RO7049389, a core protein allosteric modulator, is safe and well tolerated in healthy volunteers and demonstrates potent anti-HBV activity in a phase 1 trial

Abstract

Background and Aims: RO7049389 is an orally available small molecule, Class I HBV core protein allosteric modulator (CpAM). It induces formation of abnormal HBV core protein aggregates, which are then depleted, leading to disruption of viral assembly and potent inhibition in HBV replication. In vitro, it demonstrated potent activity against the most prevalent HBV genotypes. In the AAV‐HBV mouse model, robust HBV DNA declines of about 3.0 log10 copies/ml was observed over 56 days of dosing. Method: The ongoing Phase I study investigates the safety, tolerability, pharmacokinetics (PK), and anti‐HBV activity of RO7049389. Study Part 1 evaluates the safety and PK of single ascending doses (SAD) of RO7049389/placebo (150–2000 mg) and multiple ascending doses (MAD) (200–800 mg BID × 14 days) in healthy volunteers (HVs). Food effect is explored in SAD and MAD. Study Part 2 also explores the anti‐HBV effects of RO7049389 in untreated chronic HBV (CHB) patients. Results: 75 HVs have been dosed in this study. A blinded safety evaluation showed that RO7049389/placebo in HVs was well tolerated in the SAD and MAD cohorts. No serious AEs or AEs leading to drug discontinuation were reported, only five AEs were considered as related to RO7049389. All AEs were reported as being mild in intensity. No clinically significant changes in ECG parameters, vital signs, or laboratory safety test results were observed. A total of 55 adverse events (AEs) were reported in 36/75 HVs. In Part 2, a total of 14 AEs were reported in 3/7 patients. Across the dosing rangeRO7049389 was rapidly absorbed and eliminated from plasma. A trend of greater than dose‐proportional increases in exposure from 150 to 1000 mg, and approximately dose‐proportional increases from 1000 to 2000 mg were observed in SAD cohorts. Accumulation of RO7049389 in MAD cohorts was minimal or none. The exposure of RO7049389 was increased by about 2.2 fold when 450 mg is taken with a meal rich in high‐fat and high‐calorie. Six CHB patients completed 28 days dosing period of RO7049389 at a dose of 200 mg BID. Robust and continued HBV DNA declines from pre‐dosing levels were observed, with median (maximal) decline being 2.7 (3.4) log10 IU/mL and below the limits of detection in 3/6 patients. No treatment virologic rebound was observed. Conclusion: RO7049389 demonstrates robust anti‐HBV activity over 28 days of dosing in patients with CHB. RO7049389 was considered safe, well tolerated and with an acceptable PK profile.