Triad teams tackle diabetes

Commercial and academic researchers alike in North Carolina’s Piedmont Triad region are making headlines for their unique approaches to finding diabetes treatments.

Amy Swinderman
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PIEDMONT TRIAD, N.C.—Commercial and academic researchersalike in North Carolina's Piedmont Triad region are making headlines for theirunique approaches to finding diabetes treatments. Attracted by the commercialpotential of the diabetes epidemic—which, according to the National Institutesof Health is currently the seventh leading cause of death in the UnitedStates—scientists and laboratories in this growing research community aregenerating buzz with the multi-pronged ways they are tackling this seriousproblem, and newspapers and radio stations are spreading the word.
Most recently, Winston-Salem-based Targacept announced Feb.9 that it has initiated Phase II clinical studies of TC-6987, a modulator of thealpha7 neuronal nicotinic receptor, in both type 2 diabetes and asthma.Targacept's evolution to this trial is an interesting one: Founded in 1997 as asubsidiary of R.J. Reynolds Tobacco Co., Targacept spent its early yearsstudying the chemistry and biology of nicotine. Many of the company'sscientific papers and abstracts focused on neuronal nicotinic receptors (NNRs),a unique class of molecular targets in the body that maintain and adjustnervous system activity. This work suggested a role for NNRs in the treatmentof human disease and led to the spinoff and creation of Targacept as a publiclytraded company that has several Big Pharma alliances today.
"Initially, Targacept genuinely wanted to understand theeffects that nicotine was having on people," says Dr. David Hosford, vicepresident of clinical development at the company. "Very quickly, our scientistsrealized that they had the potential to apply some of the benefits of nicotine,while avoiding some of the bad things about it. Recently, we recognized thattailoring molecules to certain nicotinic receptors enables us to have an impacton inflammation."
Coming at diabetes from an inflammation-centered approach,Targacept believes that TC-6987, coupled with the well-established role ofalpha7 in cytokine-mediated inflammation, could benefit patients who sufferfrom the serious effects of inflammatory disorders and the limitations ofcurrent therapies.
The Phase II study in type 2 diabetes is a multicenter,double-blind, placebo-controlled, randomized parallel group trial beingconducted in the United States. The study plans to enroll about 120 adultpatients with type 2 diabetes. The study is designed to include a number ofdifferent efficacy measures that would show anti-inflammatory effects of TC-6987and inform potential future development.
Change in fasting plasma glucose, ametabolic measurement used to expose problems with insulin function, frombaseline to end of dosing for patients receiving TC-6987 as compared to placebohas been designated as the primary efficacy outcome measure. The study alsoincludes assessments of safety, tolerability and pharmacokinetics of TC-6987.
"One of the reasons this molecule works in diabetes is thatit targets another inflammatory molecule in diabetes and tumor necrosis factor(TNF), a cytokine involved in systemic inflammation," explains Dr. ChrisDvergsten, Targacept's clinical study manager. "It's part of the inflammatorycascade such that high levels of it make inflammatory conditions worse. Welowered them in a mouse model of diabetes. In our work to date, it has beensafe and well tolerated, making us confident enough to take it into a sickpopulation and know that it will be safe there, too.
"If the Phase II trial is successful, we may take it all theway to market, or try to partner with a pharma partner," Dvergsten adds.
Targacept's neighbor to the east, TransTech Pharma, is alsoattracting a lot of attention for its work in diabetes. Last year, theclinical-stage pharmaceutical company signed a deal with Forest Laboratoriesfor limited rights to its research into glucokinase activators (GKAs) tocontrol how the liver processes glucose—a deal that could garner TransTech asmuch as $1.1 billion.
Since the company's inception in 1999, TransTech has beenfocusing on not just diabetes, but also the related effects the disease has ona patient's cardiovascular health, says Dr. Adnan M. Mjalli, the company'sfounder, president and CEO.
"Half, if not more, of our company's resources are focusedon looking for innovative ways to control diabetes, as well as ways to limitrelated cardiovascular risk, both of which are part of the growing obesityproblem in the United States," Mjalli says. "To date, we've spent more than$200 million on diabetes—I'm not aware of any other company in the Triad thatspends that amount on diabetes." 
TransTech has "at least four programs in the clinic and abunch more that are not in the clinic yet," Mjalli says. The company hasidentified a series of liver-selective GKA compounds and has advanced threecompounds to Phase I trials, with one compound ready to start Phase II trials.Multiple observations suggest that a reduction in hepatic glucose utilizationmight contribute to the hyperglycemia observed in humans with type II diabetes.Thus, the pharmacological enhancement of glucokinase activity may lower bloodglucose in diabetic patients, the company believes. 
Moreover, by activating glucokinase selectively in the liverbut not in the pancreas, it may increase glucose utilization and lower bloodglucose levels without inducing excessive insulin secretion, thus reducing therisk of hypoglycemia, Targacept says. Data from early clinical experiments withTransTech's GKA compounds indicate that the licensed GKAs appear to be well toleratedwith no evidence of hypoglycemia.
Furthermore, testing to date shows that oraladministration of the compounds reduced fasting blood glucose levels.
"Our molecules not only control glucose, but also lowertriglycerides and low-density lipoprotein (LDL), two key signatures of thepotential risk of cardiovascular disease," Mjalli says. "FDA guidelines havebeen putting a lot of pressure on pharma companies to ensure that their studiesinvolve no cardio-adverse events. Our approach not only has no cardio-adverseevents, but has a cardio benefit."
Meanwhile, on the academic side, researchers at Wake ForestUniversity are honing in on the genetic causes of diabetes. Funding fordiabetes research across several of the university's departments totaled about$33 million last year, says Dr. Donald Bowden, director of the university'sSchool of Medicine Center for Diabetes Research.
"Diabetes research spans a wide range of areas here at WakeForest, from people doing research in cell and animal models of diabetes, allthe way up through studies of treatments in clinical trials in a population ofpeople in our community who have diabetes," Bowden says.
Bowden's lab focuses on understanding "the mechanisms bywhich one person develops diabetes, and one who doesn't," he says.Specifically, he and his colleagues are probing how genetics contribute to theincidence of diabetes in minority populations.
"Each minority group has a spectrum of genes that contributeto their risk of developing diabetes," Bowden explains. "We have a very largecollection of DNA from people with and without diabetes—the largest single suchcollection in the business. One of the rationales for doing this kind ofresearch is that if we find genes we can prove make a person more likely todevelop diabetes, we can also target that gene and the pathway that may beinvolved in it to develop ways to improve or reduce a person's risk ofdeveloping diabetes. This is something a pharma company might be interested inif they are trying to find a pathway that allows them to alter how peoplemetabolize glucose."
Ultimately, Wake Forest researchers hope that this approachwill enable pharma companies and doctors to tailor treatments toindividuals—treatments not just for diabetes, but other diseases and conditionsthat are diabetes-related.
"With diabetestreatments, you can treat patients, but not return them to the metabolic statethey were in before they developed diabetes," Bowden says. "This is a new,prominent area of research. We're trying to understand that if you returnsomebody to a normal level of glucose, is that going to prevent or delay badthings from happening to people with diabetes, like heart disease and kidneydisease."
Editor's Note: Over the last two years, ddn has been reporting on variouspharma/biotech hotspots, and the news coming out of the Triad is a great opportunity to explore what's going on in this growing researchcommunity. Click here to view our related blog post topic, "Spotlight on the Triad."

Amy Swinderman

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