PRION DISEASE
&
PENTOSAN POLYSULPHATE
IN THE UK
Richard Knight
NCJDSU
University of Edinburgh
Scotland
PRION DISEASE & PPS
I
GENERAL INTRODUCTION
II
PENTOSAN POLYSULPHATE
III
UK PATIENTS
IV
CONCLUDING POINTS
I
GENERAL INTRODUCTION
DIFFERENT BACKGROUNDS
DIFFERENT PERSPECTIVES
TREATMENTS: HOW DO YOU EVALUATE THEM?
• IN THE ‘TEST TUBE’
TREATMENTS: HOW DO YOU EVALUATE THEM?
• IN THE ‘TEST TUBE’
TREATMENTS: HOW DO YOU EVALUATE THEM?
PROTEINS & CELLS ARE NOT ANIMALS
TREATMENTS: HOW DO YOU EVALUATE THEM?
• IN ANIMALS
TREATMENTS: HOW DO YOU EVALUATE THEM?
RODENTS ARE NOT HUMANS
TREATMENT AT TIME OF INFECTION
IS NOT THE SAME AS
TREATING CLINICALLY ILL ANIMALS
TREATMENTS: HOW DO YOU EVALUATE THEM?
• IN THE ‘TEST TUBE’
• IN ANIMALS
• IN HUMANS
X
TREATMENT
REAL DISEASE BENEFIT
SYMPTOM RELIEF
TOXIC SIDE EFFECTS
TREATMENT
REAL DISEASE BENEFIT
SYMPTOM RELIEF
TOXIC SIDE EFFECTS
SYMPTOMS
NOT ALWAYS
EASY TO TELL
THE DIFFERENCE
DISEASE
PROCESS
TREATMENT
REAL DISEASE BENEFIT
SYMPTOM RELIEF
TOXIC SIDE EFFECTS
TWO TREATMENT SITUATIONS
CLINICAL ILLNESS
PREVENTION
ANY SIDE EFFECTS
MAY BE OF DIFFERENT SIGNIFICANCE
DISEASE
PEOPLE VARY
TREATMENT
SPORADIC
GENETIC
IATROGENIC
VARIANT
PERSON
DISEASES VARY
TREATMENT
TREATMENT REQUIRES DIAGNOSIS
THE DIAGNOSTIC PROCESS IS NOT SIMPLE
NO SIMPLE ‘CJD TESTS’
TREATMENT IDEALLY REQUIRES
EARLY DIAGNOSIS
STOPPING BRAIN DISEASE PREVENTS FURTHER DAMAGE
REPAIR OF EXISTING BRAIN DAMAGE IS PROBLEMATIC
DIAGNOSIS OF CJD IS OFTEN ‘LATE’
TREATMENT IDEALLY REQUIRES
EARLY DIAGNOSIS
STOPPING BRAIN DISEASE PREVENTS FURTHER DAMAGE
REPAIR OF EXISTING BRAIN DAMAGE IS PROBLEMATIC
DIAGNOSIS OF CJD IS OFTEN ‘LATE’
TREATMENT IDEALLY REQUIRES
EARLY DIAGNOSIS
STOPPING BRAIN DISEASE PREVENTS FURTHER DAMAGE
REPAIR OF EXISTING BRAIN DAMAGE IS PROBLEMATIC
DIAGNOSIS OF CJD IS OFTEN ‘LATE’
TREATMENT IDEALLY REQUIRES
EARLY DIAGNOSIS
STOPPING BRAIN DISEASE PREVENTS FURTHER DAMAGE
REPAIR OF EXISTING BRAIN DAMAGE IS PROBLEMATIC
DIAGNOSIS OF CJD IS OFTEN ‘LATE’
MAY BE SEVERE, IRREVERSIBLE, DAMAGE
II
PENTOSAN POLYSULPHATE
PENTOSAN POLYSULPHATE: PPS
BEECH WOOD DERIVED
PENTOSAN POLYSULPHATE: PPS
BEECH WOOD DERIVED
ESTABLISHED DRUG
NON-PRION DISEASE
PENTOSAN POLYSULPHATE: PPS
IN PRION DISEASE ?
