Neurodevelopmental disorders program Basmisanil for Intellectual Disability in
Neurodevelopmental disorders program Basmisanil for Intellectual Disability in Down Syndrome Xavier Liogier d’Ardhuy
Three focus areas of p. RED Neuroscience Industry-leading portfolio blazing new trails Psychiatric disorders Schizophrenia Leading glutamatergic approaches Neurodegenerative disorders Alzheimer’s disease Parkinson’s disease Intervene at an early stage, co-develop Diagnostics tests Neurodevelopmental disorders Autism, Fragile X, Down syndrome Advances in genetics allow to target the disease at its cause 2
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 Tractability Understanding of key targets and ways to develop therapies Diseases affecting growth, development and maturation of the central nervous system. • Autism/Autism Spectrum Disorders (ASD) • Genetic disorders, i. e. Fragile-X syndrome, Down syndrome, Rett syndrome, Tuberous sclerosis 3
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 Levothyroxine Oral anti-diabetic agents Ocular abnormalities, cataracts, chronic sinusitis, chronic ear infections Antibiotics (for infections) Polycytemia, thrombocytopenia, thrombocytosis, leukocytosis, increased risk of leukemia Chemotherapy (for 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 4
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 Anticonvulsants Stimulants -adrenergic agonists Antipsychotics SSRIs Acetylcholinesterase inhibitors 5
Translational research in Down Syndrome Using mouse models to learn about underlying pathophysiology Human genotype Human phenotype Down syndrome Mouse genotype Drug development Mouse phenotype Therapeutic strategy Ts 65 Dn mouse model Muriel Davisson 1990 6
Therapeutic potential of GABAA antagonism in DS Excessive GABA-mediated inhibition causes cognitive impairment Excessive inhibitory (GABAergic) synaptic function Ts 65 Dn mouse model of DS in DS Control Ts 65 Dn BZDs GABA antagonism rescues cognitive deficits 7
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 (a 1 -6, 1 -3, , 1 -3, ) • GABAA positive modulators: (Valium) anxiolytic, muscle relaxant, sedative, hypnotic and anticonvulsant agents – however cognitive impairment • GABAA negative modulators: enhance cognition Atack– et al. , Froestl et al. , and 2011 anxiogenic effects but 2003; proconvulsant 8
GABAA 5 NAMs (Basmisanil) rescue brain functional deficits seen in Ts 65 Dn mice J NEUROSCI Synaptic function (Long-term potentiation) Reverses cognitive deficit 9
Jean-Baptist (JB) 10
Basmisanil Clinical Development Plan Overview Basmisanil considered safe and well tolerated MD in DS Screening BP 28947 Ph 2 b- BP 27832 CLEMATIS DS PET Phase 3 age 12 -30 26 wks, age 12 -30 Non-Drug BP 29589 26 wks, age 6 -11 Non-Drug, 26 wks, age 12 -30 Ph 2 A MD WP 28760 Phase 3 age 6 -11 26 wks FU 6 wk age 6 -11 Hypothesis Generating Hypothesis Confirming Studies 11
Learnings from the non-drug study in adults and adolescents with Down syndrome Global Scores Adaptive Behavior Comp. Communication Domains Daily Living Skills Socialisation ü Suitable ü Confirm the AB profile ü Sensitive (age group differences) VABS II selected as one of the primary endpoints for next studies ü Stable over time 12
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 13 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 NIH DOWN SYNDROME Establishing what constitutes treatment benefit in people with DS OUTCOME MEASURES WORKING GROUP Identifying outcome measures for clinical trials The Approach 14
Doing now what patients need next 15
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