'GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next?'

 Next week, 50 medical experts from the Karolinska Institutet in Stockholm will meet to award the 2023 Nobel Prize for Physiology or Medicine. The vote takes place on Oct. 2, but betting-minded scientists are already beginning to make their picks for who might take home the gold.

Seasoned Nobel prognosticators will point out that the medicine prize often cycles between super-basic molecular biology and inventions that actually cure people. Last year’s award for paleogenomics falls more toward the former, suggesting an advance with a more clinical focus could well be in the Nobel Assembly’s sights this year. There are many compelling candidates, including the mRNA technology that helped halt the Covid-19 pandemic. But the explosive impact of metabolism-correcting, weight-moderating drugs like Ozempic, Wegovy, and Mounjaro also has some prize forecasters wondering if perhaps the discoveries that have led up to these treatments might find their way to the Nobel spotlight.

Maybe that’s just recency bias talking. These drugs, based on the GLP-1 hormone, seem to be everywhere at the moment — helping people control their diabetes and lose weight, and offering hope that they might also reduce the risk of cardiovascular disease or even, one day, treat drug and alcohol addiction. Many researchers STAT has spoken to in recent months while covering this medical revolution have noted that it has Nobel promise, if not this year, then sometime soon.

Then the question obviously becomes, who gets it? These blockbuster drugs didn’t appear overnight. The journey from discovery of the GLP-1 hormone to treatments for diabetes and then obesity was a long and stuttering one, spanning more than four decades and involving hundreds of researchers across academia and the pharmaceutical industry.

“Certainly this class of drugs, both what they’ve already done and their potential, is enormous and worthy of a consideration around these large prizes,” said Randy Seeley, director of the Michigan Nutrition Obesity Research Center, who has followed the development of these drugs and has consulted for companies making them. But “how you attribute credit is really complicated.”

Other prestigious awards have already gone to a trio of scientists involved in generating some of the earliest insights about the GLP-1 hormone. Historically, the Nobel Prize Assembly has also tended to lean toward honoring basic research. And, as critics have pointed out over the years, by elevating just one, two, or at most, three researchers, the Nobels distort the history of science “by personalizing discoveries that are truly made by groups of individuals.”

That reality hangs heavy especially over a decision about GLP-1 and other gut-hormone based drugs, given how much additional science had to be done to convert the hormones to effective, and then even more effective, drugs. All of the steps from discovering the hormone, to the translational work, to making the drugs “were necessary to get us to the place that we are,” Seeley said. “Which was the hardest, which was the most innovative? I don’t know.”

There was also a lot of luck along the way, like the finding that targeting GLP-1 receptors could lead to substantial weight loss. And there’s no way to assign credit for that. “We’re doing things with these drugs that don’t mimic the biology,” said Seeley. “So understanding the biology alone didn’t get us there, but it was absolutely necessary before we could move on to the next phase.”

Each new leap in understanding may not be prize-worthy in isolation, but with each one, the door cracked open wider, expanding the number of people who could benefit from GLP-1 and other gut-hormone-based treatments. And that, Nobel or not, is worth understanding.

Fish guts and rat organs: The discoverers of GLP-1

It was the summer of 1979. “My Sharona” was on all the radio stations, Ridley Scott’s “Alien” had just premiered, and off the coast of Cape Cod, a deep-sea trawler was on the hunt for a slimy creature of another kind: the American anglerfish.

Much to his relief, Richard Goodman didn’t have to go out in a boat to nab his wide-mouthed quarry. By the time he arrived in Woods Hole, after a two-hour drive from Boston, a local fisherman would have a handful of the slick-skinned seabed dwellers lined up and waiting for him on the docks at the Marine Biological Laboratory. One by one, the spectacled young doctor carefully sliced them open with a scalpel, then from the sticky tissue surrounding their guts, plucked out dozens of lima bean-sized lumps of flesh and dropped them into a flask of liquid nitrogen. Inside each one was an endocrinologist’s goldmine: hundred of thousands of copies of the instructions for making metabolic hormones.

Only a few years before, scientists in Boston and California had come up with revolutionary new techniques for isolating genes and finding out how they worked. Recombinant DNA technology promised to bring bodily processes into molecular resolution, and biomedical research labs all across the country were rushing to learn these freshly minted methods. The lab where Goodman worked at Massachusetts General Hospital was one of the top places applying them to the study of hormones, and its leader, Joel Habener, had amassed serious funding to go after as many as possible.

