A rare achievement for a rare disease

U-M researchers’ work goes from discovery to drug, for Gaucher disease and perhaps more

James Shayman, M.D., one of two U-M scientists who led the development of the drug eliglustat tartrate, now sold as Cerdelga

James Shayman, M.D., one of two U-M scientists who led the development of the drug eliglustat tartrate, now sold as Cerdelga

It took more than 40 years, and a lot of dedication. But an idea born and nurtured in University of Michigan laboratories is now making a difference in the lives of patients with a rare disease.

For one of the first times, a drug developed first at U-M, and then further by a company, made it through all the steps it takes to reach patients around the world.

And even though the disease it treats only affects about 10,000 people worldwide, it’s become a product that a company can sell and doctors can prescribe to their patients. In this case, it’s patients with the debilitating and potentially fatal rare condition called Gaucher disease.

It’s the first unique chemical entity developed at U-M, and the fifth U-M medication or vaccine, to make it all the way to approval by the U.S. Food and Drug Administration. And it’s for a disease that truly needed new options.

From a million small discoveries

The achievement shows the importance of the esoteric, even obscure, research that goes on in university laboratories every day, with the ultimate goal of helping patients worldwide with even the rarest diseases.

Scientific teams at the U-M Medical School and beyond can spend their entire career studying the tiniest details of how cells, molecules, genes and organs work.

The odds that any one of them will make a discovery that you could call a “breakthrough”, with immediate importance for patients, aren’t high.

But the million small discoveries and advances they make add up to a body of knowledge that others can use – including the drug companies that can take an idea to the marketplace.

It can also bring patients the buzzed-about concept of “precision medicine”, says the surviving leader of the original research effort, U-M medical professor James Shayman, M.D.

“Rare diseases are the model by which precision medicine moves forward.” – James Shayman, M.D.

“It’s important to note that rare disease research and treatment really is the purest model of precision medicine,” he says. “We tend to think about precision medicine as it’s applied to common problems like diabetes and cancer. But rare diseases are the model by which precision medicine moves forward.”

A new option

The drug that got its start at U-M is called eliglustat tartrate. It’s sold under the name Cerdelga.

Before it was available, Gaucher patients only had intravenous medications as their first option for treatment. The two-hour infusion treatment sessions every two weeks aim to replace a substance called an enzyme that their body doesn’t make enough of.

Now, they can work with their doctors to see if Cerdelga might be right for them. It actually causes the body to make less of the toxic waste product, called glucosylceramide, that builds up in the bodies of people with Gaucher disease and damage the spleen, liver and bones.


Norman Radin, Ph.D., in his U-M laboratory in the late 1970s

This is called substrate reduction therapy – a concept that originated in the lab of the late U-M chemist Norman Radin, Ph.D. toward the end of his career. He teamed with Shayman to develop the concept and test it in animals.

By the late 1990s, Radin had retired from U-M and Shayman’s work was looking very promising. But it took more years of research, and outreach to industry by Shayman and U-M Tech Transfer, to take it to the next step.

A company licensed the rights to develop the drug from U-M in 2000, and carried out clinical trials of the drug in Gaucher patients – including the largest Gaucher disease drug trial ever done. Radin died in early 2013 knowing the drug was showing promise, and that his original idea had borne fruit.

The eventual results were strong enough to merit approval from the FDA to sell it in the U.S. in August 2014. Other countries also approved it in 2015.

Just this month, Gaucher experts from around the country published recommendations for exactly how the drug should be used. And evidence from the earliest patients to get the drug shows that it appears to treat Gaucher’s bone complications better than other options.

Interestingly, research in animals published just this month raised the possibility that the drug could be studied as a potential treatment for some people with a type of blood cancer called multiple myeloma. If this pans out, it could mean that the use of eliglustat won’t be so rare after all.

“Rare diseases are a window to understanding much more common disorders,” says Shayman. “And what starts as research and development of therapeutics in rare disease often leads to wider and more extended uses.”

Moving on

The Shayman lab's team is now working on solving mysteries about other rare diseases that stem from waste-handling problems inside cells.

The Shayman lab’s team is now working on solving mysteries about other rare diseases that stem from waste-handling problems inside cells.

Shayman’s U-M team that worked on eliglustat has moved on to other things – again, working at the very basic level to understand other rare diseases and how to treat them.

Fueled in part by royalties from eliglustat, they’re tackling Fabry disease, which Shayman also treats in patients who come to U-M’s kidney clinics. It’s a genetic disease that can run in families, and causes pain, heart and kidney issues, and problems with the skin and eyes. The team is working to find ways to predict which patients’ outcomes.

New targets for future drugs could emerge from current research

New targets for future drugs could emerge from current research

Like Gaucher disease, Fabry stems from problems with the waste-disposal system in the body’s cells. This system relies on tiny bubble-like structures called lysosomes, which are filled with enzymes that break down the unneeded stuff that can build up in cells. Fabry patients make too little of one of those enzymes – a different one from Gaucher patients. Both diseases are part of a family of diseases called lysosomal storage disorders.

In addition to the Fabry work, Shayman’s team is working with U-M College of Pharmacy professor Scott Larson to find ways to deliver substrate-reducing drugs into the brain. They’re funded by a Blueprint for Neurotherapeutics grant from the National Institutes of Health. If successful, their work could benefit patients with conditions such as Tay-Sachs and forms of Gaucher disease that affect the brain.

Shayman’s team has also been studying other enzymes that work inside of lysosomes, to see what happens when the genes for them don’t work correctly. They’re hoping to zero in on the causes of the dozens of other diseases known to arise from lysosome storage issues.

“Universities including Michigan have a role to play in not just finding targets for new therapies, but developing them as well,” Shayman says, especially as drug companies’ own research teams are smaller than in the past. “But the first step in developing any drug is to understand and define the target.”

Shayman quoteThose targets might be found by testing a patient who arrives in clinic with a rare disease, to see what is different in his or her genes and cells. Or it might be found by looking at a gene whose function is unknown, seeing what happens in animals when it’s not active, and then finding patients with similar symptoms. However it happens, it takes scientific persistence to make it happen.

For all his work that led to Cerdelga’s worldwide use, Shayman has received awards from the U-M Medical School, and the Office of Technology Transfer.

But the recognition that may have been most meaningful, he says, was that of the patients and families he met at a Gaucher Foundation meeting last year, many of whom participated in the eliglustat trials.

“As a physician scientist, it was a fairly unique experience,” he recalls. “And a remarkably satisfying outcome.”

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