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.

Background: RO7049389, a hepatitis B virus (HBV) core protein allosteric modulator being developed for the treatment of chronic HBV infection, was found to be safe and well tolerated in healthy participants (part 1 of this study). The objective of this proof-of-mechanism study (part 2) was to evaluate the safety, pharmacokinetics, and antiviral activity of RO7049389 in patients with chronic HBV infection.
Methods: This was a multicentre, randomised, placebo-controlled, phase 1 study. Patients with chronic HBV infection who were not currently on anti-HBV therapy were enrolled at 11 liver disease centres in Hong Kong, New Zealand, Singapore, Taiwan, and Thailand. Seven patients per dose cohort were randomly assigned (6:1) to receive oral administration of RO7049389 at 200 mg or 400 mg twice a day, or 200 mg, 600 mg, or 1000 mg once a day, for 4 weeks, or matching placebo. Randomisation was via interactive voice web response system-generated numbers, with study participants, investigators, and site personnel masked to treatment allocation. The primary endpoint of the study was safety of RO7049389 and its antiviral effect on HBV DNA concentration at the end of treatment, assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02952924.
Findings: Between May 21, 2017, and April 3, 2019, 62 patients were screened for eligibility, and 37 eligible patients were enrolled in five dose cohorts sequentially. All adverse events were of mild or moderate intensity. Among the 31 patients who received RO7049389, the most common adverse events were headache (in five [16%] of 31 patients), increased alanine aminotransferase (ALT; five [16%]), increased aspartate aminotransferase (AST; four [13%]), upper respiratory tract infection (four [13%]), and diarrhoea (three [10%]). The most common moderate adverse events were ALT increase (three [10%]) and AST increase (two [6%]), and there were no serious adverse events. At the end of 4 weeks treatment, mean HBV DNA declines from baseline in RO7049389-treated patients were 2·44 log ₁₀ IU/mL (SD 0·98) in the 200 mg twice a day group, 3·33 log ₁₀ IU/mL (1·14) in the 400 mg twice a day group, 3·00 log ₁₀ IU/mL (0·54) in the 200 mg once a day group, 2·86 log ₁₀ IU/mL (0·79) in the 600 mg once a day group, and 3·19 log ₁₀ IU/mL (0·33) in the 1000 mg once a day group versus 0·34 log ₁₀ IU/mL (0·54) in the pooled placebo patients.
Interpretation: RO7049389 was safe and well tolerated and demonstrated antiviral activity over 4 weeks of treatment in patients with chronic HBV infection. These findings support further clinical development of RO7049389 as a component of novel combination treatment regimens for patients with chronic HBV infection.
Funding: F Hoffmann-La Roche.
Competing Interests: Declaration of interests M-FY is serving as advisor or consultant for AbbVie, Aligos, Arbutus, Bristol-Myers Squibb, Dicerna, Finch Therapeutics, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank, and Roche and receives grant or research funding from Assembly, Arrowhead, Bristol-Myers Squibb, Fujirebio, Gilead Sciences, Merck Sharp and Dohme, Springbank, Sysmex Corporation, and Roche. EG is a member of the Advisory Board or Speakers' Bureau for AbbVie, Aligos, Arbutus, Arrowhead, Assembly, Dicerna, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Novartis, Roche, and Vir Bio. TT received research funding from Merck, Roche, Janssen, and Vir Biotech. XZ, YJ, MT, AL-D, VC, ZX, RK, and QB are full-time employees of F Hoffmann-La Roche. SF was a full-time employee of F Hoffmann-La Roche during the study. XZ, AL-D, VC, RK, and QB have stock ownership in F Hoffmann-La Roche. RK also has stock ownership in Novartis and Alcon. XZ, MT, and QB have a patent pending for a method of treating HBV infection with a core protein allosteric modulator (P35735-WO-1). CS declares no competing interests.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)