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Back When Byetta Began

Science is too big for one person working alone in a laboratory. It’s “a group effort,” as even the most recent winner of the Nobel Prize in Medicine, Andrew Z. Fire, said this week.

That’s the conventional wisdom. Yet just one person, Dr. John Eng, is responsible for the discovery of Byetta. The Food and Drug Administration approved this powerful new diabetes medication on April 29, 2005.

Already about half a million people are using it to control their blood glucose and to lose weight, myself included. At this point Byetta has taken off even faster than Lantus insulin did.

Dr. Eng certainly stood “on the shoulders of giants” as the French philosopher Bernard of Chartres said some 900 years ago. The 17th century scientist Isaac Newton, who repeated the saying, usually gets the credit for that wise phrase.

One of those giants was Dr. Eng’s mentor, Dr. Rosalyn S. Yalow, who won the 1977 Nobel Prize in Medicine for the development of radioimmunoassays of peptide hormones. After becoming an endocrinologist, Dr. Eng wanted to do endocrine research and worked in her lab at the VA Medical Center in New York for 18 years until she retired.

“The history of endocrinology is discovery of hormones,” Dr. Eng told me in April 2002 when I interviewed him for the first article ever published about the medication that became Byetta. At that time it still went by the name exendin.

“The first hormones that were discovered were those in the greatest abundance, like insulin,” he said. “In research we always want to find something new, and I am no exception.”

He thought that there might still be hormones out there waiting to be discovered. Radioimmunoassays couldn’t help Dr. Eng find them, because those assays aren’t a good way to discover new hormones. But there were other shoulders for Dr. Eng to stand on.

In the 1970s Victor Mutt and Kazuhiko Tatemoto at the Karolinska Institutet in Stockholm, Sweden found a way to isolate new hormones. They used chemical assays.

So Dr. Eng decided to use chemical assays to look for the new hormones that he thought were out there and that he so much wanted to find. But where to look?

It happened about then that Jerry Gardner’s group at the National Institutes of Health in Bethesda, Maryland, noticed reports that venom sometimes leads to pancreatitis. Since they were interested in what can cause pancreatitis, they screened a lot of the compounds of venom that can stimulate the pancreas, because overstimulating the pancreas is one way that pancreatis can occur. It was in the venom of the Gila monster, formally named Heloderma suspectum, that they found what they were looking for.

Dr. Eng read about that and thought, “Wow! That’s great.” So he ordered some Gila monster venom from a lab in Utah, as he told me when I interviewed him in 2002.

He found a sequence never before described. One of his responsibilities to science then was to name it. Since it is an EXocrine secretion that has an ENDocrINe function, he named it exendin.

Then Dr. Eng had to show that exendin had biological activity. “Otherwise, it’s just another peptide.”

In a series of journal articles starting in 1990 he proved that activity and that exendin acts on the glucagon-like peptide 1 (GLP-1) receptor. The Journal of Biological Chemistry published his initial findings. His first article on exendin from the Gila monster came out in the April 15, 1992, issue of The Journal of Biological Chemistry. This article is so important in the history of diabetes that a free full-text version of it is online.

So, what’s so important about exendin’s GLP-1 action? A scientist named Joel Habener at the Massachusetts General Hospital had found that GLP-1 has a unique and powerful activity. Many hormones stimulate insulin secretion, but GLP-1 stimulates insulin secretion only when our blood glucose level is high.

But GLP-1 itself breaks down in a matter of minutes, so the only way that we could use it would be by a continuous infusion drip. Not fun.

The form of exendin that Dr. Eng synthesized from the Gila monster, however, stays in our bloodstream for hours. It then became clear to Dr. Eng that it could be a valuable medication for people with diabetes.

So he tried to get the Veterans Administration, where he has spent his entire career, to patent his invention. But at that time the VA was only interested in patenting inventions that were specific to veterans, like spinal cord injury, loss of limbs, or prostheses.

“That put me in a difficult position,” he told me, “because it meant I had to essentially make a bet. Patenting it came out of my pocket with no guarantee that anything would come of it.”

He filed his patent application on exendin in 1993. Two years later the United States Patent and Trademark Office issued patent 5,424,286 to him.

Then, he went around to try to interest the drug companies. At Lilly he met with people in chemistry, manufacturing, and physiology all day long for a half-hour each. “It was like a job interview.”

They turned him down. But the biotech firms like Amylin Pharmaceuticals are willing to take more risks than big companies like Lilly. And in October 1996 Dr. Eng negotiated a license with Amylin, which was finally able to offer Byetta to people with diabetes last year.

All along the way the Byetta story has been full of ironies. One of the first was the fact that while Lilly turned down the chance to develop Byetta alone, it was the company that Amylin turned to in order to jointly market it.

Another is that Dr. Eng had never seen a Gila monster when he invented Byetta. It was only a year or two ago that he finally got to see one, he told me when we talked again this week. He was in a film about Gila monsters made by a wildlife expert in England that U.S. public television showed.

One of the strangest ironies is that none of Dr. Eng’s research articles or his patent on extendin even mention the weight loss that it often leads to. I asked him this week when he first realized that it could lead to weight loss.

“I didn’t,” he replied. It was only in the Amylin’s Phase 3 trials that the weight loss became apparent.

Finally, Dr. Eng told me that he hasn’t been able to prescribe Byetta. He can’t, because it isn’t in the VA formulary. “That’s ironic,” he says.

This article is based on an earlier version of my article published by HealthCentral.

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