Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B

Abstract

Background and aims: RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This two-part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed.

Approach and results: Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1-4.0 mg/kg), or placebo. Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg or placebo every month for a total of 2 doses (Part 2a) or RO7062931 at 3.0 mg/kg every 2 weeks, 3.0 mg/kg every week (QW), or 4.0 mg/kg QW or placebo for a total of 3-5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity. Common AEs included self-limiting injection site reactions and influenza-like illness. Supradose-proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In patients with CHB, RO7062931 resulted in dose-dependent and time-dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log₁₀ IU/mL) independent of HBeAg status.

Conclusions: RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supradose-proportional exposure at doses of 3.0-4.0 mg/kg was indicative of partial saturation of the ASGPR-mediated liver uptake system. Dose-dependent declines in HBsAg demonstrated target engagement with RO7062931.

Trial registration: ClinicalTrials.gov NCT03038113.

FIG. 1

Study design. Part 1: single ascending dose cohorts in healthy volunteers. Parts 2a and 2b: multiple‐dose cohorts in patients with CHB.

FIG. 2

Volunteer and patient flow through the study for (A) Part 1 single ascending dose in healthy volunteers and (B) Part 2 multiple dosing in patients with CHB.

FIG. 3

Mean change from baseline in select (hepatic, hematologic, renal) safety laboratory parameters in patients with CHB receiving placebo or RO7062931: (A) ALT (U/L), (B) aspartate aminotransferase (U/L), (C) activated partial thromboplastin time (sec), (D) platelets (10⁹/L), (E) creatinine (μmol/L), and (F) blood urea nitrogen (mmol/L). Abbreviations: Fu, follow‐up; Q1M, every 1 month.

FIG. 4

Plasma and urine RO7072931 PK. Plasma concentration‐time profiles for RO7062931 over (A) 24 hours and (B) 168 hours after single doses (0.1‐4.0 mg/kg) in healthy volunteers; (C) mean plasma AUC_0‐inf versus total milligram dose in healthy volunteers; the dashed line is a linear regression line of the observed AUC at the doses of 0.1, 0.3, and 1 mg/kg in HVs. The orange line is a loess regression line of the observed AUC in HV. (D) Mean % dose eliminated in urine in the first 8 hours postdose in healthy volunteers and patients with CHB. Error bars indicate standard deviation. Abbreviations: AUC_0‐inf, area under concentration‐time curve extrapolated to infinity; HV, healthy volunteers.

FIG. 5

Mean log₁₀ (IU/mL) change in HBsAg from baseline in patients with CHB receiving placebo or (A) RO7062931 0.5‐3.0 mg/kg QM or (B) RO7062931 3.0 mg/kg QW or Q2W or 4.0 mg/kg QW. (C) RO7062931 3.0 mg/kg QW according to HBeAg status. Error bars indicate standard error; (D) maximum log₁₀ change from baseline in HBsAg in patients with CHB receiving RO7062931 (0.5‐3.0 mg/kg QM; 3.0 mg/kg QW or Q2W, or 4.0 mg/kg QW) or placebo. Error bars indicate 95% confidence intervals.