1. CAMD and Critical Path Institute Introduction: Accelerating drug development through regulatory science Diane Stephenson, Ph.D. Executive Director, CAMD Critical Path Institute

2. Critical Path Institute Consortia Coalition Against Major Diseases UNDERSTANDING DISEASES OF THE BRAIN Critical Path to TB Drug Regimens TESTING DRUG COMBINATIONS Multiple Sclerosis Outcome Assessments Consortium DRUG EFFECTIVENESS IN MS Polycystic Kidney Disease Consortium NEW IMAGING BIOMARKERS Patient-Reported Outcome Consortium DRUG EFFECTIVENESS Electronic Patient-Reported Outcome Consortium DRUG EFFECTIVENESS Predictive Safety Testing Consortium DRUG SAFETY Seven global consortia collaborating with 1,000+ scientists and 41 companies  Biomarkers  Clinical Outcome Assessment Instruments  Clinical Trial Simulation Tools  Data Standards 2

3. C-Path Online Data Repository MSOAC 3 Published Dec 2013 www.cdisc.org/therapeutic

4. Coalition Against Major Diseases: Tools to Advance Effective Treatments for Alzheimer’s and Parkinson’s Disease 4 Government/Regulatory participants Non-profit research members Industry members Not listed: Numerous Key opinion leaders/academic experts

5. Alzheimer’s Disease: the High Unmet Need for New Therapies 5 High risk and increasing cost for AD drug development Lack of biomarkers for decision making Huge uncertainty in design of clinical trials Highly variable subpopulations recruited into randomized clinical trials Inadequate outcome measures for assessing efficacy of drugs in predementia stages ProblemGapCAMD Approach Regulatory endorsed clinical trial simulation tool Regulatory biomarker qualification for enrichment in randomized clinical trials Innovative/sensitive clinical outcome assessment for efficacy of novel drug candidates No effective therapy for modifying disease progression

6. CAMD AD clinical trial simulation tool: First regulatory endorsed disease model 6 “Model-based drug development was one of the goals defined in FDA’s 2004 Critical Path Initiative report, and this new tool sets the stage for applying new technologies to accelerating medical product development,” Janet Woodcock, FDA

7. 7 Nine companies 24 trials ~6500 Patients total Data first had to be remapped in order to be pooled Modeling depends on Data!

8. CAMD Recognizes Teva for Their Data Contribution to Parkinson’s Disease. Teva received an award for being the only member organization to contribute clinical trial data for Parkinson’s disease to CAMD. This data is critically enabling for our PD biomarker team and our PD modeling efforts. Watch this space!.

9. Alzheimer’s Disease: the High Unmet Need for New Therapies 9 High risk and increasing cost for AD drug development Lack of biomarkers for decision making Huge uncertainty in design of clinical trials Highly variable subpopulations recruited into randomized clinical trials Inadequate outcome measures for assessing efficacy of drugs in predementia stages ProblemGapCAMD Approach Regulatory endorsed clinical trial simulation tool Regulatory biomarker qualification for enrichment in randomized clinical trials Innovative/sensitive clinical outcome assessment for efficacy of novel drug candidates No effective therapy for modifying disease progression

10. Pre-dementia Clinical Outcome Assessment (pCOA) Tool Project 10 Objective: Advance through a formal regulatory path a composite clinical outcome assessment tool as a primary outcome measure for pre-dementia AD trials Impact: Regulatory accepted / qualified clinical outcome measure to be applied across targets and industry stakeholders

11. Alzheimer’s Disease (AD) Stages Risk factors; family history, old age, ApoE4 genotype, TBI, mutations No symptoms, or subtle cognitive deficits (memory complaints) Emerging biomarker evidence of AD pathology Mild cognitive impairment (MCI) Amnestic Mild Cognitive Impairment (aMCI) - episodic memory deficits aMCI combined with biomarker evidence of AD pathology = Prodromal AD AD diagnosis based on clinical symptoms; cognitive deficits & dementia of the AD type Biomarker evidence of AD pathology may increase specificity of diagnosis (?) Cognitive, Functional & Behavioral deficits Mild Moderate Severe Current diagnosis & treatment Cognitive Impairment MCI / Prodromal AD Symptoms Memory complaints Pre-Symptomatic No apparent symptoms Pre-DementiaDementia Johan Luthman 11

12. How to Measure Deficits in the Pre-Dementia Stages of AD? Cognitive, Functional & Behavioral deficits Mild Moderate Severe Current diagnosis & treatment Cognitive Impairment MCI / Prodromal AD Symptoms Memory complaints Pre-Symptomatic No apparent symptoms Pre-DementiaDementia Established Instruments to measure cognition lack sensitivity & responsiveness in early stages of the AD disease process –The regulatory standard Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) developed for more advanced stages of disease –In Mild, Prodromal & Presymptomatic AD, ceiling/floor effects of ADAS-Cog limit the ability to detect and follow the disease progression Johan Luthman 12

