May 19, 2006

Diabetes therapy research gets boost from tech transfer

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Billy Hudson, Ph.D., is working on a compound that may prevent kidney damage caused by diabetes.
Photo by Anne Rayner

Diabetes therapy research gets boost from tech transfer

NephroGenex Inc. has acquired commercial rights to a compound identified by Vanderbilt University Medical Center scientist Billy G. Hudson, Ph.D., that may prevent diabetic neuropathy — kidney damage caused by diabetes.

Hudson co-founded the North Carolina-based biotechnology company in 2004 to help translate basic research discoveries — including the compound he discovered, pyridoxamine (brand name Pyridorin) — into new drugs for the treatment of kidney disease.

“Kidney disease is a special challenge for drug development, owing to the diversity of drug response among patients,” explained Hudson, director of the Vanderbilt Center for Matrix Biology.

“NephroGenex is a new biotech company spun out from Vanderbilt with a novel approach to get the right drug to the right patient — a form of personalized medicine.”

Chronic high levels of glucose in the bloodstream, a hallmark of diabetes, can cause “oxidative stress” through production of oxygen-containing reactive compounds that damage tissues throughout the body. Pyridorin is a vitamin B6 derivative that can scavenge and inactivate these damaging compounds in the kidney.

In two Phase II clinical trials, Pyridorin has been shown to slow the progression of diabetic neuropathy, NephroGenex officials announced last week. The company also has signed a licensing agreement with Vanderbilt covering use of Pyridorin as a treatment for acute renal failure.

“We were surprised to see such a dramatic increase in oxidative stress-induced reaction products in acute renal failure patients, even when compared to end stage renal disease patients on dialysis,” said T. Alp Ikizler, M.D., medical director of Vanderbilt's Outpatient Dialysis Unit, in a company news release.

“These oxidative reaction products have been thought to play a significant role in the inflammatory response seen in organ failure and other critical care conditions. Our results highlight their potential pathogenic significance in (acute renal failure).”

Company officials said they plan to evaluate Pyridorin as a treatment to reduce the severity of acute renal failure, and to decrease the mortality rate among acute renal failure (ARF) patients in the intensive care unit.

“Approximately 100,000 cases of ARF develop in critically ill patients in the U.S. each year,” said J. Wesley Fox, Ph.D., president and CEO of NephroGenex, in the news release. “If pyridoxamine proves effective against ARF, it may also have application to other types of organ failure syndromes, such as acute respiratory distress syndrome and acute pancreatitis, where oxidative stress is also believed to be a significant contributing factor.”

Fox is a former postdoctoral student of Hudson's at the University of Kansas. In the early 1990s, they were studying the extracellular matrix, the spaces between cells that shape tissues and influence a host of cellular processes

Chronic exposure to high levels of glucose can alter matrix proteins, a process called glycation, in a way that can induce oxidative stress, inhibit kidney function and which ultimately can lead to kidney failure. Fox challenged his mentor to find a drug that would prevent these diabetes-induced matrix changes.

“I said, 'That sounds good, but I don't really have the money to do that,'” Hudson recalled in an interview last year. Fox replied that he would find the money if Hudson worked on the drug.

In 1994, Fox, Hudson and colleagues at the Karolinska Institute in Sweden founded BioStratum, a biotech company dedicated to pursuing the matrix as a drug target. Within a couple of years, Hudson and his colleagues at Kansas had reported that pyridoxamine could prevent the glycation-related pathology that contributes to diabetic kidney disease.

Hudson continued his work when he moved to Vanderbilt in 2002, and in 2004 founded NephroGenex with his collaborator at the Karolinska Institute, Karl Tryggvason, M.D., Ph.D.

Included in the licensing agreement with BioStratum are second-generation compounds, including BST 605, which “exhibits significantly improved potency over Pyridorin, and has successfully completed initial preclinical efficacy and toxicity studies,” NephroGenex officials announced last week.

Because the progression of diabetic kidney disease varies significantly from patient to patient, large, lengthy clinical trials are necessary to determine whether a new treatment is effective.

NephroGenex is applying advances in molecular urinalysis to distinguish between patients, called “progressors,” whose disease progresses rapidly, from patients with slow progressing disease. Studying the more rapid “progressors” will reduce the number of patients needed for the definitive Phase III clinical trials, and the time and cost required to conduct them, company officials said.

Hudson is the Elliot V. Newman Professor of Medicine and Biochemistry.