treating an ultra-rare condition: clinician-led

Treating an ultra-rare condition: clinician-led repurposing for

Wolfram syndrome

Timothy Barrett

University of Birmingham

Birmingham, UK

Findacure scientific conference

London 2017

t.g.barrett@bham.ac.uk

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

www.euro-wabb.org

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

£20,000

£40,000

£60,000

£80,000

£100,000

£0

£20,000

£40,000

£60,000

£80,000

£100,000

£120,000

£140,000

£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