Phenylketonuria (PKU) is an autosomal recessive inborn error of L-phenylalanine (L-Phe) metabolism which is caused by deleterious variants in the gene coding for the phenylalanine hydroxylase (PAH) enzyme. The PAH enzyme catalyses the conversion of phenylalanine (Phe) to tyrosine (Tyr), a precursor of several neurotransmitters, hormones, skin, hair, and eye pigments. Elevated concentration of Phe and secondary metabolites and lower Tyr concentration in blood and in brain cause degenerative neuropathology, neurological symptoms, and intellectual deficits, together with poorly or non-pigmented skin and hair, and musty odor which are characteristic in untreated patients with PKU (1, 2).
This Phase 1/Phase 2 study is designed to assess the safety and efficacy of escalating doses of SAR444836 treatment in participants with PKU. The data collected will help to evaluate whether this adeno-associated virus (AAV) vector which delivers the functional human PAH gene into hepatocytes is effective in the treatment of PKU disease. The expression of PAH gene in hepatocytes is expected to provide steady low plasma levels of Phe similar to those observed in healthy individuals, preventing marked fluctuations caused by normal dietary protein intake.
The study is divided into 2 parts including a dose escalation phase (Stage 1A) and a dose expansion phase (Stage 1B).