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(1) Rolfe Winkler and Ben Cohen, Monster Diet Drugs Like Ozempic Started With Actual Monsters; Studies of Gila monsters and anglerfish laid the groundwork for today's blockbusters. Wall Street Journal, Jul1, 2023, at page A1.
https://www.wsj.com/articles/oze ... anglerfish-8c9c1ff2
Note:
(a)
(i) The article is free.
(ii) The article talked about Gila monster and anglerfish. But it did not explain how either or both led to Ozempic. Sp O will.
(iii) Rolf
https://en.wikipedia.org/wiki/Rolf
(b)
(i) Gila monster
https://en.wikipedia.org/wiki/Gila_monster
("The name 'Gila' refers to the Gila River Basin in the U.S. states of Arizona and New Mexico, where the Gila monster was once plentiful, * * * The Gila monster produces venom in modified salivary glands at the end of its lower jaws, unlike snakes, whose venom is produced in glands behind the eyes. * * * The venom of a Gila monster is normally not fatal to healthy adult humans")
(ii) Gila River
https://en.wikipedia.org/wiki/Gila_River
("Popular theory says that the word 'Gila' was derived from a Spanish contraction of Hah-quah-sa-eel, a Yuma [Native American tribe] word meaning 'running water which is salty' ")
Gila is a Spanish word: the letter g in Spanish is always pronounced the same as letter h in English. So both Gila River and Gila monster have g pronounced as h.
(c) anglerfish
https://en.wikipedia.org/wiki/Anglerfish
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Before there was Ozempic or Mounjaro, there were fish guts and Gila monsters.
The blockbuster diabetes drugs that have revolutionized obesity treatment seem to have come out of nowhere, turning the diet industry upside down in just the past year. But they didn’t arrive suddenly. They are the unlikely result of two separate bodies of science that date back decades and began with the study of two unsightly creatures: a carnivorous fish and a poisonous lizard.
In 1980, researchers at Massachusetts General Hospital wanted to use new technology to find the gene that encodes a hormone called glucagon. The team decided to study Anglerfish, which have special organs that make the hormone, simplifying the task of gathering samples of pure tissue.
They hired a Cape Cod fisherman to find the slimy bottom-feeders known for their sharp teeth and lightbulb-like lure. The fisherman tossed his catch on the dock, where two young scientists dissected “the ugliest fish you could ever imagine,” said Dick Goodman, one of those postdocs.
After plucking out organs the size of Lima beans with scalpels, they dropped them into liquid nitrogen and drove back to Boston. Then they determined the genetic sequence of glucagon, which is how they learned that the same gene encodes related hormones known as peptides. One of them was a key discovery that would soon be found in humans, too.
It was called glucagon-like peptide-1 and its nickname was GLP-1.
After they found GLP-1, others would determine its significance. Scientists in Massachusetts and Europe learned that it encourages insulin release and lowers blood sugar. That held out hope that it could help treat diabetes. Later they discovered that GLP-1 makes people feel fuller faster and slows down emptying of food from the stomach.
But there was a problem: GLP-1 vanishes from the human body nearly as fast as it is secreted, chewed up by enzymes and washed away by the kidneys in minutes. That meant there was little chance of developing the magic peptide into a drug.
To investigate whether it helped diabetics, scientists had to infuse GLP-1 intravenously. Studies showed it worked, lowering blood sugar. But some also foreshadowed the main side effect that plagues today’s GLP-1-mimicking drugs: nausea.
David Nathan, a MassGen physician scientist who led a 1991 study, still remembers what happened when they increased the dose: “One person leaned over the side of his chair and threw up on my shoes.”
The key to the first drug would come from a serendipitous discovery inside another odd-looking animal.
Around the time Goodman was cutting open fish, Jean-Pierre Raufman was studying insect and animal venoms to see if they stimulated digestive enzymes in mammals.
“We got a tremendous response from Gila monster venom,” he recalled.
It was a small discovery that could have been forgotten, but for a lucky break nearly a decade later when Raufman gave a lecture on that work at the Bronx Veterans Administration. John Eng, an expert in identifying peptides, was intrigued. The pair had collaborated on unrelated work a few years before. Eng proposed they study Gila monsters.
