Perfusionist Todd Bender, L.C.P., administers a drug developed at Vanderbilt to treat pulmonary hypertension in children during bypass surgery. (photo by Neil Brake)
Trial expanded for drug therapy created at VUMC
Pam Berry, R.N., talks with Kenya Harris, whose daughter, La’Lani, is taking part in the trial. (photo by Neil Brake)
The first large, multi-center trial of a drug developed at Vanderbilt to treat dangerous pulmonary hypertension in children has been launched.
The drug, Citrupress, is an intravenous form of the amino acid citrulline, which the body produces naturally and which is also found in watermelon rinds.
“About 20,000 or more children every year in the U.S. could benefit from this,” said Rick Barr, M.D., chair of the Division of Pediatric Critical Care and co-inventor of the new drug. “We know about 20 percent of children who have heart surgery with use of the bypass pump develop pulmonary hypertension, or high blood pressure in the lungs. In our early studies we have found our formula appears to prevent pulmonary hypertension from developing.”
So far, Barr and colleagues have enrolled approximately 60 children at the Monroe Carell Jr. Children's Hospital in the study. Beginning this month, seven more medical centers around the country and five international centers will join the study. The goal of enrolling 500 young heart patients could be reached as early as next year, Barr said.
“Citrulline is an amino acid we all make in our bodies naturally, and it does exist in large amounts in watermelon,” said Barr. “What we found from our research is that some children, when under the stress of congenital heart defect surgery using the heart/lung bypass machine, slow — or even stop — the production of their own citrulline. We found that was a strong indicator for development of pulmonary hypertension after surgery.”
Six-month-old La'Lani Harris is one of Vanderbilt's first study participants. She needed open heart surgery with the use of the heart/lung bypass machine for repair of a complex heart birth defect. Surgery took place Jan. 10, performed by David Bichell, M.D., chief of Pediatric Cardiac Surgery.
During surgery, a large amount of either Citrupress or placebo is pushed into the fluid circulating in the heart/lung bypass machine.
“It's a key time because it is at the height of the stress on the heart, said Pam Berry, R.N., the research nurse enrolling patients in the Vanderbilt arm of the study. “Then four to 48 hours after surgery more is administered by IV. At 48 hours, we know most children resume producing their own Citrulline again.”
La'Lani's parents may not know if she actually received the medication, but they say they were happy to participate in the study, especially since early trials found no side effects.
“That combined with the fact Citrupress is manufactured from a natural substance, and citrulline is a substance our bodies make anyway, means this drug could be very safe to use,” Barr said. “That is important because it may allow us to give the drug to anyone without genetic testing to prove who might benefit the most.”
The other centers that are now beginning to enroll patients are: Riley Children's Hospital in Indianapolis, Texas Children's Hospital, St. Louis Children's Hospital, the University of California, San Francisco Children's Hospital, Cincinnati Children's Hospital, and Hope Children's Hospital in Chicago. Five hospitals in the United Kingdom, Argentina and Thailand are also involved.
VUMC-created drug winding through approval process
Vanderbilt researchers, along with the Office of Technology Transfer and Enterprise Development, are working with commercial partner Asklepion Pharmaceuticals to guide the new drug Citrupress through the patenting and commercialization process.
This appears to be the first time a drug formulated at Vanderbilt has made it to Phase III trials under orphan drug status (drugs developed to serve low-frequency diseases).
The drug, an intravenous form or the amino acid citrulline, is being studied for prevention of pulmonary hypertension in children undergoing open-heart surgery.
“We see a lot of hopes and dreams come through the door and it is especially gratifying to be involved in the evolution of an early-stage invention through to a product that can have real impact for treating disease,” said Janis Elsner, associate director of the Office of Technology Transfer and Enterprise Development.
Brentwood-based Asklepion has a licensing agreement with Vanderbilt for further development of the drug as a commercial product as it moves through its first large-scale, international trial. But the drug's discovery and testing has been guided by a team of Vanderbilt researchers and physicians.
Marshall Summar, M.D., director of the program in translational genetics in the Vanderbilt Center for Human Genetics Research has been involved throughout the process.
“This is an excellent example of teamwork in discovery,” said Summar. “I like simple, and this is simple. This all comes down to our understanding of the nitric oxide cycle. The knowledge that replacing one chemical that dips at a critical part of the cycle — when the body is under unusual stress — could apply to so many things. And citrulline is such a simple and innocuous supplement, that's what makes this so exciting."
Broad testing is under way to garner Food and Drug Administration approval. In addition to the pediatric heart surgery study, there are clinical trials planned for bronchopulmonary dysplasia, status asthmaticus and hepatic veno-occlusive disease.
The Investigational Drug Pharmacy will manage the clinical drug supplies for each trial site as well as randomization. Vanderbilt's Computational Genomics manager, David Sexton, built the Web-based tool for sites to use.
Ann Kavanaugh, M.D., associate professor of Pediatric Cardiology, and Jeff Canter, M.D., M.P.H., associate professor of Medicine in the Center for Human Genetics, will work with Summar and Rick Barr, M.D., chair of Pediatric Critical Care and co-inventor of the new drug, on aspects of data collection and analysis.
“This is an excellent example of teamwork in discovery and it goes all the way back to a conversation I had with one of our chemotherapy experts, Brian Christman, years ago which sparked the initial idea, then to work with a neonatal researcher regarding the urea cycle and finally to Dr. Barr,” said Summar.