New Drug Could Treat Parkinson's
More than 6 million people suffer from Parkinson's disease worldwide, and that number is predicted to double by the year 2030. Current treatment with L-dopa drugs leaves much to be desired. Most patients — as many as 80 percent — who take L-dopa drugs develop dyskinesia, a painful involuntary movement disorder, within five years.
Now a new drug for Parkinson's disease is on the horizon. Sandhya Kortagere, PhD, associate professor of microbiology and immunology at the College of Medicine, has designed a drug that offers a promising alternative without the dyskinesia, "a side effect as dangerous as the original symptoms themselves," according to Kortagere.
The compound developed by Sandhya Kortagere, PhD, shows great promise.
Known as PCT-3010, the compound developed by Kortagere modulates both dopamine and norepinephrine in the brain to reduce motor and other symptoms.
Kortagere began studying dopamine receptors while pursuing her doctorate. During her postdoc years, she deepened her study of a class of receptors called the D2-like, which includes D2, D3 and D4 receptors. The D3 receptors were widely acknowledged to be difficult to understand, but Kortagere believed they might hold the key to a breakthrough and persisted in her studies, using computational models and in vitro and in vivo techniques — a unique aspect of her work. Her research demonstrated that dopamine agonists used to treat Parkinson's induce tolerance in D3 receptors. "This we thought was a main issue with a lot of the dopamine drugs," she explains. "They lose efficacy over time due to the tolerance and also cause side effects such as dyskinesia, whose molecular mechanisms are still not well understood."
Through computational models and in vitro experiments, Kortagere was able to show that D3 receptors behaved differently than D2 receptors, which are otherwise very similar. In addition, other researchers have shown that the levels of D3 receptors are altered in Parkinson's patients and those with dyskinesias. "In the presence of dopamine agonists, you could actually see a very different conformation or change in the D3 receptors," she observes. "This formed the basis for the whole project."
Kortagere tested this hypothesis using a small molecule. "My lab has developed a platform technology called the hybrid structure-based method, where we use biophysical, experimental inputs, and we designed the small molecule using this hybrid technology. We only wanted to affect the D3 receptor and alter its signaling since that was the end point we wanted to measure."
Kortagere also wanted to measure her drug compound's ability to take away the tolerance induced by other agonists such as dopamine. "Our compound did block those effects," she relates.
"When we started doing more molecular studies, we discovered that the compound has very atypical properties of signaling," she continues. "It modifies the kinetics of the D3 receptors in addition to altering the signaling properties. This was the kind of molecule we were looking for."
The next level of studies showed that Kortagere's drug compound improves the motor deficits associated with Parkinsonian symptoms, and reduces L-dopa-induced dyskinesia. "When I saw that, I said, 'It's going to be a new therapy.' If you look at videos of dyskinetic patients, it's gut wrenching. So I decided I should take this further. If we can make a difference in even one of those patients' lives, it would be worth all the effort. That is my goal."
To obtain funding to take research beyond academia is challenging, Kortagere acknowledges. But, undeterred, she went to Drexel's Office of Technology Commercialization and applied for a $100,000 grant from the Drexel Ventures Innovation Fund. The grant enabled her to study the pharmacokinetic properties of her compound and to evaluate if her compound was drug-like and whether it could be developed as a drug. The results were positive.
Next, Kortagere applied for and received a $100,000 award from the Coulter-Drexel Translational Research Partnership program, which she used to further validate the drug. "We were very happy with initial proof of concept studies," she says.
Kortagere also studied the compound's ability to lessen the cognitive deficits that Parkinson's patients often experience. "These deficits are very mild when the disease starts, and they progress as the disease progresses," she explains. "There is some evidence that cognitive deficits start at least 10 years earlier than the motor deficits." Her experiments have shown that her compound reduces those cognitive deficits.
Kortagere went back to the Coulter program for a second year of funding, requesting $150,000. The oversight committee was so impressed with her accomplishments that they gave her a $232,000 grant, large enough to support longer toxicology and safety studies required by the U.S. Food and Drug Administration.
"We are developing drugs that are probably going to make a change in the treatment of Parkinson's," says Kortagere. "We are now raising funds that can match the Coulter grants to continue our work." Kortagere estimates that clinical trials will begin in about two years. "If everything progresses the way we have planned, we hope to go to the FDA for an investigational new drug submission at the end of 2017 and receive approval by early 2018. Then we expect clinical trials to begin," she says.
In the meantime, Kortagere is looking ahead to commercialization. Working with Heather Rose, JD, PhD, licensing manager with Drexel's Office of Technology Commercialization, she has filed international patent applications and has created a company, PolyCore Therapeutics LLC, to commercialize the drug. Kortagere serves as chief scientific officer of the startup; Jim Harris, a retired Merck executive with extensive experience in Parkinson's drugs and commercialization, is CEO. PolyCore's goal is to raise enough funds to partner with a strategic pharmaceutical company to take the drug further into clinical trials.
From Discovery to Commercialization
Taking a drug from discovery to patent to commercialization is a lengthy process with many potential pathways. Drexel’s Office of Technology Commercialization helps Drexel scientists navigate this complex process.
When should you apply for a patent?
“As a nonprofit academic institution with a mission to further research and help the public grow knowledge, we are obligated to publish research,” says Heather Rose, licensing manager in the Office of Technology Commercialization. “However, once a patentable invention has been publically disclosed, such as in a publication, in most countries around the world one is precluded from filing for patent protection on the same invention. In the United States, there is a limited exception that allows an inventor one year after public disclosure to file a patent.”
For this reason, Drexel filed a provisional patent on Sandhya Kortagere’s work (see cover story) soon after it was disclosed to the Office of Technology Commercialization.
A provisional patent application isn’t a true application, says Rose. “It serves as a ‘stake in the ground’ for one year, protecting your discovery while you decide whether to pursue a patent,” she explains. “If you decide to do so, you need to file a conversion application. At that point, it becomes a real patent application.”
Another option for filing is a Patent Cooperation Treaty application. The PCT application reserves your right to file in 148 countries around the world that participate in the treaty. This buys filers another 18 months to decide in which countries they want to file. After that, prosecution (review) starts. ”For Dr. Kortagere, we filed a provisional and a PCT application upon receiving the invention disclosure, and then went international in India, Japan, China and Europe because Parkinson’s is a global disease,” Rose says. “She has been issued patents in the U.S. and Australia and is awaiting prosecution in the other countries.”
Scientists generally have two choices for commercialization of their discovery: licensing the intellectual property to an existing company or forming a startup company. The decision is based on how far away from market the product is. If a discovery has a long way to go to get to the market, a startup is usually a necessary step.
“Therapeutics are generally six to 10 years and several million dollars away from market,” says Rose. Drexel’s Office of Technology Commercialization helps to match scientists with individuals who can bring business expertise to the startup and assist in fund raising for strategic de-risking. Rose paired Kortagere with Jim Harris, now CEO of PolyCore Therapeutics.
In this case, the scientist has also been diligent about talking to potential pharmaceutical partners. “Although it’s too early in the research for a pharmaceutical company to jump in, Dr. Kortagere is laying important groundwork now by asking for feedback and learning what companies are looking for,” Rose says. “A lot of people are interested in her project.”
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