Native to the U.S. southwest, Gila monsters (pronounced: HEE-luh) are poisonous lizards measuring 20 inches with powerful jaws and black-and-orange beaded skin. Adults eat four meals per year, and live most of their lives below ground, slowly digesting energy stored in their tails.
Eng and Raufman studied powdered Gila monster venom ordered from the Miami Serpentarium, whose owner survived 172 snake bites over the years as he produced venom for research.
Eng isolated a small peptide that he called Exendin-4, which they found was similar to human GLP-1.
Eng then tested his new peptide on diabetic mice and found something intriguing: It not only reduced blood glucose, it did so for hours. If the same effect were to be observed in humans, it could be the key to turning GLP-1 into a meaningful advance in diabetes treatment, not just a seasickness simulator in an IV bag.
Hoping that he could sell it to a pharmaceutical company that would develop it into a drug, Eng filed for a patent in 1993.
Jens Juul Holst, a pioneering GLP-1 researcher, remembers standing in an exhibit hall at a European conference next to Eng. The two had put up posters that displayed their work, hoping top researchers would stop by to discuss it. But other scientists were skeptical that anything derived from a lizard would work in humans.
“He was extremely frustrated,” recalled Holst. “Nobody was interested in his work. None of the important people. It was too strange for people to accept.”
After three years, tens of thousands of dollars in patent-related fees and thousands of miles traveled, Eng found himself standing with his poster in San Francisco. This time, he caught the attention of Andrew Young, an executive from a small pharmaceutical company named Amylin.
“I saw the results in the mice and realized this could be druggable,” Young said.
When an Eli Lilly executive leaned over his shoulder to look at Eng’s work, Young worried he might miss his chance. Not long after, Amylin licensed the patent.
They worked to develop Exendin-4 into a drug by synthesizing the Gila monster peptide. They weren’t sure what would happen in humans. “We couldn’t predict weight loss or weight gain with these drugs,” recalled Young. “They enhance insulin secretion. Usually that increases body weight.” But the effect on slowing the stomach’s processing of food was more pronounced and Young’s team found as they tested their new drug that it caused weight loss.
To get a better understanding of Exendin-4, Young consulted with Mark Seward, a dentist raising more than 100 Gila monsters in his Colorado Springs, Colo., basement. The lizard enthusiast’s task was to feed them and draw blood. One took exception to the needle in its tail, slipped its restraint and snapped its teeth on Seward’s palm—the only time he’s been bitten in the decades he’s raised the animals. “It’s like a wasp sting,” he said, “but much worse.”
Nine years after the chance San Francisco meeting between Eng and Young, the Food and Drug Administration approved the first GLP-1-based treatment in 2005.
The twice-daily injection remained in the bloodstream for hours, helping patients manage Type 2 diabetes. Eng would be paid royalties as high as $6.7 million per year for the drug, according to federal government data available after 2015. “It was a long journey,” said Eng.
The proof of concept pushed other pharmaceutical companies to make more-effective and longer-lasting GLP-1 drugs.
At first, Novo Nordisk executives had little interest in GLP-1 drugs. They gave priority to Novo’s main business of selling insulin. “A lot of people didn’t believe in it,” says Jens Larsen, international medical director for the Danish company. He stopped his own mid-1990s study of IV-infused GLP-1 when patients on a higher dose started vomiting. The research was shelved until 2001.
The Gila monster-derived drug gave them a push, said Larsen: “It made companies more aware that this could be a serious competitor and we had to step up and put more people on it.”
Novo kept at it, working on its own drug that more closely resembled the human peptide. With some clever chemistry it bumped up this drug’s time in the body to a day. Its first GLP-1 drug, the once-daily shot liraglutide, would receive FDA approval in 2010.
Seven years later came its longer-lasting diabetes drug, the once-weekly shot semaglutide. As it turned out, it was also the best of the drugs for weight loss, making it the first blockbuster in the category. A higher dose was approved in 2021 to treat obesity.
Those two approved doses are better known today by their brand names: Ozempic and Wegovy.
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发表于 7-15-2023 12:37:53
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, whereas all mammalians have three: glucagon, GLP- amd GLP-2]. Two glucagon-related peptides were subsequently identified in the rat, hamster, bovine, and human proglucagon sequence") (citations omitted)