The new technology made it possible to take mRNA — the messages cells use to produce proteins — and turn it into DNA, which could then be sequenced, and even spliced into bacteria to create biomolecular factories. It turned a six-month process into something you could do in an afternoon. The trick, though, was you needed a lot of mRNA.

Goodman was interested in a hormone called somatostatin, which is produced in the brain and the pancreas. But the brain proved too noisy; too many other peptides being produced. The pancreas was better — it only made a few things besides somatostatin, namely insulin and glucagon and only in one kind of cell, the islet cells. In humans and other mammals, the islets, true to their name, are dispersed throughout the pancreas like a far-flung archipelago. It might take months just to get enough mRNA to start experiments.

So Goodman turned to the anglerfish, which conveniently packs its islet cells into fleshy packages called Brockmann bodies that are big enough to be visible to the human eye.

Pretty soon he was growing colonies of bacteria spliced with bits and pieces of fish DNA and screening them with radioactive probes to identify the one carrying the gene for somatostatin. Not long after he’d successfully done that, a new postdoc named P. Kay Lund with an interest in gut peptides arrived in the lab. Using Goodman’s anglerfish DNA-containing bacterial library, Lund identified for the first time the genetic sequence for the precursor to glucagon, a hormone that increases blood sugar. But she and Goodman soon realized the sequence didn’t stop there.

What they had discovered, and published in a 1982 paper, is that the gene for the glucagon precursor actually contained the code for three peptides: glucagon, and two novel hormones expressed in the gut. A year later, a team led by Graeme Bell at Chiron Corporation in California cloned and sequenced the versions found in humans and other mammals, which they dubbed GLP-1 and GLP-2, for glucagon-like peptides.

Goodman describes his own contributions to the GLP-1 story as “trivial.” During that early era of molecular biology, people were identifying new genes and peptides all the time. The really profound thing, he said, was to make the next leap and ask, “What does GLP-1 actually do?”

There were a couple of groups of researchers, some in Boston and some in Denmark, who jumped.

In 1983, Svetlana Mojsov, a chemist with a background in glucagon and an interest in GLP-1, joined Mass General’s endocrine unit. An expert in peptide synthesis, she hypothesized that the active structure of GLP-1 was actually a smaller fragment of the full molecule, a truncated version she called GLP-1(7-37). In a series of laborious experiments with rat tissues, she discovered that this molecule naturally existed in the gut, right where she expected it to be.

Starting in 1964 with Neil McIntyre’s seminal study at Hammersmith Hospital in London, researchers had observed that when people eat sugar, they experience higher insulin levels than when they get sugar injected into their bloodstream. This suggested that the gut must secrete an insulin-stimulating substance in response to meals. In the 1970s, researchers identified a hormone called GIP they thought fit the bill, but it turned out not to be the full story. With GLP-1 (7-37),  Mojsov believed she had found the so-called “missing incretin.”

As she was writing up a paper on these findings, a postdoc in Habener’s lab, Gerhard Heinrich, reached out to her. He had more data on the genetic sequence and wanted to combine their findings, which they did in a paper published in September 1986.

Meanwhile, Mojsov had also begun supplying peptides and other reagents to another Habener postdoc assigned to unraveling the GLP-1 mystery, an endocrinologist named Dan Drucker. He had also found GLP-1 (7-37) in experiments in cell lines. In February of 1987, Mojsov, Weir, and Habener published another paper showing GLP-1(7-37) stimulated insulin secretion in rat pancreases. Drucker’s data were published a few months later, in May. (Mojsov’s contributions were downplayed for decades, but she’s now started to fight for recognition.)

Around this same time, a University of Copenhagen team led by Jens Juul Holst published a report that came to the same conclusions.

The Danish team’s first experiments were failures. When they synthesized a peptide from the newly discovered GLP-1 gene sequence and dripped it into the isolated pancreas of a live pig, nothing happened. Puzzled, they turned to a colleague, Thue Schwartz, who had recently returned to Copenhagen from a postdoc with Donald Steiner at the University of Chicago, where he learned the same types of peptide sequencing techniques Mojsov excelled in. There, he had discovered a hormone called pancreatic polypeptide, which had a rather unique cleavage pattern. He hypothesized that something similar might be happening with GLP-1, which he and Holst said led the Danish group to independently hone in on the 7-37 fragment.

