Safety, pharmacokinetics and antiviral activity of AHB‑137 in healthy volunteers and chronic hepatitis B patients: a phase 1a/1b study.

BACKGROUND/PURPOSE: AHB-137 is a novel antisense oligonucleotide targeting a conserved 3'-terminal region of HBV mRNA. This phase 1a/1b study evaluated the safety, pharmacokinetics (PK), and antiviral activity of AHB-137 in Chinese healthy volunteers (HVs) and chronic hepatitis B (CHB) patients.

METHODS

In Phase 1a, 52 HVs received single ascending doses (75-450 mg) or multiple ascending doses (MAD; 150 or 300 mg) of AHB-137 or placebo. In Phase 1b, 20 HBeAg-negative, nucleos(t)ide analogue (NA)-suppressed CHB patients with baseline HBsAg 100-1000 IU/mL received MAD AHB-137 (150 or 300 mg) or placebo (8:2), and 2 patients with baseline HBsAg 1000-3000 IU/mL received open-label AHB-137 300 mg. MAD comprised 6 subcutaneous doses over 4 weeks including loading doses on Days 4 and 11, with safety, PK and virologic follow-up assessments.

RESULTS

No serious adverse events, deaths or discontinuations occurred. Most treatment-related adverse events were Grade 1-2, including injection site reactions, pyrexia, and asymptomatic lab abnormalities. Transaminase elevations were self-limiting; one Grade 3 ALT elevation in the 300 mg CHB cohort coincided with rapid HBsAg loss. PK showed rapid absorption (Tmax 3-5 h), dose-proportionality, and a terminal half-life of 128-195 h without meaningful accumulation. In CHB patients, 4 weeks of AHB-137 induced dose-dependent HBsAg reductions (mean maximum - 1.1 vs. - 2.1 log10 IU/mL at 150 vs. 300 mg), 50.0% of the 300 mg cohort achieved ≥ 2 log10 IU/mL reduction. Preliminary HBsAg loss was observed in a small subset of patients during follow-up.

CONCLUSION

AHB-137 demonstrated favorable safety, predictable PK, and dose-dependent HBsAg reductions, including HBsAg loss, supporting its further development for CHB functional cure.

REGISTRATION NUMBER: ClinicalTrials.gov. number: NCT06115993. Chinadrugtrials.org.cn. number: CTR20232098.