Critical Path for Alzheimer's Disease

Overview

The Problem

More than six million Americans and 55 million persons worldwide are living with dementia. Alzheimer’s disease (AD) is the most common form of dementia and may contribute to 60–70% of cases. However, dementia describes only the end stage of Alzheimer’s disease (AD). New estimates indicate that 416 million persons worldwide are currently living with the AD disease across the disease continuum – a number driven by an estimated ~300 million individuals worldwide living with preclinical AD. As the U.S. population aged 65 and older continues to grow, so too will the number and proportion of Americans with AD or other dementias. Without meaningful and effective therapies, the number of people with confirmed Alzheimer’s disease dementia is projected to rise to nearly 13 million within the United Stated by 2050 and 153 million worldwide. This estimate does not include persons in the predementia stages of disease, which provides a window of opportunity for prevention.   

While two disease-modifying therapies (aducanumab and lecanemab) have received regulatory (FDA) approval over the last few years, there is still a critical need for continued development of novel therapeutic interventions to address the complete spectrum of people living with AD, considering the vast heterogeneity in the underlying biology and pathological progression of the disease. Challenges in clinical research and drug development include selecting the optimal patient population for evaluating novel mechanisms of action (patient stratification), ability to pick up the earliest signals of the disease (early stages of AD including pre-symptomatic), selection of the right endpoints and outcome assessments, molecular signatures of disease biology and pathology (biomarkers), treatment effect assessments, and correlations of the outcome assessments with clinical meaningfulness.  

The Solution

CPAD is a global, neutral convener, bringing together diverse stakeholders across industry, regulatory agencies, and academia within a pre-competitive forum under a data-driven, regulatory framework to accelerate therapeutic innovation in AD. 

Leveraging the intellectual brain power and wealth of scientific knowledge gained from patient-level data contributions within the CPAD consortium, we identify the most critical unmet needs in AD and use our core competencies in data management, aggregation, and analysis, to facilitate informed decision making in AD drug development.

The Impact

CPAD’s regulatory success include the development of:

  • Two clinical trial simulation tools:
    • for mild-to-moderate AD which received endorsements from EMA and FDA (2013); and  
    • for amnestic mild cognitive impairment which received a Letter of Support (LOS) from EMA (2018).  
  • Endorsement from EMA (2011) and a LOS from FDA (2015) for hippocampal volume as an enrichment biomarker in AD trials. 
  • A LOS from FDA for exploratory prognostic biomarkers in cerebral spinal fluid (CSF) analytes for enrichment in AD trials (2015).  
Patient focused icon

Addressing critical unmet needs in Patient-Focused Drug Development (PFDD) by incorporating the voice of patients, drug developers in industry and academia, and regulatory agencies

MIDD Icon

Focus on Model-Informed Drug Development (MIDD) through generation of novel, regulatory-endorsed quantitative drug development tools (DDTs) and solutions

Therapeutic trial icon

Therapeutic innovation, optimization of trial design, development of novel analytical and statistical methodologies aimed at meaningful therapies in Alzheimer’s disease

The compelling value proposition for contributing clinical trial data to CPAD included the structure of CPAD as a neutral convener and the opportunity to supplement with high-quality clinical data from other contributors, for the goal of developing regulatory-grade quantitative tools to support drug development, regulatory approvals and access.

Michael C. Irizarry
SVP & Deputy Chief Clinical Officer, Eisai & CPAD Industry Co-Director

Regulatory Successes

CPAD is currently leading the following pre-competitive working groups:

Tau-PET Harmonization Working Group FAQ Icon

Aims to validate a scale to quantify tau deposition across cohorts and tracers, which will facilitate a comparable and generalizable evaluation of the underlying biology and pathophysiology of tau deposition in the complete spectrum of AD progression, from early to late stages.

Tau-PET Surrogacy Working Group: FAQ Icon

Aims to evaluate the evidentiary considerations needed for utility and acceptance of tau deposition and changes in tau following treatment as a reasonably likely surrogate endpoint in AD.

Quantitative Modeling Working Group: FAQ Icon

Conducts quantitative analyses to better understand the underlying biology of AD and to develop disease progression models that will serve as the basis for quantitative models and clinical trial simulation tools used to facilitate informed decision making in the drug development process and optimize patient and endpoint selection, as well as the design of efficacy studies.

Letters of Support

Letter of Support for an exploratory prognostic biomarker for enrichment in AD trials FAQ Icon

The US Food and Drug Administration (FDA) issued a Letter of Support for cerebral spinal fluid (CSF) analytes Aβ1-42, total-tau, and phosphor-tau as exploratory prognostic biomarkers for enrichment in AD trials.

US FDA Letter of Support (February 26, 2015)

This letter, issued to CAMD, describes the FDA’s thoughts on early intervention in AD, and the importance of identifying patients with mild cognitive impairment (MCI) who are likely to develop further cognitive impairment within the time frame of a clinical trial, to potentially lead to therapies with greater impact. The FDA encourages the inclusion of these exploratory CSF biomarkers in clinical trials to evaluate their utility in clinical trial enrichment.

