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Mayo scientist Ronald J. Marler, D.V.M., Ph.D., combines a wealth of experience in drug development with an intense determination to bring better and safer drugs to patients.
This is a story about a novel compound that shows promise as a treatment for patients with congestive heart failure. It is also a parable about the critical importance of collaboration and teamwork. The most exotic element in the story is the green mamba, a venomous snake of tropical Africa. The central figures are John C. Burnett, Jr., M.D., and Ondrej Lisy, M.D., Ph.D., at Mayo Clinic Rochester, who together designed and tested this new compound to hasten drug development and make it ...
The supporting cast is a cohort of people across Mayo Clinic with very different talents but one passion: to get new, better and safer drugs to patients more quickly. Then, there is a twist that makes this a hopeful story not just for people with heart disease, but also for all patients waiting patiently for new treatments stalled in the drug discovery pipeline. Earlier this year, the Food and Drug Administration (FDA) introduced a strategy that can accelerate the testing of promising new drugs in patients.
The race is on: Mayo researchers John C. Burnett, Jr., M.D., and Ondrej Lisy, M.D., Ph.D., are working as fast as they can to develop a new drug for congestive heart failure.
To set the stage, it must be acknowledged that getting a drug from the laboratory to the patient is something like running a marathon in high heels. To the bystander, it seems like an excruciating and inefficient process. Consider the track record: The estimated cost of developing just one new drug ranges from $800 million to $1.1 billion. Often a decade or more of preclinical research occurs before a potential new drug is even tested in patients.
Fewer than one in 10 new drugs ever reaches the marketplace. In 2000, the FDA approved 98 new drugs; in 2005, the number dropped to 15. The primary reason for this precipitous decline is the soaring cost of drug development. There are fewer and fewer applications for new therapies because innovators are concentrating efforts on drugs that promise to bring the highest return in the marketplace.
Dr. Burnett makes a habit of reviewing scientific literature on venomous snakes. He is particularly interested in snakes whose venom contains proteins called natriuretic peptides. Concentrated in venom, these proteins cause rapid dilation of blood vessels. While this is bad news for the snake's prey, natriuretic peptides hold great hope for people suffering from heart disease and hardening of the arteries (atherosclerosis).
"In 1998, we began to work with a novel peptide isolated from the venom of the green mamba," he explains. "We wanted to develop a compound that possessed properties that would be safer and more effective than drugs currently available to patients." To do this, Dr. Burnett and Dr. Lisy created what is called a "designer" or synthetic peptide by chemically bonding a part of the green mamba peptide with a complementary peptide found in endothelial cells that line the human heart and blood vessels.
At this point, they patented their novel peptide. After very promising experimental studies, they began to collaborate with Mayo Medical Ventures (MMV) to explore ways to get the compound into patients. MMV provides the expertise to bring the discoveries of Mayo Clinic's clinical investigators to the marketplace. "Our job is to commercialize the intellectual property of our Mayo colleagues with the goal of helping patients," says Steven Van Nurden, director of Technology Commercialization for Mayo Medical Ventures.
In 1999, MMV licensed the highly promising designer peptide to a technology investment and management company, while Dr. Burnett and his laboratory continued to do preclinical experiments to test its potential as a treatment for heart disease. In 2004, the company returned the discovery to Mayo Clinic. "It didn't click," explains Susan L. Stoddard, Ph.D., the technology licensing manager for MMV. "They couldn't find the right commercial partners. We have a good relationship with this company, and they want to keep the door open, so this made sense for everyone."
Dr. Burnett, understandably eager to move his peptide to clinical tests in patients, began making steps to apply to the FDA for an Investigational New Drug application — or what is known in the research world as an IND. Taking this traditional drug-development pathway would have likely involved many more years of preclinical research, but fortunately at this point Dr. Burnett had a conversation with Ronald J. Marler, D.V.M, Ph.D., who in 2004, joined Mayo Clinic Arizona as associate director for research and Research Alliances and professor of Molecular Pharmacology and Experimental Therapeutics.
Dr. Marler has 30 years' experience in the pharmaceutical industry working to bring drugs to the marketplace. He understands minutely the FDA regulatory process, and he has an abiding passion to streamline drug discovery. His philosophy of drug development is guided by a number of maxims, one of which is "Don't do something because it has always been done that way" — which is precisely what he proposed to Dr. Burnett.
Dr. Marler suggested that a quicker way for Dr. Burnett to test his novel peptide in human subjects would be to apply for an Exploratory IND. The FDA introduced this set of drug-study guidelines in January 2006 as a means of accelerating the process of drug development in the United States.
The Exploratory IND requires less extensive toxicology and safety studies in animal models. It then allows a clinical investigator to administer a drug to a very limited number of people for a very short duration at a dose that ensures the safety of the subjects.
The story of a promising treatment for congestive heart failure and ... The importance of collaboration and teamwork.
"When the Mayo team met with FDA representatives to discuss the approval process, they were quite excited," says Dr. Burnett. "They encouraged us to move forward fast on submitting the IND and gave us some good advice."
Within a few days of this encouraging meeting, a venture capital group approached MMV about forming a new pharmaceutical company around this novel peptide. As part of the licensing agreement, Mayo Clinic will continue to guide the science by performing the preclinical pharmacology studies and conducting the Phase I human trials as part of the Exploratory IND.
Dr. Burnett's green mamba saga, in his opinion, has been a wonderful convergence of cooperation. "This is a great example of Mayo collaboration," he says. "It wouldn't have happened without the seed money Mayo Clinic put into the program over time. Dr. Stoddard and MMV managed the technology transfer exceedingly well, and we couldn't have done this without Dr. Marler's expertise in the regulatory area."
While the final chapter of this exciting story has not yet been written, Dr. Burnett and his colleagues are hopeful that the finale will be a drug that improves the lives of patients with heart disease. The steps along the way have spawned a collaborative process at Mayo Clinic that will undoubtedly spur clinical innovation and streamline the drug discovery process well into the future.
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