VRON-0200 alone and in combination with investigational antivirals for participants with chronic hepatitis B virus infection receiving stable nucleos(t)ide therapy: a phase 1b, randomised, open-label, multicentre trial

Background Functional cure treatments for hepatitis B virus (HBV) have been restricted by their inability to restore anti-HBV immunity, often leading to viral rebound after treatment. VRON-0200 is a novel immunotherapy for functional cure of HBV that contains a checkpoint modifier together with HBV core and polymerase (pol) antigens—but not surface antigens—to enhance, broaden, and prolong T-cell responses with the aim to prevent after treatment viral rebound and improve functional cure response rates. We report the safety, tolerability, immunogenicity, and antiviral efficacy of VRON-0200 alone and in combination with investigational antivirals in participants with chronic HBV infection receiving nucleos(t)ide therapy. Methods This phase 1b, randomised, open-label, multicentre trial included participants with chronic HBV infection aged between 18 and 55 years who had normal liver function, were receiving stable nucleos(t)ide therapy, and had non-detectable HBV DNA for 12 months or more. Participants with baseline HBsAg of less than 500 IU/mL were randomised to receive an intramuscular VRON-0200 prime alone on day 1 or with a VRON-0200 boost on day 91. In group 1, participants were randomised to receive either a low prime dose (1×10 10 viral particles) of chimpanzee adenovirus serotype 7 (AdC7; group 1a) or chimpanzee adenovirus serotype 6 (AdC6; group 1b) by intramuscular injection, with group 1a participants receiving an AdC6 boost at day 91. In group 2, participants were randomised to receive either a high prime dose (5×10 10 viral particles) of AdC7 (group 2a) or AdC6 (group 2b) by intramuscular injection, with group 2a participants receiving an AdC6 boost at day 91. In group 3, participants with baseline HBsAg of less than 1000 IU/mL were randomised to receive an intramuscular VRON-0200 prime, followed by six monthly doses of elebsiran plus tobevibart starting on day 28, alone, or with a VRON-0200 boost on day 196. The primary endpoint was to evaluate the safety and tolerability of VRON-0200, with additional immunological (interferon-γ [IFN-γ] enzyme-linked immunosorbent spot [ELISpot]) and virological assessments (HBsAg and HBV DNA) performed. IFN-γ ELISpot responses were assessed using a one-sided paired t-test (day 28 vs baseline), whereas a two-sided paired t-test was used to compare responses between day 154 and day 91 in participants receiving either the prime alone or prime–boost regimen. This study was registered at ClinicalTrials.gov (NCT06070051) and is active and fully enrolled. Findings Between Oct 26, 2023, and March 17, 2026, 35 participants were enrolled (groups 1 and 2, n=27; group 3, n=8): 28 (80%) were male, 30 (86%) were Asian, and 34 (97%) were HBeAg negative. The median participant age was 46 years (range 37–55). Median baseline HBsAg was 179 IU/mL (range 16–623) in group 1, 149 IU/mL (10–563) in group 2, and 469 IU/mL (12–1169) in group 3. VRON-0200 was well tolerated, with 38 treatment-related adverse events reported (four of grade 2, 34 of grade 1); no treatment-related serious adverse events, discontinuations, or clinical laboratory abnormalities, including liver function test results, were reported. In groups 1 and 2, at day 360, 23 (85%) of 27 participants had sustained or continued HBsAg declines (12 [52%] of 23 had reductions of >50%) and four (15%) participants had declines of 1 log 10 IU/mL or more from baseline. 12 participants had long-term follow-up to 846 days after VRON-0200 prime dosing; 11 (92%) of 12 participants had continued HBsAg declines, with seven (58%) having HBsAg concentrations of less than 10 IU/mL, four (33%) having less than 0·5 IU/mL, and two (17%) having less than 0·05 IU/mL (lower limit of detection [LLOD]). A boost dose was not observed to improve HBsAg declines. At day 28, IFN-γ ELISpot responses significantly increased 3·2 fold from baseline (p=0·007); however, these responses were not observed to be associated with HBsAg declines. In group 3, the addition of investigational antivirals resulted in rapid and profound HBsAg declines within 7 days (all seven [100%] participants treated with elebsiran plus tobevibart had HBsAg concentrations <2 IU/mL; one [14%] had HBsAg concentrations below the LLOD), regardless of baseline HBsAg concentrations. At day 196 (28 days after the last antiviral dose), all participants had HBsAg concentrations below 0·5 IU/mL (three [43%] of seven participants had HBsAg concentrations below the LLOD), and at day 259 (91 days after the last antiviral dose), six (86%) of seven participants had HBsAg concentrations that remained below 0·5 IU/mL and one (14%) had HBsAg concentration that remained below the LLOD. Interpretation VRON-0200 alone or with investigational antiviral agents had no observed safety concerns and was well tolerated. Despite not targeting HBsAg, a single VRON-0200 dose induced broad and sustained anti-HBV immunity in most participants. When combined with antivirals, rapid and profound HBsAg declines were observed in all participants. This novel approach, in which anti-HBV immunity is sparked (ie, primed) with VRON-0200 and then fanned (ie, boosted) by HBV removal, could position VRON-0200 as a key agent for a future HBV functional cure. Funding Virion Therapeutics, LLC.