Pharmacogenetics of siponimod: A systematic review

Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation. [Display omitted] •The CYP2C9 * 2 (rs1799853) and * 3 (rs1057910) are related to the metabolism of siponimod.•For Siponimod, the FDA and EMA require CYP2C9 genotyping before treatment starts.•Other CYP2C9 variants not reported by FDA/EMA result in a variable metabolism by CYP2C9.•CYP2C9 * 2-based recommendations are contradictory compared to other no-function alleles.•The FDA/EMA might recommend CYP2C9 * 4-* 6, * 8, and * 11-* 13 test, and not the CYP2C9 * 2.