Effect of Large Neutral Amino Acids in Adults With Classical Phenylketonuria

Standard treatment for Phenylketonuria (PKU) involves a lifelong, phenylalanine-restricted diet. Strict adherence to the diet is crucial, but often challenging. Large neutral amino acid (LNAA) supplementation is a potential alternative therapeutic approach for PKU management. The proposed mechanism involves competitive inhibition of phenylalanine (Phe) transport across the blood-brain barrier by high-dose LNAA, leading to reduced brain Phe levels. However, further investigation is needed to validate its efficacy and safety for PKU management.

A randomized, open-label, crossover trial will be conducted to assess the safety and efficacy of LNAA supplementation in PKU patients. After completion of the crossover study, participants will have the option to participate in an open-label extension study aimed at evaluating the long-term safety and efficacy of LNAA.

A healthy control group will be recruited to obtain baseline outcome measures. This project is expected to provide much-needed insights into the potential of LNAA in PKU management. The study also aims to gain a deeper understanding of the underlying pathophysiology of the disease. Finally, this work could lead to more personalized management strategies for PKU patients.

Patients ≥ 18 years of age with Classical PKU molecularly confirmed via the finding of two pathogenic variants in the phenylalanine hydroxylase (PAH) gene and/or historical evidence of Phe concentrations ≥1200 μmol/L in the medical history

Inclusion criteria

• Treatment initiation within the first month of life
• Intelligence quotient over 84, based upon the baseline neuropsychological evaluation
• Conventional dietary treatment up to minimum 15 years of age
• Signed informed consent
• Willing and able to comply with the protocol and study procedures

Exclusion criteria

• Unable or unwilling to adhere to the requirements of the study
• A female who is pregnant or breastfeeding or planning to get pregnant during the study period
• Concomitant medication that may interfere with the PET analysis, as judged by the investigator
• A serious neuropsychiatric disease that could interfere with the subject's ability to participate in the study at the discretion of the investigator
• Concomitant treatment with BH4 supplementation (sapropterin) or Pegvaliase-pqpz (PALYNZIQ)
• Failing to submit at least one blood Phe home sample during the year before study initiation
• Standard MRI contraindications
• Body weight over 110 kg