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ALG-020572, an Antisense Oligonucleotide for the Treatment of Chronic Hepatitis B Virus Infection Discontinued for Drug-Induced Liver Injury.

Kosh Agarwal·Dan Forton·Yoh Zen·Min Wu·Tse-I Lin·Kha Le·Sushmita Chanda·Lawrence Blatt·John Fry·Ed Gane
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Abstract

Current treatment options for chronic HBV infection are suboptimal in that they fail to suppress HBsAg levels. ALG-020572 is an antisense oligonucleotide designed to reduce viral protein synthesis through degradation of HBV mRNA. ALG-020572-401 was a double-blind, randomized, placebo-controlled trial consisting of two parts. Part 1 (single-ascending doses) evaluated the pharmacokinetics, safety and tolerability of single doses of ALG-020572 or placebo in healthy participants. In Part 2 (multiple dosing), participants with non-cirrhotic HBeAg-negative, virologically suppressed chronic HBV infection were administered up to 7 doses of ALG-020572 to evaluate safety, pharmacokinetics and antiviral activity. In Part 1, 32 participants were randomized to ALG 020572 or placebo. Single doses of ALG-020572 up to 480 mg were well tolerated. The most common treatment-emergent adverse event reported was injection site reaction. ALG-020572 was rapidly absorbed and plasma exposures increased with dose. In Part 2, 8 participants with non-cirrhotic HBeAg-negative virologically suppressed chronic hepatitis B infection were enrolled and received up to 7 doses of ALG-020572. The study was prematurely discontinued after 4 participants experienced significant alanine aminotransferase elevations that were subsequently attributed to drug-induced liver injury. Single doses of ALG-020572 demonstrated a favourable pharmacokinetic and safety profile in healthy participants. Unexpectedly, ALG-020572 was poorly tolerated in participants with chronic HBV infection, resulting in the early termination of the study and further development of ALG-020572 due to idiosyncratic drug-induced liver injury, suggesting caution is required in the development of this class of drugs. Trial Registration: Registered at clinicaltrials.gov: NCT0500102.

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AdultFemaleHumansMaleMiddle AgedYoung AdultAntiviral AgentsChemical and Drug Induced Liver InjuryDouble-Blind MethodHepatitis B virusHepatitis B, ChronicOligonucleotides, AntisensePlacebosTreatment OutcomeHBsAgantisense oligonucleotideschemical and drug‐induced liver injurychronic hepatitis Bhepatitis B virusClinical Trial, Phase IJournal ArticleRandomized Controlled Trial

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Kosh Agarwal, Dan Forton, Yoh Zen, Min Wu, Tse-I Lin, Kha Le, Sushmita Chanda, Lawrence Blatt, John Fry, Ed Gane. 2026. ALG-020572, an Antisense Oligonucleotide for the Treatment of Chronic Hepatitis B Virus Infection Discontinued for Drug-Induced Liver Injury.. https://doi.org/10.1111/jvh.70224

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