OVERVIEW OFSEP: COHORT INNOVATION DAY 105

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1 : Observatoire Français de la Sclérose en Plaques ITMO Santé publique Lyon Sandra Vukusic, M.D., Ph.D. Professor of Neurology Lyon University Hospital OVERVIEW AT A GLANCE > Neurology > Multiple Sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and MS-related diseases > Coordination: Prof. Sandra Vukusic > Consortium: Claude Bernard Lyon 1 University, Lyon University Hospital & EDMUS Foundation > Funding: ANR & ARSEP Foundation contact@ofsep.org KEY FACTS & FIGURES > Inclusions and follow-up on-going Nearly 50,000 enrolled patients (50 % of French MS patients) > Unlimited follow-up period ( 600,000 person-years) > Collection of clinical and MRI data in all centers using EDMUS in daily clinical practice and willing to participate (to date: 32) > Biobanking: serum, plasma, DNA, PBMC, urines, CSF, faeces, depending on the subgroup of patients > Linkage in progress to French administrative databases (SNIIRAM ) is a nationwide cohort that aims at improving the clinical, biological and imaging systematic longitudinal follow-up of patients with MS in France. Beside its research objectives, it should also increase the quality, efficiency and safety of patients care. About 50,000 patients are followed in 32 MS clinics and networks using the European Database for Multiple Sclerosis (EDMUS) software. It is open both to academic and industrial researchers. First Patient Included (EDMUS) Biobank open for scientific projects creation MRI database open for scientific projects Clinical database open for scientific projects Positioning > is one of the largest MS cohort worldwide, it is the only one with a standardized and systematic collection of clinical, imaging and biological data > includes four nested cohorts of specific interest: Clinically Isolated Syndromes (CIS), Radiologically Isolated Syndromes (RIS), Primary Progressive MS course (PPMS) and NMOSD > is currently involved in an international collaboration with four other registries (BigMS data project) for harmonizing datasets and studying the feasibility of common research projects > is already collaborating with industrials, through phase IV clinical studies, data transfer or analysis COHORT INNOVATION DAY 105

2 LEADERSHIP Bruno BROCHET, M.D., Ph.D., professor of Neurology at Bordeaux-Segalen University and Head of the department of Neurology at the Bordeaux University Hospital MS specialist and creator of the MS Clinic of Bordeaux Researcher in the mixed research unit Inserm/Bordeaux University Neuroinflammation : Imaging and treatment of Multiple Sclerosis MS clinical activity and research since 25 years Network > President scientific advisory board LFSEP (Ligue Française contre la Sclérose en plaques) and member scientific advisory board ARSEP (Association Française contre la Sclérose en plaques) > Past president of the Club Francophone de la Sclérose en Plaques > Steering committee member of LabeX TRAIL > Co-President of the Scientific committee, Member of the Executive committee of and of the Steering committee Current collaborations: > Most French MS centers > Harvard Medical School, MA (USA) > Kessler Foundation, NJ (USA) > BICAMS consortium (Brief International Cognitive Assessment for MS), an international initiative to recommend and support a cognitive assessment that is brief, practical and universal More than 100 papers in peer-reviewed journals Sandra VUKUSIC, M.D., Ph.D., Professor of Neurology at the Lyon University Hospital Neurologist and epidemiologist working since 1998 on the description of the natural history of MS, prognosis, vaccines and pregnancy Network > Member of the Scientific Committee of the TYSEDMUS study > Member of the executive board of the Société Francophone de la Sclérose en Plaques and of the Collège des Enseignants de Neurologie > Member of the International Committee for Clinical Trials in MS (ECTRIMS and NMSS) > Member of the ARSEP scientific committee (Association pour la Recherche sur la Sclérose en plaques), of the Société Française de Neurologie. Current collaborations > PI of industrial clinical trials in MS Michel CLANET, Head of Department of Neurosciences, Toulouse University Hospital Involved in the field of Multiple Sclerosis for over 30 years Leader of the department of Neurosciences of the Toulouse University Hospital. Member of the research unit Inflammatory diseases of the central nervous system: mechanisms and therapy Network > Past president of ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) > President of the French Neurological Society in 2011 > Current president of the National University Council in Neurology > Member of the steering committee of the French Observatory of Multiple Sclerosis Creation the french network on genetic susceptibility in MS (REGENSEP) Currently participating to an international trial of autologous mesenchymal stem cells in the treatment of MS SCIENTIFIC NETWORK & MANAGEMENT gathers a network of French neurologists, neuro-radiologists and biologists is divided into three working groups including experts from all centers in France: > Clinical Working Group >> Leader: Prof. Jérôme de Sèze, neurologist (Strasbourg) >> + 1 neurologist per Clinical center > Biological Working Group >> Leader: Prof. David Laplaud, neurologist (Nantes) >> + 1 neurologist and 1 biologist of each Biological Resource Center (BRC) > Neuro-Imaging Working Group >> Co-leaders: Prof. François Cotton (Lyon) and Prof. Vincent Dousset (Bordeaux), neuro-radiologists >> + Neurologist and neuro-radiologists from Imaging centers and engineers from INRIA (Rennes) 106 COHORT INNOVATION DAY

