PRION DISEASE &

PENTOSAN POLYSULPHATE IN THE UK

Richard KnightNCJDSU

University of EdinburghScotland

PRION DISEASE & PPS

I GENERAL INTRODUCTION

II PENTOSAN POLYSULPHATE

III UK PATIENTS

IV CONCLUDING POINTS

I

GENERAL INTRODUCTION

DIFFERENT BACKGROUNDSDIFFERENT 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

DISEASE PROCESS

SYMPTOMS

NOT ALWAYSEASY TO TELLTHE DIFFERENCE

TREATMENT

REAL DISEASE BENEFIT SYMPTOM RELIEF TOXIC SIDE EFFECTS

TWO TREATMENT SITUATIONS

CLINICAL ILLNESS PREVENTION

ANY SIDE EFFECTS MAY BE OF DIFFERENT SIGNIFICANCE

DISEASE

TREATMENT

PEOPLE VARY

PERSON SPORADICGENETIC

IATROGENIC VARIANT

TREATMENT

DISEASES VARY

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 DRUGNON-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 TREATMENTOF 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

BLEEDINGSEIZURESOTHER 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 STUDYPublished 2008

INTRAVENTRICULAR PENTOSAN POLYSULPHATE IN HUMAN PRION DISEASES: AN OBSERVATIONAL STUDY IN

THE UKI 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

0

1

2

3

4

5

15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

Duration of illness (months)

Num

ber

of c

ases

dead alive (treated)

September 2009

ALL UK vCJD DURATION OF ILLNESS

02468

1012141618202224

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100

Duration of illness (months)

Num

ber

of c

ases

dead (untreated) dead (treated PPS) alive (treated PPS)

September 2009

Intra-ventricular PPS Cases Treated in the UK

Disease Treated Currently alive

vCJD 5 4

sCJD 1 1

GSS 2 0

hGH 2 0

sCJD DURATION OF ILLNESS

020406080

100120140160180200

0 5 10 15 20 25 30 35 40 45 50

Duration of illness (months)

Num

ber

of c

ases

dead alive (untreated) alive (treated)

September 2009

+

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

IF POSSIBLE: RCTs

? OTHER ANIMAL RESEARCH

FURTHER RESEARCH ON PPS

IF POSSIBLE: RCTs

? EASIER ADMINISTRATION METHODS

TREATMENT TRIALS WITH A STRUCTURED FRAMEWORK

INTERNATIONAL COLLABORATION

TRIALS WITH UNIFORM METHODS

EUROPE: ‘THERAPRION’

EARLIER TREATMENT

EARLIER DIAGNOSIS

EARLIER TREATMENT

EARLIER DIAGNOSIS