Clevudine (DB06683): A Comprehensive Pharmacological and Clinical Review of a Potent Anti-HBV Agent Derailed by Long-Term Toxicity

Executive Summary

Clevudine is a synthetic pyrimidine L-nucleoside analog developed for the treatment of chronic hepatitis B (CHB) virus infection.[1] As an L-thymidine analogue, it represented a significant therapeutic candidate due to its potent antiviral activity, which in clinical trials proved superior to the contemporary standard of care, lamivudine.[2] A defining feature of Clevudine was its uniquely sustained post-treatment virologic suppression, a characteristic attributed to its long plasma half-life and its ability to significantly reduce the intrahepatic reservoir of covalently closed circular DNA (cccDNA).[1]

Despite this profound initial promise, the clinical development of Clevudine was ultimately curtailed by a challenging long-term safety and resistance profile. While short-term studies of up to 48 weeks demonstrated excellent efficacy and a favorable safety profile, longer-term post-marketing surveillance and retrospective studies revealed two critical liabilities. First, a significant percentage of patients developed viral breakthrough and genotypic resistance after more than one year of therapy, undermining its utility for chronic treatment.[2] Second, and more decisively, long-term administration (typically beyond eight months) was associated with a significant risk of reversible, mitochondrial myopathy.[6] This dose-limiting toxicity is mechanistically linked to the drug's own metabolic pathway and its long half-life, which leads to cumulative effects on mitochondrial function in skeletal muscle.