BH4 Responsiveness in PAH Deficiency PKU Patients

Objectives

1. Changes of blood Phe level from baseline at the 7th, 14th, and 28th day

2. Percentage of the study patients whose blood Phe level decreases for >= 30%

3. Percentage of the study patients whose Phe tolerance increase from baseline for >=50%

4. Correlation between PAH gene mutation and blood Phe level reduction

Study Design and Methodology The PAH deficiency PKU patients who failed to achieve 30% blood Phe reduction within 24-hour BH4 loading test will be enrolled to this study. Baseline protein intake will be calculated and baseline blood phenylalanine levels will be established prior to starting the trial. During the entire testing period, patients will have no dietary restrictions. Blood Phe will be measured on day 1, 7, 14 and 28 days after oral administration of 20 mg/kg KUVAN in 40 patients whose initial plasma Phe results were ≥360 umol/L. In this study, the efficacy of BH4 will be evaluated on 7, 14 and 28 days to determine whether a patient is BH4-responsive. The total duration of patient participation in the study will be up to 3 months (1 month of BH4 efficacy evaluation and up to 8 weeks of screening).

- Health status assessments：A complete physical examination will be performed at all study visits. The physical examination will include appearance, eyes, ears, nose, head, throat, neck, chest, lungs, heart, abdomen, extremities, skin and musculoskeletal system. Weight will be measured at first visit, without shoes and having removed all outwear such as jackets, sweaters or sweatshirts and heavy pocket items. Clinically significant findings at screening will be reported as medical history and as adverse event after the screening visit.

- Vital sign：Vital signs measurement will be recorded at all study visits and will include body temperature, respiration, blood pressure and heart rate after the patients has sat quietly for at least 5 minutes.

- Nutrition assessment：Baseline protein intake will be calculated from 3-day photographic food records, and baseline blood Phe level will be established after a 3-5 hour fasting prior to starting BH4 loading. During the entire testing period, patients will have no dietary restrictions, but will be asked to keep a stable diet throughout the study. Patients will be required to keep a diary and photographic food records for three days of each week containing a record of all foods and beverages ingested including synthetic and low protein containing foods. Dietary records will be reviewed by a single qualified metabolic dietician and monitored for calorie intake, natural protein intake, synthetic protein intake, and total Phe intake.

- Laboratory assessments：All routine clinical laboratory assessments will be performed by central laboratory. The laboratory evaluations will include :

- Serum nutritional biomarkers : total protein, albumin, total cholesterol, total triglyceride, LDL (low-density lipoprotein cholesterol), HDL (high-density lipoprotein cholesterol), Iron, Ferritin

- Blood phenylalanine and tyrosine : Blood phenylalanine and tyrosine levels will be measured prior to BH4 loading test, and on day 1, 7, 14 and 28 days following kuvan 20 mg/kg/day.

- PAH gene evaluation in all patients

- Urine pTerin and DHPR enzyme activity analysis - Patients with defect in the synthesis and recycling of BH4 will be excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. pTerins (neopterin and biopterin) metabolism will be analyzed in each visit.

- Dispense study drug - Subjects will receive 20 mg/kg Kuvan administered orally once daily for 28 days.