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Novel Anti-HBV Agent (VIR-2218)
Aims for Functional Cure With PEG-IFN
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AASLD-The Liver Meeting, November 4-8, 2022, Washington, DC
Mark Mascolini
Ten of 64 trial participants taking the novel anti-HBV agent VIR-2218 plus pegylated interferon alfa for HBV infection cleared hepatitis B surface antigen (HBsAg) from serum in a phase 2 trial [1]. Longer treatment with the two agents cleared HBsAg and led to anti-HBs (hepatitis B surface antibody) seroconversion at a higher rate than shorter treatment. High anti-HBs means a person has become immune to HBV and cannot be infected [2].
A small interfering ribonucleic acid (siRNA) given subcutaneously, VIR-2218 stymies HBV replication by targeting the HBx region of HBV's genome and lowers levels of HBsAg-a signal of active HBV-in people with chronic HBV infection. PEG-IFN is licensed for treatment of HBV infection and has little impact on HBsAg clearance. For most people with chronic HBV infection, functional cure will require sustained reduction of HBsAg [3]. Researchers from the University of Hong Kong and collaborators at other centers hypothesized that coupling lowered HBsAg with VIR-2218 and immune stimulation with PEG-IFN could promote HBsAg seroclearance in a higher proportion of people with HBV than VIR-2218 alone.
To test this hypothesis they conducted a phase 2 trial that enrolled 5 cohorts: Cohort 1 (15 participants): VIR-2218 every 4 weeks 6 times; Cohort 2 (15 participants): VIR-2218 every 4 weeks 6 times plus PEG-IFN weekly for 12 weeks; Cohort 3 (18 participants): VIR-2218 every 4 weeks 6 times plus PEG-IFN weekly for 24 weeks; Cohort 4 (18 participants): VIR-2218 every 4 weeks 6 times plug PEG-IFN weekly up to 48 weeks; Cohort 5 (13 participants): VIR-2218 every 4 weeks up to 13 times plus PEG-IFN weekly up to 44 weeks.
Participants had to be 18 through 65 years old with detectable HBsAg above 50 IU/mL for at least 6 months and HBV DNA below 90 IU/mL. Participants could not have significant fibrosis or cirrhosis; bilirubin or prothrombin time above the upper limit of normal; ALT or AST more than 2 times the upper limit of normal; or active HIV, HCV, or HDV infection.
Ages in Cohort 1 through 5 averaged 50.3, 46.6, 48.7, 45.2, and 48.5 years, while HBsAg level averaged 3.4, 3.2, 3.3, 2.9, and 3.4 log10 IU/mL, and percentages of participants positive for HBeAg (a signal of active HBV replication) were 26.7%, 40.0%, 38.9%, 33.3%, and 23.1%.
Through week 48, VIR-2218-related treatment-emergent adverse events occurred in 3 people (20%) in Cohort 1, 4 (26.7%) in Cohort 2, 8 (44.4%) in Cohort 3, 7 (38.9%) in Cohort 4, and 6 (46.2%) in Cohort 5. PEG-IFN-related treatment-emergent adverse events numbered 12 (80%) in Cohort 2, 12 (66.7%) in Cohort 3, 13 (72.2%) in Cohort 4, and 13 (100%) in Cohort 5. No one stopped treatment because of treatment-emergent adverse events. Serious adverse events (none related to VIR-2218) affected 1 person in Cohort 3, 1 in Cohort 4, and 1 in Cohort 5.
Grade 3 ALT elevations appeared in only 2 participants, 1 in Cohort 3 and 1 in Cohort 4. Grade 3 drops in neutrophil levels affected 2 people (13.3%) in Cohort 2, 3 (16.7%) in Cohort 3, 10 (55.6%) in Cohort 4, and 6 (46.2%) in Cohort 5. One participant in Cohort 4 had a grade 4 neutrophil decline.
Starting VIR-2218 and PEG-IFN together (the protocol in Cohorts 3, 4, and 5) tended to yield the biggest average drops in HBsAg at week 48: -1.6 log10 in Cohort 1, -1.1 log10 in Cohort 2, -1.2 log10 in Cohort 3, -1.8 log10 in Cohort 4, and -2.9 log10 in Cohort 5. HBsAg levels dropped more with VIR-2218 plus PEG-IFN than with VIR-2218 alone. More people in Cohorts 4 and 5 (the cohorts with PEG-IFN durations up to 44 and 48 weeks) attained an HBsAg below 10 IU/mL and achieved HBsAg seroclearance. Overall, longer durations of VIR-2218 plus PEG-IFN lowered HBsAg levels more than shorter durations.
Seven of 8 people with HBsAg seroclearance at week 48 were in Cohorts 4 and 5. In Cohort 5, 2 of 5 people with a baseline HBsAg below 1500 IU/mL cleared HBsAg. In the same cohort 2 of 8 participants with a pretreatment HBsAg above 1500 IU/mL attained HBsAg seroclearance. And 7 of 8 participants with anti-HBs above 10 mIU/mL at week 48 were in Cohorts 4 and 5. All told, 10 participants-including 4 in Cohort 4 and 4 in Cohort 5 cleared HBsAg at any time up to week 48. Nine of these 10 people gained anti-HBs levels above 10 mIU/mL.
References
1. Yuen M-F, Lim Y-S, Cloutier D, et al. Preliminary 48-week safety and efficacy data of VIR-2218 alone and in combination with pegylated interferon alfa in participants with chronic HBV infection. AASLD-The Liver Meeting, November 4-8, 2022, Washington, DC. Late breaker.
2. Hepatitis B Foundation. Hepatitis B blood tests. https://www.hepb.org/prevention-and-diagnosis/diagnosis/hbv-blood-tests/
3. VIR. Vir Biotechnology announces initiation of phase 2 clinical trial evaluating VIR-2218, selgantolimod and nivolumab for the treatment of chronic hepatitis B virus infection. December 9, 2021. https://investors.vir.bio/news-releases/news-release-details/vir-biotechnology-announces-initiation-phase-2-clinical-trial
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