Letter of Support for low baseline hippocampal volume as an exploratory prognostic biomarker for enrichment in AD trials FAQ Icon

The US Food and Drug Administration (FDA) issued a Letter of Support for low baseline hippocampal volume (HV) measured by magnetic resonance imaging (MRI) as exploratory prognostic biomarkers for enrichment in AD trials.

US FDA Letter of Support (March 10, 2015)

This letter, issued to CAMD, describes the FDA’s thoughts on the value of measuring hippocampal atrophy over the course of a clinical trial. The FDA encourages the exploration of the possible use of low baseline HV (as measured by MRI) for the purpose of clinical trial enrichment.

Letter of Support for Model-based CT enrichment tool for CTs in aMCI FAQ Icon

CPAD Database

The database contains, but is not limited to, demographic information, APOE4 genotype, concomitant medications, and cognitive scales (MMSE and ADAS-Cog). Limited treatment-arm data and limited AD biomarker data (biofluids, tau or amyloid positron emission tomography (PET), EEG data) is available. All data has been remapped to a common data standard (CDISC SDTM v3.1.2) such that all the data can be analyzed across all studies. It is openly available to CPAD members, as well as to external qualified researchers who submit, and are approved for, a request for access. All data are fully de-identified.

Clinical Trial Simulation (CTS) Tools for AD

A quantitative clinical trial enrichment tool to help optimize clinical trial design in the pre-dementia stages of Alzheimer’s disease, using CDR-SB as the primary endpoint. The tool is based on a disease progression model, which integrates baseline hippocampal volume, the effect of patient drop-out, and relevant sources of variability.

A clinical trial simulation tool to help optimize clinical trial design for mild and moderate AD, using ADAS-cog as the primary cognitive endpoint. The tool is based on a drug-disease-trial model that describes disease progression, drug effects, dropout rates, placebo effect, and relevant sources of variability

FDA and EMA Letters and Qualifications

“The compelling value proposition for contributing clinical trial data to CPAD included the structure of CPAD as a neutral convener and the opportunity to supplement with high-quality clinical data from other contributors, for the goal of developing regulatory-grade quantitative tools to support drug development, regulatory approvals and access.”

Michael C. Irizarry
SVP & Deputy Chief Clinical Officer, Eisai & CPAD Industry Co-Director

Timeline

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CPAD’s data collection efforts have produced the best data source in the world for exploring predictive modeling and understanding how patient selection and trial design impact Alzheimer’s drug development and help us all do better and more efficient clinical trials.

Lars Lau Raket, PhD
Senior Research Director, Eli Lilly

Working Groups

Tau-PET Harmonization Working Group FAQ Icon

Due to differences in tracer properties, instrumentation, and methods of analysis, tau-PET outcome data cannot currently be meaningfully compared or combined. CPAD is leading a pre-competitive “Tau-PET Harmonization Working Group”, in partnership with leaders from industry and academia, to test and validate a harmonized scale for quantification of tau deposition that will allow comparison and generalizability across studies, cohorts and different tau radiotracers.

A harmonized tau-PET scale will improve the utility of tau-PET in various research and drug development efforts, including for trial enrichment, monitoring tau deposition over time, spatio-temporal characterization, and its use in disease-specific anti-amyloid and/or anti-tau therapeutic research and clinical trials.

Members of the Tau-PET Harmonization Working Group
Qi Guo AbbVie Samantha Budd Haeberlein Enigma Biomedical Group
Rik Ossenkoppele Amsterdam UMC Dan Abramzon Genentech
Christopher Rowe Austin Health, Melbourne, Australia Keith Johnson Harvard
Emily Collins Avid/Eli Lilly Billy Dunn Independent Advisor
Leonardo Iacarino Avid/Eli Lilly Hartmuth Kolb Janssen
Mark Mintun Avid/Eli Lilly Ziad Saad Janssen
Michael Pontecorvo Avid/Eli Lilly Suzanne Baker LBL.gov
Jessica Collins Biogen Ioannis Pappas LONI
Matthew Hutchison Biogen Oskar Hansson Lund University
Rick Hiatt Cerveau Pedro Rosa McGill
Thom Tulip Cerveau Eric Hostetler Merck
Sulantha Sanjeewa Cerveau/Enigma Biomedical Group Yuchuan Wang Merck
Yashmin Karten CPAD Gregory Klein Roche
Sudhir Sivakumaran CPAD Matteo Tonietto Roche
Antoine Leuzy CPAD & Enigma Biomedical Group Cristian Salinas Takeda
Vincent Dore CSIRO William Jagust UCSF
Arnaud Charil Eisai Gil Rabinovici UCSF
Michael Irizarry Eisai Victor Villemagne Univ. of Pittsburgh
Lars Lau Racket Eli Lilly Tammie Benzinger Washington U in St. Louis

Tau-PET Surrogacy Working Group FAQ Icon

Tau-PET Surrogacy Working Group

Efficacy in a clinical trial can be a measure of how a patient functions, feels or survives (reflecting clinical benefit), or a validated surrogate endpoint shown to predict a specific clinical benefit (both of which can result in a Traditional Approval), or a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit (resulting in an Accelerated Approval). When using biomarkers as surrogate endpoints, it’s important to note they are not a direct measure of how a patient functions, feels, or survives. They are intended to predict and reflect a clinical benefit.

