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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