Transcript Galloway_One_year_...pps

Kuvan® the first ‘drug’ treatment
for PKU
Peter Galloway
Adult Metabolic Clinic
Glasgow Royal Infirmary
March 2010
•
serum PHE concentration (μmol/l)
Chart plotting median PHE level for all patients
diagnosed with PKU with any data since 2001
1600
Average male PHE value
1400
1200
1000
Average female PHE value
800
Upper recommended
PHE limit
600
400
200
Lower recommended
PHE limit
0
0-5
6-10
11-15
16-20
21-30
31-40
40+
Patient age (years)
•45% control their PHE levels to within current guidelines
(42% for males, 47% for females)
Serum PHE concentration (μmol/l)
Chart plotting median lowest PHE level for all
patients diagnosed with PKU with any data since
2001
1400
Average lowest male PHE
value
1200
1000
Average lowest female PHE
value
800
600
Upper recommended
PHE limit
400
200
Lower recommended
PHE limit
0
0-5
6-10
11-15
16-20
21-30
Patient age (years)
31-40
40+
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
O
NH
HN
H2N
N
NH
CH CH CH3
OH OH
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.
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
Blood Phenylalanine (mmol/L)
2000
20 mg/kg
(BH4)
1500
PKU non-responder
1000
20 mg/kg
PKU responder
10 mg/kg
500
BH4 def.
Hours
0
0
4
8
12
24
48
72
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
Abdominal pain
Nausea
Flatulence
Vomiting
Decreased appetite
Headache
Fatigue
Tremor
%
5
5
3
2
2
2
10
3
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?