>>33846 (OP)(from NY Times)
We Know Where New Weight Loss Drugs Came From, but Not Why They Work
The empty auditoriums, Gila monsters, resistant pharmaceutical executives and enigmas that led to Ozempic and other drugs that may change how society thinks about obesity.
Aug. 17, 2023
Updated 9:38 a.m. ET
Every so often a drug comes along that has the potential to change the world. Medical specialists say the latest to offer that possibility are the new drugs that treat obesity — Ozempic, Wegovy, Mounjaro and more that may soon be coming onto the market.
It’s early, but nothing like these drugs has existed before.
“Game changers,” said Jonathan Engel, a historian of medicine and health care policy at Baruch College in New York.
Obesity affects nearly 42 percent of American adults, and yet, Dr. Engel said, “we have been powerless.” Research into potential medical treatments for the condition led to failures. Drug companies lost interest, with many executives thinking — like most doctors and members of the public — that obesity was a moral failing and not a chronic disease.
While other drugs discovered in recent decades for diseases like cancer, heart disease and Alzheimer’s were found through a logical process that led to clear targets for drug designers, the path that led to the obesity drugs was not like that. In fact, much about the drugs remains shrouded in mystery. Researchers discovered by accident that exposing the brain to a natural hormone at levels never seen in nature elicited weight loss. They really don’t know why.
“Everyone would like to say there must be some logical explanation or order in this that would allow predictions about what will work,” said Dr. David D’Alessio, chief of endocrinology at Duke, who consults for Eli Lilly among others. “So far there is not.”
Although the drugs seem safe, obesity medicine specialists call for caution because — like drugs for high cholesterol levels or high blood pressure — the obesity drugs must be taken indefinitely or patients will regain the weight they lost.
Dr. Susan Yanovski, a co-director of the office of obesity research at the National Institute of Diabetes and Digestive and Kidney Diseases, warned that patients would have to be monitored for rare but serious side effects, especially as scientists still don’t know why the drugs work.
But, she added, obesity itself is associated with a long list of grave medical problems, including diabetes, liver disease, heart disease, cancers, sleep apnea and joint pain.
“You have to keep in mind the serious diseases and increased mortality that people with obesity suffer from,” she said.
The drugs can cause transient nausea and diarrhea in some. But their main effect is what matters. Patients say they lose constant cravings for food. They find themselves satisfied with much smaller portions. They lose weight because they naturally eat less — not because they burn more calories.
And results from a clinical trial reported last week indicate that Wegovy can do more than help people lose weight — it also can protect against cardiac complications, like heart attacks and strokes.
But why that happens remains poorly understood.
“Companies don’t like the term trial and error,” said Dr. Daniel Drucker, who studies diabetes and obesity at the Lunenfeld-Tanenbaum Research Institute in Toronto and who consults for Novo Nordisk and other companies. “They like to say, ‘We were extremely clever in the way we designed the molecule,” Dr. Drucker said.
But, he said, “They did get lucky.”
A Lonely Origin Story
In the 1970s, obesity treatments were the last thing on Dr. Joel Habener’s mind. He was an academic endocrinologist starting his own lab at Harvard Medical School and looking for a challenging, but doable, research project.
He chose diabetes. The disease is caused by high blood sugar levels and is typically treated with injections of insulin, a hormone secreted by the pancreas that helps cells store sugar. But an insulin injection makes blood sugar plummet, even if levels are already low. Patients have to carefully plan injections because very low blood sugar levels can result in confusion, shakiness and even a loss of consciousness.
Two other hormones also play a role in regulating blood sugar — somatostatin and glucagon — and little was known then about how they are produced. Dr. Habener decided to study the genes that direct cells to make glucagon.
That led him to a real surprise. In the early 1980s, he discovered a hormone, GLP-1, that exquisitely regulates blood sugar. It acts only on insulin-producing cells of the pancreas, and only when blood sugar rises too high.
