Some hesitant about newly FDA-approved drug Amyvid

On Friday, the Food and Drug Administration approved a drug representing over a decade’s hard work for two Perelman School of Medicine faculty members — but not everyone is proud.

Amyvid was created by assistant Radiology professor Daniel Skovronsky and Radiology professor Hank Kung. College junior Mateen Moghbel doesn’t think the drug should enter the market, and he is backed by Hospital of the University of Pennsylvania professor of Radiology Abass Alavi, as well as other Penn faculty and researchers.

The FDA approved the drug as a tool to help diagnose Alzheimer’s disease by indicating the level of amyloid plaque deposits in patient’s brains.

Amyloid plaque was first discovered by German doctor Alois Alzheimer when he looked inside the brain of the first Alzheimer’s disease patient. There, he found abnormal clumps of a protein, the amyloid deposits. Alzheimer’s is characterized by these deposits: if they are not found in a patient’s brain then that patient does not have the disease.

And in 1991, two British scientists suggested the accumulation of amyloid plaque actually causes Alzheimer’s. This theory, called the amyloid hypothesis, has fueled research in the field of Alzheimer’s for the past 20 years.

Abnormal levels of amyloid plaque can develop in Alzheimer patients several years before other symptoms appear, such as memory loss. Until now, the only way to observe the plaque was to perform a post-mortem biopsy of the brain.

So Penn researchers Daniel Skovronsky and Hank Kung decided to develop Amyvid. It is a dye, or tracer, that reveals amyloid plaque. A radioactive compound in the drug binds to plaque particles and makes them visible in PET brain scans.

Seeing amyloid plaque in living patients could allow scientists to test the amyloid hypothesis, better understand Alzheimer’s and maybe even diagnose the disease earlier on.

But there are many skeptics and some of the most vocal ones come from Penn. They have raised doubts on Amyvid’s ability to trace amyloid plaque as well as the scientific theory that underpins its use.

Moghbel’s Project
Moghbel, a biological basis of behavior major, is one of them. Last summer, he drafted a scientific editorial disputing the drug’s reliability and its usefulness in diagnosing Alzheimer’s. It was published in October in the European Journal of Nuclear Medicine and Molecular Imaging.

Moghbel’s editorial was co-written with Babak Saboury, a clinical research fellow at HUP, and then reviewed and signed by a handful of leading researchers in the field, including Alavi. Not only was it downloaded about 1,200 times in only three months — breaking a record in the modern history of the journal — but it also triggered a rebuttal from 24 prominent scientists defending the drug, though among them, 18 had a recorded conflict of interest.

According to the editorial, the tracer is not specific enough — it binds to particles other than amyloid, distorting the results from PET scans. The editorial argued that results obtained with Amyvid identified amyloid in areas that typically contain low levels of the plaque.

“They haven’t done the tests to show this binds specifically to amyloid,” Moghbel said.

Furthermore, the editorial argued, amyloid imaging is not viable because the plaque particles are too small for PET scans to pick up. In other words, the technique’s ability to map the plaque could be limited by its spatial resolution, since the scans cannot detect the individual plaque particles.

Finally, the authors questioned the key assumption underpinning the tracer’s utility. According to them, the amyloid hypothesis “is still a matter of debate and has recently been challenged” by a series of ineffective anti-amyloid drugs.

Moghbel does not want to see families hurt by drugs that may be unnecessary or even harmful. He knows from personal experience that patients are eager to treat the disease at all costs. His grandfather passed away from Alzheimer’s, and if the tracer had existed while he was alive, he said, “he would have done it, no questions asked.”

Moghbel’s family history motivated his research project, and he said he still hopes to participate in diagnosing or treating Alzheimer’s. He also sees potential in amyloid imaging. “It’s a very exciting approach,” he says. He believes, however, that these techniques are not yet ready for widespread use. “We’re not disagreeing with them,” he said, “we’re asking for more research to be done.”

Amyvid: A Penn Creation
For Amyvid, the path to FDA approval was a long and bumpy one. Twelve years ago, Kung met then-Ph.D. student Skovronsky, and found they shared a common interest in amyloid imaging. In 2004, they founded a start-up, Avid Radiopharmaceuticals, with the goal of creating a marketable tracer.

In the beginning, Skovronsky, Avid’s CEO, had a hard time finding research funds.

“I got some small business grants [at first,]” he said. Then he received $2 million in start-up funding and eventually raised $70 million in investments.

Skovronsky also had to license from Penn the ancestor of florbetapir, a compound Kung helped develop while he was a graduate student.

“Dan Skovronsky deserves a lot of credit because Penn’s environment is not really set up to develop new drugs,” Kung said.

The tracer was developed by Avid in conjunction with Kung’s lab at Penn, which is across the street. It took them a few more years to come up with a final version of the tracer. “We ended up testing 12 different compounds on humans to pick out the best one,” Skovronsky said. And that became, in 2005, florbetapir — the compound for Amyvid.

Avid was now on its way up ­— in 2010, Eli Lilly pharmaceuticals acquired it.

This article has been updated to reflect that it was Mateen Moghbel’s grandfather who passed away from Alzheimer’s, not his grandmother.

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