3 PROJECT DESCRIPTION SCIENTIFIC OBJECTIVES Describe the MS population included in the cohort Define a minimal standardized dataset for the clinical, imaging, therapeutic, medico-economic data and biological samples to harmonize data collection in MS population Conduct research on priority projects (nested cohorts) Maintain and expand the nationwide cohort of patients with MS in France Enrich the existing clinical data with imaging and medico-economic data and with biological samples Allow all researchers worldwide to access the collected data and biological samples (research project submitted to ) INNOVATIVE SCIENTIFIC FEATURES Almost half of French MS patients are included in the database Clinical data collected since 1992, standardized collection since 2013 Data collected routinely during medical visits Separate anonymised clinical, MRI and biological databases linked by a national unique identifier METHODOLOGY QUALITY EDMUS software enforces a level of data consistency and automatic cross-check of data. EDMUS uses a standardized nomenclature, a requisite for efficient data exchange and analysis Standardized clinical data, MRI protocol and biological samples have been defined Biological Resource Centers are all certified is working to address various aspects of quality management through a future ISO standard certification COHORT INNOVATION DAY 107

4 DESIGN, METHODOLOGY & TIMELINE Data analyses First Patient Included (EDMUS) creation Clinical database open for Scientific Projects Biobank open for Scientific Projects MRI database open for Scientific Projects Recruitment objectives: Sites: Inclusion criteria: all patients consulting at least once in a clinical center All clinical centers using EDMUS in daily practice and willing to participate (to date: 32), Biological Resource Centers (to date: 8), and nearly 100 MRI centres expected Multiple Sclerosis (MS), Neuromyelitis optica spectrum diseases (NMOSD) and MS-related diseases Exclusion criteria: none of the inclusion criteria INCLUSION COLLECTION Database: Sociodemographic data, MS history (neurological events and disability scale), disease modifying treatments history MRI exam Biobank: blood, urine, CSF, faeces FOLLOW-UP: Database: Clinical: at every visit (usually at least once a year) MRI: brain at least once every 3 years ; spinal cord at least once every 6 years Biobank: 1 kit at inclusion for patients in nested cohorts 108 COHORT INNOVATION DAY

5 DATABASE & BIOBANK CONTENTS DATABASE Clinical database EDMUS is a software dedicated to MS that allows to collect demographic and longitudinal clinical data, prospectively and retrospectively, at each neurologist s visit and can be used for both medical follow-up and research purposes A minimal set of data was implemented in June 2013 in order to standardize data collection Core clinical data collected by cohort correspond to following items: > Personal data > Background & socio-economics: Domestic status, employment status, family, other disease > History of neurological episodes: Date, type, semiology > History of clinical assessment: Date of exam, EDSS (Kurtzke), EGS (EDMUS Grading Scale) > History of irreversible disability: Disability levels reaching dates > MRI > History of disease-modifying treatments: Name, start date, stop date, reason for stopping Magnetic Resonance Imaging database A standardized brain and spinal cord acquisition protocol defined and validated by a group of experts. A minimal MRI follow-up consisting in at least one brain MRI every three years and one spinal cord MRI every six years Routinely acquired MRIs are centralized in a unique MRI platform in Rennes (Shanoir) MRI manufacturers have agreed to implement an box on any new or updated MRI machine Medico-economic database Linkage to national medico-economic databases (SNIIRAM in particular) is in progress BIOBANK Originality > a large scale nationwide biobank with 500 patients sampled per year Scientific objective > Biobank aims to carry out future studies on MS and related diseases (Neuromyelitis Optica) >To date, 6 nested cohorts in the are on-going. Theses cohorts have specific objectives requesting biospecimens analysis Samples > Serum, plasma, DNA, PBMC & urines > Additional samples (optional) : cerebrospinal fluid & faeces > Number of samples per patient at the inclusion: >> Serum: 10 aliquots >> Plasma: 6 aliquots >> Total blood for DNA: 2 samples >> PBMC: 2 to 4 aliquots >> Urines: 2 to 6 aliquots > Total number of samples expected : 50,000 blood (plasma, serum, blood, PBMC) and 5,000 urines samples COHORT INNOVATION DAY 109

