BH4 Responsiveness in PAH Deficiency PKU Patients

• Status: Not yet recruiting
• Trial end date: 2022-06-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Taipei Veterans General Hospital, Taiwan
• Collaborator: BioMarin Pharmaceutical

Criteria

Inclusion criteria

1. Subjects have a confirmed diagnosis of PAH deficiency PKU, defined as baseline blood Phe levels of >360 umol/L

2. Subject and/or parent or guardian must be capable of understanding and providing written informed consent

3. For PAH deficiency PKU newborns, they should be identified as non-BH4 responders by 24-hour BH4 loading test after birth

4. For PAH deficiency PKU older pediatric and adult patients, they should be identified as non-BH4 responders by 24-hour BH4 loading test and currently use Phe-restricted diet control alone

Exclusion criteria

1. Perceived to be unreliable or unavailable for study participation or, if under the age of 18, had parents or legal guardians who the investigator perceived to be unreliable or unavailable

2. Used any investigational agent other than Kuvan within 30 days of screening, or required any investigational agent or investigational vaccine prior to completion of all scheduled study assessments

3. Pregnant or breastfeeding, or considering pregnancy

4. Concurrent disease or condition that would interfere with study participation or safety (eg, seizure disorder, asthma or other condition requiring oral or parenteral corticosteroid administration, insulin-dependent diabetes, or organ transplantation recipient)

5. Serious neuropsychiatric illness (eg, major depression) not currently under medical management

6. Required concomitant treatment with any drug known to inhibit folate synthesis (eg, methotrexate)

7. Clinical diagnosis of primary BH4 deficiency

8. Patients him/herself or his/her caregivers are unable or unwilling to sign informed consent or to comply with the requirements of the study

9. Patient attend other clinical trials should not be included