RNAi agent RG6346 shows promise for treatment of chronic HBV infection
17 Nov 2023
A first-in-human randomized, phase I study has provided evidence to support the clinical development of RG6346 as a therapeutic regimen for chronic hepatitis B virus (HBV) infection (CHB), with the goal of sustained hepatitis B surface antigen (HBsAg) loss in CHB patients.
RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference (RNAi) agent that targets the HBV genome S-region.
In this study, the investigators recruited three groups of participants: group A (30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo), group B (nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg [n=6] or placebo [n=3]), and group C (participants with nucleos[t]ide-suppressed CHB received four doses of RG6346 at 1.5, 3.0, or 6.0 mg/kg [n=4 in each cohort] or placebo [n=6] every 28 days).
Four-month treatment with RG6346 showed a favourable safety profile and tolerability, with mild injection site reaction as the most common adverse event.
Self-resolving transaminase elevations with preserved liver function occurred in many nucleos(t)ide-naïve participants. On day 112, the end of RG6346 treatment in group C, HBsAg decreased by a mean of 1.39 log10 IU/ml in the 1.5-mg/kg, 1.80 log10 IU/ml in the 3.0-mg/kg, and 1.64 log10 IU/ml in the 6.0-mg/kg cohorts from baseline.
Eleven of the 12 group C participants (91.7 percent) achieved a reduction of ≥1 log10 IU/ml in HBsAg. Of these, three (27.3 percent) had sustained response at conditional follow-up on day 448.
No dose-response association was observed between RG6346 and serum HBsAg levels. The HBsAg response driven by RG6346 was independent of hepatitis B e antigen (HBeAg) status. In addition, there were moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and HBeAg levels.
“These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians,” the investigators said.