Neurodevelopmental disorders program Basmisanil for Intellectual Disability in Down Syndrome

1. Neurodevelopmental disorders programBasmisanil for Intellectual Disability in Down Syndrome Xavier Liogierd’Ardhuy

2. Three focus areas of pRED NeuroscienceIndustry-leading portfolio blazing new trails Neurodevelopmental disorders Neurodegenerative disorders Psychiatric disorders Autism, Fragile X, Down syndrome Alzheimer’s diseaseParkinson’s disease Schizophrenia Advances in genetics allow to target the disease at its cause Leading glutamatergic approaches Intervene at an early stage, co-develop Diagnostics tests

3. Neurodevelopmental DisordersExploring 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 maturationof the central nervous system. Tractability • Autism/Autism Spectrum Disorders (ASD) • Genetic disorders, i.e. Fragile-X syndrome, Down syndrome, Rett syndrome, Tuberous sclerosis Understanding of key targets and ways to develop therapies

4. Down syndrome - medical complicationsNo treatment for significant cognitive & behavioral impairments Symptom onset over time Infancy Childhood Adolescence Adulthood Pharmacological treatments CNS Developmental delays including cognitive & speech Major unmet need: agents that improve cognitive function and adaptive behavior Anticonvulsants Stimulants -adrenergic agonists Antipsychotics SSRIs Acetylcholinesteraseinhibitors ACEi, ARB, -blockers Levothyroxine Oral anti-diabetic agents Antibiotics (for infections) Chemotherapy (for leukemia) Infantile seizures Attention deficit/hyperactivity disorder (ADHD) Oppositional defiant disorder (ODD) Obsessive compulsive disorder (OCD) Anxiety / depression Early-onset dementia Cardiac Congenital heart disease Endo-crine Hypothyroidism Diabetes and obesity EENT Ocular abnormalities, cataracts, chronic sinusitis, chronic ear infections Other 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

5. Down syndrome - medical complicationsNo treatment for significant cognitive & behavioral impairments Symptom onset over time Infancy Childhood Adolescence Adulthood Pharmacological treatments CNS Developmental delays including cognitive & speech Major unmet need: agents that improve cognitive function and adaptive behavior Anticonvulsants Stimulants -adrenergic agonists Antipsychotics SSRIs Acetylcholinesterase inhibitors Infantile seizures Attention deficit/hyperactivity disorder (ADHD) Oppositional defiant disorder (ODD) Obsessive compulsive disorder (OCD) 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

6. Translational research in Down Syndrome Using mouse models to learn about underlying pathophysiology Down syndrome Ts65Dn mouse model Muriel Davisson 1990

7. Therapeutic potential of GABAA antagonism in DSExcessive 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

8. 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 (a1-6, 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

9. GABAAa5 NAMs (Basmisanil) rescue brain functional deficits seen in Ts65Dn mice J NEUROSCI Reverses cognitive deficit Synaptic function (Long-term potentiation)

10. Jean-Baptist (JB)

11. Basmisanil Clinical Development Plan Overview Basmisanil considered safe and well tolerated MD in DS Screening BP28947 Ph2b- BP27832 CLEMATIS 26 wks, age 12-30 26 wks FU Phase 3 age 12-30 DS PET Non-Drug BP29589 26wks, age 6-11 Phase 3 age 6-11 26 wks FU Non-Drug, 26wks, age 12-30 Ph2A MD WP28760 6wk age 6-11 Hypothesis Generating Hypothesis Confirming Studies

12. 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) VABS IIselected as one of the primary endpoints for next studies • Stable over time

13. Focus on Cognition and Adaptive Behaviorto demonstrate clinically meaningful outcomes • e.g. remembers 3 /10 words in the beginning vs. 5/10 words at the end of study • AND at least one of following • e.g. noticeable improvement in attention span and considered considerably more “on-task” in workshop and home setting • e.g. identifies 10 letters of the alphabet vs. all letters, upper- and lower case plus sometimes prints up to 10 words Δ RBANS ≥ +2 in list tasks Cognition CGI-I ≤ 3 Δ VABS ≥ 7 Responder Adaptive behavior Consistent change

14. 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 syndromePhenotype varies within the same condition Establishing the suitability of scales, variability, learning and practice effects Longitudinal non-drug studies FDA and EMA KOLs Obtaining feedback/agreement on the clinical endpoints NIH Down Syndrome Outcome Measures Working Group Patient-centered outcome research Establishing what constitutes treatment benefit in people with DS Identifying outcome measures for clinical trials The Challenge The Approach

15. Doing now what patients need next