Updated on December 2 nd, 2008 Information about the BH4 and PKU Research Opportunity Sponsored by: Singh Research Group Emory University Department of Human Genetics

This is a twelve month clinical trial to help us understand how Kuvan TM can affect the nutrition and health of those with PKU. This is so we can better assist the health and nutritional needs of all PKU subjects. People with PKU who volunteer to participate in this study opportunity will help us learn if, over an extended period of time, Kuvan TM can improve the following : –Muscle mass, bone density, and growth –Neurological functioning –Nutritional wellbeing which will be determined by changes in the blood levels of certain nutrients and by the nutritional quality of your diet –Quantity of necessary medical food (formula) and low protein food What is this study about and why is it important?

We are now recruiting and enrolling approximately 60 study volunteers Recruitment and Enrollment period will last until July 2009, or until the maximum subject enrollment number is reached (whichever comes first) Subjects will be followed for 12 months from start of Kuvan TM treatment *If you have tried Kuvan TM, but were considered a nonresponder because your drop in plasma Phe was less than 30%, you are still eligible to participate in this study. *For this study, if your plasma Phe drops by at least 15% you will be considered a responder and allowed to take Kuvan TM for the full one year study period. Has the study started? Who are you recruiting?

Most screening and study visits will be at the Emory Department of Human Genetics Clinic on North Decatur Road, Decatur GA. For the first and last study visits you will need to spend the night at Emory’s clinical research center located at Emory University Hospital in Atlanta GA Location for study visits

We are Enrolling 60 subjects with PKU Response to Kuvan TM will be defined as a 15% or greater decrease in plasma Phe –NOTE: If you have tried Kuvan TM and had a response greater than 15% but less than 30% you will still qualify as a responder in this clinical trial Dietary PHE and medical food will be monitored during the study Responders and nonresponders will be followed for the full 12 months 5 Study visits total 1)Screening and Baseline visit 2)Study follow-up: 4 weeks after starting Kuvan TM 3)Study follow-up: 4 months after starting Kuvan TM 4)Study follow-up: 8 months after starting Kuvan TM 5)Final visit: 12 months after starting Kuvan TM Basic Study Design

Individuals with PKU who… –Are at least 5 years of age –Have been diagnosed with Phenylketonuria –Intend to try Kuvan TM therapy, or have tried Kuvan TM and had a plasma Phe decrease between 15% and 30% –Have not taken BH4 or Kuvan TM for at least 8 weeks. –Are not pregnant –Can provide informed consent, or have a parent or legal guardian who can provide informed consent Who can volunteer to participate?

What is going to happen at each visit? Study Visit 1: –Screening and study enrollment –Height, weight, tape measurements –Blood pressure and vital signs –Provide overnight urine sample –Fasting blood sample –Indirect Calorimetry –DEXA –Fill out questionnaires Study Visits 2,3,4: –Same measures as Visit 1 except there will be no DEXA or Indirect calorimetry Final Study Visit: –Same measures as Visit 1, including DEXA and Indirect Calorimetry

All patients at the Emory Genetics Clinic who try Kuvan TM, regardless of participation in the research trial, will be expected to submit filter paper blood spots and diet records for the first few weeks they are on Kuvan TM, and monthly thereafter. This is so we can monitor your dietary PHE intake, and your blood PHE levels since this is important to your health. Additional standard care visits may be scheduled by the doctor or dietitian to properly monitor your nutrition and health Patients at the Emory Genetics Clinic who try Kuvan TM but who choose not to participate in the study will be considered responders if Plasma Phe decreases by at least 30%, which is in agreement with the current medical standard. Is there anything else I can expect?

Who do I contact with questions or concerns I may have about the research study? –You can contact the research coordinator Mary Jane Kennedy ( ). You may also submit questions via the BH4 and PKU study website. What is the website address for this research study? – Study Contact Information