Integrating ADNI results into Alzheimer's disease drug development programs

Abstract

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is providing critical new information on biomarkers in cognitively normal elderly, persons with mild cognitive impairment (MCI), and patients with mild Alzheimer's disease (AD). The data provide insights into the progression of the pathology of AD over time, assist in understanding which biomarkers might be most useful in clinical trials, and facilitate development of disease-modifying treatments. ADNI results are intended to support new AD treatment development; this report considers how ADNI information can be integrated in AD drug development programs. Cerebrospinal fluid (CSF) amyloid beta protein (Abeta) measures can be used in Phase I studies to detect any short term effects on Abeta levels in the CSF. Phase II studies may benefit most from biomarker measures that can inform decisions about Phase III. CSF Abeta levels, CSF total tau and phospho-tau measures, fluorodeoxyglucose positron emission tomography (FDG PET), Pittsburgh Compound B (PIB) amyloid imaging, or magnetic resonance imaging (MRI) may be employed to select patients in enriched trials or as outcomes for specific disease-modifying interventions. Use of biomarkers may allow Phase II trials to be conducted more efficiently with smaller populations of patients or shorted treatment times. New drug applications (NDAs) may include biomarker outcomes of phase III trials. ADNI patients are highly educated and are nearly all of Caucasian ethnicity limiting the generalizability of the results to other populations commonly included in global clinical trials. ADNI has inspired or collaborates with biomarker investigations worldwide and together these studies will provide biomarker information that can reduce development times and costs, improve drug safety, optimize drug efficacy, and bring new treatments to patients with or at risk for AD.

Figure 1

Role of biomarkers in AD drug development.

Figure 2

Relationship of clinical outcomes and biomarkers in a clinical trial of an AD disease-modifying agent.

Figure 3

AD drug development. Black arrows show the phases of drug development; the brick-colored arrows show the ADNI biomarkers that could be used in that stage. Aβ – amyloid beta protein; CSF – cerebrospinal fluid; FDG – fluorodeoxyglucose; MRI – magnetic resonance imaging; PET – positron emission tomography; PIB- Pittsburgh Compound B amyloid imaging

Figure 4

Steps in the process of biomarker qualification as specified by the FDA (Goodsaid and Frueh, 2007).