PAH Deficiency clinical trials

BH4 Responsiveness in PAH Deficiency PKU Patients

Most forms of Phenylketonuria and hyperphenylalanemia are caused by mutations in the PAH gene (phenylalanine hydroxylase) which is responsible for the conversion of Phe into tyrosine, in the presence of the molecular oxygen and cofactor tetrahydrobiopterin (BH4). To prevent mental retardation due to the buildup of neurotoxic metabolites of Phe, patients with severe PKU must be treated with a low-Phe diet starting early in their life [1]. Although Phe-restricted diet control is essential for avoiding neurological impairment, the life-long compliance with this dietary control is not optimally maintained, particularly in adulthood and adolescence [2]. Non-adherence to dietary control after successful treatment in early childhood may contribute to lower intelligence quotient (IQ), emotional and behavioral disorders, including attention deficit disorders, depression, anxiety, and agoraphobia. In recent years, another therapeutic approach for managing PKU is to supplement a synthetic form of BH4 along with diet control. Kure et al. and several other research teams had indicated that treatment with BH4 might lower down the Phe level in a subset of PKU patients [3-7]. BH4 acts as a pharmacological chaperone to stabilize mutant enzymes with disrupted tetramer assembly and increased sensitivity to proteolytic cleavage and aggregation. The BH4-supplementation therapy (Kuvan) can be used to loosen or even replace burdensome dietary treatment of PKU patients. Correct and efficient identification of BH4-responsive patients is important, both to improve the fast assessment, as well as to avoid false expectations and unnecessary costs. Unfortunately, there is still no golden standard on how to assess BH4 responsiveness most efficiently. In Taiwan, high-dose BH4 [20mg/kg] loading is the standard test to identify patients who are responsible to BH4 treatment, for PAH deficiency PKU patients with more than 30% decrease in Phe level within 24 hours after BH4 challenge were BH4-responsive patients and eligible for national health insurance coverage of continuous BH4 treatment. In clinical studies, blood Phe levels in patients who are BH4-responsive typically decrease within 24 hours after a single administration of Kuvan, although the maximal effect on blood Phe levels may take up to a month. A Phase IV open-label trial showed that of 64% of patients responded to Kuvan within 7 days whereas 10% responded between 8-28 days. To the best of our knowledge, there's no previous study which evaluated longer than 7 days BH4 response test in Asian countries, and for the purpose to help PAH deficiency PKU patients achieve optimal Phe control and neurocognitive outcomes, it's definitely worthy to extend the period of BH4 response test to identity more patients who can benefit from Kuvan treatment.