Surrogate endpoints can help improve trial efficiency and regulatory decision making. Amyloid PET was used as a surrogate endpoint that is reasonably likely to predict clinical benefit, resulting in accelerated drug approvals for AD in recent years. Yet, considering the heterogeneity of disease pathology and progression in AD, it is necessary to identify and evaluate additional biological markers which can help track disease progression and treatment effects. CPAD is leading a global, pre-competitive collaborative “Tau-PET Surrogacy Working Group” of leading experts among CPAD members, academics and consultants to explore and evaluate the readiness of tau-PET as a surrogate endpoint.

Members of the Tau-PET Surrogacy Working Group
Qi Guo AbbVie Dan Abramzon Genentech
Christopher Rowe Austin Health, Melbourne, Australia Camille Vong GSK
Emily Collins Avid/Eli Lilly Gopi Ganji GSK
Leonardo Iacarino Avid/Eli Lilly Christine Bailey GSK
Michael Pontecorvo Avid/Eli Lilly Robert Lai GSK
Eric Reiman Banner Health Thomas Bonasera GSK
Robert Alexander Banner Health Keith Johnson Harvard
Daanish Ashraf Biogen Billy Dunn Independent Advisor
Matthew Hutchison Biogen Colm McGinnity IXICO
Melanie Shulman Biogen Robin Wolz IXICO
Shuang Wu Biogen Hartmuth Kolb Janssen
Thom Tulip Cerveau Ziad Saad Janssen
Nicholas Cullen CPAD Clifford Jack Mayo Clinic
Yashmin Karten CPAD Ronald C Petersen Mayo Clinic
Antoine Leuzy CPAD & Enigma Biomedical Group Yi Mo Merck
Sudhir Sivakumaran CPAD Yuchuan Wang Merck
Arnaud Charil Eisai Gul Erdemli Novartis
Kevin McDonald Eisai Suzanne Hendrix Pentara Corp
Michael Irizarry Eisai Gregory Klein Roche
Pallavi Sachdev Eisai Matteo Tonietto Roche
Lars Lau Racket Eli Lilly Anuja Neve Roche/
Genentech
Stephen Truocchio Eli Lilly Edmond Teng Roche/
Genentech
Sergey Shcherbinin Eli Lilly Susan Yule Roche/
Genentech
Pavel Balabanov EMA Cristian Salinas Takeda
Lorenzo Guizzaro EMA William Jagust UCSF
Samantha Budd Haeberlein Enigma Biomedical Group Geert Molenberghs Univ. of Hasselt
Kevin Krudys FDA Maria Pia Sormani University of Genoa
Teresa Buracchio FDA Tammie Benzinger Washington U in St. Louis

Quantitative Modeling Working Group FAQ Icon

By integrating patient-level data from high quality AD clinical trials, models will be developed to model natural AD progression for multiple cognitive and functional endpoints, as well as biomarkers. The fitted statistical models will be applied to address unmet needs at multiple points in the clinical trial design process, reducing unnecessary PET scans by screening with accessible blood-based biomarkers, optimized patient selection, and reduced trial size (and/or increased statistical power) with the help of enrichment models that predict cognitive decline using combinations of AD biomarkers. Longitudinal biomarker data will also be modeled against longitudinal cognitive trajectories to better understand the selection of biomarker-based endpoints to measure reduction in AD pathology in response to treatment.

The disease progression models will serve as the basis for clinical trial simulation tools to facilitate informed decision making in the drug development process and optimize patient and endpoint selection, as well as design of efficacy studies. The trial design models will serve to influence core clinical trial design decisions and thereby usher in the next generation of biomarker-driven clinical trials characterized by greatly improved efficiency and reduced costs.

Approach

Critical Path for Alzheimer's Disease - strengths

In partnership with C-Path’s Quantitative Medicine Program, CPAD members, and regulatory agencies (FDA, EMA), CPAD’s Quantitative Modeling Working (QMWG) and Focus Groups identify key questions and unmet needs for the generation of comprehensive statistical analysis methodologies to capture disease progression across the entire AD continuum in line with the 2018 FDA draft guidance. The disease progression models serve as the basis for optimizing clinical trial design and patient stratification, evaluation of changes in fluid and imaging biomarkers over time, treatment effects and statistical power calculations.

Members & Partners

Advisors/Collaborators FAQ Icon

Team

Klaus Romero, MD, MS, FCP
Chief Executive Officer, Chief Science Officer

Diane Stephenson, PhD
Interim Executive Director, CPAD

Yashmin Karten, MBA, PhD
Scientific Director

Antoine Leuzy, PhD
Consultant

Colleen Jacobsen
Project Manager

Eileen Priest
Sr. Project Coordinator

Mussie Akalu, MSc
Data Manager, DCC

Robert Stafford, MA
Data Management Team Lead, DCC

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