From all the data the two groups had gathered, GLP-1, specifically the 7-37 version, was starting to look like a big deal. If it was really and truly a hormone that could increase glucose-dependent insulin secretion, then it had potential to treat diabetes. The big test would be to put it into people. And that wound up happening faster than any of the researchers involved in its initial discovery ever expected.

According to Holst, in the summer of 1987, he attended a party with Stephen Bloom, an endocrinologist then at Hammersmith. And whether it was the drinks or the belief that his team had a big enough lead that someone like Bloom, who’d never worked with GLP-1 before, couldn’t catch up, Holst spoke freely about the molecule’s therapeutic potential. Not six months later, in December of that year, Bloom’s team had proof that GLP-1 had passed the first big test.

For the generation of biotech executives who presided over the burgeoning industry’s first few decades, GLP-1 was the multibillion dollar idea that got away. Some tried and failed to turn it into a drug, most didn’t even get that far, and almost no one saw the gila monster spit coming.

In the summer of 1980, a young gastroenterologist named Jean-Pierre Raufman arrived at the National Institutes of Health eager for an interesting fellowship project. He got paired up with John Pisano, a somewhat eccentric biochemist known around the NIH for his collection of venoms — many of which he acquired from local amateur zoologists responding to his ads in the Washington Post with plastic bags filled with buzzing wasps and hornets.

Pisano sent Raufman on a venom-mining expedition, which yielded about 20 of his most intriguing samples, including from vipers, cobras, and the gila monster, a large black lizard native to the American Southwest that chews the venom in its saliva into victims with powerful jaws and deeply grooved teeth.

Raufman’s job was to drip these poisons one at a time into dishes of guinea pig pancreas, and then measure how much of a carb-digesting enzyme called amylase the cells secreted. The idea was to find substances that might be able to alter human physiology. “I didn’t know if there would be anything in it, but it certainly sounded intriguing,” he said.

After seeing the gila monster venom spur a huge spike in amylase, Raufman began to focus on better understanding exactly what was in it. Over the next few years he and his collaborators at NIH identified several new peptides and hormones they published in obscure journals.

Out of the gila monster venom they fished out a 39-amino acid peptide they named exendin-4.

Exendin-4 was totally new to science and yet curiously familiar. It was shaped almost exactly like GLP-1. But unlike GLP-1, which lasts less than a minute in the bloodstream before degrading, exendin-4 remains active for more than two hours. It was, they thought, a recipe for a potential blockbuster of a diabetes drug. But in the ’90s, they found themselves a bit ahead of their time.

That somebody was a small San Diego-based biotech startup named Amylin Pharmaceuticals, led by long-time former Eli Lilly veteran, Joseph Cook. Amylin licensed Eng’s lizard peptide in 1996, and developed a synthetic version, exenatide. Within three years, its studies found that one week of exenatide in diabetic mice could normalize blood glucose levels.

Further clinical testing showed it to be both effective and safe. In 2005, exenatide received FDA approval to treat diabetes under the name Byetta. It was a huge hit.

In blogs and early online communities, users adoringly referred to the drug as Lizzie, or Gilly — homages to its reptilian origins — as they waxed rhapsodic about its ability to not just control their blood glucose, but also melt pounds off their bodies. Gray markets sprang up to supply Byetta as a fad-diet drug, a preview to the current Wegovy and Ozempic craze.

But the important thing is that the little gila monster peptide had shown that GLP-1 receptor agonists were a viable approach for treating diabetes. “It gave the field the confirmation that we were on the right track,” said Holst.

By then, Danish pharmaceutical company Novo Nordisk had already begun a clinical trial of its own GLP-1 receptor agonist, which went by the name liraglutide. Scientists within the company believed it could be better than Byetta, and though they were testing it as a diabetes treatment, internally, they were discussing its potential for an even more widespread public health concern: obesity.

At the Hagedorn Research Institute, an academic center embedded within Novo Nordisk, a cell biologist named Ole Dragsbæk Madsen had been giving rats tumors made from islet cells to study how the cells matured and turned on insulin gene expression. But then something disturbing happened. As the animals got older and the tumors got larger, the rats began to eat less and less until they had wasted away completely.

It was as though the tumors were emitting an appetite suppressant powerful enough to kill. When Madsen’s team inspected the tumors, they found they were pumping the animals with huge amounts of GLP-1.

Lotte Bjerre Knudsen, a Novo Nordisk researcher, saw that data and thought that GLP-1 looked like it turned off appetite just as well as it could crank up insulin secretion. “So I was thinking, why on Earth shouldn’t I suggest that you could actually do both of those things at the same time with one drug?”