It was perfect, in theory, as a targeted treatment to replace sledgehammer-like insulin injections.
Another researcher, Dr. Jens Juul Holst at the University of Copenhagen, independently stumbled on the same discovery.
But there was a problem: When GLP-1 was injected, it vanished before reaching the pancreas. It needed to last longer.
Dr. Drucker, who led the GLP-1 discovery efforts on Dr. Habener’s team, labored for years on the challenge. It was, he said, “a pretty lonely field.”
When he applied to the Endocrine Society to give talks, he found himself scheduled at the very end of the last day of the annual meetings.
“Everyone had left for the airport — people were taking down the exhibits,” he said.
From the late 1980s to the early 1990s, he spoke to nearly empty auditoriums.
Dr. Eng’s Monster
Success came from a chance discovery that was not appreciated at the time.
In 1990, John Eng, a researcher at the Veterans Affairs medical center in the Bronx, was looking for interesting new hormones in nature that might be useful for medications in people.
He was drawn to the venomous Gila monster when he learned that it somehow kept its blood sugar levels stable when it did not have much to eat, according to a report from the National Institutes of Health, which funded his work. So Dr. Eng decided to search for chemicals in the lizards’ saliva. He found a variant of GLP-1 that lasted longer.
Dr. Eng told The New York Times in 2002 that the V.A. had declined to patent the hormone. So Dr. Eng patented it himself and licensed it to Amylin Pharmaceuticals, which began testing it as a diabetes drug. The drug, exenatide or Byetta, went on sale in the United States in 2005.
But Byetta had to be injected twice a day, a real disincentive to its use. Drug company chemists sought even longer-lasting versions of GLP-1.
At Novo Nordisk, chemists began by using a well-known trick. They loosely attached GLP-1 to a blood protein that kept it stable enough to remain in circulation for at least 24 hours. But when GLP-1 slips off the protein, enzymes in the blood quickly degrade it. So chemists had to alter the hormone’s building blocks — a chain of amino acids — to find a more durable variant.
After tedious trial and error, Novo Nordisk produced liraglutide, a GLP-1 drug that lasted long enough for daily injections. They named it Victoza, and the F.D.A. approved it as a treatment for diabetes in 2010.
It had an unexpected side effect: slight weight loss.
A Dismal History
Obesity had become a dead end in the pharmaceutical industry. No drug that was tried worked very well, and every one that led to even modest weight loss had serious side effects.
For a flickering moment in the late 1990s, there was hope when Dr. Jeffrey Friedman at Rockefeller University in New York found a hormone that told the brain how much fat was on the body. Lab mice genetically modified to have none of the hormone ate voraciously and grew enormously fat. Researchers could fine-tune an animal’s weight by altering how much of the hormone it got.
Dr. Friedman named the hormone leptin. Amgen bought the rights to leptin and, in 1996, began testing it in people. They did not lose weight.
Dr. Matthias Tschöp at Helmholtz Munich in Germany tells of the frustration. He left academia three decades ago to work at Eli Lilly in Indianapolis, excited by leptin and determined to use science to find a drug for weight loss.
“I was so inspired,” Dr. Tschöp said.
When leptin failed, he tried a different gut hormone, ghrelin, whose effects were the opposite of leptin’s. The more ghrelin an animal had, the more it would eat. Perhaps a drug that blocked ghrelin would make people lose weight.
“Again, it wasn’t that simple,” said Dr. Tschöp, who left Lilly in 2002.
The body has so many redundant circuits of interacting nerve impulses and hormones to control weight that tweaking one simply did not make a difference.
And there was another obstacle, noted Dr. Tschöp’s former colleague at Lilly, Dr. Richard Di Marchi, who also was an executive at Novo Nordisk.
“There was very little interest in the industry in doing this,” said Dr. Di Marchi, now at Indiana University. “Obesity was not thought to be a disease. It was looked at as a behavioral problem.”
