13 July 2010. Regulatory approval could be on the horizon for an amyloid tracer that is widely considered the frontrunner among several 18F-labeled compounds being developed for brain imaging using positron emission tomography (PET). Even the skies of Honolulu, which hosts the Alzheimer’s Association’s International Conference on Alzheimer’s Disease (ICAD) from 10-15 July 2010, could not have been sunnier than the presentation of Phase 3 histopathology data reported Sunday by Christopher Clark of Avid Radiopharmaceuticals, Philadelphia, Pennsylvania. He said he and colleagues found near-perfect correlation between PET imaging using the new tracer and amyloid load measured postmortem in the same patients. Given these encouraging results, the company plans to submit an application by late summer to the U.S. Food and Drug Administration (FDA), which could, so the company hopes, approve the compound as soon as six months thereafter under expedited review, Clark told ARF. A validated F18 PET tracer would expand the commercial availability of amyloid imaging, which has thus far been restricted largely to some 60 or so research centers worldwide.
In this study, Avid tested florbetapir (formerly 18F AV-45) in 35 people who were expected to die within six months. The idea was that imaging people near the end of their lives would minimize the time interval between PET scan and histopathological evaluation, allowing researchers to more effectively compare the two measures of brain amyloid load. To test their PET reagent’s specificity, the team also imaged 47 people who were highly unlikely to have detectable brain amyloid—namely, young, cognitively normal subjects without an ApoE4 allele. On average, less than three months elapsed between PET imaging and death, about 11 hours between death and autopsy, Clark said.
Of the 19 subjects who met NIA-Regan criteria for AD pathology, all but one were amyloid-positive on PET as judged by visual reads, and all 19 came out positive on SUVR quantification of PET data. For both PET analysis methods, all 16 who lacked postmortem AD pathology were also amyloid-negative by live brain imaging, giving the tracer 100 percent specificity in this small sample.
The data drew praise from the neuroimaging community, which might have expected as much given that florbetapir already looked promising in Avid’s analysis of six autopsy cases presented earlier this spring at the Human Amyloid Imaging meeting and in more detail at the American Academy of Neurology conference, both in Toronto (see ARF related news story).
“These data are excellent,” said Chris Rowe of the University of Melbourne. Other scientists’ informal hallway comments ranged from enthusiasm that the availability of an approved agent to image a key AD pathology would transform the clinical trial landscape, to more guarded optimism. Some scientists cautioned that even if the data withstood the FDA's review, it remained to be seen whether insurance will pay for amyloid imaging, and noted that this measure may add more value to clinical detection of early cases for research purposes than for routine diagnosis in the community.
Florbetapir appears useful for predicting whether seniors with mild cognitive impairment were likely to decline further, as reported in a separate talk at ICAD by Reisa Sperling of Brigham and Women’s Hospital in Boston. She and colleagues reported follow-up data on a florbetapir Phase 2 study. The scientists have data thus far on 138 of 184 cognitively normal, newly diagnosed MCI and AD participants in the study. After getting their brains imaged with florbetapir at baseline, the participants had their symptoms assessed every six months through phone interviews, and returned for clinical and neuropsychological evaluation at 18 months. None of the healthy seniors worsened noticeably within that timeframe, regardless of brain amyloid status. However, in the MCI group, a greater proportion of amyloid-positive subjects progressed to AD than did amyloid-negative MCI patients, suggesting that amyloid imaging using florbetapir may help identify those at risk for progressive cognitive decline. In his talk, Rowe broadly reviewed ongoing longitudinal assessments of various MCI cohorts imaged with several of the amyloid imaging agents currently in development at his center and elsewhere. The overall trend there, too, was that MCI patients who have amyloid in their brain go on to meet an AD diagnosis over the next two to four years, while amyloid-free MCI patients generally do not.—Esther Landhuis.
Gift of Water, bronze sculpture by Shige Yamada, 1997, at main entrance of the Hawai'i Convention center. Representing a spring offering water, it celebrates the Hawaiian people's generosity and sense of goodwill to newcomers. Image credit: Chris Hass