Critical Path for Alzheimer’s Disease (CPAD)

CPAD IMPACT

Stephen P. Arnerić, Executive DirectorVolker D. Kern, Senior Project Manager

www.c-path.org/cpad2

TRANSITION TO CRITICAL PATH FOR ALZHEIMER’S DISESEASE

Why

▪ To more clearly convey the consortium’s mission to the Alzheimer disease (AD) research andhealthcare communities

Forward Path

▪ Create a forum to be leveraged across the entire AD community with the goal to foster enhanceddata sharing amongst all stakeholders

▪ Develop a quantitative understanding of disease progression across the AD continuum (pre-symptomatic to dementia) with focus on biomarker dynamics, based on acquisition andavailability of data, and the ultimate goal to enable a more-informed pathway to the design ofDrug Development Tools that accelerate the delivery of treatments to effectively treat AD

www.c-path.org/cpad

FDA AD DRAFT GUIDANCE

February 15, 2018

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www.c-path.org/cpad

OVERVIEW OF THE AD DRUG DEVELOPMENT PIPELINE

J. Cummings et al., 2018

112 agents in 135 AD Trials in Phases 1, 2, and 3

[https://clinicaltrials.gov/]

A rich source of data that hasnot yet been made available to improve our understanding of AD progression

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www.c-path.org/cpad5

WHY DEVELOPING BETTER WAYS TO MEASURE PATIENT COGNITION AND FUNCTION IS CRITICAL!

https://www.gbhi.org/about/

CRITICAL REASONS

▪ Unmet need for effective treatments

▪ Economic burden to Healthcare Systems Worldwide

▪ A new therapeutic for AD has not been approved in over a decade!

▪ Any trial in AD is dependent upon the outcome measures used, and must require the necessary sensitivity and specificity -especially true for the “pre-symptomatic” stage of the disease

▪ Need for early detection assessments to detect those “at risk” for cognitive decline

www.c-path.org/cpad

FOCUS

▪ Data standards

▪ Clinical trial simulation tools from actionable data

▪ Disease progression models

▪ Biomarkers

▪ Clinical outcome assessment instruments

CRITICAL PATH INSTITUTE

Fifteen global consortia collaborating with 1,450+ scientists and 84 organizations

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www.c-path.org/cpad

CPAD QUALIFIES DRUG DEVELOPMENT TOOLS FOR CLINICAL DRUG TRIALS TREATING DEMENTIA

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www.c-path.org/cpad

MEMBERS, STAKEHOLDERS & CONTRIBUTORS

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C-Path staff advancing CPAD

Stephen P ArnerićExecutive Director

Volker D KernSenior Project Manager

Klaus RomeroDirector of Clinical Pharmacology and

Quantitative Medicine

Daniela J ConradoAssociate Director of

Quantitative Medicine

Jackson BurtonAssociate Program

Director, Quantitative Medicine

Robert StaffordSenior Data Specialist,

Data Programming Team Lead

All other C-Path support staff…

Pharmaceutical Industry

AbbVie Inc.BiogenBoehringer Ingelheim Pharmaceuticals Inc.EisaiEli Lilly and CompanyF. Hoffman La RocheJohnson & Johnson Pharmaceutical Research & Development LLCMerck, Sharp & Dohme Corp.Novartis Pharmaceuticals CorporationPfizer Inc.Takeda Pharmaceuticals

Government and Regulatory Agencies

European Medicines Agency (EMA)National Institute on Aging (NIA)National Institutes of Health (NIH)National Institute of Neurological Disorders and Stroke (NINDS)U.S. Food and Drug Administration (FDA)

Non-profit Research Organizations

Alzheimer’s AssociationAlzheimer’s Drug Discovery FoundationAlzheimer’s Research UKCHDI FoundationUsAgainstAlzheimer’s

www.c-path.org/cpad

CPAD’S GOVERNANCE STRUCTURE

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* Stephen P. Arnerić, PhD, CPAD Executive Director, Critical Path Institute** Michael Gold, MS MD, AbbVie, Vice President Neuroscience Development

