Diagnostics & Imaging Week National Editor

In the face of continuing advances in medical knowledge, there are probably two disease sectors that, specter-like, haunt the planet: in undeveloped countries, the continuing prevalence of infectious diseases; in developed countries, the prevalence of Alzheimer's disease.

While infectious diseases can be beaten back by greater access to available therapies, Alzheimer's likely to grow to epidemic proportions as a result of rapidly aging demographics presents three key questions, with, as yet, no answers: How do you diagnose it? What causes it? And perhaps most difficult of all, what are the specific features that characterize it, tell us what it is, definitively?

Autopsy is the only provider of an exact diagnosis, and two of Alzheimer's characteristics are generally associated with causation: neurofibrillary tangles in the brain, supposedly resulting from protein abnormalities, and the presence in the brain of amyloid plaques, which contain a protein called amyloid beta.

The FDA's Peripheral and Central Nervous System Advisory Panel last month met to discuss the possibility of pushing to market a new group of radiopharmaceuticals potentially useful for identifying the sources of Alzheimer's, and serving as a possible early "prognostic," if not a definitive diagnostic.

Perhaps most important of all these new imaging agents could establish the validity of key biomarkers, with these biomarkers guiding development of an in vivo diagnostic and the development of drug therapies to treat Alzheimer's, both at the earliest stages.

The half-life of the first-developed agent for imaging plaques in the brain is short, just 20 minutes, and its use expensive, factors mitigating general clinical application. But new compounds under development feature half-life times up to two hours and easier use, offering opportunities for early scanning.

Three companies at the advisory panel meeting with PET imaging agents in development and potentially useful for the identification of amyloid plaques were Bayer (Leverkusen, Germany), GE Healthcare (Waukesha, Wisconsin), and Avid Radiopharmaceuticals (Philadelphia),

Bayer is developing an 18F-labeled PET tracer called BAY 94-9172; GE Healthcare is developing GE-067. Avid is developing 18F-AV-45, showing an affinity for specific binding to amyloid pathology, and the most advanced of the three in terms of clinical assessment.

The company in June reported its launch of a Phase II clinical study of the product, saying it is the first F-18 PET amyloid imaging compound to enter multi-center clinical research studies in the U.S. for the detection of amyloid plaque in patients with varying degrees of dementia. Avid is currently conducting clinical trials at more than 25 research centers across the U.S.

Alan Carpenter, PhD, JD, vice president, business development and legal affairs for Avid, told Diagnostics & Imaging Week that the company hopes to move into a Phase II trial early next year. While offering the usual hesitance concerning how rapidly the FDA might carry out its regulatory due diligence and act on approval, he suggested that the agency is likely to fast-track the product, with the earliest marketing okay coming in 2010.

Carpenter declined to put a dollar figure on potential future sales of the product. But he said it could be blockbuster status, if defined in terms of imaging.

"From an imaging point of view, I guess you could consider it as having blockbuster potential, though markets for imaging products tend to be much smaller," Carpenter told D&IW.

He suggested that the major opportunity would be its use for finding an Alzheimer's drug, that product or products clearly having blockbuster potential.

"Given the crisis we're faced with," he said, the applications for AF-45 "address a major healthcare problem. It would be fairly widely utilized, much like radiopharmaceutical imaging of the heart."

He said that the company is already partnering with some drug developers who are using AV-45 in their research on various compounds.

Carpenter was careful to state that the company is not seeking FDA approval of the imaging agent as a diagnostic for Alzheimer's, but only of the identification of the amyloid plaques in the brain.

This makes it clear that medicine still has a ways to go to find a diagnostic or a therapy. A biomarker is not a disease, but Avid clearly hopes that its imaging agent can be used to determine if the presence of amyloid plaques is Alzheimer's defining biomarker.

It says that the use of AV-45 allows for PET imaging of amyloid plaque to be done for the first time in a community hospital or imaging clinic setting. It reports that agent has now been studied in more than 250 people, ranging from cognitively normal individuals to those with Alzheimer's disease.

Carpenter said that the late-stage development of the agent received a significant boost from the advisory committee's discussion and the direction it provided. He said that discussion validated issues of "clinical utility and histopathology" and that, overall, the FDA is showing a "keen interest" in this effort.

The "mindset" of the agency, he said, "seems to be trying to accelerate the development, or at least be supportive of the development, of these types of imaging compounds, based on what we know today."

Avid also has molecular agents in development for the imaging of Parkinson's disease/dementia with Lewy bodies and diabetes mellitus.

Michael Weiner, MD, professor of radiology at the VA Medical Center, University of California San Francisco and principal investigator of the Alzheimer's Disease Neuroimaging Initiative (ADNI), said that development of new imaging agents "is essential to catalyze trials for new therapies that may halt or even prevent Alzheimer's disease.

"Prior to this [advisory committee] meeting, there were ... unanswered questions that could have impeded the further development of amyloid imaging." And he said the committee addressed the "major obstacles to late-stage" amyloid plaque development.