Did you hear the one about the researcher who went to Arizona and discovered Byetta? There are so many stories about how exenatide was discovered and made it to the market that I thought you would like the real story. I have had a couple of opportunities to talk with Dr. John Eng, the discoverer of exenatide, and have the real story.
Dr. John Eng’s Research Found That The Saliva Of The Gila Monster Contains A Hormone That Treats Diabetes Better Than Any Other Medicine.
Lizard spit makes Dr. John Eng feel like a proud parent.
For more than 25 years Eng has unceremoniously reported to work at the Bronx Veterans Administration Medical Center in New York, where he treated thousands of people for diabetes and other hormone related diseases.
But now he shows up as a multimillionaire – thanks to his discovery that the poisonous venom of a Gila monster lizard had the potential to treat diabetes.
The endangered lizard’s poison stimulates the body’s production of insulin, a hormone that helps cells process blood sugar. It can prevent blood sugar levels from dipping perilously low, or stop it from spiking and causing damage to the liver, kidneys, eyes and limbs.
Diabetes, the inability of the body to produce proper amounts of insulin, is the fifth deadliest disease in the United States. And the number of people with type 2, or adult on-set diabetes, is growing at alarming speeds.
Exenatide, which was approved in the US in 2005 and is made to help diabetics avoid or postpone the use of insulin injection therapies when other treatments have failed. It is , according to analysts, a billion dollar a year drug.
“This (discovery) has taken on a life of its own – it’s as though it has become my fifth child,” Eng said recently. “The FDA review is a lot like one of the children taking a final exam that will determine whether they graduate from college and go off into the world to do good, and maybe help a lot of people.”
The tale of Eng’s discovering the magic that lizard venom can stimulate inside the gut is the essence of basic research that feeds a burgeoning biotechnology industry.
Besides treating patients as an endocrinologist Eng is a scientific researcher. As a young research fellow just starting out at the VA hospital, Eng worked in the laboratory of Dr. Rosalyn Yalow, a 1978 Nobel Prize winner for inventing a method to find novel hormones in different animal species.
Amylin Chairman Joseph Cook described Eng as “someone who is unusually capable to see things, particularly patterns, that others don’t see when looking at an object, or data set, or event.”
Yalow encouraged the gentle and soft-spoken Eng to work hard and think big. She stoked the Harvard College-educated man’s desire to search for something that might benefit society in a sweeping way.
Eng’s special area of research, like his mentor’s, is peptide hormones. In the late 1980s, he began trying to advance Yalow’s research by creating a new and more sensitive test that would help identify hormones with potentially untested benefits.
He did studies on the hormones of guinea pigs, and later, chinchillas. Then he looked for animal subjects that might be more difficult to analyze.
Eng came across what he thought were very interesting studies done in the early 1980s by gastroenterologists at the National Institutes of Health, who noted that the venom in certain snakes and lizards caused inflammation of the pancreas, where insulin is made. Of particular interest was the hormone in the venom of the Gila monster.
Eng thought he had developed a test that would allow him to further investigate the lizard’s venom. So he ordered some dried and preserved samples out of a catalog from a serpentarium in Utah.
Two compounds in venom
In 1992, Eng’s studies revealed that the venom contained two compounds, including one that had never been documented. He named it exendin-4.
The compound seemed to have properties similar to a human gut hormone, GLP-1, that was being researched around that time by scientists at Massachusetts General Hospital.
GLP-1 was exciting to researchers because it stimulates insulin secretion from the pancreas only when blood sugar is high, Eng said. When blood sugar levels are normal, GLP-1 seems to know not to stimulate insulin, the hormone that helps cells process blood sugar.
“That’s ideal for treating diabetic patients,” Eng said. “As a clinician working with diabetics, the struggle is to try and achieve as much glucose (blood sugar) control as you can to prevent bad complications like kidney failure, retinal disease that can cause blindness and nerve damage that causes loss of sensation in the feet.”
While insulin injections are an effective treatment, timing the dose and amount is a constant balancing act. Too much insulin causes hypoglycemia, a dangerous and sometimes fatal drop in blood sugar.
But GLP-1 seems to help the body keep the blood sugar from dropping too low, Eng said.
The problem with GLP-1, however, is that enzymes in the blood cause it to degrade quickly, Eng said. If it were to be used as a treatment for diabetics, it would have to be injected into the body almost hourly, something most people would not be willing to do.
But studies Eng performed showed that the Gila monster’s hormone, exendin-4, doesn’t degrade for hours, making it a much better candidate for a drug.
Eng took his findings to administrators at the VA, which had funded his years of research.
Typically hospitals, research institutions and universities give these discoveries to a designated office charged with determining the marketability of the science. If it is thought to have commercial value, that office then deals with the expensive and complicated process of patenting the discovery and then trying to find someone willing to pay to use it.
The VA, however, said it wasn’t interested in patenting Eng’s discovery because it did not address a veteran-specific ailment, such as spinal cord damage or some other combat injury, he said.
Path to a patent
Eng was convinced his discovery had the potential to offer relief to diabetics like the ones he treated every day. He also knew it would wither and die if it wasn’t patented.
