RO7049389

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.

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.

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 log₁₀ IU/mL (SD 0·98) in the 200 mg twice a day group, 3·33 log₁₀ IU/mL (1·14) in the 400 mg twice a day group, 3·00 log₁₀ IU/mL (0·54) in the 200 mg once a day group, 2·86 log₁₀ IU/mL (0·79) in the 600 mg once a day group, and 3·19 log₁₀ IU/mL (0·33) in the 1000 mg once a day group versus 0·34 log₁₀ IU/mL (0·54) in the pooled placebo patients.

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.

F Hoffmann-La Roche.

Coproporphyrins (CP‐I and CP‐III) in plasma are considered potential markers for assessing liver organic anion‐transporting polypeptide transporter OATP1B activity and monitoring OATP1B‐mediated drug‐drug interactions (DDIs) in clinical settings. However, the effect of altered renal clearance (CLrenal) on CP‐I and CP‐III plasma exposure has rarely been examined. Therefore, the purpose of this study is to further evaluate CP‐I and CP‐III as clinical endogenous markers for OATP1B activity and to investigate the impact of CLrenal on DDI assessments for the first time. In this study, 18 healthy participants were recruited to receive RO7049389 (a potential inhibitor of OATP1B) 800 mg twice daily for 6 days and a single dose of pitavastatin (a probe drug of OATP1B) before and after RO7049389 treatment. Plasma concentrations of pitavastatin, CP I, CP III, and the amounts of CP‐I and CP‐III excreted in urine were measured. Seventeen healthy participants completed the study. After multiple doses of RO7049389, the area under the plasma concentration–time curve from time 0 to 12 hours of pitavastatin increased 1.95‐fold (90% confidence interval [CI], 1.58‐2.41), while for CP‐I and CP‐III it increased 3.00‐fold (90%CI, 2.35‐3.82) and 2.84‐fold (90%CI, 2.22‐3.65), respectively. Concurrently, the CLrenal of CP‐I decreased by 31% (90%CI, 23%‐39%), and that of CP‐III decreased by 70% (90%CI, 61%‐77%). In conclusion, CP‐I and CP‐III in plasma display the potential to be applied as endogenous markers for the evaluation of OATP1B inhibition in clinical trials. While renal transporters contribute significantly to the CLrenal of CP‐III, it would be better to investigate the impact of the CLrenal on plasma exposure of CP‐III during clinical DDI assessments.