Role of Biomarkers and Clinical Markers in patient selection and monitoring in PD. Ken Marek Institute for Neurodegenerative Disorders Feb 22, 2018

Transcription

1 Role of Biomarkers and Clinical Markers in patient selection and monitoring in PD Ken Marek Institute for Neurodegenerative Disorders Feb 22, 2018

2 Disclosure Co-founder of Molecular Neuroimaging LLC PET and SPECT imaging services Owner of invicro Consultant GEHC, Lilly, Merck, Piramal, Pfizer, Sanofi, Roche, LTI, Oxford Biomedica, UCB, Denali, Takeda

3 PD - Major Challenges for PD Therapeutics Progression in inevitable Motor and non-motor disease features Heterogeneity is a hallmark of disease Subsets of PD with likely different etiology, disease course, response to therapy Approx 50% of PD patients will start DA meds in 12 months Degeneration begins long before symptoms arise - Where does PD begin, when does PD begin, how does PD progress during the pre-diagnostic period

4 Imaging Biomarkers - What Standardization of biomarker acquisition and analyses Assay methods Imaging Acquisition Reliability of the measure Test retest reliability Multi-center poolability Reproducible over time Quality control of the measure Established criteria for data analysis Numbers of subjects not evaluable Limitations of the measure Sensitivity to change Dynamic range - floor effect

5 Biomarkers - Who Age, Gender, Ethnicity Stage of disease - defined by motor symptoms - defined by cognitive impairment - defined by biomarker profile Genetic cohort SNCA, LRRK2, GBA Disease meds PD Progression Developing a Biomarker-defined cohort

6 Biomarker outcome Biomarkers - When Natural History of Neurodegenerative Disorders Preclinical Prodromal Symptomatic Diagnosis Time

7 Clinical markers Cognition Behavior Depression Apathy Anxiety Autonomic Constipation Bladder Sexual Cardiac Olfaction Sleep - RBD SENSOR Tech Passive activity Motor analysis Speech Sleep Environment Biomarkers for PD Imaging Phenotomics SPECT/PET-Dopamine-DAT/VMAT2 SPECT/PET-FDG, MIBG, synuclein, tau, amyloid, inflammation, synaptic density MRI-DTI, Free Water, Functional MRI Nigral Ultrasound Genetics (Synuclein, LRRK2, GBA) DNA RNA Methylation IPS cells Laboratory (Omics, focused analytes) CSF Blood Tissue

8 Cohort DAT Imaging Biomarker focused cohorts MR Imaging Genetic Blood CSF IPSC Wearables Tissue PPMI X X X X X X X S4 X X X X X X PDBP X X X Denopa X X X X Harvard Biomarker study China PD Biomarker Personalized Parkinson Project X X X X X X X X X X X PARS X X X X X

9 Rate of SWEDD is higher in earlier Stages of PD PPMI

10 DAT Deficit Scans without evidence of dopaminergic deficit SWEDD

11 PRECEPT study - FOLLOWUP IMAGING AND CLINICAL OUTCOMES BY SWEDD STATUS AT BASELINE Mean (SD) for Change in [ 123 I] ß-CIT and UPDRS, Percent (CI) for need for DA treatment. * indicates p < 0.01

12 Requirements for Biomarker Infrastructure Parkinson s Progression Markers Initiative Beginning in March 2007, MJFF worked with industry and clinical and biomarker researchers to identify how we can continue to promote biomarker discovery efforts, accelerate and improve biomarker verification studies, and establish biomarkers strategies for disease modifying PD trials Specific Data Set Appropriate biomarker defined population (PD, healthy, prodromal, genetic) Correlative samples (DNA, RNA, Bood, CSF, IPSC DAT Imaging, Amyloid imaging, MRI/DTI/RS Standardization Uniform collection of data and samples Uniform storage of data and samples Strict quality control/quality assurance Access/Sharing Data available to research community data mining, hypothesis generation & testing Samples available for studies

13 PPMI Study MJFF- Michael J. Fox Foundation for PD Research PPMI Steering Committee ISAB- Industry Scientific Advisory Board Clinical Core Statistics Core CSOC- Clinical Study Oversight Committee PPMI Sites Imaging Core Biorepository Bioinformatics Core Biospecimen access Patient advisory committee Genetics core Bioanalytics Core Data access Prodromal cores Path Core Tissue access

14 PPMI FUNDING PARTNERS PPMI is sponsored and partially funded by The Michael J. Fox Foundation for Parkinson s Research. Other funding partners include a consortium of industry players, non-profit organizations and private individuals. 14

