Phase 1 Trial Data Support Safety, Efficacy of Novel Hepatitis B Treatment

Results from a phase 1 trial published in the Lancet Gastroenterology & Hepatology support the safety and tolerability of novel agent RO7049389 for the treatment of chronic hepatitis B virus (HBV) infection. Over 4 weeks of treatment, RO7049389 also demonstrated substantial antiviral activity. These results support the further investigation of RO7049389 as a component in the treatment regimen for chronic HBV infection.

RO7049389 is a core protein allosteric modulator that has demonstrated anti-HBV effects in cell-based assays and animal studies. To better understand its effects in humans, investigators conducted a phase 1, multicenter, placebo-controlled trial at 11 liver disease treatment centers in Hong Kong, New Zealand, Singapore, Taiwan, and Thailand.

Adult patients with chronic HBV were randomized in a 6:1 ratio to receive 4 weeks of oral RO7049389 or matched placebo at 1 of the following doses: 200 mg twice daily, 400 mg twice daily, 200mg once daily, 600 mg once daily, or 1000 mg once daily. Patients and study site personnel were blinded to treatment allocation. To assess efficacy, investigators measured HBV DNA levels at baseline and at the end of follow-up. Substantial reductions in HBV DNA concentrations were taken to indicate antiviral activity. Adverse events were monitored throughout the trial duration.

A total of 37 patients were enrolled in the study between 2017 and 2019. A total of 31 patients received RO7049389; 6 patients received placebo. Demographic and clinical characteristics were comparable between dosing groups. The majority of patients were men (n=23; 62%), Asian (n=32; 87%), and had HBV genotype B (n=17; 46%) or C (n=16; 43%).

Among the 31 patients who received RO7049389, 19 reported adverse events. The most common treatment-emergent adverse events were headache (n=5; 16%), increased alanine transaminase (ALT) levels (n=5; 16%), increased aspartate aminotransferase (AST) levels (n=4; 13%), upper respiratory tract infection (n=4; 13%), and diarrhea (n=3; 10%). All adverse events resolved or had begun resolving by the final follow-up visit.

All 5 RO7049389 dosing groups experienced declines in plasma HBV DNA over 4 weeks of treatment. Mean HBV DNA decreases from baseline were the following: 2.44 log₁₀ IU/mL in the 200 mg twice daily group, 3.33 log₁₀ IU/mL in the 400 mg twice daily group, 3.00 log₁₀ IU/mL in the 200 mg once daily group, 2.86 log₁₀ IU/mL in the 600 mg once daily group, and 3.19 log₁₀ IU/mL in the 1000 mg once daily group. By comparison, the mean decline in the pooled placebo group was just 0.34 log₁₀ IU/mL. Greater RO7049389 doses did not appear to confer greater antiviral activity.

Per these data, RO7049389 appears to be a safe, tolerable, and effective means of treating chronic HBV. The primary study limitations were the small study cohort and short treatment duration. Further investigation in larger-scale and later-phase trials are warranted.

“These results provide proof of mechanism for further clinical development of RO7049389 as a component of novel combination anti-HBV regimens for patients with chronic HBV infection,” authors wrote. “One trial evaluating the efficacy and safety of multiple combination therapies in patients with chronic HBV is currently underway,” they noted.

Disclosure: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Yuen MF, Zhou X, Gane E, 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. Published online July 5, 2021. doi: 10.1016/S2468-1253(21)00176-X