Imdusiran Shows Safety and Tolerability as Potential Functional Cure for Chronic Hepatitis B: Study

The investigators performed a series of 1a/b phase studies involving 11 hospitals and specialist clinics based in Australia, New Zealand, Thailand, Hong Kong, South Korea, and Moldova. In part 1 of the study, a double-blind and single ascending dose method was used to investigate the health of participants within ages 18 to 45 years, randomized into groups receiving a single injection of imdusiran 60 mg, 180 mg, or 360 mg subcutaneously and a placebo matched in dosage. In parts 2 and 3, the participants were adults between 18 and 65 years old with documented chronic hepatitis B status, with or without the presence of hepatitis B e-antigen (HBeAg).

The chronic hepatitis B subjects had to have stable nucleos(t)ide therapy, baseline HBsAg of at least 250 IU/mL, and no evidence of liver cirrhosis in screening ultrasonograms. Participants in part 2 were administered a single dose of 60 mg, 90 mg, or 180 mg, whereas those in part 3 were administered multiple injections of 60 mg or 90 mg at intervals of 4, 8, or 12 weeks for a duration of 48 weeks.

Key findings:

• Recruitment and medication to 83 subjects who received a minimum of one dose of either the active imdusiran or the placebo were successful.
• On the dates from July 16 to August 30, 2019, there was randomization of 18 male healthy subjects on a 2:1 ratio, which had 12 subjects receive the active imdusiran while six others were given the placebo.
• In the process of screening subjects between September 3, 2019, and June 11, 2020, there were 43 infected subjects with chronic hepatitis B, from whom 22 subjects (15 male and seven female) were recruited. From the dates of April 30, 2020, to June 26, 2021, there were 43 patients recruited for the long-term and multidose study.
• In all populations studied, zero patients withdrew from imdusiran use due to adverse events, there were zero dose-related toxic trends observed, and there were zero mortalities.
• In the healthy population, the most common adverse events that happened among two or more patients involved limited self-limiting alanine aminotransferase elevations (n=2), short-term dizziness (n=2), and site reactions associated with medical devices (n=3).
• In the single-dose chronic hepatitis B population, there was injection site pain (n=5), headaches (n=4), and short-term mild liver enzyme elevations alanine aminotransferase (n=3) and aspartate aminotransferase (n=2).
• The long-term repeat-dose cohort experienced mild grade 1 events, including incidental coronavirus infections (n=18), injection-site pain (n=8), injection-site redness (n=4), and fatigue (n=3).

Conclusively, the safety and tolerability profile of both single and multiple doses of imdusiran was favorable in both healthy subjects as well as in subjects with chronic hepatitis B, thus promoting drug development of imdusiran as a promising drug for the future targeting functional cure of chronic hepatitis B. This highly successful accomplishment serves as a landmark in the elimination campaign of chronic viral hepatitis globally, highlighting the capability of GalNAc-siRNA drugs in overcoming the conventional limitations of daily antiviral drugs.

Reference:

Yuen, M.-F., Gane, E., Holmes, J. A., Strasser, S. I., Leerapun, A., Sukeepaisarnjaroen, W., Tangkijvanich, P., Berliba, E., Jucov, A., Kim, Y. J., Lim, Y.-S., Thi, E. P., Eley, T., Gray, K. R., Medvedeva, E., Sharma, V., Espiritu, C., Ganchua, S. C., Paratala, B. S., … Sims, K. D. (2026). The small interfering RNA imdusiran as single and multiple doses in healthy, randomised individuals and non-randomised individuals with chronic hepatitis B (AB-729-001): a phase 1a/b trial. The Lancet. Gastroenterology & Hepatology. https://doi.org/10.1016/S2468-1253(26)00058-0