The winning molecule, called liraglutide, entered clinical testing in 2000 as an injectable drug to treat diabetes, and would eventually be approved by the FDA, as Victoza in 2010. But even as far back as 1995, as Knudsen’s team was screening some of their early designs in mice, they saw that in addition to increasing insulin secretion, GLP-1 agonists made them eat less.

In the mid-1990s, there was a lot of debate about what was behind this effect. Researchers had been finding GLP-1 receptors in places outside the pancreas — including the vagal nerve, which connects the gut to the brain. Based on human experiments, Holst hypothesized that GLP-1 caused slower emptying of the stomach, which sent a signal through the vagal nerve signifying fullness.

The FDA approved liraglutide as Saxenda in 2014 and semaglutide as Wegovy in 2021. Knudsen, who is now a chief scientific adviser at Novo Nordisk, told STAT that based on mouse studies her team has conducted, the more dramatic weight loss is most likely a result of the fact that semaglutide’s chemical structure makes it easier to slip into the brain, particularly into areas involved with signaling feelings of fullness.

While the exact mechanism behind Wegovy’s effectiveness remains a bit murky, the impact of the drug is already clear. Wegovy has generated demand so explosive it has prompted manufacturing shortages, insurer pushback, and social media bans on celebrities and influencers promoting it. In 2022, prescriptions in the U.S. for Wegovy, Ozempic — which is approved for diabetes but often prescribed off-label for weight loss — and similar obesity drugs hit 9 million.

Cultural mavens have dubbed this the age of Ozempic and Wegovy, but actually, the treatments are already starting to fade. Pharmaceutical companies are quickly moving past drugs that target just GLP-1 and now going after additional hormone targets in the hopes of achieving even greater weight loss.

Eli Lilly’s Mounjaro, which is awaiting regulatory approval to treat obesity, activates receptors for GLP-1 and a similar hormone called GIP and leads to about 20% weight loss. Lilly is also developing a “triple G” drug, which additionally targets glucagon. It induced 24% weight loss in a recent trial, the greatest amount seen yet with an obesity treatment.

This next frontier of obesity drug development stems in large part from the work of Matthias Tschöp and Richard DiMarchi.

Fast forward to 2003. Tschöp was newly an associate professor of medicine at the University of Cincinnati when he received a phone call from DiMarchi, an experienced peptide chemist. They had met at Lilly, where DiMarchi was the executive responsible for endocrine research. DiMarchi had just left the company and become a professor of chemistry at Indiana University, and also wanted to develop obesity treatments that combine multiple drug targets.

They began a two-decade-long collaboration, with DiMarchi making new compounds and Tschöp conducting biological tests.

They started with a list of over a dozen gut hormones that could be potential targets. One that they homed in on was glucagon.

DiMarchi and Tschöp continued to probe other combinations, and another hormone they settled on was glucose-dependent insulinotropic polypeptide, or GIP.

GIP is similar to GLP-1 in that it’s considered an “incretin,” a gut hormone that triggers insulin secretion, but products based on GIP had disappointed as drug candidates for diabetes. Additionally, there had been data showing that mice with GIP receptors knocked out didn’t gain as much weight on a high-fat diet, suggesting to the field that blocking GIP could be a way to treat obesity.

Still, the researchers wanted to try to activate GIP. DiMarchi created new dual agonists, targeting GLP-1 and GIP receptors, and in mice, they found these compounds to be more effective at weight loss than existing drugs that target just GLP-1. The dual agonists also lowered blood sugar and increased insulin secretion in mice, monkeys, and humans. The results suggested that activating GLP-1 receptors could be “the gate opener for releasing additional GIP power,” Tschöp said. This study was published in 2013.

Similar to the story of GLP-1 drugs, the weight loss effects of targeting glucagon and GIP could have only been achieved with drugs that could chronically activate hormone receptors across the body, drugs with effects that are more potent and widespread in the body than the natural hormones that are secreted. That shows how important a role chemical formulation and drug design play beyond just understanding the biological effects of natural hormones, DiMarchi said.

“If we had similarly invested in the chemical optimization of other endocrine hormones, would we have similarly gotten spectacular results? How much has been left on the cutting [room] floor because the tests were with molecules that were not suitably optimized to show what we’ve seen with the state-of-the-art medicinal agents?” he said. “That is the huge opportunity that is before us right now.”

https://www.statnews.com/2023/09/30/weight-loss-ozempic-nobel-prize-science/