COORDINATING COMMITTEE

C-Path*

Executive

Director

Industry**

Co-Director

Government Agencies

Regulatory Agencies

Academic Experts

Patient Advocacy Organizations

Philanthropies

Pharmaceutical Industry

Research Foundations

Advisors

CPAD WORKING GROUPS

www.c-path.org/cpad

CPAD TEAMS/WORKING GROUPS

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▪ Imaging Biomarker Team

▪ Modeling & Simulation Team

▪ Fluid Biomarker Team

▪ Digital Drug Development Tools Team

▪ Ad-hoc/limited-duration Teams

Create Drug Development Tools for Alzheimer disease and related dementias

Common Data Standards

Integrated, actionable Databases

Quantitative Modeling

Aims for Regulatory Acceptance of Biomarkers/Endpoints

Advancing regulatory science through cross-disciplinary collaboration

www.c-path.org/cpad11

2008

2010

2011

2012

2013

2015

2018

……. Coalition Against Major Diseases launched on August 13, 2008

……. First integrated database of anonymized, patent-level clinical data for AD

……. First AD CDISC standards (v1.0); v2.0 published in 2013

……. AD biomarker qualified by EMA

……. AD Clinical Trial Simulation Tool endorsed by EMA and FDA

……. FDA Letters of Support for AD biomarkers

……. Consortium name change to Critical Path for Alzheimer’s Disease

……. Funding received to curate & expand the database with up to 10 prioritized Clinical Trials

KEY CONSORTIUM ACHIEVEMENTS

The Consortium was rebranded in January 2018 to convey the current Focus and Mission

On August 13, 2018, the consortium celebrated its 10th Anniversary

Leveraging CPAD’s core strengths for the future

……. EMA Letter of Support for aMCI Model

……. 4 AD trials from Servier integrated into database

2017 ……. Concise Informed Consent Form published

……. Joined GAAIN

www.c-path.org/cpad

RECENT CONSORTIUM-LED PUBLICATIONS

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26 Publications Neville et al., Alz. Res., 2015

www.c-path.org/cpad

569 Total Applicants

350 Distinct Institutions

from

Industry

Abbvie; Allergan; AstraZeneca; Biogen; Biomarkable; CoreLab; Daewong; Eisai; GE Healthcare; IBM; Johnson & Johnson; Lundbeck; Merck; NeuroCog; Novartis; Pentara; Pfizer; Siemens; SAS

Academia & Foundations

Amherst College; Arizona State Univ.; Bill & Melinda Gates Foundation; CHDI Foundation; Duke Univ.; Fraunhofer Institute; Goethe Univ.; Harvard Univ.; Karolinska Institute; King’s College London; Michael J Fox Foundation; Rockefeller Univ.; Seoul National Univ.; Univ. of Oxford; Yale Univ.

Government & Other

NIH; Neurology Today; Gigatrust

CPAD DATABASE UTILIZATION (as of September 30, 2018)

303

7 6

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131

84USE BY SECTORSAcademia: 259Pharmaceutical: 167Other: 70Non-profit: 32Government: 11

USE BY REGIONNorth America: 56%South America: 1%Europe: 24%Africa: 1%Asia: 16%Australia: 2%

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28 Clinical Trials6,995 Anonymized Patients

www.c-path.org/cpad

AD CLINICAL TRIAL SIMULATION (CTS) TOOL FOR MILD-TO-MODERATE AD – REGULATORY PATH

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▪ On June 12, 2013 the FDA determined the CTS tool was “Fit for Purpose”