6 TECHNICAL MODALITIES & SPECIFICATIONS ORGANIZATION Biobank spreads over 8 certified BRCs linked to clinical sites which enroll patients Biological sample collection, treatment and short-time storage is organized and performed by BRCs Procedure harmonization is ensured by team through a specific protocol for biobanking precising processes for sample collection, treatment and storage Each BRC provides the long-term conservation of biological samples. For safety reasons, all samples stored at -80 C are duplicated in two separate containers Each biological sample is identified with a patient-specific barcode SPECIFICATIONS Patients already included in cohort and presenting one of the following specificities are being sampled: Clinically Isolated Syndrome (CIS), Radiologically Isolated Syndrome (RIS), NeuroMyelitis Optica (NMO) also known as Devic s disease, Primary-progressive multiple sclerosis (PPMS), Progressive Multifocal Leukoencephalopathy (PML), Acute Disseminated Encephalomyelitis (ADEM) First sampling in november 2013 Biobank is supervised by the biological working group lead by Pr David Laplaud and Nathalie Dufay. Regrouping neurologist committed in sampling and BRC leaders, biological working group aims at set-up the multi-site biobanking, defined sampling strategies and follow biobank enrollment. Protocol for the biological samples collection exists A minimum dataset for each sample is available comprising Edmus ID (to link with clinical database), BRC ID (to follow sample in each site), patient information, date of the written inform consent, basic clinical data and basic data on treatment at sampling date. Two times per year, export on biobank database is performed to implement general database Label of quality: All BRCs have been AFNOR certified, according to French biological research center standard NF S Biobank procedures have been developed by the biological working group in order to apply standardized methods for sample collection, treatment and conservation (Standard Operating Procedure) biological samples are available 110 COHORT INNOVATION DAY

7 BIOLOGICAL SAMPLE COLLECTION & ACCESS Biological specimens Origin Quantity available per aliquot No. of aliquots No. of patient expected to be sampled per year Storage conditions At Baseline before treatment : Serum Blood (dry tubes) 500 µl C Plasma Blood (EDTA tubes) 500 µl C PBMC Blood (CPT tubes) 10x10 6 cells/ml 2 to C DNA Whole blood not available Half at 4 C & half at -20 C Urines Urines 500 µl 2 or C Cerebrospinal Fluid (CSF) Lumbar Puncture 500 µl C CSF cells CSF 200 µl C Faeces Faeces 2-3 g C BIOBANK SAMPLE ACCESS MODALITIES A charter has been drawn up to govern relationships between and any persons using the cohort resources, in accordance with both ethical guidelines for the collection of human products, laws and regulations governing the collection of samples, their treatment and storage, and all related provisions Biological samples, including DNA are accessible to academic as well as to industrial research teams Specific biological samples access will be granted upon a collaborating request form for research projects available on website Biological samples can be transferred to academic or private teams according to modalities defined in a material transfer agreement Biological samples are shareable with a foreign company BIOLOGICAL SAMPLE ANALYSES Projects are already on-going on the biobank to: > Find biomarkers that predict the evolution of the disease in early years according to immunological treatments received > Patient risk stratification > Improve disease-specific antibody detection, determine its diagnostic added value, its predictive value DNA extractions are performed by Genethon which is specialized in processing samples for DNA extraction COST A financial estimation of the biological samples is in progress A price list of the cost of each biological sample is not yet available COHORT INNOVATION DAY 111

