treating an ultra-rare condition: clinician-led
TRANSCRIPT
Treating an ultra-rare condition: clinician-led repurposing for
Wolfram syndrome
Timothy Barrett
University of Birmingham
Birmingham, UK
Findacure scientific conference
London 2017
Peter, Kelly- Wolfram syndrome
• Presented aged 6 yrs with 6 week h/o
wt loss, lethargy.
• O/E glucose 16mmol/L, no ketones.
Insulin
• 11 yrs referred by optician as everything
going grey.
• Ophthalmologist: optic atrophy
• Adults: ataxia, diabetes insipidus,
neuropathic bladder, bulbar palsy, brain
atrophy
Wolfram syndrome: warning!
• Rare- 1:700,000
• Single gene disorder
• Life limiting
• Multisystem
• Neurodegeneration
• No cure, no treatment
• Failure to diagnose patterns!
• Too rare for doctors to learn!
• Little or no research!
• Inadequate patient information!
• Failure to treat properly!
Wolfram syndrome timeline
1938 1995
1998 2005 2013
2014
2015 2016
2016 2017
First report by Dr Wolfram, Mayo clinic
First description of natural history and inheritance
Gene identified
Mechanism ER stress
Drug target p21cip1
Drug screen
EMA/FDA ODD Valproate
Biomarkers identified
Funding for Phase I trial Dantrolene,Phase II trial Valproate
2011
EURO-WABB Registr
y
EMA/FDA ODD Dantrolene
1995 Natural History
(Barrett T et al, Lancet 1995;346:1458-63)Collier D et al, Am J Hum Genet 199659:855-863)
1998 Gene identified WFS1
(Inoue H et al Nature Genetics 1998;20:143-8)(Hardy C et al Am J Hum Genet 1998)
The power of mothers
• First international Wolfram research meeting, Paris 2009
Nolwen Le Floche
GOAL
• Find a cure for Wolfram syndrome
– Reverse the disease process
– Restore useful vision
• Gene therapy
• Slow down or halt progression of disease
– New medicines
– Existing medicines repurposed for Wolfram ✓
2013: Identification of drug targets
(Gharanei et al Hum Mol genet 2013)(Fonseca S et al JCI 2013)
Role of WFS1 in cell cycle regulation
Expression of p21cip1 protein per cell,
measured as fluorescence units. The
expression of p21cip1 is significantly
reduced in all WFS1-depleted cell
lines compared with control cells
(CL)
The percentages of cells in G2
phase in each cell line, by
p21cip1 expression
(Gharanei et al Hum Mol genet 2013)
Role of WFS1 in cell cycle regulation
Percentages of cells showing apoptosis in each cell
line, by p21cip1 expression.
(Gharanei et al Hum Mol genet 2013)
2014: Drug screen of repurposed drugs
• Selection:
• Compounds known to increase p21cip1
expression
• Drugs already licensed for use in children
• Drugs that cross blood brain barrier
High content cytometry
Glucose tolerance test in WFS1 KO mice
Black circles: vehicle; red squares: valproic acid; green triangles:
diazepam
(Terasmaa, Koks et al, 2011)
The proposed treatment: Sodium
Valproate
• Anticonvulsant, licensed for treatment of epilepsy, bipolar disorder
• Mechanism: potentiation of GABA inhibition
• Wolfram: alteration of cell cycle kinetics, increased p21cip1 expression, reduced apoptosis, increased Wolfram protein expression, increased ER chaperone expression.
• Licensed for use in children
• Crosses blood-brain barrier
• Decades of pharmakokinetic, safety data
• Well established side effect profile
Hypothesis
• Chronic sodium valproate administration will slow the rate of progression of neurodegeneration in Wolfram syndrome by 50% compared with current standard of care.
2014 Application to European Medicines Agency for orphan drug designation
Application to EMA for protocol
assistance
• Highest quality evidence – RCT
• Would accept lower level of significance
• PROMS as endpoints
• Pivotal study
• Would consider approval under ‘exceptional circumstances’
Patient relevant outcome measures
Phase II efficacy study
• A Phase II, Multicentre, International, Randomised, Double-blind, Efficacy and Safety trial of Sodium Valproate, in paediatric and adult patients with Wolfram syndrome
• Primary objective (A)– To determine efficacy of sodium valproate on clinical parameters:
• Visual acuity
• MRI Pons Volume
• Primary objective (B)– To assess the safety and tolerability of sodium valproate administered
orally at a maximum dose of 40mg/kd/day in divided doses in patients with Wolfram syndrome.
• To show efficacy of valproate with 80% power to detect at least a 60% reduction in rate of progression of visual acuity and brainstem volume
Findacure Budget Impact Model
£142,388£138,375
£144,251
£157,249
£170,805
(£40,000)
(£20,000)
£0
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£80,000
£100,000
£0
£20,000
£40,000
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£120,000
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£160,000
£180,000
1 2 3 4 5
Year
Savings
Total yearly savings Renal/neurogenic bladder Diabetes insipidus and other endocrine
Diabetes mellitus Optic atrophy Sensorineural hearing loss
Neurological development Psychiatric disorders Sodium valproate
Paediatric specialist service Adult specialist service
Summary
• Patient support groups drive research
• Repurposed drugs may be quicker route to treatment
• Trial design in neurodegenerative disease
– Need biomarker for early stopping before clinical endpoints
• EMA protocol assistance- helpful
• Patient involvement in trial design
Acknowledgments
This presentation arises from the Euro-WABB project which has received funding from the European Union, in the framework of the Health Programme
Zsuzsa NagyDewi AstutiMalgosia ZatykaRenuka DiasUna MartinKaren MorrisonRajat GuptaAndrew PeetMartin WilsonKristian BrockLucinda Billingham
Sulev KoksTammy HersheyPatrick Yu Wai ManVirginie PicardFumi UranoMarc PeshanskiMiguel Lopez de HerediaVirginia NunesJulia RohayemLisbeth TranebjaergVeronique Paquis-FlucklingerWojciech MolinariGema Esteban BuenoPietro MaffeiRichard SinnottNIHR RD-TRC
Nolwen Le Floche
Tracy Lynch
ISPAD
“No man is an island,
entire in itself. Every
man is a piece of the
continent, a part of
the mainland.”
John Donne 1572-1631