PENTOSAN POLYSULPHATE: PPS
IN PRION DISEASE ?
PENTOSAN POLYSULPHATE: PPS
IN PRION DISEASE ?
PENTOSAN POLYSULPHATE: PPS
IN PRION DISEASE ?
?
PENTOSAN POLYSULPHATE: PPS
ORAL or IV: DOES NOT ENTER BRAIN
PENTOSAN POLYSULPHATE: PPS
ORAL or IV: DOES NOT ENTER BRAIN
NEED DIRECT ACCESS TO BRAIN
INTRA-VENTRICULAR ADMINISTRATION
INTRA-VENTRICULAR ADMINISTRATION
INTRA-VENTRICULAR ADMINISTRATION
INTRA-VENTRICULAR ADMINISTRATION
CURRENT PPS TREATMENT
OF PRION DISEASE
POTENTIAL PPS PROBLEMS
PROBLEMS WITH CATHETER
SURGERY: DAMAGE / BLEEDING
POST SURGERY: INFECTION
INTRA-VENTRICULAR ADMINISTRATION
PROBLEMS WITH PUMP
&
CONNECTING TUBE
POTENTIAL PPS PROBLEMS
PROBLEMS WITH PPS
BLEEDING
SEIZURES
OTHER TOXICITY
III
PPS TREATMENT IN THE UK
UK PPS TREATMENT
• NO ORGANISED CLINICAL TRIAL
• COLLECTION OF INFORMATION
ON A FEW INDIVIDUALS
WHO CHOSE TREATMENT or
WHOSE FAMILIES CHOSE TREATMENT
ONE ORGANISED OBSERVATIONAL STUDY
Published 2008
INTRAVENTRICULAR PENTOSAN POLYSULPHATE IN
HUMAN PRION DISEASES: AN OBSERVATIONAL STUDY IN
THE UK
I Bone, Belton L, Walker AS, Darbyshire J
European Journal of Neurology 2008, 15:458-464
www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC003453
MRC STUDY PATIENTS
• 2 hGH CJD
NO OBVIOUS BENEFIT
• 2 GSS
NO OBVIOUS BENEFIT
• 3 vCJD
2/3 POSSIBLE BENEFIT
(ALIVE LONGER)
MRC STUDY PATIENTS
• 2 hGH CJD
NO OBVIOUS BENEFIT
• 2 GSS
NO OBVIOUS BENEFIT
• 3 vCJD
2/3 POSSIBLE BENEFIT
(ALIVE LONGER)
MRC STUDY PATIENTS
• 2 hGH CJD
NO OBVIOUS BENEFIT
• 2 GSS
NO OBVIOUS BENEFIT
• 3 vCJD
2/3 POSSIBLE BENEFIT
(ALIVE LONGER)
MRC STUDY PATIENTS
• 2 hGH CJD
NO OBVIOUS BENEFIT
• 2 GSS
NO OBVIOUS BENEFIT
• 3 vCJD
2/3 POSSIBLE BENEFIT
(ALIVE LONGER)
MRC STUDY PATIENTS
• 2 hGH CJD
NO OBVIOUS BENEFIT
• 2 GSS
NO OBVIOUS BENEFIT
• 3 vCJD
2/3 POSSIBLE BENEFIT
(ALIVE LONGER)
MRC STUDY PATIENTS
• SOME PROBLEMS DUE TO INTRAVENTRICULAR
ADMINISTRATION (NO MAJOR ONES)
• NO PROBLEMS DUE TO PPS ITSELF
MRC STUDY PATIENTS
• SOME PROBLEMS DUE TO INTRAVENTRICULAR
ADMINISTRATION (NO MAJOR ONES)
• NO PROBLEMS DUE TO PPS ITSELF
PRESENT UK SITUATION
Intra-ventricular PPS
Cases Treated in the UK
Disease
Treated
Currently alive
vCJD
5
4
sCJD
1
1
GSS
2
0
hGH
2
0
Intra-ventricular PPS
Cases Treated in the UK
