Prospects for improving cognition in people with Down syndrome. Omar Khwaja MD PhD Translational Medicine Leader F.Hoffman-La Roche AG

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1 Prospects for improving cognition in people with Down syndrome Omar Khwaja MD PhD Translational Medicine Leader F.Hoffman-La Roche AG

2 Basic facts at a glance Founded 1896 in Basel, Switzerland Founding families still hold majority stake Employing 80,000 people Currently active in 150 countries on all continents Leadership in research-focused pharmaceuticals 8 million Swiss Francs on R&D in 2011 Focused on treatments where there is a high unmet need Early CNS drug development increasingly focused on neurodevelopmental conditions Down syndrome Fragile X syndrome Autism Spinal Muscular Atrophy

3 Down Syndrome: a high unmet medical need Challenges in independence with day-to-day activities, that include: Education Leisure Travel Home Employment

4 Early intervention for a more independent life Greater independence in daily living activities Improved social skills

5 Down Syndrome High unmet medical need Affects over 30,000 newborns in the US, Japan, China and 5 EU countries Chronic condition 23,000 5,000 Worldwide incidence of DS 5,430 22,500 No treatment available that improves cognitive function Incidence 4,000 3,000 2,000 1,000 3, , US EUG5 Japan China UK Germany France Spain Italy US UK DE FR SP IT JP CH 1:800 1:1000 1:800 1:700 1:700 1:1200 1:1000 1:800 Methodology: UNDP birth cohort data has been used to calculate total DS incidence per country

6 Ts65Dn: a mouse model of Down Syndrome Mirrors the human condition Down syndrome Alterations Ts65Dn mouse Trisomy 21 Behaviour Hyperactivity Attention deficits Learning and memory deficits Neuromorphological Neuronal density Abnormal dendritic spines Size of temporal cortex, hippocampus and cerebellum Proliferation and survival of cells in the dentate gyrus

7 Learning and memory require balance between inhibition and excitation in the brain GABA Glutamate

8 In Down syndrome there appears to be excessive inhibition by GABA neurons GABA Glutamate

9 About the investigational Roche drug RG1662 Being investigated for enhancing cognition and memory functions in Down Syndrome Mechanism of action: GABA system Safety and tolerability in healthy volunteers studies allow for clinical trials in adults with Down Syndrome

10 Roche is currently conducting 2 trials BP25543 Drug study in people with DS BP25612 Non-drug study in people with DS

11 Study BP25543 Objectives Primary Objective Assess the safety and tolerability of RG1662 in young adults with Down Syndrome Secondary Objective How is the drug handled by the body? (pharmacokinetics) Exploratory objectives Explore the effect of RG1662 on cognition Explore biomarkers

12 Overview of Study Design Emory University Duke University Rush University UCSD University of Colorado University of Arkansas Johns Hopkins University

13 Study Design Overview Cohort 3 Screenin g Baseline (TBD or placebo) Safety Committee Review Cohort 2 Screenin g Baseline (160mg or placebo twice daily) Safety Committee Review Screenin g Baseline Treatment Period (80mg or placebo twice daily) Follow-up 7 weeks 1 week ~5 weeks 2 weeks

14 Safety Review Safety reviewed by Investigators, the sponsor and an Independent Safety Committee Stopping rules in place

15 Selected Inclusion Criteria Males and females aged 18 to 30 with Down Syndrome Able to give assent Have verbal skills to participate in assessments For allowed medications, treatment stable for 8 weeks prior to randomization

16 Selected Exclusion Criteria Major Depressive Disorders not adequately controlled by an SSRI or SNRI Evidence or clinical diagnosis of dementia Thyroid dysfunction not adequately controlled or stabilized on treatment Abnormal cardiovascular function History of convulsions/epilepsy (with the exception of a single isolated uncomplicated febrile seizure), severe head trauma or CNS infections EEG seizure pattern at baseline

17 Exploratory Efficacy Assessments Attention Reaction times via a computerized test Memory Immediate memory Short term memory Delayed memory Language Fluency Associations Adaptive Function

18 Study BP25612 Objectives (Non-Drug Study) Primary Objective To assess the performance and reliability of scales and measures of Cognitive function Memory Adaptive behavior Activities of Daily Living Impact on Caregivers

19 Overview of Study Design France, Spain, UK and US University of Arizona Duke University 90 participants Teenagers and adults with DS years Study duration = up to 27 weeks Approximately 3 visits

20 Summary As people with Down syndrome live longer healthier lives the major challenges they face are in education, employment and independent living Mouse models of Down syndrome help scientists understand the brain biology of Down syndrome Selectively decreasing GABA inhibition rescues the memory and learning problems in DS mouse models RG1662 is under study for safety and tolerability in people with DS

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