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Review

Assessing the developing pharmacotherapeutic landscape in hepatitis B treatment: a spotlight on drugs in phase II clinical trials

ORCID Icon, , &
Pages 127-140 | Received 25 Feb 2022, Accepted 04 May 2022, Published online: 15 May 2022

References

  • Seto WK, Lo YR, Pawlotsky JM, et al. Chronic hepatitis B virus infection. Lancet. 2018 Nov 24;392(10161):2313–2324.
  • Razavi-Shearer D, Gamkrelidze I, Nguyen MH, Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018 Jun;3(6):383–403.
  • Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut. 2015 Dec;64(12):1972–1984.
  • Tu T, Budzinska MA, Shackel NA, et al. HBV DNA integration: molecular mechanisms and clinical implications. Viruses. 2017 Apr 10;9(4):75.
  • Park JJ, Wong DK, Wahed AS, et al. Hepatitis B virus–specific and global T-Cell dysfunction in chronic hepatitis B. Gastroenterology. 2016 Mar;150(3):684–695.e5.
  • Anderson RT, Choi HSJ, Lenz O, et al. Association between seroclearance of hepatitis B surface antigen and long-term clinical outcomes of patients with chronic hepatitis B virus infection: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2021 Mar;19(3):463–472.
  • Mak LY, Seto WK, Hui RW, et al. Fibrosis evolution in chronic hepatitis B e antigen-negative patients across a 10-year interval. J Viral Hepat. 2019 Jul;26(7):818–827.
  • Mak LY, Hui RW, Fung J, et al. Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B. J Hepatol. 2020 Oct;73(4):800–806.
  • Yeo YH, Ho HJ, Yang HI, et al. Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis. Gastroenterology. 2019 Feb;156(3):635–646.e9.
  • Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008 Feb;48(2):335–352.
  • Wong DK, Huang FY, Lai CL, et al. Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma. Hepatology. 2011 Sep 2;54(3):829–836.
  • Fisicaro P, Valdatta C, Massari M, et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology. 2010 Feb;138(2):682–93, 693.e1–4.
  • Mak LY, Seto WK, Yuen MF. Novel antivirals in clinical development for chronic hepatitis B infection. Viruses. 2021 Jun 18;13(6):1169.
  • Seto WK, Fung J, Cheung KS, et al. Body-mass index is associated with fibrosis regression during long-term nucleoside analogue therapy in chronic hepatitis B. Aliment Pharmacol Ther. 2016 Nov;44(10):1071–1079.
  • Yuen MF, Seto WK, Chow DH, et al. Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease. Antivir Ther. 2007;12(8):1295–1303.
  • Cheung KS, Mak LY, Liu SH, et al. Entecavir vs tenofovir in hepatocellular carcinoma prevention in chronic hepatitis B infection: a systematic review and meta-analysis. Clin Transl Gastroenterol. 2020 Oct;11(10):e00236.
  • Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560–1599.
  • Berg T, Simon KG, Mauss S, et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study. J Hepatol. 2017 Nov;67(5):918–924.
  • Seto WK, Hui AJ, Wong VW, et al. Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study. Gut. 2015 Apr;64(4):667–672.
  • Wong VW, Wong GL, Yan KK, et al. Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010 Jun;51(6):1945–1953.
  • Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008 Aug;135(2):459–467.
  • Sleijfer S, Bannink M, Van Gool AR, et al. Side effects of interferon-alpha therapy. Pharm World Sci. 2005 Dec;27(6):423–431.
  • Yuen MF, Wong DK, Fung J, et al. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008 Oct;135(4):1192–1199.
  • Seto WK. Hepatitis B virus reactivation during immunosuppressive therapy: appropriate risk stratification. World J Hepatol. 2015 Apr 28;7(6):825–830.
  • Mason WS, Cullen J, Moraleda G, et al. Lamivudine therapy of WHV-infected woodchucks. Virology. 1998 May 25;245(1):18–32.
