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Center for Global Research Data

Development of model-informed drug development tools for Alzheimer’s Disease

Lead Investigator: Sudhir Sivakumaran, Critical Path Institute
Title of Proposal Research: Development of model-informed drug development tools for Alzheimer’s Disease
Vivli Data Request: 7587
Funding Source: Critical Path Institute is supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) and is 54.2% funded by the FDA/HHS, totaling $13,239,950, and 45.8% funded by non-government source(s), totaling $11,196,634. Support for the CPAD consortium is also provided by consortium members, including AbbVie Inc., Bioclinica, Biogen, Eisai, Eli Lilly and Company, F. Hoffman La Roche, GE Healthcare, Imeka, IXICO plc., Janssen Research & Development LLC, Merck, Sharp & Dohme, Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals, Unlearn.AI, Inc, Alzheimer’s Association, Alzheimer’s Research UK, and the Cure Huntington’s Disease Initiative (CHDI) Foundation.
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Recent estimates indicate that the number of people worldwide living with dementia is expected to rise to 139 million cases in 2050. Alzheimer’s disease (AD) accounts for an estimated 60% to 80% of cases of dementia. Despite the looming public health crisis due to AD, therapies available in the U.S. for the last two decades only treated the symptoms of the disease. There is a pressing need for effective therapeutic interventions and there is a growing interest in intervening earlier in the disease process. This requires a robust understanding of disease progression across all stages of disease. The Critical Path for Alzheimer’s Disease (CPAD) is a nonprofit, pre-competitive consortium of the Critical Path Institute (C-Path). CPAD focuses on integrating precompetitive patient-level data from high quality Alzheimer’s disease (AD) clinical trials and observational studies, and transforming those data into actionable knowledge to advance novel regulatory-grade quantitative drug development tools. We develop mathematical models of disease progression that will enable a user to simulate clinical trials in Alzheimer’s disease. The trial simulations will allow the user to identify the appropriate patients for a trial as well as understand how the trial should be designed in terms of number of patients. The simulations are meant to help companies design their trials more effectively, reducing trial cost and time, and reduced patient burden.

We plan to develop mathematical models of disease progression that will enable a user to simulate clinical trials in Alzheimer’s disease. Modelling approaches for disease progression models will utilize mixed-effects modeling as it readily has several advantages including incorporation of fixed observable effects to explain variability, incorporation of random unexplained variability between subjects with flexibility to include additional hierarchies (inter-study variability), flexibility in handling repeated measurements within individuals with different amount of and different spacing of time points, and ability to easily generate predicative simulations through Monte Carlo sampling. We will incorporate Clinical Outcomes Assessments and biomarkers (dependent variables). The selection of these dependent variables will be informed by the availability of relevant information, as well as the clinical meaningfulness, interpretability, as well as regulatory and drug development relevance of each proposed dependent variable. We will include apolipoprotein E4 allele (APOE4), sex, baseline age, baseline severity, other genetic and demographic data, as well as multiple biomarker candidates as covariates. The trial simulations will allow the user to identify the appropriate patients for a trial as well as understand how the trial should be designed in terms of number of patients. The simulations are meant to help companies design their trials more effectively. The trial simulation tool will benefit patients by reassuring them that they will be able to enroll in more efficiently designed clinical trials in the future.

Requested Studies:

Effect of LY3202626 on Alzheimer’s Disease Progression as Measured by Cerebral ¹⁸F-AV-1451 Tau-PET in Mild Alzheimer’s Disease Dementia
Data Contributor: Lilly
Study ID: NCT02791191
Sponsor ID: 16223

Effect of γ-Secretase Inhibition on the Progression of Alzheimer’s Disease: LY450139 Versus Placebo
Data Contributor: Lilly
Study ID: NCT00594568
Sponsor ID: 7666

Effect of LY450139 a y-Secretase Inhibitor, on the Progression of Alzheimer’s Disease as Compared With Placebo
Data Contributor: Lilly
Study ID: NCT00762411
Sponsor ID: 11271

Open-Label Extension for Alzheimer’s Disease Patients Who Complete One of Two Semagacestat Phase 3 Double-Blind Studies (H6L-MC-LFAN or H6L-MC-LFBC)
Data Contributor: Lilly
Study ID: NCT01035138
Sponsor ID: 5930