3Chart plotting median PHE level for all patients diagnosed with PKU with any data since 2001 Average male PHE valueAverage female PHE valueUpper recommendedPHE limitLower recommendedPHE limit45% control their PHE levels to within current guidelines (42% for males, 47% for females)
4Chart plotting median lowest PHE level for all patients diagnosed with PKU with any data since 2001 Average lowest male PHEvalueAverage lowest female PHEvalueUpper recommendedPHE limitLower recommendedPHE limit
7Phenylalanine ammonia lyase An enzyme found widely in yeasts and red-purple coloured plants and used in the synthesis of anthocyanins. It breaks down phenylalanine to hydrocinnamic acidCan be extracted from plants or synthesised by engineered E. coli bacteriaCould be used to break down phenylalanine in the intestine, preventing its absorption and allowing liberalisation of the dietEasily destroyed by gastric acid and attempts to engineer a robust protected source of PAL have been abortive over more than 15 years…..Recently subcutaneous injection of pegylated enzyme has been successful in a mouse model of PKUFirst human trials involving 25 individuals in 2009
10Tetrahydrobiopterin First reported 1963 by Kaufmann Proc. National Academy of Science, 1968: 5:and first suggested role in 1975.Journal of Biological Chemistry, 1975, 25:
11In 1999Kure reported 4 of 5 mild PKU, BH4 loading produced reductions in blood phenylalanineJournal of Paediatrics, 1999: 135:
12Availability April 2009 – Launch of Kuvan Sapropterin licensed for use in Phenylketonuria in those over 4 years of age for the treatment of hyperphenylalaninaemia who have been shown to be responsive to such treatment.
138 year old may need 1-4 tablets/day Info:How is Kuvan taken?Dose?5-20 mg/kg body weight100 mg tabletsDissolved in water and taken one per day8 year old may need 1-4 tablets/dayAdult male may need 7-14 tablets/day
15Possible Mechanisms for the BH4-Responsiveness Km mutants with reduced affinity for BH4Chaperon-like activity of BH4Induction of PAH expression by BH4PAH mRNA stabilizationBetter assembly/stabilisationPossible Mechanisms for failure to respondTruncated proteinMissing BH4 Binding Area
16Tetrahydrobiopterin Loading Test in Patients with Hyperphenylalaninemia20 mg/kg (BH4)PKU non-responder20 mg/kgBlood Phenylalanine (mmol/L)PKU responder10 mg/kgBH4 def.Hours
21WHAT IS A RESPONSE > 30% reduction in phenylalanine While remaining on a constant protein intakeAlso need to be able to take an increased protein intakeHow long to show you respond?
22Levy et al: test withBH4 10mg/kg/day for up to28 days
23Blau N: Guidelines for the definition of BH4 responsiveness should include the following investigations…...Single loading test with 20 mg/kg BH4 and monitoring of phe at 0,8,12,(15?) and 24 hoursReduction of phe of over 20-30% an indicator for a trial of BH4 at initial doses of 10mg/kg/day over several weeksTitration of the individual BH4 requirement (5-20mg/kg/day)to maintain optimal phe levelsDetermination of the daily phenylalanine toleranceGenotyping
24KUVAN Does it have other benefits than just reduction in levels? Not formally tested.Anecdotally – what does this mean?
25Side-effects from Kuvan %DiarrhoeaAbdominal painNausea 3Flatulence 2Vomiting 2Decreased appetite 2Headache 10Fatigue 3Tremor4 in 489 had severe SEs – migraine, headache, vomiting andlow platelet countNo patient discontinued the study from side-effects.
26Why not give to everyone? Small proportion benefit1 in 5 30% reduction; 1 in 20 major dietary changeTesting will be over a monthif don’t respond effect ?Could start based on genetic testing.Cost
27Other Issues Age it should be started? How long should it be continued?e.g. Childhood/end of schoolingLifelongIf difficult complying with low protein diet,? compliance with tablets.Monitoring while on treatmentOther areas – pregnancy?
28Current Progress - Where is Europe? Where is UK? What do you feel we should be doing?