The experimental drug baricitinib reduced a key sign of kidney damage in people with diabetic kidney disease, according to results from a controlled Phase II study. University of Michigan Medical School researchers presented the data at the American Diabetes Association Scientific Sessions, held this past week in Boston.

A team led by Matthias Kretzler, MD, and Frank Brosius, MD, had worked for years to pinpoint the importance of a cell-signaling system called JAK-STAT in diabetic kidney disease.

They plowed through data on abnormal genetic activity in diseased human kidney tissue, and studied specially bred mice,  and eventually demonstrated that JAK-STAT was over-active in multiple kidney cells damaged by diabetes.

JAK-STAT also plays a key role in diseases where immune-system cells attack normal tissues – such as rheumatoid arthritis. Lilly scientists had developed baricitinib to calm the painful, inflamed joints of RA patients, and had received FDA permission to do trials that showed the drug’s safety and impact.

When they learned that Kretzler was scheduled to speak about his research to another group at Lilly, they went to his talk and raised the possibility of using baricitinib against diabetic kidney disease. The international clinical trial, which enrolled 129 adult patients, began 14 months after that meeting.

“This is the first example of implementing precision medicine in diabetic kidney disease, which affects 8 million Americans and will surely affect more as the growing diabetes epidemic continues,” says Kretzler. “It shows that the full translational research pipeline is in place, where we can study disease mechanisms, test our findings in model systems, identify drug candidates, find the right partners to take it to a clinical trial, and complete the trial – in 42 months.”

How the drug affects diabetic kidney disease
The trial showed baricitinib reduced a measure of kidney dysfunction called urinary albumin/ creatinine ratio or UACR, substantially compared with placebo after six months. It also showed that patients had lower levels of two compounds in urine or blood that indicate inflammation in the kidneys, called IP-10 and sTNFR2. The only significant side effect was mild anemia in the group that received the highest dose, which was expected based on previous research.

Brosius directed the animal research studies and co-led the multi-institutional clinical trial. He notes that treatment of diabetic kidney disease costs the U.S. billions of dollars yearly. Currently, the standard approach to treating kidney damage in people with diabetes is to control blood pressure using decades-old drugs called ACE inhibitors and ARBs.

“The long-term effects of America’s obesity and diabetes epidemics means that millions more kidneys are at risk. So America urgently needs new approaches to stem the damage that diabetes inflicts on kidney cells,” says Brosius, who heads U-M’s Division of Nephrology and the Michigan Kidney Translational Core Center that helped support this work. “So does the world, as nations like China feel the effects of obesity and diabetes epidemics.”

The new trial results are the first step in determining if baricitinib or other drugs that act on the JAK-STAT system could fight these effects. But they also show promise of combining basic university research, which can uncover specific targets for precise-acting drugs, with drug compounds developed by pharmaceutical companies.

Even drugs left on the shelf years ago, or already in use for other diseases, could be tested for new uses based on research findings from teams like the U-M group.

The U-M Medical School’s Business Development team helped make the linkage between U-M and Lilly possible, and has brokered other agreements under which companies sponsor research by U-M teams to find specific targets for drugs.

 “Not only does system biology works for finding new drug targets and repurposing drug compounds that already have been tested safely in humans. It can work quickly,” says Kretzler.

Read the abstract of the results presented at the ADA meeting: http://www.abstractsonline.com/pp8/#!/3699/presentation/12757

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