Testing treatments for Intellectual Disabilities: Lessons from Fragile X Syndrome

Dr Andrew Stanfield

Conflicts of Interest

Research grant funding from Novartis and Roche for trials in fragile X syndrome

Consultancy fees to Patrick Wild Centre from Novartis and Roche

Intellectual Disabilities

Severity IQ Approx.

Prevalence

Examples of adaptive functioning

Mild 50 - 69 1.5 – 2 % May work, may live independently but usually need some support, communication mildly affected, specific educational difficulties

Moderate 35 – 49 Marked problems in school, may develop some independence but will need a lot of support, obvious communication / language use difficulties

Severe 20 – 24 Little or no structured verbal communication, require continuous care, no awareness of personal dangers, body functions compromised

Profound <20 0.05% Severe limitation in self-care, continence, communication, mobility. Continuous and high level care.

0.5%

Begin in childhood, lifelong

A lesson from Rett Syndrome

Guy et al. Science (2007)

http://biorxiv.org/content/early/2016/06/16/049056

McRae et al (DDD study)

Fragile X Syndrome

Caused by mutation on the X chromosome leading to a lack of Fragile X Mental Retardation Protein (FMRP)

Most common inherited cause of intellectual disability in males (approx 1/4000 males, 1/8000 females)

Syndromic physical features

High rates of autism and ADHD

Figure taken from Oostra and Willemsen. Biochimica et Biophysica Acta (2009) 467-477

FMR1 knockout mouse-audiogenic seizures-inhibitory avoidance extinction -prepulse inhibition-dendritic spine morphology-synaptic protein synthesis

Rescue Strategies

Cross with 50% mGluR5 knockout

mGluR5 antagonists

Can rescue many parts of the phenotype

Levenga et al 2011

Normal

dendrite

Fragile X

syndrome

Michalon et al 2012

Clinical Trials

Why did they not work?

Why did they not work?

Is the theory wrong?

Did the drugs not actually target mGluR5?

Are mice and humans different in how the brain reacts to medications – i.e. findings don’t translate?

Was something wrong with the trials?- adequate power?- wrong dose?- too short?- participants too old?- wrong outcome measures?

Better Trial Design

Adequate Power

Mavoglurant and basimglurant trials were adequately powered

Recruitment of people with rare neurodevelopmental disorders is difficult

Mavoglurant trials recruited from ~ 35 sites over 3 years to get approx. 320 people

Scotland – ‘hub and spoke’ model

Barriers to Trial Participation

Barriers to clinical trial participation in fragile X syndrome (Eley et al, in prep)

Participant age / length of trials

Mavoglurant- 12 – 45 year olds- 12 weeks of treatment

Basimglurant- 14 – 45 year olds- 12 weeks of treatment

Participant age / length of trials

Mavoglurant- 12 – 45 year olds- 12 weeks of treatment

Basimglurant- 14 – 45 year olds- 12 weeks of treatment

Preclinical Studies- Oldest started Rx at 4 weeks- Duration typically > 2weeks- (Mouse lifespan ~ 2 years)

Participant age / length of trials

test longer treatment durations in younger people

test shorter treatment durations in older animals

Peter Kind lab

Combining Interventions?

Sonya Campbell

Outcome Measures

Primarily behavioural to date

Based largely on parental report

Susceptible to placebo effect

Outcome Measures

i) feasible and acceptable to the target population

ii) shown to capture impairment in the population under study

iii) capable of capturing variation in the target population

iv) clinically meaningful or a marker for something clinically meaningful

v) reliable

vi) objective

vii) capable of demonstrating changes over time

Outcome Measures

Eye tracking Functional MRI

Sue Fletcher-Watson Andrew McKechanie

Lessons learned?

Preclinical data should inform trial design

Consider combination studies

Pre-recruitment work with participants / families

Consider long single blind placebo run-in

Measure objective changes and later outcome

Acknowledgements

Sonya Campbell

Sarah Eley

Sue Fletcher-Watson

Peter Kind

Andrew McKechanie

Sally Till

Everyone who has taken part in the studiesFragile X Society

RS Macdonald Charitable Trust

Baily Thomas Charitable Fund

Novartis

Roche

www.patrickwildcentre.com

@PWCentre The Patrick Wild Centre