15 PPMI STUDY DETAILS: SYNOPSIS STUDY POPULATION ASSESSMENTS/ CLINICAL DATA COLLECTION BIOLOGIC COLLECTION Shared Data and Biosamples» 423 de novo PD subjects (newly diagnosed and unmedicated)» 196 age-and gendermatched healthy controls» 64 SWEDD subjects» 67 individuals with prodromal PD (hyposmic, RBD)» 550 LRRK2 or GBA (PD manifest and nonmanifesting family members)» Motor assessments» Neuropsychiatric/neurob ehavioral testing» Autonomic, olfaction, sleep DaTSCAN, AV133, Amyloid, DTI/RS MRI Sensor Data» DNA, RNA» Serum, whole blood and plasma collected at each visit; urine annually» CSF collected at baseline, 6mo 12 mo and then annually» IPSC in subset» Samples aliquotted and stored in central biorepository» Post mortem tissue > 1,500,000 Data downloads > 100 Sample requests via BRC Ancillary study development» 50 Synuclein (PD manifest and non-manifesting family members)» Subjects followed for 5 to 13 years

16 Eligibility for P-PPMI Hyposmic Subjects RBD Subjects DAT imaging 80% Mild to moderate DAT 20% Min to No-DAT Min to No-DAT Eligible for PPMI Not eligible for PPMI

17 HOW DOES GENETIC RECRUITMENT WORK? The WRI process can be scaled and customized

18 PD Clinical Outcomes TIME TO START PD MEDICATIONS MDS-UPDRS TOTAL 5 yr

19 DaTscan SBR 4 yr

20 CSF α-synuclein re-analysis in 2016 by ELISA in (1) PD and healthy subjects until 36 months follow-up (2) in prodromal subjects until 12 months follow-up *BioLegend total asyn ELISA

21 MDS-UPDRS/DAT TOTAL SAMPLE SIZE MDS UPDRS TIME Mean (SD) Change From Baseline Power 1 Year 7.5 (11.6) 80% 90% 2 Year 10.4 (12.9) 80% 90% TIME Mean (SD) Change From Baseline Power 1 Year -11% (15.1) 80% 90% 2 Year -17% (16.1) 80% 90% Reduce By 100% DAT Imaging Reduce By 100% Reduce by 50% Reduce by 50% Reduce by 25% Reduce by 25%

22 Imaging Biomarkers Beyond DA Modality Ligand Target Utility in Clinical Studies SPECT DaTSCAN Dopamine Transporter Use at all sites eligibility criteria and progression marker MRI DTI DATA IN PD, POSSIBLE VALUE IN PD Fractional Sub-study defined by camera exploratory data for disease anisotropy (FA) progression PET DTZB, AV133, PE2I VMAT2 Monoamine marker -not available for multi-site PET FDG Glucose Metabolism Possible progressive changes in cognitive and motor patterns Ultrasound Substantia Nigra Likely not progression marker PET FBP/FBB/Flute Amyloid Possible progressive changes in cognitive SPECT MIBG Cardiac sympathetic function Likely not sensitive progression marker MRI Free Water/Resting State Early finding suggest PD/Heathy difference Pilot data/limited data in PD PET/SPECT TSPO, P2X7 Inflammation Inflammatory changes possibly early PET/SPECT SV2a Synaptic integrity Early and progression PET/SPECT Tau Tau Progression of cognition Early development PET/SPECT alpha-synuclein Early development PET/SPECT LRRK2/GBA Early development

23 PPMI FLUID BIOMARKERS UPDATE Analyte/Platform Source Investigator ApoA1 and EGF Plasma Alice Chen-Plotkin, MD, MSc IGF-1 Serum Maria Teresa Pellecchia, PhD Gcase activity and sphingolipids Whole blood, CSF, and plasma PI: Pablo Sardi, PhD, Sanofi mrna and mirna sequencing RNA from whole blood PI: Kendall van Keuren-Jensen, PhD, TGen Foundation PI: Kendall van Keuren-Jensen, PhD, TGen Foundation Neurofilament Light Chain YKL-40 Whole blood, CSF, and plasma Whole blood, CSF, and plasma TREM2 Whole blood, CSF, and plasma Catechoalmines CSF Thomas Kremer, PhD, Roche IPS cells Skin, blood CDI

