OC-036 A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury

Abstract

Introduction Lumiracoxib is a selective COX-2 inhibitor that was developed for the symptomatic treatment of osteoarthritis and acute pain. Concerns over liver injury, primarily at chronic doses >100 mg once daily, led to the withdrawal of lumiracoxib in most major drug markets worldwide. A genome-wide association study was performed to identify genetic markers associated with lumiracoxib-related liver injury. Methods Using DNA (n=10 057) collected during the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), a multistaged case-control pharmacogenetic study was conducted to identify genetic markers associated with the risk of developing elevations of liver aminotransferases (ALT/AST) during treatment with lumiracoxib. TARGET was a 52-week, gastrointestinal clinical safety outcomes study which demonstrated that lumiracoxib (400 mg once daily) reduced the risk of a definite or probable upper GI ulcer complication by 79% compared to NSAIDs (naproxen 500 mg twice daily and ibuprofen 800 mg three times daily) in non-aspirin treated osteoarthritis patients. Results Several single nucleotide polymorphisms (SNPs) from the MHC class II region on chromosome 6 were found to be associated with liver aminotransferase elevations five times the upper limit of normal (>5×ULN) in patients treated with lumiracoxib (top SNP p=2.8E-10). These findings were replicated in an independent set of patients with elevated aminotransferases (>3×ULN) (top SNP p=4.4E-12). To further refine the association results, HLA genotyping and analysis were conducted and a very strong association was identified (top HLA allele p=6.8E-25). Conclusion The study described here identified a highly significant association between HLA alleles and lumiracoxib-related liver injury. These results offer the potential to improve the safety profile of lumiracoxib by excluding patients at elevated risk for developing liver injury.