Pharmaceutical and biotechnology companies typically invest hundreds of millions of dollars and a dozen years or more developing a drug. They are not willing to make such a risky investment without the assurance they get from a patent – knowing they are the only company with access to the crucial science behind the drug
By the time his discovery was two years old, Eng had convinced his wife that they should hire attorneys themselves to patent the drug.
“Psychologically, the process was pretty tough,” Eng recalled. “Every month you get a bill from patent lawyers. And there’s no end to it. It’s a scary venture because there are no guarantees and no landmarks where you can say, ‘OK, I’m halfway across the river.’ ”
At the end of the second year, the patent was approved. But that posed yet another problem: What to do with it.
“I had problems paying the patent bills,” he said. “Developing a drug candidate requires hundreds of millions of dollars. I don’t have the resources, or the expertise, or the access to people who do.”
So Eng went on a roadshow.
“I called up every pharmaceutical company with a name that was familiar and said I had a patent that could be useful in developing a treatment for diabetes.”
But big pharmaceutical companies move slowly. And they are adverse to risk.
By September 1996, Eng was frustrated with his failure to find a home for exendin-4. He decided to present his findings at the American Diabetes Association annual meeting in San Francisco. He stood with other presenters in a conference hall next to a poster describing his research and hawked it to anyone who would listen.
Andrew Young, the head of physiology at Amylin Pharmaceuticals, read Eng’s poster and was immediately interested. Amylin, which had also been researching peptide hormones with the interest of treating diabetes, had experience with GLP-1. But the company’s researchers were frustrated, like many others, with the rapidity with which it degraded, Young recalled.
“What was notable about Eng’s work with the Gila monster was that it didn’t degrade for four to 24 hours,” Young said.
Lilly shows interest
As he read Eng’s poster, a researcher from the pharmaceutical giant Eli Lilly & Company leaned over Young’s right shoulder to read. Young knew that Lilly, which manufactures synthetic insulin, had been working on its own peptide hormone. It would be a race to secure Eng’s work.
Young immediately called together Amylin’s vice presidents of research, marketing and business development, who were also attending the conference, and explained the significance of Eng’s discovery. Before they left San Francisco, the group had initiated talks with Eng about getting access to his science.
Meanwhile, Young called his Amylin colleagues in San Diego and instructed them to buy as much exendin-4 as they could and begin running animal tests as quickly as possible.
The ability for small biotech companies to move quickly, and their ability to take on risks, can sometimes give them an advantage over the deep pockets of big pharmaceutical companies.
By the time Amylin hosted Eng at a meeting in San Diego four weeks later, its scientists had discovered several other properties about exendin-4 that even Eng had not known, Young said. And the company had filed for patents on its work, which would complement Eng’s intellectual property, he said.
“I think that was part of our leverage with him and part of his attraction to working with Amylin – he knew it would enhance the value of his science,” Amylin chief operating officer Dan Bradbury recalls. “I think he also saw that we are passionate about what we want to do. And that, I think, is why he chose to work with the little company in San Diego, rather than Lilly.”
Eng described his negotiations with both Amylin and Lilly as being worlds apart.
“At Amylin, I walked into a conference room filled with people and they said ‘this is everyone who counts, so start talking,’ ” Eng recalled.
“The Lilly experience was very different. They had a full day of me meeting with people every half hour, in every department. I felt like it was a job interview for my compound.”
In October 1996, Eng licensed his discovery to Amylin.
Three years later, despite research showing promise for the drug, Amylin executives considered cutting the exenatide program to conserve cash and stay alive. Instead, Amylin reduced its staff from 300 to 37.
Exenatide survived, executives said, because it was a pipeline to the future for the company should it survive the hard financial times.
A shot in the arm
Then in 2002, Lilly gave Amylin a $325 million shot in the arm by agreeing to work with the biotech company on exenatide. Lilly beat out several other enthusiastic pharmaceutical companies seeking to a cut on the potential of exenatide.
Eng said the ironic twist comforted him.
“I thought Lilly’s interest, money and expertise increased the chances of the compound becoming a drug and helping diabetics,” Eng said.
Much of the licensing deal between Eng and Amylin is confidential. Eng said Amylin reimbursed him for the money he spent patenting exendin-4. He also received stock options when Amylin was trading around $10.50. Yesterday shares traded at $18.18 at the close of market.
Neither party would say what percentage of the drug’s eventual profits were promised to Eng, but Bradbury said it is commensurate with typical licensing deals made by research institutions. It is not unusual for such deals to pay the research institution around 1 percent.
But the doctor, who is still treating patients and who is also responsible for introducing the electronic records keeping system at the hospital, says he hasn’t stopped to think about the money.
“Really, how many fancy meals can you eat?” he said when asked about the potential windfall. “And I’m pretty sure I’m still going to have to take out the garbage, although my wife might give me a one-day reprieve.
“I have four wonderful children and a wonderful wife and everyone is in good health . . . so I already consider myself rich.”
He said he’s spent more time thinking about lizards and prescriptions than money.
He’s had other firsts, thanks to his drug. He had his first face-to-face encounter with a Gila monster last summer, when a British television production company flew him to the Arizona desert, where they taped a story on his discovery.
“It really is a beautiful lizard,” Eng said. “Like many other animal species it is under pressure from development and other environmental concerns. “The question is, what other animal has something to teach us that can be of future value? And plants, too? We will never know their value if they are gone.”