BACKGROUND & AIMS:RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference (RNAi) agent targeting the HBV genome S-region. We investigated safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers (HVs) and patients with chronic hepatitis B (CHB).
METHODS:This first-in-human, adaptive, randomized, double-blinded, phase I study recruited 3 groups of participants: Group A, 30 HVs 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 analog-naïve CHB participants received single-dose RG6346 at 3.0 mg/kg (n=6) or placebo (n=3); Group C, nucleos(t)ide-suppressed CHB participants received 4 doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n=4 in each cohort) or placebo (n=6).
RESULTS:RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in HBsAg was 1.39, 1.80, and 1.64 log10 IU/mL in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. 11 of 12 participants (91.7%) in Group C achieved ≥1 log10 IU/mL reduction in HBsAg [3 of 11 (27.3%) had the response sustained at conditional follow-up Day 448]. No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of HBeAg status. Moderate-to-marked sustained reductions of HBcrAg, HBV RNA, HBV DNA (in nucleos[t]ide analog-naïve participants), and HBeAg levels were observed.
CONCLUSIONS:These favourable safety and pharmacodynamic data support the clinical development of RG6346 as a backbone of a finite antiviral treatment regimen aiming for sustained HBsAg loss in patients with CHB.
IMPACT AND IMPLICATIONS:Currently available therapies for chronic hepatitis B infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favourable safety profile as well as marked and durable reductions in HBsAg. These results support the continued development of RG6346 as a backbone of a finite treatment regimen aiming for high functional cure rates and are important for HBV researchers and physicians.
CLINICAL TRIAL NUMBER:ClinicalTrials.gov NCT03772249.