A First-in-Human study of AHB-137, an unconjugated antisense oligonucleotide, in healthy subjects and patients with chronic hepatitis B

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BACKGROUND AND AIMS: AHB-137 is a novel ASO targeting a conserved region near the 3' end of all HBV mRNA. This first-in-human phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and antiviral efficacy in healthy subjects and chronic hepatitis B (CHB) patients. APPROACH AND RESULTS: Forty healthy subjects were randomized into 4 placebo-controlled single ascending dose (100-450 mg, 6:2 AHB-137:placebo) cohorts and one multiple-dose (MD; 300 mg, 6:2) cohort receiving 4 weekly subcutaneous doses with a day 4 loading dose (5 doses). Twenty-four virally suppressed, HBeAg-negative CHB patients on stable nucleos(t)ide analog therapy were enrolled: 4 in an open-label 300-mg MD cohort (5 doses) and 20 in 2 placebo-controlled 300-mg MD cohorts (4:1, stratified by baseline HBsAg), receiving an additional loading dose on day 11 (6 doses). Treatment-related adverse events occurred in 73% of healthy subjects and 71% of CHB patients and were primarily mild or moderate injection-site reactions and headaches. No treatment-related serious adverse events, discontinuations, or deaths were observed. PK profiles showed rapid absorption ( Tmax 2.96-5.50 h), dose-proportional exposure, no significant accumulation, long terminal half-life (150-220 h), and minimal renal excretion. In CHB patients, AHB-137 treatment led to a rapid HBsAg decline (mean 0.7-1.0 log 10 IU/mL). HBsAg loss (<0.05 IU/mL) for at least one time point was observed in 3 patients, including 2 with baseline HBsAg <1 IU/mL and 1 with baseline HBsAg <1.5 IU/mL. CONCLUSIONS: In this phase 1 study, AHB-137 demonstrated an acceptable safety profile, predictable PK, and rapid and prolonged HBsAg reductions, supporting further evaluation of dosing and treatment duration in CHB.

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