Safety, pharmacokinetics, and pharmacodynamics of the antisense oligonucleotide RO7239958 in healthy volunteers and adults with chronic hepatitis B infection.

Poly(A) RNA polymerases D5 and D7 (PAPD5, PAPD7) are host factors that stabilize hepatitis B virus (HBV) RNA transcripts. RO7239958, a liver-targeted locked nucleic acid (LNA) antisense oligonucleotide (ASO), induces intracellular degradation of PAPD5- and PAPD7-encoding messenger RNAs (mRNAs). This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of RO7239958 in healthy volunteers and adults with chronic hepatitis B (CHB) receiving standard-of-care antiviral therapy. Forty healthy volunteers were randomized (4:1) to single ascending subcutaneous doses of RO7239958 (0.1, 0.3, 1.0, or 1.5 mg/kg) or placebo. Based on a population PK model built to predict liver exposure, two parallel CHB cohorts (n = 8 and n = 7 per cohort) were randomized to two 4-weekly doses of RO7239958 (0.2 or 0.4 mg/kg) or placebo. RO7239958 plasma exposure increased more than dose-proportionally at dose levels of 1.0 and 1.5 mg/kg, suggesting saturation of liver uptake. RO7239958 was generally well tolerated in healthy volunteers; transaminase elevations occurred at the highest doses, including one reversible Grade 3 elevation. The PK model indicated that doses of 0.2 and 0.4 mg/kg would reduce PAPD5 and PAPD7 mRNA by 50% and 62%, respectively, with minimal liver toxicity. Consistent with predictions, RO7239958 was well-tolerated and safe in patients. At 0.4 mg/kg, the maximum reduction from baseline in serum hepatitis B surface antigen was observed on Day 43 (mean decline 0.2 log10 IU/mL; range 0.0-0.5 log10 IU/mL). While RO7239958 showed a potentially narrow therapeutic window, PAPD5 and PAPD7 remain potential therapeutic targets in HBV curative strategies.CLINICAL TRIALSThis study was registered at NCT03762681.