▪ On September 19, 2013 the EMA determined the CTS tool was “Qualified for Use”

www.c-path.org/cpad15

DEMONSTRATED UTILITY OF THE CLINICAL TRIAL SIMULATION TOOL IN MILD-TO-MODERATE AD

Crossover Parallel

91 weeks 78 weeks

• Better power

• ~50% cost savings• 13 weeks less time

Balancing power, sample size, and duration, given varying effect magnitudes

www.c-path.org/cpad

97 Total Applicants

72 Distinct Institutions

from

Industry

AbbVie; Astellas; Biogen; Boehringer Ingelheim; Denali Therapeutics; Eisai; Eli Lilly; Genentech; GlaxoSmithKine; H. Lundbeck; Hoffmann-La Roche; Merck; Pfizer; Regeneron; Trigemina

Academia

Emerson College; Imperial College London; Karolinska Institute; London School of Economics; McGill University; PondicherruUniversity; Universidad Nacional del Litoral; University of Alabama; University of Arizona; University of Bordeaux; University of Manchester; University of Rochester; University of Texas; USC; Washington University

Government, Non-Profit, & Other

FDA; HHS; Medical Genetics Center; RTI; Certara; dMed Biopharmaceuticals; ETHOS Health Communications; IBM; PentaraCorp.; Pleroo Research

CPAD CTS TOOL UTILIZATION (as of September 30, 2018)

USE BY SECTORSAcademia: 42Pharmaceutical: 34Other: 14Non-profit: 3Government: 4

USE BY REGIONNorth America: 64%South America: 1%Europe: 18%Africa: 3%Asia: 14%Australia: 1%

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61

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1

17

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www.c-path.org/cpad

MCI PROGRESSION MODEL – EMA

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Letter of Support

October 30, 2018

LINK

www.c-path.org/cpad

DIGITAL DRUG DEVELOPMENT TOOLS

WHAT

• Data (signal output) collected from a biosensor that measures a biological response

HOW

• Continuous physiological monitoring with devices (wearables/smart phones, clothing, implants/ ingestibles, remote biosensors)

WHY

• Improve our understanding of real-time changes in FUNCTION during the progression of life in health and disease

• Improve the efficiency of AD clinical trials to accelerate the delivery of novel treatments

• Deliver precision care

Biometric Monitoring Devices (BMDs) as Regulatory-Accepted DDTsFor Specific Contexts-of-Use

KEY CONTEXTS-OF-USE

• Patient Selection

• Understand disease progression

• Measure treatment responses

• Deliver precision care

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www.c-path.org/cpad

THE VISION: DEVELOP AN END-TO-END ALZHEIMER DISEASE MODEL ACROSS THE DISEASE CONTINUUM

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How and when do these factors interact to influence disease progression?

…and treatment response?

www.c-path.org/cpad20

PATIENT SELECTION AND EVALUATION FOR CLINICAL TRIALSRequires a Comprehensive Assessment =

Patient & Physician Reported Outcomes• Cognition (MMSE, CDR-SB, etc.)

• Behavior (sleep/mood scales – QOL-AD, GDS)

• Motor function (UDPRS)

• Sensation (NRS, etc.)

• Balance & Coordination

• Autonomic

SymptomsSigns

Observer/Performance OutcomesGenetics Examination Temperature

Vision Forgetfulness Infection Mobility

GI/Lung/ Kidney EKG EEG/

Glucose tests function HR/BP Sleep/ Fatigue

Imaging Modalities

Real World Data

Wearable & Remote BMDs

www.c-path.org/cpad

CONTINOUS MEASUREMENT IS RELEVANT AND CRITICAL!

Which patient is rapidly declining?

Courtesy of Dr. Jeff Kaye

baseline 12 months 24 months

• These data highlight the challenge of infrequent cross-sectional assessments

• Understanding vector trends (the relevant 90+%)in individual continuous performance would be more reflective of true long-term trends in performance/health maintenance, i.e., Aligned with Precision Medicine Objectives!

• GOAL: Validate BMD Assessments as DDTs to identify the “right patients”, enhance Clinical Trial efficiencies, and enable tailored treatment approaches

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www.c-path.org/cpad

GOAL: A GLOBAL INTEROPERABLE AD DATA REPOSITORY OF SHARED DATA

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