  • Wong DK, Seto WK, Fung J, et al. Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos(t)ide analogues of different potency. Clin Gastroenterol Hepatol. 2013 Aug;11(8):1004–10.e1.
  • Lai CL, Wong D, Ip P, et al. Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B. J Hepatol. 2017 Feb;66(2):275–281.
  • Seto WK, Wong DK, Fung J, et al. A large case-control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance. Hepatology. 2012 Sep;56(3):812–819.
  • Mak LY, Wong DK, Cheung KS, et al. Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection. Aliment Pharmacol Ther. 2018 Jan;47(1):43–54.
  • Mak LY, Cloherty G, Wong DK, et al. HBV RNA profiles in patients with chronic hepatitis B under different disease phases and antiviral therapy. Hepatology. 2021 Jun;73(6):2167–2179.
  • Cornberg M, Lok AS, Terrault NA, et al. Guidance for design and endpoints of clinical trials in chronic hepatitis B - report from the 2019 EASL-AASLD HBV treatment endpoints conference. Hepatology. 2019 Nov 12. DOI:10.1002/hep.31030.
  • Yuen MF, Lai CL. Hepatitis B in 2014: HBV research moves forward–receptors and reactivation. Nat Rev Gastroenterol Hepatol. 2015 Feb;12(2):70–72.
  • Watashi K, Urban S, Li W, et al. NTCP and beyond: opening the door to unveil hepatitis B virus entry. Int J Mol Sci. 2014 Feb 19;15(2):2892–2905.
  • Stockdale AJ, Kreuels B, Henrion MYR, et al. The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol. 2020 Sep;73(3):523–532.
  • Bogomolov P, Alexandrov A, Voronkova N, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016 Sep;65(3):490–498.
  • Wedemeyer H, Schöneweis K, Bogomolov PO, et al. 48 weeks of high dose (10 mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV co-infection. J Hepatol. 2020;73:S52–S53.
  • Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2020–2030.
  • Oehler N, Volz T, Bhadra OD, et al. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. Hepatology. 2014 Nov;60(5):1483–1493.
  • Mouzannar K, Fusil F, Lacombe B, et al. Farnesoid X receptor-α is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo. Faseb J. 2019 Feb;33(2):2472–2483.
  • Erken R, Andre P, Roy E, et al. Farnesoid X receptor agonist for the treatment of chronic hepatitis B: a safety study. J Viral Hepat. 2021 Dec;28(12):1690–1698.
  • Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019 Jun;18(6):421–446.
  • Yuen MF, Wong DK, Schluep T, et al. Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment. Gut. 2021 Mar 12.
  • Hui RW, Mak LY, Seto WK, et al. RNA interference as a novel treatment strategy for chronic hepatitis B infection. Clin Mol Hepatol. 2022 Feb 17. DOI:10.3350/cmh.2022.0012.
  • Wooddell CI, Yuen MF, Chan HL, et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med. 2017 Sep 27;9(409). DOI:10.1126/scitranslmed.aan0241.
  • Gane E, Lim YS, Cloutier D, et al. Safety and antiviral activity of VIR-2218, an X-targeting RNAi therapeutic, in participants with chronic hepatitis B infection: week 48 follow-up results. J Hepatol. 2021;75:S287.
  • Gane E, Locarnini S, Lim TH, et al. Short interfering RNA JNJ-3989 combination therapy in chronic hepatitis B shows potent reduction of all viral markers but no correlate was identified for HBsAg reduction and baseline factors. J Hepatol. 2021;75:S289.
  • Streinu-Cercel A, Gane E, Cheng W, et al. A phase 2a study evaluating the multi-dose activity of ARB-1467 in HBeAg positive and negative virally suppressed subjects with hepatitis B. J Hepatol. 2017 Dec 31;66(1):S688–S689.
  • Yuen MF, Berliba E, Sukeepaisarnjaroen W, et al. editors. Low HBsAg levels maintained following cessation of the GalNAc-siRNA, AB-729, in chronic hepatitis B patients on nucleos(t)ide analogue therapy. US: AASLD The Liver Meeting; 2021.
