Pegvaliase treatment normalizes blood neurotransmitter metabolites in adults with phenylketonuria

Phenylketonuria (PKU) is caused by deficient activity of phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine (Phe) to tyrosine (Tyr), leading to a toxic accumulation of Phe and reduced Tyr in the blood and brain. Abnormal Phe and Tyr levels in the brain disrupt normal neurotransmitter biosynthesis and may contribute to the cognitive and psychiatric deficits observed in individuals with PKU. Blood neurotransmitter metabolites (NTMs) may serve as biomarkers that reflect neurotransmitter levels in the brain. In this study, blood NTMs correlated with brain NTMs and neurotransmitters in wild-type and PAH-deficient mice treated with PAH gene therapy. Pegvaliase is an enzyme substitution therapy that lowers blood Phe levels and is approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 μmol/L) despite prior management. The current work evaluated the relationship between blood NTMs and blood Phe in pegvaliase-treated, Phase 3, PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) study participants (Pegvaliase Group; N = 109). At baseline, individuals in the Pegvaliase Group had lower levels of the NTMs homovanillic acid (HVA), 3-methoxy-4-hydroxyphenyl glycol (MOPEG), and 5-hydroxyindoleacetic acid (5HIAA), and higher levels of the NTM phenylacetylglutamine (PAG) than age- and sex-matched healthy controls. PAG levels correlated positively with Phe levels (r = 0.833; p < 0.001), while HVA, MOPEG, and 5HIAA levels correlated negatively with Phe levels (r = -0.588, -0.561, and -0.857, respectively; all p < 0.001) across all timepoints. In participants with longitudinal NTM measurements available at baseline, 12 months, and 24 months (Pegvaliase Subgroup; n = 91), blood NTM levels improved from baseline with pegvaliase treatment at 12 months and 24 months, and median levels were normalized with blood Phe level reductions below 360 μmol/L after 24 months of treatment with pegvaliase, including in participants with blood Phe <30 μmol/L. In conclusion, blood NTM levels correlated with blood Phe levels, and pegvaliase improved blood NTM levels in a large cohort of individuals with PKU.