes in viral antigens in both treatment arms were similar, and no drug interaction was seen between vebicorvir and entecavir. During treatment, two patients had HBV DNA rebound, with no resistance breakthrough seen.

“The coprimary endpoints were met, with vebicorvir plus entecavir resulting in significantly greater reductions in HBV DNA from baseline at weeks 12 and 24 compared to placebo plus entecavir,” the researchers said.

Moreover, “[p]atients receiving vebicorvir plus entecavir demonstrated faster and deeper levels of HBV DNA suppression than those receiving placebo plus entecavir,” they added.

The combination therapy of vebicorvir and entecavir had a similar safety profile to placebo plus entecavir. All treatment-emergent AEs and laboratory abnormalities were grade 1 or 2, and no deaths, serious AEs, or evidence of drug-induced liver injury occurred. The most common AEs in either group were headache, pruritus, and alanine transaminase (ALT) increase.

“Among patients who had normal ALT levels at baseline, ALT elevations were grade 1 or 2, similar between treatment groups, and consistent with the natural history of patients with chronic HBV with active viral replication,” the researchers said.

“This is in contrast to grade 3 or 4 ALT elevations reported with some other core inhibitors,” they added. [ILC 2019, abstract FRI-219]

These findings were consistent with those from the phase Ib study. [Lancet Gastroenterol Hepatol 2020;5:152-166]

“Core inhibitors hold promise as a novel treatment in chronic HBV, as capsid assembly and disassembly are critical steps in virus production as well as generation of covalently closed circular DNA,” the researchers said. [J Med Chem 2017;60:6461-6479]

“Vebicorvir is a novel core inhibitor that induces altered, nonfunctional core protein assembly,” they added. [Antimicrob Agents Chemother 2020;64:e01463-1420; Lancet Gastroenterol Hepatol 2020;5:152-166]