Metabolic Solutions tests new product

October 10, 2008
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Two scientists who helped develop the current leading treatment for type 2 diabetes during their years with the Upjohn Co. are entering into second phase clinical trials in Kalamazoo, Grand Rapids and 12 other locations on a drug that could turn out to be the primary new drug for type II diabetes, the most common form.

Jerry Colca, Ph.D., and Rolf Kletzien, Ph.D., have both spent their careers working on treatments for type II diabetes. Both were leaders in diabetes discovery with Upjohn and its successors until their retirement in 2005. The two co-founded Metabolic Solutions in January 2006.

The lead compound of the drug they developed performed well in two successful Phase I trials conducted recently at the Jasper Clinic in Kalamazoo. The first trial involved 40 healthy individuals and the second 48 healthy individuals. In a Phase I trial, clinicians try to determine whether the drug is safe in the human system; they don’t try to prove the drug works on people with the disease, explained Mark Olesnavage, CEO of Metabolic Solutions.

Now in the Phase IIa trials, they’re seeking human data proof that the drug works with the diabetic population. Data from Phase IIa trials probably won’t be available until late spring 2009, Olesnavage added. That data will be used to plan for a longer, Phase IIb study involving more diabetics, which will launch in late 2009. 

“It’s a critical study for the company,” Olesnavage stressed. “Pre-clinical studies with animals suggest that this compound can deliver significant pharmacological benefit without some of the complications inherent in current therapies for type II diabetes.”

He noted that current leading therapies for the disease can cause side effects such as weight gain and edema, as well as the potential for congestive heart failure and bone loss.

Over time, diabetes can damage the heart, blood vessels, eyes, kidneys and nerves. Too, it’s one of the leading causes of kidney failure. The American Diabetes Association estimates 17.9 million people have been diagnosed with diabetes, while some 5.7 million — one in four people — aren’t even aware they have the disease.

Up until 1989, the only treatments being used for type II diabetes just caused the pancreas to secrete more insulin, Colca said. Meanwhile, scientists at Upjohn and the Japanese firm of Takeda Pharmaceutical Co. had discovered insulin-sensitizing thiazolidineiones, or TZDs, which make the body’s cells more sensitive to insulin, so less is needed to move glucose from the blood into the cells. They began doing research on compounds that would affect insulin sensitivity. The researchers hypothesized that they could affect insulin sensitivity rather than just release insulin, Colca explained. The first drug they came up with that made it into the clinical setting was Piolitazone, a drug that falls into the TZD class of drugs. The drug has been marketed domestically since 1999 under the brand name Actos.

“Now you could treat diabetes not just by releasing more insulin but really get at the cause of it, which was increasing the way insulin works on target cells,” Colca explained. “At the time, nobody really knew how those drugs worked in molecular terms: they just worked. But a hypothesis came out of the Upjohn group and Rolf’s research that these compounds worked by activating the nuclear receptor called PPAR gamma, or PPARy. That was in the mid-1990s.”

From that point on, pharmaceutical companies tried to make activators of that nuclear receptor, but Colca and Kletzien’s research group believed that was the wrong direction: They believed direct activation of the nuclear receptor should be avoided. However, the momentum that steered researchers in the direction of PPARy continues to this day, Colca noted. Over the last 15 years, more than 50 compounds have been tested in attempts to activate PPARy and all have failed, he pointed out.

“Meanwhile, the standard bearer, the best compound, is still the first one that we were developing in the middle 1980s — Actos. It’s still the market leader today in this class of drugs,” Colca said. But both current treatments for type II diabetes — Actos and Avandia — can generate unwanted side effects such as fat deposits, increased fluid retention and changes in the vascular and circulating lipids. There are other classes of drugs that have been approved for diabetes but they concentrate more on lowering blood glucose, Colca said. There have been no new approved diabetic medications in the TZD class of drugs other than Actos and Avandia.

“What occurred to Rolf and I after working in the field so long was that all those bad side effects were through this nuclear receptor PPAR gamma,” Colca said. “In fact, most people believe that those side effects are due to PPAR gamma activation. We realized that the really beneficial effects of the drugs are on a totally different target, in a different part of the cell: They actually work on the part of the cell that creates energy, the mitochondria. It’s a novel target that we’re still defining. That’s our unique insight: that these drugs can be improved by optimizing their effect on a different target and taking away their ability to activate this nuclear receptor.”   

The drug Metabolic Solutions is developing with the aid of its Michigan-based partners targets risk factors associated with TZDs. The company has development partnerships with research laboratories and business services firms in the Kalamazoo and Grand Rapids areas. It’s tapping the expertise of many professional people with years of experience — people just like Colca and Kletzien who were employed in R&D at the large drug companies and stayed in West Michigan when those companies left. In a previous interview with the Business Journal, Colca said there is enough expertise in West Michigan to build an entire drug company around the compound Metabolic Solutions has developed.

The company believes its first product — trademarked Mitoglitazone — could be approved for patients by 2013. Colca, Kletzien and their team are also evaluating combinations of the drug with other agents to control key cardiovascular risk factors. As Colca pointed out, most people with diabetes don’t die of diabetes — they die from cardiovascular disease. He said in a study published by another group last year, Piolitazone was the first drug shown to actually reduce heart attacks and strokes in type II diabetic patients. Olesnavage said the company is hopeful there’s a chance its product will lower blood pressure.

“If we’re successful in coming up with an improved insulin sensitizer that doesn’t have the side effects, it would mean a significant improvement in therapy,” Colca said. “We could change the way the disease is treated so it will be treated earlier, and that will have more impact on health care outcomes.” 

The Granholm Administration announced Thursday that Metabolic Solutions was one of 17 companies selected by the Strategic Economic Investment and Commercialization board to share nearly $30 million from the 21st Century Jobs Fund. Metobolic Solutions was awarded $2.4 million. The awards go to companies that are on the brink of turning their scientific or technological innovation into a product or service. 

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