At U-M, 40 Years Of Gaucher Research Rewarded With FDA Approval

On August 19, the FDA approved eliglustat (Cerdelga) for the rare genetic disorder Gaucher disease. Marketed by the Genzyme division of Sanofi (NYSE: SNY), it’s a pill, which gives at least some of the 10,000 Gaucher patients worldwide an alternative to the intravenous infusions currently on the market. But it also represents something else: the culmination of four decades of research at the University of Michigan, from concept through clinical trials, that the drug’s inventor just missed seeing come to fruition.

“Really, [the drug] is the result of a 42-year project,” says Jim Shayman, a U-M nephrologist trained in lipid biology and pharmacology. The research was initiated by Norman Radin, a U-M neurochemist. Radin died last year in California at the age of 92.

Gaucher affects the body’s organs and tissues, causing an enlarged spleen and liver, bone lesions, and painful neurologic complications. It is caused by a defective enzyme called glucocerebrosidase, which malfunctions and allows a glycolipid—a fat-sugar molecule—called glucosylceramide to accumulate in organs, white blood cells, and bone marrow, and it can result in the spleen growing to 50 times its normal size. This often-deadly accumulation is known as a lysosomal storage disease, and Gaucher is one of many.

Other Gaucher treatments, including Genzyme’s pioneering drug Cerezyme, replace the defective enzyme. But Radin’s work was based on a different idea: preventing the production of glycolipids. “In 1972, Norm decided that the best approach [was] to find a small molecule to block the synthesis of glycolipids,” says Shayman, who began working with Radin on Gaucher drug research in 1988.

By the time Radin retired, they had isolated a lead compound. In a major breakthrough, Shayman’s group optimized this compound and successfully demonstrated it to be active and effective in mouse models of lysosomal storage diseases. “A lot of the science was directed at understanding what’s blocking the pathways,” Shayman explains.

Shayman considered forming a startup to bring the drug to market, but the decision was made instead to license the product to Genzyme in 2000. “We worked with them over the next few years on studies to get approval for clinical trials,” he says.

Eventually, the drug was the subject of phase 3 clinical testing, with 400 patients in 60 medical centers in 29 countries, which was the largest Gaucher trial ever conducted. Further clinical study is needed, but Shayman also believes Cerdelga could potentially be more effective than traditional treatments in preventing bone loss.

Shayman admits that he was initially skeptical that Radin’s treatment idea would work. The compounds they were working with at first weren’t specific enough, and Shayman worried that blocking the pathway to synthesis of glycolipids would be toxic. But today, he says having the drug approved by the FDA has “led to a feeling of professional satisfaction and fulfillment that, quite frankly, I never anticipated I would experience. It happens so rarely to people working in academia.”

Shayman says that Radin passed away knowing his drug was moving toward FDA approval: “He lived long enough to know clinical trials were positive and would likely be successful.”

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