FDA advisory panel today with Bayer, GE Healthcare on imaging biomarkers in Alzheimer’s will affect disease modification drug trials

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Bayer, GE Healthcare and Avid Radiopharmaceuticals will meet with the FDA advisory panel today to discuss the development of new imaging markers for use in Alzheimer’s disease (AD). The Advisory Committee Meeting is aimed at providing specific recommendations based on clinical utility towards the design of Phase III diagnostic imaging studies in AD.

Two defining features of Alzheimer’s disease in the brain are amyloid plaques and neurofibrillary tangles, or tau. The plaques contain a protein called amyloid-beta, while the tangles are made of a protein called tau. The current, widely accepted amyloid hypothesis traces Alzheimer’s to plaque deposits, whereas the tau hypothesis links the disease to protein abnormalities.

There are some key concerns before approval of these imaging agents, several key opinion leaders said, including the validation of the binding properties of these new imaging agents to beta-amyloid, a key structural hallmark of this neurological disorder.

There is no single test that accurately diagnoses AD, and physicians have to rely on a variety of assessments, ranging from cognitive to laboratory tests to make a ‘probable’ diagnosis. A definitive diagnosis can only be made upon autopsy, upon examination of brain tissue for the presence of amyloid plaques and neurofibrillary tangles.

The neocortical amyloid-beta plaque deposits, or ‘amyloid plaques,’ occur early in the disease, years before the onset of clinical symptoms. The availability of a non-invasive, imaging biomarker capable of detecting amyloid-beta in the brain to facilitate early and accurate in vivo disease detection of AD is a major unmet medical need.

The current imaging agent used is a PET tracer called Pittsburgh Compound-B (PIB), the first compound to non-invasively monitor the brains of people with Alzheimer’s. However, the agent has a relatively short half-life of 20 minutes, which hinders its potential use as a routine clinical diagnostic agent. It has not been validated in a prospective study comparing imaging results to histopathological measurements of amyloid plaque in the brain.

New agents in development, with an approximate half-life of two-hours, all hope to be indicated for PET imaging of amyloid plaque pathology in the brain to aid in the evaluation of patients with signs or symptoms of cognitive impairment. They could also be used to monitor patient response to disease modifying drugs in development.

Dr G. William Rebeck, associate professor of neurology at Georgetown University Medical Center, who will be presenting at the FDA panel, told Pharmawire that the problem is PET tests are expensive, and not every clinic has access to a PET scanner. The current accuracy of diagnosing AD is between 90-95%. “Do you need an expensive routine test to get that last few percent? Probably not.”

But for cases where there is something unusual, and an individual presents atypical symptoms, they may want to get a PET scan, said Rebeck. Companies will have to conduct more validation studies, and time seems to be the only limitation, as they have to wait to conduct patient autopsies, he added.

“The thing that I worry about is a number of clinical [drug] trials are coming up negative. If there is not something encouraging, people will lose interest in conducting these expensive trials,” said Rebeck.

Dr William Hall, director of the Center for Healthy Aging at the University of Rochester School of Medicine, said a lot of theories have come and gone. The fundamental unanswered question of whether amyloid is in fact the culprit remains unknown. “We might be barking up the wrong trees right now,” he said.

“A biomarker is not the same as the cause of the disease. It might be along for the ride, which complicates current research,” Hall said.

These new imaging agents will be a ‘huge boom’ for clinical trials, Rebeck said. From a research standpoint, it will be a very interesting reagent to use because researchers will be able to see how much amyloid accumulates before the symptoms of dementia kick in.

Bayer is developing a new F-18 labelled PET tracer called BAY 94-9172, and GE Healthcare is developing GE-067. Avid Radiopharmaceutical’s AV-45 also shows high affinity specific binding to amyloid pathology.

”We expect a lot of failed biomarkers,” said Dr Daniel Skovronsky, CEO of Avid Radiopharmaceuticals. It’s a turning point for the field as a whole, and there is a push from the industry and the FDA, he said.

Skovronsky said radiopharmaceutical agents are quite safe when using tracer doses, and a few micrograms are given per imaging session. These agents are unlikely to be toxic, and the FDA recognizes the safety of these compounds. Although it is easier to conduct trials for imaging agents, compared to therapeutics - one challenge that remains is the establishment of a clear reference standard.

When asked about the possibility of developing a control or ‘standard of truth’ so that autopsy is not required, Skovronsky said this is one of the challenges of being a leader in the space, but Avid is ready to surmount this hurdle, he said.

Dr Gregory Jicha, assistant professor of neurology, University of Kentucky, Sanders-Brown Center on Aging, said there is such a huge push to try to get the FDA to accept a biomarker as a surrogate marker for anti-amyloid drugs. “It’s not just to make money, but is intrinsically linked to all of the clinical trials [involving disease modifying drugs],” he said.

If we can get the FDA to accept reduction in amyloid plaque as a surrogate marker for the disease state, all we have to do is come up with drugs to influence this biomarker for drug approval. But Jicha cautioned that 40% of normal people have significant amyloid deposition in their brain. Before clinical adoption, a baseline standard of how normal individuals respond to these imaging agents needs to be established. Patients with dementia with Lewy bodies also have a similar abundance of amyloid and are as extensive in AD.

Dementia with Lewy bodies is a type of dementia characterized by abnormal levels of Lewy bodies, a nervous system protein.

