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Clinical Trial
. 2024 Apr;30(2):191-205.
doi: 10.3350/cmh.2023.0422. Epub 2024 Jan 8.

Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients

Affiliations
Clinical Trial

Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients

Jinlin Hou et al. Clin Mol Hepatol. 2024 Apr.

Abstract

Background/aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients.

Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks.

Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1-2, and no linvencorvir-related serious adverse events were reported.

Conclusion: 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Keywords: Capsid assembly modulator; Chronic hepatitis B; Linvencorvir; Phase 2; RO7049389.

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Conflict of interest statement

Conflicts of Interest

Jinlin Hou received grants from Bristol Myers Squibb and Johnson & Johnson; and declared other financial or non-financial interests with AbbVie, Arbutus, Bristol Myers Squibb, Gilead Sciences, Johnson & Johnson, and Hoffmann-La Roche.

Edward Gane is an advisory committee or review panel member for AbbVie, Arbutus, Arrowhead, Assembly Biosciences, Availa, Clear B Therapeutics, Dicerna, Finch Therapeutics, Gilead Sciences, Janssen, Novartis, Hoffmann-La Roche, and Vir Bio; and has received speaking and teaching fees from AbbVie, Aligos, DrugFarm, Enanta, Gilead, GlaxoSmithKline, Janssen, Merck, and Novartis.

Sheng-Shun Yang has received speaking fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Ipsen, and Merck Sharp & Dohme, and served as an advisory board member for AbbVie, Gilead Sciences, Hoffmann-La Roche, Sysmex, and Ipsen.

Seng Gee Lim received payment or honoraria for lectures from Gilead, Janssen, Hoffman-La Roche, Sysmex and GSK; served as advisory board member for Gliead, Abbot, Hoffmann-La Roche, GSK, Janssen, Sysmex, Abrutus, Assembly, and Grifols; served in leadership role in ICE-HBV, HBV Forum, AASLD Asia Pacific Advisory Board, and ANRS-MIE Advisory Board; and receipt of research support from Gilead, Abbot, Hoffmann-LaRoche, Sysmex, Fibronostics, and Merck.

Man-Fung Yuen serves as advisory board member/ consultant for and/or received research funding from AbbVie, Aligos Therarpeutics, AiCuris, Antios Therapeutics, Arrowhead Pharmaceuticals, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Bluejay Therapeutics, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, and Hoffmann-La Roche, Vir Biotechnology.

Rozalina Balabanska, Wenhong Zhang, Jiming Zhang, Tien Huey Lim, Qing Xie, Chau-Ting Yeh, Xieer Liang, Piyawat Komolmit, Apinya Leerapun, Ting-Tsung Chang, Tsung-Hui Hu, Wan-Long Chuang, and Barbara Leggett declare no competing interests.

Zenghui Xue, Ethan Chen, Yuchen Zhang, Qiaoqiao Xie and Wen Zhang are employees of Hoffmann-La Roche. Qingyan Bo and Xue Zhou were former employees of Hoffmann-La Roche.

Figures

Figure 1.
Figure 1.
Study design. NUC, nucleos(t)ide analogue; HBV, hepatitis B virus; LLOQ, lower limit of quantification; CHB, chronic hepatitis B; QD, once a day; NUC, nucleos(t)ide analogue; Peg-IFN, pegylated interferon; HBsAg, hepatitis B surface antigen.
Figure 2.
Figure 2.
Trial profile.
Figure 3.
Figure 3.
Mean HBV DNA levels over 72 weeks. (A) Three cohorts overall and (B) HBeAg-positive and HBeAg-negative subgroups of treatment-naïve patients in Cohorts B and C. *Excluded one non-compliant patient during the FU period. **One patient was retreated with NUC from Week 60. Error bars represent standard deviation. HBV, hepatitis B virus; EOT, end of treatment; FU, follow-up; NUC, nucleos(t)ide analogue; Peg-IFN, pegylated interferon.
Figure 4.
Figure 4.
Mean HBV RNA levels over 72 weeks. Error bars represent standard deviation. HBV, hepatitis B virus; EOT, end of treatment; LLOQ, lower limit of quantification; NUC, nucleos(t)ide analogue; Peg-IFN, pegylated interferon.
Figure 5.
Figure 5.
HBsAg (A), HBeAg (B) and HBcrAg (C) mean changes from baseline* over 72 weeks. *Patients with baseline value below the LLOQ were excluded from change from baseline analysis. HBsAg ≥4 log means baseline HBsAg level ≥4 log10 IU/mL; HBsAg <4 log means baseline HBsAg level <4 log10 IU/mL. Error bars represent standard deviation. EOT, end of treatment; HBsAg, hepatitis B surface antigen; HBcrAg, hepatitis B core-related antigen; LLOQ, lower limit of quantification; NUC, nucleos(t)ide analogue.
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