A First-in-Human study of AHB-137, an unconjugated antisense oligonucleotide, in healthy subjects and patients with chronic hepatitis B
Edward J. Gane, Yao-Chun Hsu, Chi-Yi Chen, Shyamasundaran Kottilil, Eric Lawitz, Ira M. Jacobson, Paul Yien Kwo, Lung-Yi Mak, Wai-Kay Seto, Joel V. Chua, Di Zhao, Tingting Lu, Bingxia Lu, Xiao Qiu, Yilei Wen, Yeming Pan, Mingyue Chen, Miao Wang, Chen Yang, Audrey H. Lau, Chengyong Yang, Guofeng Cheng, Wan-Long Chuang, Christian Schwabe, Man-Fung YuenBackground & 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.
Methods:
Forty healthy subjects were randomized into four 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 four weekly subcutaneous doses with a Day 4 loading dose (5 doses). Twenty-four virally suppressed, HBeAg-negative CHB patients on stable nucleos(t)ide analogue therapy were enrolled: four in an open-label 300-mg MD cohort (5 doses) and 20 in two placebo-controlled 300-mg MD cohorts (4:1, stratified by baseline HBsAg), receiving an additional loading dose on Day 11 (6 doses).
Results:
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 (T max 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 timepoint was observed in three patients, including two with baseline HBsAg <1 IU/mL and one 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.