13. Efforts to Develop Improved Clinical Outcome Measure Instruments Individual industry & academic efforts have proposed more sensitive and responsive instruments in early stage AD Some components (“items”) of currently used Instruments, especially cognitive measures, are more sensitive in earlier stages of AD (e.g., delayed word recall, orientation, word recognition) Leading proposals include items from ADAS-Cog, CDR-SB and MMSE as a Composite Clinical Endpoint emphasizing cognitive measures of performance Proposals are based on selection of key items from existing Instruments to develop a new composite clinical score Two general approaches: Improved weighting of ADAS-Cog items, Additional content to ADAS-Cog with items from other instruments (CDR-SB, MMSE etc.) Johan Luthman 13

14. Composite Endpoints Presented at ADNI PPSB Data Mining Session April 2012 ADAS-Cog MMSE CDR-SB AVLT FAQ Nandini Raghavan, Janssen 14

15. Pathway for New Composite and Cognition Instrument 1) Various Composite & Cognition Scores developed by Industry and Academic Groups Eisai, AZ, Janssen, ADAS-Cog Plus (Dan Mungas), Merck, etc. 2) ADNI PPSB Clinical End Points Working Group 1.Mapping proposals from #1 2.Identifying all available databases (e.g., prior MCI trials) for validation 3.Selecting candidate Instrument(s) for Mild, Prodromal, and pre- symptomatic AD to move to #3 Harmonization of Efforts Regulatory Qualification 3) CAMD (Critical Path Institute): pCOA Project 1.Data analyses on candidates selected in #2 2.Submission Qualification request to FDA and EMA 3.Aim for approved new Instrument (as primary or secondary EP) 2008-2013 2012-2014 2013-2016 15

16. FDA issues draft guidance on early AD: alignment with pCOA 16 Feb 2013 “Because many of the assessment tools used to measure functional or global impairment in patients with dementia have not been validated for use in these early stage patients, we consider the use of a composite scale, validated in early stage patients to assess both cognition and function as a single primary efficacy outcome measure, to be appropriate.”

17. EMA recognizes need for improvements in AD 17 Three major issues have been important for assessment of recent and future clinical trial protocols in AD and other dementias: 1. New research diagnostic criteria are used in clinical trials for different stages of AD, 2. The potential use of several biomarkers in the different stages of drug development, 3. The use of appropriate outcome measures with adequate clinical relevance to be used at any stage of the disease continuum.

18. CAMD pCOA Project Progress to Date Project Concept Proposal Letter of Intent to FDA Letter of Intent to EMA Aug 2, 2013 Mar 26, 2013 Aug 5, 2013 Project Concept Proposal Mar 26, 2013 Response from FDA Response from EMA Oct 23, 2013 Oct 28, 2013 CAMD Launch meeting ADNI PPSB data mining session April, 2012 April 16-17, 2013 FDA and EMA are collaborating in qualification across all stages 18

19. Graded evaluation of a clinical outcome measure  Statistically significant effect  Effect size  Clinically meaningful effect No clear consensus on a single definition for clinically meaningful difference in randomized controlled trials Multiple perspectives:  Patient (Patient reported outcome – PRO)  Caregiver  Clinician  Statistician  Payer  Healthcare economist  Investor  Regulator  Etc. What is Clinically Meaningful Effect? 19

20. Critical for Success: Aligning across consortia 20 Improved outcome measure

21. CAMD sharing learnings from AD across CNS diseases 21 Parkinson’s disease Multiple Sclerosis (MSOAC) Traumatic Brain Injury ALS Neuropsychiatric conditions

22. Acknowledgements: CAMD pCOA team (stage 1) 22 Alzheimer’s Association—Maria Carrillo, Dean Hartley AFA—Eric Sokol AstraZeneca—Kristin Hannesdöttir, Tina Olsson Boehringer Ingelheim—Mark Gordon, David Brill, Jana Podhorna Bristol-Myers Squibb—Jesse Cedarbaum, Rob Berman Critical Path Institute—Diane Stephenson, Ann Robbins, Stephen Joel Coons CROnos—Pamela Keenan Eisai—Veronika Logovinsky, Andy Satlin, Ira Do, Martin Rabe, Jinping Wang, Johan Luthman Eli Lilly—Richard Mohs, Alette Wessels, Robin Pitts Wojcieszek, Janice Hitchcock Eric Siemers FDA—Ashley Slagle, Marc Walton Janssen—Gary Romano, Nandini Raghavan, Michael Ropacki, Jerry Novak Medical Care Corp—Dennis Fortier, Rod Shankle Merck—David Hewitt, Bach Yen Nguyen, Tamra Goodrow Novartis—Richard Meibach, J Michael Ryan Pfizer—Rachel Schindler, Brian Harvey Ad hoc: Suzanne Hendrix, Pete Snyder, Paul Maruff, Bob Stern

23. Acknowledgements 23 C-Path Staff Martha Brumfield, CEO Lynn Hudson, CSO Steve Broadbent, COO Klaus Romero, Director, Clinical Pharmacology Stephen Joel Coons, Executive Director, PRO Consortium Data Team Jon Neville, Marty Cisneroz, Bob Stafford CAMD Industry Co-director: Mark Gordon, Boerhinger Ingelheim C-Path gratefully acknowledges the support of the Tucson Community Robin Shane, CAMD Project Coordinator Hemaka Rajapaske, CAMD Senior PM Ann Robbins, regulatory consultant