It will be very difficult to get physicians to accept biological data as an indicator of an underlying disease process, said Jicha. He gave the example of a recent patient who was 50-years old, reported memory complaints and tested positive on both the PET scan and CSF test, but did not meet the clinical diagnosis of AD. Upon further diagnosis, her physician, who was the director of a major Alzheimer’s Center, told her she had anxiety, said Jicha.

Dr John Morris, director of the WUSTL Alzheimer’s Disease Research Center, said PIB is unlikely to be the agent that gets out in the clinic, as it is limited to use in advanced medical centers that have a cyclotron. A cyclotron is a type of particle accelerator, which is essential to create radioactive elements, if clinics want to use PIB as an imaging agent.

“PIB is not going to be revolutionary. Maybe one of the Avid compounds will be that agent,” said Morris.

If the data continue to be accumulated and the expectations are that amyloid imaging is a valid marker of AD, I think it’s going to revolutionize the diagnosis of patients who have dementia, as well as pre-dementia patients.

Imaging biomarkers and a cerebrospinal fluid (CSF) specificity test may be used together for better specificity and accuracy of diagnosis. “But it will be pretty costly to do all these studies on everyone who walks through the door,” said Jicha, who rarely does a PET or CSF test. A referral consultation has a diagnostic accuracy of 90% or better in many cases.

Skovronsky suggested that using a sequence of several biomarkers would be ideal in the screening process. If a cheap, easy, and sensitive diagnostic could be developed, even if it were nonspecific, it could be used as a screening test to identify appropriate patients for imaging, which would be more specific, he said.

A major issue is APOE allele testing in people, as different varieties of the molecule shift the odds of developing dementia. The American Academy of Neurology advises against this genetic test, said Jicha, as there is no current treatment, but it can increase the diagnostic certainty. “The argument is telling patients if we have a way to change the outcome. Otherwise you’re just giving patients bad news,” said Jicha.

Yet physicians said that these new imaging agents will hopefully be used to help screen patients who may be at risk for Alzheimer’s, and show mild cognitive impairment, but have not progressed to AD. Patients who report positive CSF, PET, and APOE status tests, but report no cognitive functional decline may be good candidates for PET scans, said Jicha. “The move towards biomarkers is not just to make money for companies, but to open the door to treat people in a pre-dementia state,” he said.

According to studies by the Mayo Clinic, Jicha said the prevalence of MCI in the population over age 65 is about 20%. These companies have to opportunity to increase the market significantly, as one-fifth of the population over 65 could take the medication and these imaging tests.

There may also be false positives, such as individuals who test PIB positive, due to amyloid deposits in their brains, but do not have dementia. There is also the possibility of PIB binding in other conditions, such as prion diseases, although it is very rare, said Rebeck.

Dr David Holtzman, Head of the Department of Neurology at Washington University School of Medicine in St. Louis, said there is already strong evidence that PIB is imaging amyloid protein from several publications. “I think with amyloid imaging and ancillary CSF tests, we can identify now those who have AD pathology in vivo without a biopsy.”

Amyloid imaging is currently not approved for anything other than research use, said Holtzman. Rebeck also agreed that a negative amyloid PET scan would be useful to rule out AD as a current diagnosis for the elderly subject presenting for evaluation of clinically identified progressive cognitive impairment - one of the key questions raised at the meeting.

Dr Richard Frank, vice president of medical affairs and clinical strategy at GE Healthcare, said the company’s lead molecule, GE-067, targets insoluble forms of amyloid. GE has also performed research on soluble oligomers, which led to the subsequent collaboration with Eli Lilly.

“There has been a lack of clarity from the FDA and the companies are hoping to understand the regulatory pathway after the meeting,” Frank said.

While many critics question the use of such a diagnostic as there are no disease modifying agents on the market, there are many benefits of such a test, said Frank. The imaging of amyloid beta plaques would confirm that the patient is a proper candidate for a disease modifying therapy in development.

The diagnostic could ultimately play a critical role in early intervention. The current treatment paradigm in AD is analogous to treating a cardio patient with statins after they have already had two heart attacks and implanted stents. He likened amyloid imaging to serum cholesterol levels, and said that patients need to be treated earlier before they show memory loss.

Imaging agents may also be useful after initiation of therapy to ensure the patient is gaining some benefit, that is to say, they are receiving the right drug at the right dose. If the post-treatment test does not show improvement, the regimen could be individualized, that is to say the dose could be increased, dose in intervals could be shortened, or the drug could be changed, Frank said.

Dr Edward Zamrini, director of clinical trials for the Center for Alzheimer’s Care at the University of Utah Hospital, said amyloid imaging is a tremendous advance, although there is no ultimate proof that the presence of amyloid plaques is equal to the degree of clinical pathology.

However, aggregate data and science are moving toward molecular diagnosis rather than symptomatic diagnosis, said Zamrini. Imaging the tau tangles in conjunction with amyloid plaques would also provide better positioning, and there is a clinical initiative to correlate clinical progression with an amyloid imaging agent.

“I don’t think there are any major hurdles. The one thing is what you do with an individual who is PIB positive, who is not demented,” said Rebeck. Although there is a growing body of literature supporting imaging agents such as PIB, more validation studies need to be conducted before clinical adoption, physicians agreed.

The FDA advisory meeting is a historic step, and shows the urgency to develop an imaging agent for use in AD, as the agency normally doesn’t hold a committee this early in the development process. “The impetus for this meeting is the unmet clinical need, and the push from the medical community to develop new therapeutics. PET is the fastest growing piece of imaging,” said Skovronsky.

“It’s a whole new approach to treating this disease,” said Rebeck. But the important thing to remember is we’re talking about a biomarker, not a cure, added Hall.

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