  • Yuen MF, Lim TH, Kim W, et al. editors. HBV RNAi inhibitor RG6346 in Phase 1b-2a trial was safe, well tolerated, and resulted in substantial and durable reductions in serum HBsAg levels. US: AASLD The Liver Meeting; 2020.
  • Yuen MF, Lim YS, Cloutier D, et al. Preliminary results from a phase 2 study evaluating VIR-2218 alone and in combination with pegylated interferon alfa-2a in participants with chronic hepatitis B infection. Hepatology. 2021;74:63A.
  • Gane E, Yuen MF, Kim DJ, et al. Clinical Study of single-stranded oligonucleotide RO7062931 in healthy volunteers and patients with chronic hepatitis B. Hepatology. 2021 Oct;74(4):1795–1808.
  • Yuen MF, Heo J, Kumada H, et al. Results after 12 weeks treatment of multiple doses of GSK3389404 in chronic hepatitis B (CHB) subjects on stable nucleos(t)ide therapy in a phase 2a double-blind, placebo-controlled study. Hepatology. 2019;70:433A. 2020.
  • Yuen M-F, Heo J, Jang J-W, et al. Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial. Nat Med. 2021 Oct 01;27(10):1725–1734.
  • Vaine M, Cressey T, Balakrishnan A, et al. Discovery and characterization of EDP-721, a novel hepatitis B virus RNA destabilizer. J Hepatol. 2021;75:S740.
  • Hui RW-H, Mak L-Y, Seto W-K, et al. Role of core/capsid inhibitors in functional cure strategies for chronic hepatitis B. Current Hepatol Reports. 2020 Sep 01;19(3):293–301.
  • Zhang H, Wang F, Zhu X, et al. Antiviral activity and pharmacokinetics of the hepatitis B virus (HBV) capsid assembly modulator GLS4 in patients with chronic HBV infection. Clin Infect Dis. 2021 Jul 15;73(2):175–182.
  • Zhang M, Zhang J, Tan Y, et al. Efficacy and safety of GLS4/ritonavir combined with entecavir in HBeAg-positive patients with chronic hepatitis B: interim results from phase 2b, multi-center study. J Hepatol. 2020;73:S878–S880.
  • Yuen M-F, Zhou X, Gane E, et al. Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial. Lancet Gastroenterol Hepatol. 2021;6(9):723–732.
  • Janssen H, Hou J, Asselah T, et al. Efficacy and safety results of the phase 2 JNJ-56136379 JADE study in patients with chronic hepatitis B: interim week 24 data. J Hepatol. 2020;73:S129–S130.
  • Yuen MF, Agarwal K, Gane EJ, et al. Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial. Lancet Gastroenterol Hepatol. 2020 Feb;5(2):152–166.
  • Yuen MF, Agarwal K, Gane EJ, et al. The second-generation hepatitis B virus (HBV) core inhibitor (CI) ABI-H2158 is associated with potent antiviral activity in a 14-day monotherapy study in HBeAg-positive patients with chronic hepatitis B (CHB). Hepatology. 2019;70:1497A.
  • Zoulim F, Lenz O, Vandenbossche JJ, et al. JNJ-56136379, an HBV capsid assembly modulator, is well-tolerated and has antiviral activity in a phase 1 study of patients with chronic infection. Gastroenterology. 2020 Aug;159(2):521–533.e9.
  • Yuen MF, Agarwal K, Ma X, et al. Antiviral activity and safety of the hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg-positive chronic hepatitis B infection in a long-term extension study. J Hepatol. 2020;73:S140.
  • Fung S, Sulkowski M, Lalezari J, et al. Antiviral activity and safety of the hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg-negative chronic hepatitis B infection. J Hepatol. 2020;73:S51.
  • Gane E, SulkowskI M, Ma X, et al. Viral response and safety following discontinuation of treatment with the core inhibitor vebicorvir and a nucleos (t)ide reverse transcriptase inhibitor in patients with HBeAg positive or negative chronic hepatitis B virus infection. J Hepatol. 2021;75:S736.
