Kuvan® the first ‘drug’ treatment for PKU Peter Galloway Adult Metabolic Clinic Glasgow Royal Infirmary March 2010

Chart plotting median PHE level for all patients diagnosed with PKU with any data since 2001 Average male PHE value Average female PHE value Upper recommended PHE limit Lower recommended PHE limit 45% control their PHE levels to within current guidelines (42% for males, 47% for females)

Chart plotting median lowest PHE level for all patients diagnosed with PKU with any data since 2001 Average lowest male PHE value Average lowest female PHE value Upper recommended PHE limit Lower recommended PHE limit

Target blood Phe levels <360 mmol/L Treatment Target blood Phe levels <360 mmol/L Phe-restricted diet  Large Neutral Amino Acids  Gene therapy  Enzyme replacement with rPAL  Tetrahydrobiopterin (BH4) 

Phenylalanine 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 acid Can be extracted from plants or synthesised by engineered E. coli bacteria Could be used to break down phenylalanine in the intestine, preventing its absorption and allowing liberalisation of the diet Easily 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 PKU First human trials involving 25 individuals in 2009

Tetrahydrobiopterin

Tetrahydrobiopterin First reported 1963 by Kaufmann Proc. National Academy of Science, 1968: 5:1085-93 and first suggested role in 1975. Journal of Biological Chemistry, 1975, 25: 4777-4781

In 1999 Kure reported 4 of 5 mild PKU, BH4 loading produced reductions in blood phenylalanine Journal of Paediatrics, 1999: 135: 375-378

Availability 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.

8 year old may need 1-4 tablets/day Info: How is Kuvan taken? Dose? 5-20 mg/kg body weight 100 mg tablets Dissolved in water and taken one per day 8 year old may need 1-4 tablets/day Adult male may need 7-14 tablets/day

21% regulatory domain 62% catalytic domain 5% tetramerization domain Blau & Erlandsen 2004

Possible Mechanisms for the BH4-Responsiveness Km mutants with reduced affinity for BH4 Chaperon-like activity of BH4 Induction of PAH expression by BH4 PAH mRNA stabilization Better assembly/stabilisation Possible Mechanisms for failure to respond Truncated protein Missing BH4 Binding Area

Tetrahydrobiopterin Loading Test in Patients with Hyperphenylalaninemia 20 mg/kg (BH4) PKU non-responder 20 mg/kg Blood Phenylalanine (mmol/L) PKU responder 10 mg/kg BH4 def. Hours

Burton et al PKU 001

Patients in PKU-003

PKU-003 Absolute phenylalanine before and after BH4

PKU-003 Change in phenylalanine with BH4

WHAT IS A RESPONSE > 30% reduction in phenylalanine While remaining on a constant protein intake Also need to be able to take an increased protein intake How long to show you respond?

Levy et al: test with BH4 10mg/kg/day for up to 28 days

Blau 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 hours Reduction of phe of over 20-30% an indicator for a trial of BH4 at initial doses of 10mg/kg/day over several weeks Titration of the individual BH4 requirement (5-20mg/kg/day)to maintain optimal phe levels Determination of the daily phenylalanine tolerance Genotyping

KUVAN Does it have other benefits than just reduction in levels? Not formally tested. Anecdotally – what does this mean?

Side-effects from Kuvan % Diarrhoea 5 Abdominal pain 5 Nausea 3 Flatulence 2 Vomiting 2 Decreased appetite 2 Headache 10 Fatigue 3 Tremor 2 4 in 489 had severe SEs – migraine, headache, vomiting and low platelet count No patient discontinued the study from side-effects.

Why not give to everyone? Small proportion benefit 1 in 5 30% reduction; 1 in 20 major dietary change Testing will be over a month if don’t respond effect ? Could start based on genetic testing. Cost

Other Issues Age it should be started? How long should it be continued? e.g. Childhood/end of schooling Lifelong If difficult complying with low protein diet, ? compliance with tablets. Monitoring while on treatment Other areas – pregnancy?

Current Progress - Where is Europe? Where is UK? What do you feel we should be doing?