Disease
Treated
Currently alive
vCJD
5
4
sCJD
1
1
GSS
2
0
hGH
2
0
vCJD
DURATION OF ILLNESS > 20 MONTHS
September 2009
vCJD
DURATION OF ILLNESS > 20 MONTHS
Number of cases
5
4
3
2
1
Duration of illness (months)
dead
September 2009
alive (treated)
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
0
24
22
20
18
16
14
12
10
8
6
4
2
0
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Number of cases
ALL UK vCJD
DURATION OF ILLNESS
Duration of illness (months)
dead (untreated)
September 2009
dead (treated PPS)
alive (treated PPS)
Intra-ventricular PPS
Cases Treated in the UK
Disease
Treated
Currently alive
vCJD
5
4
sCJD
1
1
GSS
2
0
hGH
2
0
Number of cases
sCJD
DURATION OF ILLNESS
200
180
160
140
120
100
80
60
40
20
0
0
5
10
15
20
25
30
35
40
45
Duration of illness (months)
dead
September 2009
alive (untreated)
alive (treated)
50+
IV
CONCLUDING REMARKS
PPS
NOT A CURE
• HIGHLY PROBABLE: PROLONGS DISEASE IN VARIANT CJD
• NO GOOD EVIDENCE FOR BENEFIT IN OTHER FORMS OF CJD
• NO EVIDENCE OF TOXICITY FROM PPS ITSELF
• INTRAVENTRICULAR ADMINISTRATION IS NOT EASY
PPS
NOT A CURE
• HIGHLY PROBABLE: PROLONGS LIFE IN VARIANT CJD
• NO GOOD EVIDENCE FOR BENEFIT IN OTHER FORMS OF CJD
• NO EVIDENCE OF TOXICITY FROM PPS ITSELF
• INTRAVENTRICULAR ADMINISTRATION IS NOT EASY
PPS
NOT A CURE
• HIGHLY PROBABLE: PROLONGS LIFE IN VARIANT CJD
• NO PRESENT EVIDENCE FOR OTHER FORMS OF CJD
• NO EVIDENCE OF TOXICITY FROM PPS ITSELF
• INTRAVENTRICULAR ADMINISTRATION IS NOT EASY
PPS
NOT A CURE
• HIGHLY PROBABLE: PROLONGS LIFE IN VARIANT CJD
• NO PRESENT EVIDENCE FOR OTHER FORMS OF CJD
• NO EVIDENCE OF TOXICITY FROM PPS ITSELF
• INTRAVENTRICULAR ADMINISTRATION IS NOT EASY
PPS
NOT A CURE
• HIGHLY PROBABLE: PROLONGS LIFE IN VARIANT CJD
• NO PRESENT EVIDENCE FOR OTHER FORMS OF CJD
• NO EVIDENCE OF TOXICITY FROM PPS ITSELF
• INTRAVENTRICULAR ADMINISTRATION IS NOT EASY
FURTHER RESEARCH ON PPS
? OTHER ANIMAL RESEARCH
IF POSSIBLE: RCTs
FURTHER RESEARCH ON PPS
? EASIER ADMINISTRATION METHODS
IF POSSIBLE: RCTs
TREATMENT TRIALS WITH A STRUCTURED FRAMEWORK
INTERNATIONAL COLLABORATION
TRIALS WITH UNIFORM METHODS
EUROPE: ‘THERAPRION’
EARLIER TREATMENT
EARLIER DIAGNOSIS
EARLIER TREATMENT
EARLIER DIAGNOSIS