Effect of COMT and UGT1A Variants on Clinical Response to Opicapone in Parkinson's Disease

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease. Symptomatic treatment is based on dopaminergic replacement. With disease progression, the initial benefit of levodopa becomes inconsistent, and motor complications emerge. One strategy used to maintain stable levodopa plasma levels throughout the day is the use of opicapone, a catechol-O-methyltransferase (COMT) inhibitor. Despite its efficacy, there is variability in the therapeutic response and development of adverse events to this drug. Variants in the COMT and UGT1A genes have been proposed to modulate the effect of this medication, either positively or negatively. OBJECTIVE: To assess the impact of COMT and UGT1A genetic variants on opicapone efficacy in PD patients. METHODS: We conducted a retrospective study of 237 PD patients treated with opicapone between May 2017 and June 2025. The COMT rs4818, rs4680, rs4633 and rs6269, and UGT1A rs1105880 SNPs were genotyped. Three established COMT activity haplotypes (low, medium, and high) were evaluated alongside clinical characteristics and treatment response. RESULTS: COMT rs4818 and rs6269 heterozygosity was associated with improvement in motor fluctuations. The low activity COMT haplotype was associated with improved motor fluctuations, whereas the medium activity COMT haplotype showed only a nominal protective association against dyskinesia worsening. The UGT1A rs1105880 dominant model was significantly associated with improvement in motor fluctuations. No variant was associated with treatment discontinuation. CONCLUSIONS: These results suggest that COMT and UGT1A genotyping may contribute to personalized therapy in PD, although prospective validation is needed.