The Gila Monster Will See You Now

From the Wikipedia article on Exenatide, marketed under the name of Byetta, the first commercial GLP-1 weight loss drug:

During the early 1980s, Jean-Pierre Raufman worked as a postdoctoral researcher at the National Institutes of Health for John Pisano, an ‘eccentric biochemist’ who specialized in collecting venoms from various animals and looking for novel substances that could affect human physiology.  

In the course of this work, Raufman focused on investigating the Gila monster because he was curious about how it only eats once or twice per year. He discovered molecules in the monster's saliva ‘that caused inflammation of the pancreas in test animals’. He later recalled: ‘We got a tremendous response from Gila monster venom’.

When Raufman gave a lecture about his findings, his research piqued the curiosity of John Eng, an endocrinologist at the Veterans Administration Medical Center in New York City. Eng had trained under Rosalyn Sussman Yalow, who shared the 1977 Nobel Prize in Physiology or Medicine for development of the radioimmunoassay technique.

In 1992, Eng used that technique to isolate a novel substance from Gila monster venom which he called exendin-4. He tested exendin-4 on diabetic mice and discovered that it was not only effective for reducing blood glucose but was effective for several hours. 

This was an enormously significant clinical finding, because it was GLP-1's extremely short half-life which had defeated earlier attempts to turn that substance into a drug. Attempts to bypass that issue by infusing patients in clinical tests with very high doses of GLP-1—in order to overcome its rapid metabolism in the bloodstream — had produced extremely severe nausea, followed by immediate vomiting.

Eng's employer, the U.S. Department of Veterans Affairs, turned out to have no interest in obtaining a drug patent on exendin-4, so Eng filed the patent application himself in 1993.  He then spent three years on fruitless efforts to persuade the pharmaceutical industry to develop exendin-4 into a drug.

Jens Juul Holst, a GLP-1 expert, later recalled seeing the skepticism which Eng encountered when he tried to present his work on a poster at industry conferences: ‘He was extremely frustrated ... Nobody was interested in his work. None of the important people. It was too strange for people to accept’.

At a 1996 American Diabetes Association conference in San Francisco, Eng finally caught the attention of scientist Andrew Young of Amylin Pharmaceuticals, who immediately recognized exendin-4's potential and arranged for his company to license Eng's patent.

Young was excited to see Eng's poster at the conference summarizing his findings, but then noticed an Eli Lilly and Company executive reading the same poster, and he became worried that Lilly might beat Amylin to a license.  When Eng arrived at Amylin's San Diego headquarters, he was astonished to discover how much information Amylin's scientists had already figured out about exendin-4 in the brief period of time after Young saw his poster, which convinced him that Amylin was the right company to partner with. Amylin went on to create exenatide, a synthetic version of exendin-4, and later formed an alliance with Lilly in 2002 to bring the drug to market.

Exenatide was predicted by Amylin scientist Alain Baron to begin undergoing the Food and Drug Administration's approval process in 2004. Exenatide was approved by the FDA in April 2005, for people whose diabetes is not well controlled on other oral medications.  This was a landmark event which proved that targeting the GLP-1 receptor was a viable strategy and inspired other pharmaceutical companies to focus their research and development on that receptor.

In 2011, Lilly and Amylin dissolved their partnership, with Amylin keeping the rights to exenatide. Meanwhile, Lilly had been awakened to the possibilities of this class of drugs and continued to develop newer drugs of the same class. 

By October 2024, the blockbuster drug tirzepatide had transformed Lilly into the most valuable drug company in the world.

Read that last line again.  Wow!