  • Cai D, Evanhcik M, Yan R, et al. Second generation Hepatitis B Virus core inhibitors ABI-H2158 and ABI-H3733 have enhanced potency and target coverage for both antiviral inhibition and covalently closed circular DNA establishment activities. J Hepatol. 2021;75:S290–S290.
  • Yuen MF, Chuang WL, Peng CY, et al. EDP-514, A potent pangenotypic class II Hepatitis B virus core inhibitor, demonstrates significant HBV DNA and HBV RNA reduction sin a phase 1b study in viremic, chronic hepatitis B infected patients. Hepatology. 2021;74:505A–506A.
  • Gane EJ, Yuen MF, Jucov A, et al. Safety, pharmacokinetics (PK), and antiviral activity of the capsid assembly modulator (CAM) ALG-000184 in subjects with chronic hepatitis B (CHB). Hepatology. 2021;74:516A–517A.
  • Yoo BC, Kim JH, Chung YH, et al. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology. 2007 May;45(5):1172–1178.
  • Jang JH, Kim JW, Jeong SH, et al. Clevudine for chronic hepatitis B: antiviral response, predictors of response, and development of myopathy. J Viral Hepat. 2011 Feb;18(2):84–90.
  • Squires KE, Mayers DL, Bluemling GR, et al. ATI-2173, a novel liver-targeted non-chain-terminating nucleotide for Hepatitis B virus cure regimens. Antimicrob Agents Chemother. 2020 Aug 20;64(9). DOI:10.1128/AAC.00836-20.
  • Mayers D, Jucov A, Anastasiy I, et al. Phase 1 results for ATI-2173, a novel active site polymerase inhibitor nucleotide, in HBV-infected subjects. J Hepatol. 2021;75:S743–S743.
  • Vaillant A. Nucleic acid polymers: broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection. Antiviral Res. 2016 Sep;133:32–40.
  • Bazinet M, Pântea V, Placinta G, et al. Safety and efficacy of 48 weeks REP 2139 or REP 2165, tenofovir disoproxil, and pegylated interferon Alfa-2a in patients with chronic HBV infection naïve to nucleos(t)ide therapy. Gastroenterology. 2020 Jun;158(8):2180–2194.
  • Kao CC, Nie Y, Ren S, et al. Mechanism of Action of Hepatitis B Virus S-antigen Transport-inhibiting Oligonucleotide Polymers, STOPSTM, Molecules. Mol Ther Nucleic Acids. 2021;27:335–348.
  • Aligos Therapeutics. Aligos halting further development of STOPS drug candidate, ALG-010133 2022 cited 2022 Jan 20. Available from: https://investor.aligos.com/news-releases/news-release-details/aligos-halting-further-development-stopstm-drug-candidate-alg
  • Kawasaki T, Kawai T. Toll-Like Receptor Signaling Pathways [Review]. Front Immunol. 2014 Sep 25;5. 5 DOI:10.3389/fimmu.2014.00005.
  • Mifsud E, Tan A, Jackson D. TLR agonists as modulators of the innate immune response and their potential as agents against infectious disease [Review]. Front Immunol. 2014 Mar 03;5:5. 10.3389/fimmu.2014.00005.
  • Agarwal K, Ahn SH, Elkhashab M, et al. Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. J Viral Hepat. 2018 Nov;25(11):1331–1340.
  • Balabanska R, Yuen MF, Cottreel E, et al. editors. Targeting TLR7 with RO7020531: phase 1 study of the safety, PK, PD and antiviral activity in patients with chronic hepatitis B not receiving antiviral therapy. US: AASLD The Liver Meeting; 2021.
  • Gane E, Dunbar PR, Brooks A, et al. Efficacy and safety of 24 weeks treatment with oral TLR8 agonist, selgantolimod, in virally-suppressed adult patients with chronic hepatitis B: a phase 2 study. J Hepatol. 2020;73:S52.
