It took more than 40 years, and a lot of dedication. An idea born and nurtured in an obscure university research laboratory is now making a difference in the lives of patients with a rare disease.

Its journey shows just how hard it is for a new drug to make it through all the steps to reach patients around the world.

The condition it treats, Gaucher disease, only affects about 10,000 people worldwide but is debilitating and potentially fatal. Patients truly needed new options. Decades after the glimmer of an idea, that new option is available and has become a product that a company can sell and doctors can prescribe.

From a million small discoveries

The journey 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 team members 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 one of the two original leaders of the research that led to the drug: University of Michigan Medical School professor 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 by the company Genzyme as capsules, under the name Cerdelga.

Before it was available, Gaucher patients only had intravenous medications as their first option for treatment. Two-hour infusion treatment sessions every two weeks aimed to replace an enzyme that their body didn't make enough of.

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

This is called substrate reduction therapy — a concept that originated in the lab of 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 and Shayman's work was looking promising. But it took more years of research, and outreach to industry by Shayman and the U-M Office of Technology Transfer, to take it to the next step.

Eventually, in 2000, Genzyme licensed the rights from U-M to develop the drug. Over the next 13 years, Genzyme paid for clinical trials of the drug in Gaucher patients — including the largest Gaucher disease drug trial ever done. Radin died in early 2012 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 Food and Drug Administration in August 2014 to sell Cerdelga in the U.S. Other countries approved it in 2015. U-M receives royalties from its sale, but sold a portion of its royalties in 2014 to fuel more research.

Recently, Gaucher experts from around the country published recommendations for exactly how the drug should be used. Evidence from the earliest patients who were prescribed the drug show that Cerdelga appears to treat Gaucher's bone complications better than other options.

Research in animals also raised the possibility that the drug could be studied as a potential treatment for some people with the blood cancer 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                                                                                       

Now, Shayman's U-M team is studying 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 patients' outcomes, and drawing part of its funding from Shayman's share of royalties from eliglustat.

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 that of 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 Larsen, Ph.D., 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 lysosomes, to examine the consequences when the genes for them don't work correctly. The team hopes 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."

Testing a patient who arrives in clinic with a rare disease, to see what is different in his or her genes and cells, or looking at a gene whose function is unknown, seeing what happens in animals when the gene is not active, and then finding patients with similar symptoms, can help identify these targets. 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 —including U-M's top honor for research, the Distinguished University Innovator award.

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."