EE-TP St George's treatment

Question 1

Erythrocyte encapsulated thymidine phosphorylase (EE-TP) - what is it?

Answer 1

 Researched at St George’s
 Take patients’ blood and separate red blood cells
 Encapsulate thymidine phosphorylase and infuse back into patient
 To increase half-life of thymidine phosphorylase
 Decrease immunogenic reactions against enzyme

Question 2

Challenges of EETP

Answer 2

Challenges

Small patient population
 200 patients identified globally

Limited disease reporting
 Insufficient natural history data
 Small number of case studies

Clinical challenges
 Heterogenous presentation
 Misdiagnosed, diagnostic delays
 Few clinicians with disease expertise

Complex IMP and manufacturing process
 Recombinant E. Coli thymidine phosphorylase (bacteria)
 Autologous erythrocyte
 Automated encapsulation at multiple clinical trial sites
 EE-TP infused within 30mins – has short half life

Question 3

EE-TP supply chain

Answer 3

 Italy – cell culture/fermentation and purification of thymidine phosphorylase
 UK – TYMP sterilised and filled into glass bottles
 International clinical trial sites – thymidine phosphorylase encapsulated into erythrocytes
 Released for infusion

Problems faced:
 Difficult to get regulatory approval everywhere to get license

Question 4

Navigating the license holder/QP issues

Answer 4

 Proposed a centralised license holder providing QP release of EE-TP manufactured at decentralised CT sites

Question 5

Strategies used to develop EE-TP

Answer 5

Compassionate treatment programme

Engaged with different groups of expertise

Question 6

Compassionate treatment programme

Answer 6

 Supplied to fulfil a need
 Authorised by local clinician
 10 years of patient exposure to EE-TP
 Collected data on efficacy, dosing and safety

Question 7

Engaged with different groups of expertise

Answer 7

 Patient advocacy groups and patients – inform on study design and assess participation burden
 International key opinion leaders – geographical location of patients + Suitable end point measure
 Pre-clinical expertise – study design support clinical development, look at dosing levels and toxicity
 Qualified person = advise on manufacture and supply chain
 Regulators MHRA/EMA – Orphan drug designation and protocol assistance
 Contract research organisation – clinical trial operation and rare disease experience + marketing success record

Question 8

EE-TP compassionate treatment clinical data

Answer 8

5 patients treated

Clinical response
	Neurological improvements
	Bilateral muscle power 
	Sensory ataxia
	Balance and gait
	Fine finger functioning 
	Walk longer distances
	Climb stairs without assistance

GI related improvements
	Taste
	Swallowing
	Decrease in nausea and vomiting
	Increase body weight

Adverse reactions
 2/5 patients
 Redness of face and neck
 Eliminated with oral steroids

End points: capture clinical effect in presence of phenotypic variability
 Check GI and neurological symptoms
 Check quality of life
 Safety
 Pharmacodynamics outcomes
 Exploratory variables – surrogate outcomes

Question 9

Obtained UK regulatory approval

Answer 9

 For phase 2 safety, tolerability, pharmacodynamics and efficacy of EE-TP
 Open label study
 Multiple dose
 Over 2 years