  • Janssen HL, Lim Y-S, Kim HJ, et al. Safety and efficacy of oral TLR8 agonist, selgantolimod, in viremic adult patients with chronic hepatitis B. J Hepatol. 2021;75:S757–S758.
  • Nie L, Xu XX, Xiang LX, et al. Mutual regulation of NOD2 and RIG-I in zebrafish provides insights into the coordination between innate antibacterial and antiviral signaling pathways. Int J Mol Sci. 2017 May 27;18(6):1147.
  • Yuen MF, Coffin CS, Elkhashab M, et al. SB 9200 an oral selective immunomodulator is safe and efficacious in treatment-naive, non-cirrhotic HBV patients: results from Cohort 1 of the ACHIEVE trial. Hepatology. 2017;66:22A. 2018.
  • Gane E, Verdon DJ, Brooks AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J Hepatol. 2019 Nov;71(5):900–907.
  • Wang G, Qian J, Cui Y, et al. A phase IIa trial of subcutaneously administered PD-L1 antibody ASC22 (Envafolimab) in patients with chronic hepatitis B. Hepatology. 2021;74:62A.
  • Wang G, Cui Y, Xie Y, et al. editors. HBsAg loss in chronic hepatitis B patients with subcutaneous PD-L1 antibody ASC22 (Envafolimab) plus nucleos(t)ide analogs treatment: interim results from a phase 2b clinical trial. US: AASLD The Liver Meeting; 2021.
  • Zhang X, Huang K, Zhu W, et al. Targeting inhibitor of apoptosis proteins (IAPs) enhances intrahepatic antiviral immunity to clear hepatitis B virus infection in vivo. J Hepatol. 2020;73:S5–S6.
  • Fergusson JR, Wallace Z, Connolly MM, et al. Immune-Mobilizing monoclonal T cell receptors mediate specific and rapid elimination of hepatitis B-Infected cells. Hepatology. 2020 Nov;72(5):1528–1540.
  • Vandepapelière P, Lau GK, Leroux-Roels G, et al. Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine. 2007 Dec 12;25(51):8585–8597.
  • Ma H, Lim TH, Leerapun A, et al. Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study. JHEP Rep. 2021 Dec;3(6):100361.
  • Lok AS, Pan CQ, Han SH, et al. Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B. J Hepatol. 2016 Sep;65(3):509–516.
  • Al Mahtab M, Akbar SMF, Aguilar JC, et al. Treatment of chronic hepatitis B naïve patients with a therapeutic vaccine containing HBs and HBc antigens (a randomized, open and treatment controlled phase III clinical trial). PLoS One. 2018;13(8):e0201236.
  • Lee HW, Park JY, Hong T, et al. A prospective, open-label, dose-escalation, single-center, phase 1 study for GC1102, a recombinant human immunoglobulin for chronic hepatitis B patients. Hepatology. 2018;68:268A–269A.
  • Agarwal K, Yuen MF, Wedemeyer H, et al. A phase 1 study evaluating the neutralizing, vaccinal monoclonal antibody VIR-3434 in participants with chronic hepatitis B virus infection. J Hepatol. 2021;75:S288.
  • Yuen MF, Asselah T, Jacobson IM, et al. editors. Efficacy and safety of the siRNA JNJ-3989 and/or the capsid assembly modulator JNJ-6379 for the treatment of chronic hepatitis B virus infection: results from the phase 2b REEF-1 study. US: AASLD The Liver Meeting; 2021.
  • Buti M, Rodriguez-Frias F, Jardi R, et al. Hepatitis B virus genome variability and disease progression: the impact of pre-core mutants and HBV genotypes. J Clin Virol. 2005 Dec;34(Suppl 1):S79–82.
  • Wu HL, Huang LR, Huang CC, et al. RNA interference-mediated control of hepatitis B virus and emergence of resistant mutant. Gastroenterology. 2005 Mar;128(3):708–716.

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