DRUG-induced liver injury led to the discontinuation of ALG-020572 development after a clinical trial identified significant alanine aminotransferase elevations in patients with chronic hepatitis B virus (HBV) infection.
ALG-020572 was an antisense oligonucleotide designed to reduce viral protein synthesis by promoting degradation of HBV messenger RNA. The ALG-020572-401 trial was a double-blind, randomised, placebo-controlled study conducted in two parts.
Part 1 assessed single ascending doses in healthy participants, evaluating pharmacokinetics, safety and tolerability. A total of 32 participants were randomised to receive ALG-020572 or placebo. Single doses of up to 480 mg were well tolerated, with injection site reactions reported as the most common treatment-emergent adverse event. ALG-020572 was rapidly absorbed, and plasma exposure increased with dose.
Part 2 evaluated multiple dosing in eight patients with non-cirrhotic, hepatitis B e antigen (HBeAg)-negative, virologically suppressed chronic HBV infection. Participants received up to seven doses of ALG-020572.
Drug-induced liver injury emerged as the principal safety concern during Part 2. Four of the eight patients experienced significant alanine aminotransferase elevations, which were subsequently attributed to drug-induced liver injury.
The trial was consequently discontinued prematurely. This represented a notable contrast with the findings from Part 1, where single doses of ALG-020572 had demonstrated a favourable safety and pharmacokinetic profile in healthy participants.
The findings indicated that the tolerability observed following single-dose administration in healthy participants did not translate to repeated dosing in patients with chronic HBV infection. The occurrence of drug-induced liver injury in half of the patients enrolled in Part 2 prompted the termination of the study.
The emergence of drug-induced liver injury resulted in both early trial termination and discontinuation of further ALG-020572 development. The liver injury was characterised as idiosyncratic, with the findings prompting caution regarding the development of this class of drugs.
The results highlighted the importance of assessing safety in patients with the target condition during clinical development. Although ALG-020572 was well tolerated at single doses in healthy participants, repeated administration in patients with chronic HBV was associated with an unexpected safety signal.
For future development of antisense oligonucleotides targeting HBV, the findings provide a clear safety consideration. The authors concluded that caution was required in developing this drug class following the identification of drug-induced liver injury during multiple dosing.
Reference
Agarwal K et al. ALG-020572, an antisense oligonucleotide for the treatment of chronic hepatitis b virus infection discontinued for drug-induced liver injury. J Viral Hepat. 2026;33(9):e70224.
Featured Image: Aliaksandr Marko on Adobe Stock
Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.
