Critical Path for Alzheimer's Disease

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.

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

CPAD’s regulatory success includes 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).

CPAD’s approach is key to the success of the program. To read more, click here.

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.

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.

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.

• Abbvie
• Alzheimer’s Association
• ASCNeuron
• Biogen
• Cerveau
• CHDI Foundation
• Clario
• Eisai
• Invicro
• Ixico
• Johnson & Johnson
• Life Healthcare
• Lilly
• Novartis
• Novo Nordisk
• Rainwater Charitable Foundation
• Roche
• TauRX
• Unlearn

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

• Antoine Leuzy, PhD (Enigma Biomedical Group)
• Ioannis Pappas, PhD (LONI/GAAIN, USC)
• Brian Gordon, PhD (Washington U in St. Louis)
• Chengjie Xiong, PhD (Washington U in St. Louis)
• Duygu Tosun-Turgut, PhD (UCSF)
• Guoqiao Wang, PhD (Washington U in St. Louis)
• Nusrat Rabbee, PhD (Alladapt)
• Rhoda Au, PhD (Boston University)
• Robert Alexander, MD (Banner Health)
• Sheng Luo, PhD (Duke University)
• Vijaya Kolachalama, PhD (Boston University)
• Yan Li, PhD (Washington U in St. Louis)
• Hartmuth Kolb, PhD (Enigma Biomedical Group)