New clinical uses for old hypertension drug leads to several patents

Long translational research road delivers

University of South Florida neuroscientist R. Douglas Shytle's discovery of successful new clinical uses for mecamylamine, a drug once used to treat hypertension, has led to several issued patents on mecamylamine and related compounds. Earlier this month, Shytle, associate professor and research scientist at the USF Center of Excellence for Aging and Brain Repair and the USF Silver Child Development Center, received the university's 2009 "Excellence in Innovation" award.

The award recognizes Shytle's translational research achievements in developing new intellectual property based on clinical research and novel pharmacological discoveries which have led to newly commercialized therapeutics. His most recent success is with a new experimental antidepressant, known as TC-5214, which is covered by USF patents and licensed to Targacept, Inc., a clinical-stage biopharmaceutical company that develops neuronal nicotinic receptor therapeutics. Targacept recently announced the positive results on TC-5214 as add-on treatment in a large clinical trial of adult patients with treatment-resistant major depressive disorder.

While the Innovation Award encourages USF faculty to "think out of the professorial box," for Shytle the road leading "out of the box" and to the success of TC-5214 was long, winding, and strewn with professional and emotional ups and downs as well as moments both serendipitous and Eureka.

"TC-5214 is a unique form of an old Merck drug called 'mecamylamine,' once used to treat severe hypertension in the 1950s," Shytle said. "Because later research suggested that mecamylamine interacted with brain nicotine receptors, we thought it might have a variety of therapeutic effects similar to nicotine, but without the side effects and addiction."

Building on earlier USF clinical research using transdermal nicotine to treat patients with Tourette's syndrome (characterized by body movements (tics) and vocalizations), Shytle, worked closely with USF professors, Archie A. Silver, MD; David Sheehan, MD; and Paul Sanberg, PhD, DSc, to investigate the effects of mecamylamine in Tourette's patients to see if it could help control their symptoms, as observed with nicotine.

"After carefully designing and conducting a large clinical trial in children with Tourette's syndrome in 1999, we were shocked and disappointed to find that the drug had no effect on the tic symptoms," Shytle said. "After reading several reports about how many antidepressants appeared to be interacting with nicotine receptors the same way as mecamylamine did, we decided to go back and take a second look at the data from our clinical trial. And there it was, like finding a gold nugget buried under the sand, clear evidence for an antidepressant effect of mecamylamine, but not for the placebo, in those Tourette's subjects who had depressive symptoms."

Based on those clinical findings, the researchers published a hypothesis paper in the prestigious journal, Molecular Psychiatry, proposing that nicotine receptor blockade might represent a novel pharmacological target for achieving therapeutic antidepressant properties. That hypothesis has now been supported by three clinical trials with mecamylamine, one by a group at Yale and two larger studies conducted by Targacept. The latest trial was conducted using TC-5214, a unique form of mecamylamine, predicted by the USF patents to be more effective with fewer side effects when compared to the older parent drug.

The results of this study are expected to have profound implications for the future treatment of major depression, making TC-5214's impact on the market potentially huge.

"The Excellence in Innovation Award that Dr. Shytle received is a testament to the kind of creative translational research that attracts excellent industry partners, like Targacept, who have the vision and technical expertise to take our intellectual property to the next level of commercial development," said Sanberg, associate vice president for research and innovation at USF.

The USF license agreement with Targacept includes a percentage of sublicense and milestone payments as well as a royalty stream through 2021 should the drug achieve FDA approval.

Shytle is an inventor on several USF patents in addition to four on mecamylamine and related compounds.