Linvencovir: Paving the way for functional cure in hepatitis B

Jiwon Yang; Jonggi Choi

doi:10.3350/cmh.2024.0149

Functional cure, defined as unquantifiable hepatitis B virus (HBV) DNA and sustained hepatitis B surface antigen (HBsAg) loss, is the ultimate goal of antiviral treatment for chronic hepatitis B (CHB) [1,2]. With currently available antiviral treatments, such as nucleos(t)ide analogues (NUCs), functional cure is rarely achievable despite long-term treatment, necessitating innovative, finite new antiviral treatments [3-5]. Numerous compounds have been under development to achieve functional cure. Fortunately, some have been successful in proving their efficacy, although the efficacy remains unsatisfactory [6,7]. Hou et al. reported the efficacy, safety, and pharmacokinetics of Linvencovir, a novel small-molecule capsid assembly modulator (CAM), in Part 3 of the phase 1/2 study [8]. Previous reports demonstrated Linvencovir’s favorable safety and pharmacokinetic profiles in healthy volunteers and viremic patients with CHB.9,10 This study assessed the efficacy in three different cohorts; 32 Linvencovir-treated patients receiving NUCs, 10 Linvencovir-treated treatment-naïve patients in combination with NUCs, and 30 Linvencovir-treated treatment-naïve patients in combination with NUCs and peginterferon for 48 weeks, followed by an additional 24 weeks of observation without Linvencovir but with NUCs.

Unfortunately, no patient achieved functional cure at week 24 post-study treatment, which was the primary endpoint of this study. HBV DNA was effectively suppressed in all three cohorts, as expected using NUCs. Notably, serum HBV RNA was also successfully suppressed in the majority of patients by Linvencovir, despite a rebound increase after withdrawal. However, HBsAg titer, another important marker to predict functional cure, was not sufficiently decreased despite the combination of NUC and Linvencovir.

In terms of safety, Linvencovir was tolerable without significant concern in its use alongside NUCs, which is satisfactory. Collectively, Linvencovir in this Part 3 phase 1/2 study showed limited efficacy, especially in achieving functional cure, unlike previous studies using newly developed compounds for functional cure [9,10]. Considering the mechanism of action in HBV natural history, treatment with CAM might not be sufficient to achieve functional cure effectively. Combination therapy with another class of drugs, such as siRNA or immunomodulators, could be an option to further increase the rate of functional cure, which has been partly evaluated in other studies. However, this small step is important in paving the way for functional cure.

ACKNOWLEDGMENTS

This study was supported by grants from the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (No. 2021R1G1A1009506).

FOOTNOTES

Authors’ contribution

J Yang and J Choi were responsible for drafting and finalization of the manuscript.

Conflicts of Interest

J Choi has received a research grant from Gilead Sciences. J Yang has nothing to disclose.

Abbreviations

HBV

hepatitis B virus

HBsAg

hepatitis B surface antigen

CHB

chronic hepatitis B

NUCs

nucleos(t)ide analogues

CAM

capsid assembly modulator

REFERENCES

1. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: From discovery to regulatory approval. Hepatology 2017;66:1296-1313.

2. Mak LY, Hui RW, Fung J, Seto WK, Yuen MF. The role of different viral biomarkers on the management of chronic hepatitis B. Clin Mol Hepatol 2023;29:263-276.

3. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022;28:276-331.

4. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-1599.

5. Lee CH, Choi GH, Choi HY, Han S, Jang ES, Chon YE, et al. Core indicators related to the elimination of hepatitis B and C virus infection in South Korea: A nationwide study. Clin Mol Hepatol 2023;29:779-793.

6. Yuen MF, Agarwal K, Ma X, Nguyen TT, Schiff ER, Hann HL, et al. Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection. J Hepatol 2022;77:642-652.

7. Yuen MF, Lim SG, Plesniak R, Tsuji K, Janssen HLA, Pojoga C, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection. N Engl J Med 2022;387:1957-1968.

8. Hou J, Gane E, Balabanska R, Zhang W, Zhang J, Lim TH, et al. Efficacy, safety and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients. Clin Mol Hepatol 2024;30:191-205.

9. Feng S, Gane E, Schwabe C, Zhu M, Triyatni M, Zhou J, et al. A Five-in-one first-in-human study to assess safety, tolerability, and pharmacokinetics of RO7049389, an inhibitor of hepatitis B virus capsid assembly, after single and multiple ascending doses in healthy participants. Antimicrob Agents Chemother 2020;64:e01323-20.

10. Yuen MF, Zhou X, Gane E, Schwabe C, Tanwandee T, Feng S, 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;6:723-732.