NEW YORK (Reuters Health) – RO7049389, a hepatitis B virus (HBV) core protein allosteric modulator, appears safe and shows antiviral action in patients with chronic HBV infection, according to a small company-funded study.
“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,” researchers write in The Lancet Gastroenterology and Hepatology.
The investigational drug inhibits HBV replication by preventing pregenomic RNA encapsidation during capsid assembly, Dr. Qingyan Bo of Roche Innovation Centre Shanghai, in China, and colleagues note. It has shown anti-HBV effects in cell-based assays and in animal models and has been deemed well tolerated in phase-1 clinical trials with healthy participants.
To further evaluate its safety and antiviral activity, the researchers studied the drug in patients with chronic HBV infection who were treatment-naive or had stopped HBV treatment more than six months before screening. Participants were randomly assigned to five dose cohorts. They received oral RO7049389 at 200 mg or 400 mg twice a day, or 200 mg, 600 mg, or 1,000 mg once a day or matching placebo.
In all, 35 patients, 31 of whom received RO7049389, completed the four-week treatment course and were included in the analysis. Declines in plasma HBV DNA were observed in all active-treatment groups, with no apparent dose-dependent differences. These ranged from -2.44 to -3.33 log10 IU/mL from baseline. In placebo patients, the corresponding value was 0.34 log10 IU/mL.
Declines in HBV RNA followed the same trend as HBV DNA.
There were no serious adverse events, and most adverse events in the active-treatment groups were mild. The most common moderate adverse events were alanine aminotransferase (ALT) increases (in three patients) and increased aspartate aminotransferase (AST) in two patients.
Other adverse events included headache and respiratory-tract infection. All resolved or were resolving at the last follow-up visit.
“There were no clinically significant changes in the ECG parameters, vital signs, or laboratory safety data other than ALT or AST concentration,” the researchers write. These elevations were not seen in an earlier study of healthy volunteers, but “In clinical practice, transient ALT elevations (ALT flares) among patients with chronic HBV infection are not always harmful.”
However, the authors point out that distinguishing between ALT flares “that reflect the host immune-mediated response to clear HBV-infected hepatocytes and those related to drug induced liver injury remains challenging.”
The study was funded by F. Hoffmann-La Roche, which is developing RO7049389. Several authors are employed by the company.
Dr. Bo did not respond to requests for comments.
SOURCE: https://bit.ly/3rfzRPR The Lancet Gastroenterology and Hepatology, online July 5, 2021.
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