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

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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