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

3. 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)

4. 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

5. 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) 

7. 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

8. Tetrahydrobiopterin

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

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

12. 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.

13. 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

14. 21% regulatory domain 62% catalytic domain 5% tetramerization domain
Blau & Erlandsen 2004

15. 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

16. 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

17. Burton et al
PKU 001

18. Patients in PKU-003

19. PKU-003 Absolute phenylalanine before and after BH4

20. PKU-003 Change in phenylalanine with BH4

21. 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?

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

23. 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

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

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

26. 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

27. 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?

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