24 Imaging DA ligand with improved power Assay - exploratory AMP Discovery Baseline and 6 month changes longitudinal assessment, sample size Biomarkers Challenges/Opportunities Data to develop clinical outcomes - phenoconversion, cognition Integration of Genetics Data driven biomarker strategies to establish PD subsets who Develop clinical outcomes (cognition, gait, autonomic) Progression at different rates (fast vs slow) May respond to specific therapy

25 Wearable Challenges/Opportunities Implementing widely in PPMI Integration into clinic visit Retention and compliance Multiple cohorts Managing data Open source data Developing Key goals Assess prodromal PD cohorts Assess progression Assess drug response Comparison with in clinic visit

26 Verily Watch and bed sensor Passive collection of Data US based Shared data Roche Wearable Plans for 2018 Phone Ap Passive and Active collection of Data EU based Shared Data

27 PPMI Data Sharing

28

29 PPMI Long-term f/u at home FOUND - Goal for all subjects to enroll Opportunity to continue to communicate with subjects and acquire follow-up information Environmental questionnaire Path core Goal for all subjects to enroll Path core will continue contact subjects to plan for post-mortem Novel assessments Wearables Ongoing phone/home visits

30 Pre-synaptic Dopaminergic Imaging 123 I ß-CIT- DAT 18 F AV-133- VMAT2 18 F-DOPA- AADC Healthy Parkinson disease

31 PPMI SITES UNITED STATES» Emory University (Atlanta, GA)» John Hopkins University (Baltimore, MD)» University of Alabama at Birmingham (Birmingham, AL)» Parkinson s Diseases and Movement Disorders Center of Boca Raton (Boca Raton, FL)» Boston University Medical Center (Boston, MA)» Northwestern University (Chicago, IL)» University of Cincinnati (Cincinnati, OH)» Cleveland Clinic (Cleveland, OH)» Baylor College of Medicine (Houston, TX)» Institute of Neurodegenerative Disorders (New Haven, CT)» Columbia University Medical Center (New York, NY)» Beth Israel Medical Center (New York, NY)» University of Pennsylvania (Philadelphia, PA)» Oregon Health Sciences University (Portland, OR)» University of Rochester (Rochester, NY)» University of California at San Diego (San Diego, CA)» University of Washington / VA Puget Sound (Seattle, WA)» Banner Sun Health Research Institute (Sun City, AZ)» The Parkinson s Institute (Sunnyvale, CA)» University of South Florida (Tampa, FL) EUROPE/MIDDLE EAST» Attikon University Hospital (Athens, Greece)» Hospital Clinic de Barcelona (Barcelona, Spain)» University of Innsbruck (Innsbruck, Austria)» Paracelsus-Elena Klinik (Kassel, Germany)» Imperial College London (London, UK)» Pitié-Salpêtrière Hospital (Paris, France)» University of Salerno (Salerno, Italy)» Hospital Universitario Donostia (San Sebastian, Spain)» Tel Aviv Sourasky Medical Center (Tel Aviv, Israel)» Norwegian University of Science and Technology (Trondheim, Norway)» University of Tuebingen (Tuebingen, Germany) AUSTRALIA» Macquarie University (Sydney, Australia) 31

32 NEED for BIOMARKERS Improve diagnostic accuracy (enrich a study population) Identify subsets that might develop clinical outcomes Identify subsets that might respond to therapy Assess disease progression Evaluate efficacy of disease modifying therapeutic Measurement prior to onset of motor symptoms Phase 2 - provide an efficacy signal to increase confidence for subsequent Phase 3 Phase 3 studies - enrich the study sample and provide objective outcomes of that reflect clinical benefit

33 PPMI Deliverables Operational SOPs, Enrollment/retention, CSF, DAT, DTI Tools to establish biomarker-defined PD cohorts IPD, prodromal, genetic Data to inform study design longitudinal assessment, sample size Data to examine baseline and early change predictors of progression Data to develop clinical outcomes - phenoconversion, cognition Data to develop biomarker outcomes imaging, biofluids, genetic risk Data to establish PD subsets who Develop clinical outcomes (cognition, gait, autonomic) Progression at different rates (fast vs slow) May respond to specific therapy

34 PPMI ENROLLMENT GROUP Consented Enrolled (n) Withdrawn Active Complete PD Subjects Healthy Controls SWEDD Subjects Prodromal -Hyposmic Prodromal-RBD LRRK2 PD Cohort LRRK2 UA Cohort SNCA PD Cohort SNCA UA Cohort GBA PD Cohort GBA UA Cohort PD Registry UA Registry TOTAL