Transcript Roche Template - El Corte Inglés

Neurodevelopmental disorders program
Basmisanil for Intellectual Disability in Down Syndrome
Xavier Liogier d’Ardhuy
Three focus areas of pRED Neuroscience
Industry-leading portfolio blazing new trails
Psychiatric
disorders
Schizophrenia
Leading glutamatergic
approaches
Neurodegenerative
disorders
Alzheimer’s disease
Parkinson’s disease
Neurodevelopmental
disorders
Autism, Fragile X,
Down syndrome
Intervene at an early stage, Advances in genetics allow to
co-develop Diagnostics tests target the disease at its cause
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Neurodevelopmental Disorders
Exploring uncharted territories
Large unmet needs
No disease modifying therapies, partially
efficacious symptomatic therapy
Emerging science
Insights into the molecular
pathophysiology of NDDs from genetics
Diseases affecting growth, development and
maturation of the central nervous system.
Tractability
Understanding of key targets and ways to
develop therapies
• Autism/Autism Spectrum Disorders (ASD)
• Genetic disorders, i.e. Fragile-X syndrome, Down
syndrome, Rett syndrome, Tuberous sclerosis
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Down syndrome - medical complications
No treatment for significant cognitive & behavioral impairments
Symptom onset over time
Infancy
Childhood
Adolescence
Adulthood
Pharmacological treatments
Developmental delays including cognitive & speech
CNS
Infantile seizures
Attention deficit/hyperactivity disorder (ADHD)
Oppositional defiant disorder (ODD)
Obsessive compulsive disorder (OCD)
Major unmet need:
agents that
improve cognitive
function and
adaptive behavior
Anxiety / depression
Cardiac
Early-onset dementia
Endocrine
EENT
Stimulants
-adrenergic agonists
Antipsychotics
SSRIs
Acetylcholinesterase inhibitors
ACEi, ARB, -blockers
Congenital heart disease
Hypothyroidism
Diabetes and obesity
Other
Anticonvulsants
Ocular abnormalities, cataracts, chronic sinusitis, chronic ear infections
Polycytemia, thrombocytopenia, thrombocytosis, leukocytosis, increased risk of leukemia
Sources: European Down Syndrome Association “Health Care Guidelines for People with Down Syndrome”; Merck Manual 2010, CDC-NCBDDD (National Center
on Birth Defects and Developmental Disabilities) and National Down Syndrome Society; Cohen WI. 2006. Current Dilemmas in Down Syndrome clinical care:
Celiac disease, thyroid disorders, and atlanto-axial instability. Am J Med Genet Part C Semin Med Genet 142C: 141-148
Levothyroxine
Oral anti-diabetic agents
Antibiotics (for infections)
Chemotherapy (for leukemia)
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Down syndrome - medical complications
No treatment for significant cognitive & behavioral impairments
Symptom onset over time
Infancy
Childhood
Adolescence
Adulthood
Pharmacological treatments
Developmental delays including cognitive & speech
CNS
Infantile seizures
Attention deficit/hyperactivity disorder (ADHD)
Oppositional defiant disorder (ODD)
Obsessive compulsive disorder (OCD)
Major unmet need:
agents that
improve cognitive
function and
adaptive behavior
Anxiety / depression
Early-onset dementia
Sources: European Down Syndrome Association “Health Care Guidelines for People with Down Syndrome”; Merck Manual 2010, CDC-NCBDDD (National Center
on Birth Defects and Developmental Disabilities) and National Down Syndrome Society; Cohen WI. 2006. Current Dilemmas in Down Syndrome clinical care:
Celiac disease, thyroid disorders, and atlanto-axial instability. Am J Med Genet Part C Semin Med Genet 142C: 141-148
Anticonvulsants
Stimulants
-adrenergic agonists
Antipsychotics
SSRIs
Acetylcholinesterase inhibitors
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Translational research in Down Syndrome
Using mouse models to learn about underlying pathophysiology
Human
genotype
Human
phenotype
Mouse
genotype
Drug
development
Mouse
phenotype
Down syndrome
Therapeutic
strategy
Ts65Dn mouse model
Muriel
Davisson
1990
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Therapeutic potential of GABAA antagonism in DS
Excessive GABA-mediated inhibition causes cognitive impairment
Excessive inhibitory (GABAergic) synaptic function in DS
Ts65Dn mouse model of DS
Control
Ts65Dn
BZDs
GABA antagonism rescues cognitive deficits
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GABAA Receptors: mediators of inhibitory
synaptic transmission
GABA
binding
site
Benzodiazepine
allosteric
binding site
•
Ligand-gated chloride channels
•
Pentamers assembled from 19 members of this family
(1-6, 1-3,1-3, , , , 1-3, )
•
GABAA positive modulators: (Valium) anxiolytic, muscle
relaxant, sedative, hypnotic and anticonvulsant agents
– however cognitive impairment
•
GABAA negative modulators: enhance cognition
– but proconvulsant and anxiogenic effects
Atack et al., 2003; Froestl et al., 2011
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GABAA 5 NAMs (Basmisanil) rescue brain
functional deficits seen in Ts65Dn mice
J NEUROSCI
Synaptic function
(Long-term potentiation)
Reverses cognitive deficit
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Jean-Baptist (JB)
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Basmisanil Clinical Development Plan Overview
Basmisanil considered
safe and well tolerated
MD in
DS
Screening
BP28947
DS PET
Ph2b- BP27832
CLEMATIS
26 wks, age 12-30
Phase 3
age 12-30
26 wks
FU
Non-Drug
BP29589
26wks, age 6-11
Non-Drug,
26wks, age 12-30
Phase 3
age 6-11
26 wks
FU
Ph2A MD
WP28760
6wk age 6-11
Hypothesis
Generating
Hypothesis Confirming Studies
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Learnings from the non-drug study in adults and
adolescents with Down syndrome
Global Scores
Adaptive Behavior Comp.
Communication
Domains
Daily Living Skills
Socialisation
 Suitable
 Confirm the AB profile
 Sensitive (age group differences)
 Stable over time
VABS II selected as one of the
primary endpoints for next studies
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Focus on Cognition and Adaptive Behavior
to demonstrate clinically meaningful outcomes
e.g. remembers 3 /10 words
in the beginning vs. 5/10
words at the end of study
Δ RBANS ≥ +2
in list tasks
Cognition
Responder
AND at least one of following
e.g. noticeable improvement in
attention span and considered
considerably more “on-task” in
workshop and home setting
Adaptive behavior
Δ VABS ≥ 7
CGI-I ≤ 3
Consistent change
e.g. identifies 10 letters of the
alphabet vs. all letters, upperand lower case plus
sometimes prints up to 10
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words
Addressing the main challenge
No single measure
currently exists that
meets all criteria for an
ideal clinical and
regulatory endpoint
that can be used to
evaluate treatment for
Down syndrome
Phenotype varies within
the same condition
The Challenge
LONGITUDINAL
NON-DRUG STUDIES
Establishing the suitability
of scales, variability,
learning
and
practice
effects
FDA AND EMA
KOLS
Obtaining
feedback/agreement on the
clinical endpoints
PATIENT-CENTERED
OUTCOME RESEARCH
Establishing what
constitutes
treatment benefit
in people with DS
NIH DOWN SYNDROME
OUTCOME MEASURES WORKING GROUP
Identifying outcome
measures for clinical
trials
The Approach
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Doing now what patients need next
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