THE COALITION AGAINST MAJOR DISEASES: TOWARD U.S. FDA QUALIFICATION OF HIPPOCAMPAL VOLUME AS A BIOMARKER FOR ENRICHMENT IN CLINICAL TRIALS FOR PRE-DEMENTIA STAGES OF ALZHEIMER'S DISEASE

Abstract

The development of therapeutic agents for pre-dementia stages of Alzheimer's disease (AD) poses the challenge of selecting homogeneous cohorts of individuals for clinical trials. Trial enrichment via prognostic biomarkers provides one means of doing so. In pre-dementia patients, hippocampal atrophy is associated with progression to dementia. CAMD is pursuing regulatory qualification of baseline intracranial volume-adjusted hippocampal volume (ICV-HV) as an enrichment biomarker in pre-dementia trials, supported by a model-based analysis, through the development of a quantitative description of disease progression. To assess the utility of ICV-HV as a prognostic biomarker for clinical trial enrichment, patient-level data from three sources – the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2 observational studies, and the Investigation Into Delay to Diagnosis of Alzheimer's Disease With Exelon (InDDEx) clinical trial – have been standardized to the Clinical Data Interchange Standards Consortium (CDISC) therapeutic-area standards for AD. Briefing documents and face-to-face meetings have been held with the US FDA to finalize the proposed Context of Use Statement for the biomarker, as well as the intended statistical analysis plan. The analysis dataset, consisting of pre-dementia patient-level data from ADNI-1 (n≈305), late pre-dementia from ADNI-2 (n≈122) and InDDEx (n≈394), has been standardized and curated. Imaging data have been re-processed, and ICV-HV was determined by two image analysis algorithms, namely LEAP™ and FreeSurfer™. As per guidance from FDA, temporal changes in Clinical Dementia Rating Scale Sum-of-Boxes (CDR-SB) will be described by a non-linear mixed-effects model. Along with ICV-HV, sex, baseline age and disease severity, and apolipoprotein E genotype will be included as covariates. Clinical trial simulations using the Monte Carlo technique will be performed to compare the statistical power by sample size in trials with and trials without ICV-HV enrichment. The full qualification document will be submitted to the FDA by 3Q 2017. This ongoing biomarker qualification effort with the FDA highlights the importance of understanding disease progression quantitatively to support the qualification of ICV-HV for prognostic purposes. If ICV-HV demonstrates utility in clinical trial enrichment, qualification of this biomarker can streamline drug development programs in AD by insuring the right patients are enrolled into our trials.