How does beta-amyloid imaging work?
Dr. Sabbagh: In contrast to techniques designed to indirectly estimate levels of brain amyloid plaques from Aβ levels in plasma or cerebral spinal fluid, imaging techniques utilizing radiolabeled PET tracers that bind to the aggregated Aβ peptides in amyloid plaques have the potential to directly assess relative brain amyloid plaque pathology. The current amyloid imaging techniques include 11C-labeled (11C) agents such as Pittsburgh compound B (11C-PiB) or 18F-ligands (18F) such as florbetapir F 18 (18F-AV-45), 18F-flutemetamol (18F-GE067), florbetaben (18F-BAY94- 9172), and 18F-FDDNP. There is a direct correlation between Aβ-containing amyloid plaques and in vivo [(11)C]PIB retention measured by PET imaging. Because (11)C is not ideal for commercialization, [(18)F]3’-F-PiB (Flutemetamol), (18) F-AV-45 (Florbetapir), and (18)F-BAY-949 (Florbetaben) are undergoing extensive Phase II and III clinical trials and florbetapir is approved.
Q What patients are appropriate for beta-amyloid testing?
Dr. Sabbagh: The current CMS recommendations are to limit the utility of amyloid imaging to applicability in clinical trials. CMS released a statement on July 3 proposing coverage with evidence development (CED), which allows use only for patients in clinical trials addressing the effectiveness of these scans. An expert panel of amyloid imaging researcher published consensus guidelines for appropriate use. According to the Alzheimer’s Association (published in Alzheimer’s and Dementia 2013), the Amyloid Imaging Taskforce (AIT) concluded that amyloid imaging could potentially be helpful in the diagnosis of people with cognitive impairment when considered along with other clinical information, and when performed according to standardized protocols by trained staff. In addition, they emphasized that the decision whether or not to order amyloid imaging should be made only after a comprehensive evaluation by a physician experienced in the assessment and diagnosis of cognitive impairment and dementia, and only if the presence or absence of amyloid would increase certainty in the diagnosis and alter the treatment plan.
According to the AIT, appropriate candidates for amyloid PET imaging include:
- Those who complain of persistent or progressive unexplained memory problems or confusion and who demonstrate impairments using standard tests of cognition and memory.
- Individuals meeting tests for possible Alzheimer’s, but who are unusual in their clinical presentation.
- Individuals with progressive dementia and atypically early age of onset (before age 65).
Beyond these guidelines, amyloid imaging might be useful to predict amyloid burden in asymptomatic people that might be useful to predict who might be at risk for development of symptoms. For example, in early symptomatic people (MCI), the presence of positive amyloid scan predicts future progression to AD. More importantly, a negative scan predicts with a high negative predictive value that a patient will not develop AD in the next several years.
What is florbetaben?
Dr. Marwan Sabbagh: Florbetaben (BAY 94-9172 or ZK 6013443) is a positron emission tomography (PET) imaging agent for detection/exclusion of cerebral betaamyloid when compared to postmortem histopathology. Florbetaben (18F) is a promising 18F-labelled amyloidtargeted PET tracer in clinical development. In a Phase II study with florbetaben, 81 participants with probable Alzheimer’s disease and 69 healthy controls were assessed. As reported by Barthel et al.Lancet Neurol. 2011), independent visual assessment of the PET scans showed a sensitivity of 80 percent (95% CI 71-89) and a specificity of 91 percent (84-98) for discriminating participants with Alzheimer’s disease from healthy controls. The SUVRs in all neocortical grey-matter regions in participants with Alzheimer’s disease were significantly higher (p<0.0001) compared with the healthy controls, with the posterior cingulate being the best discriminator. Linear discriminant analysis of regional SUVRs yielded a sensitivity of 85 percent and a specificity of 91 percent.
How does florbetaben differ from other beta-amyloid imaging agents, and why is there a need for it in general?
Dr. Sabbagh: Florebetaben does not differ significantly from other imaging agents in the class in terms of technical characteristics. However, it was studied more rigorously in the Phase III program than its peers in that the study was performed internationally and for the first time, evidence was obtained on a regional level in matched brain tissue and for different b-amyloid plaque types. These favorable efficacy data support the potential of PET imaging with florbetaben as the tracer to improve confidence in the diagnosis of AD.
What clinical data was used to support the submission of florbetaben? As lead investigator, can you share any information on the Phase III study filed with the FDA?
Dr. Sabbagh: 216 end-of-life subjects underwent florbetaben PET scans. Post mortem brain histopathology was obtained in 31 subjects. Six pre-defined regions in each brain were analyzed centrally and scored for neuritic and diffuse b-amyloid plaques by a consensus panel consisting of three neuropathologists blinded to clinical diagnosis and imaging data. Regional visual and quantitative assessment of florbetaben PET images was performed using a newly developed MRI-based method ensuring exact tissue match. Additionally, subject-level whole brain visual assessment was performed by three blinded readers and compared with the subject-level whole-brain histopathology as determined by the on-site histopathologist according to CERAD criteria.
Visual assessment of florbetaben uptake in regional matched tissue sections based on the majority results of the three blinded readers over the compiled six brain ROIs against the result of the regional consensus histopathological analysis over the identical six brain regions revealed sensitivity of 77.4 percent (95% CI: 65.4-89.4%) and specificity of 94.2 percent (95% CI: 88.6-99.8%). Regional florbetaben uptake ratios correlated significantly (apart from those for the atrophic hippocampus/parahippocampal gyrus) with histopathology scores for b-amyloid (r=0.45 to 0.69, p=0.0135 to <0.0001).
In the subject-level whole brain visual and histopathological assessment, florbetaben PET images showed a sensitivity of 100 percent (95% CI: 80.5-100.0%) and a specificity of 91.7% (95% CI: 80.6-100%). Tracer uptake ratios did not differ with plaque type (neuritic/diffuse or diffuse; p=0.168). This trial verifies b-amyloid as a florbetaben target.
What is the expected timeline for bringing florbetaben to market?
Dr. Dinkelborg: In March 2013, Piramal Imaging announced it submitted florbetaben F18 to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in the visual detection of beta-amyloid in the brains of adults with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) and other causes of cognitive decline.
If approved by the FDA and EMA, Piramal Imaging expects florbetaben F18 will be available in the US and Europe in early 2014.
What’s next for the company? Can you share any updates on research or data?
Dr. Ludger Dinkelborg: Piramal Imaging’s portfolio of promising radiopharmaceuticals includes a number of projects that have advanced already into clinical development. Beyond AD and related dementias, Piramal Imaging is working on developing several pipeline compounds to address major clinical needs in oncology and in the cardiovascular area.
Marwan Sabbagh, MD is Director, Banner Sun Health Research Institute and Research Professor of Neurology, University of Arizona College of Medicine, Phoenix.
Ludger Dinkelborg, PhD is Director of the Board, Piramal Imaging SA.