8 RESEARCH COLLABORATION OPPORTUNITIES Proof of concept Translational research > Investigation of diffusion tensor imaging metrics of deep grey matter nuclei and their potential association with mobility and neuropsychological function > Characterization of late onset ( 50 years) of neuromyelitis optica and neuromyelitis optica spectrum disease, and to analyze their predictive factors of disability and death Pre-clinical Phase I Phase II > Optimization of aquaporin-4 (AQP4) antibody detection and assessment of the influence of the increased sensitivity of the assay on the demographic and disease-related characteristics of a group of AQP4-Ab-negative patients Clinical development > Determine the prognostic value of intrathecal synthesis in a cohort of patients with relapsing-onset MS taking into consideration demographic and imaging parameters. > Definition of standards for routine MRI follow-up > Characterization of the development and natural history of contrast-enhanced lesions by weekly following relapsing remitting MS patients Phase III Phase IV Product approval Outcomes research > Real-life use of a dedicated drug: Observational follow-up of patients treated in France > Paediatric MS: evaluation of pronostic factors of socioprofessional performances in young adults > Survival estimation in MS patients and compare mortality with that of the French general population > Assessment of rituximab as a maintenance therapy in refractory neuromyelitis optica. > Evaluation of the impact of early redosing of natalizumab after delivery on the risk of post-partum relapses in women with very active multiple sclerosis > Evaluation of the efficacy of mitoxantrone on clinical and neuroradiological parameters of patients who had a relapse of neuromyelitis optica spectrum BIBLIOGRAPHY Translational research > Leray, E., et al., Excess Mortality in Patients with Multiple Sclerosis Starts at 20 Years from Clinical Onset: Data from a Large-Scale French Observational Study. (2015). PLoS ONE (10) > Cavallari, et al., Microstructural Changes in the Striatum and Their Impact on Motor and Neuropsychological Performance in Patients with Multiple Sclerosis. (2014). PLoS ONE (9) > Collongues, et al., Characterization of neuromyelitis optica and neuromyelitis optica spectrum disorder patients with a late onset. (2014). Multiple Sclerosis Journal (20) > Marignier, R., et al., Aquaporin-4 antibody-negative neuromyelitis optica: Distinct assay sensitivity-dependent entity. (2013). Neurology (80) Clinical development > Moroso, A., et al., Does cerebrospinal fluid analysis add predictive value to magnetic resonance imaging for long term irreversible disability in patients with early multiple sclerosis? (2015). Journal of the Neurological Sciences (354) > Cotton, F., et al.,, a nationwide cohort of people with multiple sclerosis: Consensus minimal MRI protocol. (2015). Journal of Neuroradiology (42) > Hannoun, S., et al., Weekly multimodal MRI follow-up of two multiple sclerosis active lesions presenting a transient decrease in ADC. (2015). Brain and Behavior (5) Outcomes research > Collongues N., et al., Efficacy of rituximab in refractory neuromyelitis optica., (2015). Multiple Sclerosis Journal. Vukusic, S., et al. Natalizumab for the prevention of post-partum relapses in women with multiple sclerosis. (2015). Multiple Sclerosis Journal (21) > Cabre, P., et al., Efficacy of mitoxantrone in neuromyelitis optica spectrum: clinical and neuroradiological study. (2013). Journal of Neurology, Neurosurgery & Psychiatry (84) 112 COHORT INNOVATION DAY

9 RIC-MEL: Network for Research and Clinical Investigation on Melanoma ITMO Santé publique Nantes Prof. Brigitte DRENO Professor of Dermatology, Chairman of the Department of Dermatology, Nantes Hospital, Director of the Cancer Research Center of Nantes University Hospital, Director of the Biotherapy Clinical Investigation Center (Inserm 0503) and of the GMP Unit of Cell and Gene Therapy OVERVIEW AT A GLANCE > Onco-dermatology: Melanoma > All patients with melanoma > Coordinated by Prof. B. DRENO and Prof. C. LEBBE > Nantes University Hospital sponsorship > Funded by CeNGEPS and industrial partners > Key words: Cancer - Melanoma - Database - Epidemiology - Translational research - Clinical trials Prof. Céleste LEBBE Professor of Dermatology, Head of the Skin Cancer Unit in the Department of Dermatology, Saint-Louis Hospital, Paris, Coordination of clinical research on melanoma in Saint Louis Hospital, Paris, Coordination of a platform of melanoma experimental models in Inserm U976 KEY FACTS & FIGURES > Status: on-going, inclusion started in March 2012 > No completion date is defined > Around 2,000 enrolled expected patients per year > 14,316 patients included on December 17 Th, 2015 > Follow-up from inclusion until death > National multicentric cohort: 41 General Hospitals, 6 centers de lutte contre le cancer (Cancer Centers) and 1 Hôpital d Instruction des Armées (Army Hospital) Aims of the RIC-Mel network are to promote translational research, to optimize the achievements of clinical trials and to support basic research. Aim of the RIC-Mel database is to give a permanently updated mapping of melanoma treated in France with the key information needed for any research projects First patient included 2013 First data analysis (industrial partnership) 2014 Second and Third Data Analysis (HAS request and industrial partnership) Positioning > The RIC-Mel database is linked to the clinico-biologicoradiological database MELBASE dedicated to metastatic melanoma stage IV and unresectable stage III (settingup by Saint-Louis hospital, Paris. Coordinated by Prof. C. LEBBE and Prof. B. DRENO) > To date, the RIC-Mel cohort is the only one in France to take the census of the active file of melanoma patients > Currently, four partnerships with pharmaceutical companies are on-going > The RIC-Mel database aims to be opened to academic and new industrial patnerships COHORT INNOVATION DAY 113