11 May 2012. Hot on the heels of FDA approval for the amyloid imaging ligand Amyvid (florbetapir), results of a multicenter Phase 3 autopsy trial suggest the closely related PET tracer florbetaben accurately images plaques and may prove useful for diagnosis of Alzheimer’s disease. Marwan Sabbagh, Banner Sun Health Research Institute in Sun City, Arizona, presented those data at the 64th annual meeting of the American Academy of Neurology, held 21-28 April 2012 in New Orleans, Louisiana. In a separate presentation, David Wolk, University of Pennsylvania, Philadelphia, reported on a smaller Phase 3 autopsy study of flutemetamol, another amyloid ligand that is being developed for brain imaging.
Research indicates that florbetaben loiters in the brains of people with, or at risk for, Alzheimer’s disease. The ligand also seems to identify patients with mild cognitive impairment that progresses to AD within the next few years (see ARF related news story). But is florbetaben accurately detecting amyloid plaques? Sabbagh and colleagues conducted a histopathology validation study to determine if those areas of the brain that light up with the ligand are also amyloid hot spots. This same work was done to validate PIB and florbetapir in the past.
The researchers recruited 214 patients who were near the end of their life (10 of them without a dementia diagnosis) for florbetaben PET scanning at 17 different centers in the U.S., Europe, Japan, and Australia. Postmortem, they sectioned and analyzed 31 brains from this cohort to compare ligand binding and amyloid load among six regions of interest (middle frontal gyrus, striate and parastriate occipital cortices, hippocampus, anterior cingulate cortex, posterior cingulate cortex/precuneus, and cerebellar cortex). They also compared florbetaben PET scans to a histopathological visual assessment algorithm in a subject-level analysis typical of those used in clinical settings. The region of interest (ROI) analysis showed good correlation between florbetaben binding and amyloid pathology, Sabbagh said, with the ligand supporting an overall sensitivity of 77 percent and a specificity of 94 percent. Those numbers rose to 100 and 92 percent, respectively, in the subject-level analysis.
Wolk and colleagues ran flutemetamol scans on 68 patients 55 years of age or older who had a life expectancy of less than one year. On autopsy, the researchers found that uptake of the ligand strongly correlated with plaque pathology, with a sensitivity and specificity of 86 and 92 percent, respectively. Both florbetaben and flutemetamol showed good inter-rater variability, a prerequisite for use in a clinical diagnostic setting. Wolk and colleagues also found tight correlation between flutemetamol uptake and Aβ plaque load in biopsies of patients with normal-pressure hydrocephalus. Some of these patients also develop AD-like pathology. Indeed, those patients tend to be the ones who respond poorly to cerebrospinal fluid shunting, a standard treatment for hydrocephalus.
GE Healthcare develops flutemetamol. Bayer Healthcare developed florbetaben (see ARF related news story), but recently sold its entire portfolio of imaging agents to Piramal Healthcare, an Indian company. Sabbagh believes that Piramal will file for FDA approval for florbetaben in the near future, and some media outlets are reporting as much (see, e.g., Reuters).—Tom Fagan.