The Quirky History of Weight Loss Drugs

Rolfe Winkler is a reporter for The Wall Street Journal covering digital health. In this podcast, Motley Fool host Ricky Mulvey caught up with Winkler to discuss:

• The origins and science behind weight loss drugs.
• The challenge of selling lizard venom research to pharmaceutical companies.
• What decades-old research on anglerfish reveals about modern side effects for Ozempic.
• And why it's "not too hard" to keep dozens of Gila monsters in your basement.

To catch full episodes of all The Motley Fool's free podcasts, check out our podcast center. To get started investing, check out our quick-start guide to investing in stocks. A full transcript follows the video.

This video was recorded on July 30, 2023.

Rolfe Winkler: It's basically telling all these pharmaceutical executives, hey, look at what I got here. I got this peptide that actually has these great effects in diabetic mice for an extended period of time, you should license this. Most of them said, no, what are you talking about? It's a lizard venom, I'm not going to inject that in humans. That sounds crazy.

Mary Long: I'm Mary Long and that's Wall Street Journal reporter Rolfe Winkler, co-author of a story titled Monster Diet Drugs like Ozempic Started With Actual Monsters. The market possibility for these monster treatments have caught investors attention. It's one reason why the drugmakers working on these products, like Eli Lilly and Novo Nordisk, have outpaced the market's return by 20 percentage points over the past 12 months. But overnight sensations can take decades to create. These blockbuster treatments trace back to previously obscure research on deep sea fish and venomous lizards. Ricky Mulvey caught up with Winkler to discuss the science behind weight loss drugs, what the early research reveals about today's side effects and what it's like to be bitten by a Gila monster.

Ricky Mulvey: Weight loss drugs, including Ozempic and Wegovy started with Anglerfish and possibly venomous lizards. Rolfe, I really enjoyed the story you wrote with Ben Cowen, and it enlighten me about the very strange and long path that these drugs take.

Rolfe Winkler: It was a fun one to write. They have interesting history. You'd think that as fast as Ozempic as captured the zeitgeist in the past, I don't know, eight, nine months. You think they came out of nowhere. But this class of drugs actually, the first one was approved in 2005. Their development science behind them dates back to 1980.

Ricky Mulvey: It starts possibly with the Anglerfish. These bottom-feeding fish that are known for their luminescent fin raise, which attracts little tiny fish which they then eat, but they also are able to create this hormone that shows up in the weight loss drugs today. Can you describe how that works a little bit?

Rolfe Winkler: Well, yeah. The connection there is, Anglerfish are these ugly, disgusting fish that have incredibly sharp teeth, these carnivorous bottom feeders. The connection there is really, you may have heard of these drugs, sometimes referred to as GLP-1 receptor agonists. Basically they mimic a hormone in the human body called GLP-1 Ozempic and Wegovy do. Mounjaro, the other big drug it mimics too hormones, but GLP-1 is a star player here. The Anglerfish is central because it was in research on Anglerfish dating back to 1980 that helped us identify this hormone. It was first identified in the Anglerfish and then later in humans. Then they discover that this hormone actually has what they call insulinotropic effects, which means it stimulates insulin release in the body. If you want me to get into it, the reason they went with Anglerfish, also a fun part of the story. Back in 1980, there's this new technology called Recombinant DNA, it really launched the biotechnology revolution. It helped us create the first synthesized human insulin, for instance.

Basically, I'm going to butcher this, but it's a cloning tool. Really brilliant invention back in the '70s, but people were afraid of it, as they are of many new technologies like AI. They thought that what they do in Recombinant DNA is they take bacteria often, and they'll splice different kinds of DNA together and then put it into bacteria that will propagate that DNA. People worried, wait, what if this gets in the water supply? There were restrictions in Massachusetts where these researchers were working, they couldn't do this work on mammals and so they decided, well, can we do it in cold-blooded animals? They said yeah, and they were able to do that. They went fishing for Anglerfish. They hired a guy to go catch this stuff, throw it on the dock. It ended up being lucky because the Anglerfish actually have a special organ that produces the hormones they wanted to study, which made it easy for them to get samples of pure tissue. Anyway, that was really the science that led to the discovery of GLP-1, which is the all-important hormone that we're mimicking inside today's drugs.

Ricky Mulvey: Today's drugs have somewhat solved a similar problem that the GLP-1 presents, which is that it vanishes from the body quickly, and it makes people nauseous, but one of the ways they were able to delay it vanishing comes from scientists studying animal venoms.

Rolfe Winkler: Having discovered this human hormone called GLP-1, that was early '80s fast-forward to 1986, 1987, they discovered what it did that it had these effects that stimulated insulin release, but they also discovered that it disappears, it gets chewed up by enzymes in the body in minutes and gets washed away by the kidneys. You can't really just inject GLP-1 into humans and hope it'll be a good drug because it's just gone really instantly. To test it, just to see if it had these effects, they were looking at insulin stimulation. They're thinking, well maybe this is good for diabetes. They had to infuse people with an IV like a constant drip, which is not anybody's idea of a marketable pharmaceutical walking around with an IV poll, but they wanted to study it to find it had these effects. Sure enough, when you're mainlining it, if you turn up the dose, it just made people puke, which foreshadows today's side effects from these drugs. The next interesting side road in this whole story was another animal, Gila monsters. They're native to the American Southwest. They actually make a hormone inside their body that is similar to GLP-1. The amino acid structure of this hormone inside the Gila monsters is 50% homologous, is the word, to human GLP-1. The person who discovered this was a scientist at the Bronx Veterans Administration of all places who happen to be an expert in identifying peptides. He met a guy who done Gila monster work dating back to 1980. They proposed a collaboration.

They identified this hormone, they put it into mice, and they learned that, wait a minute, it actually helps the mice control their diabetes. Crucially, it does it for 24 hours. I don't remember if it was exactly 24, but it was for many hours. That Bronx Veterans Administration researcher, his name was John Ang. He thought, this is interesting. I'm going to patent this, and then I'm going to try and sell it to pharmaceutical companies. That is a long multiyear process, and it was expensive, and he's on the road, posturing at conferences, that's they call it posturing because you do some scientific research and the people who are throwing the conference, they're not going to let you give a talk on your research. What they'll do is they'll let you put up a poster in a conference hall and stand next to it. For him nobody wanted to talk to him, but it had to have been a pride swallowing experience a little bit. Series with this poster of this work he's done with Gila monsters venom. It was a derivative of basically their venom where they found this peptide. He's basically telling all these pharmaceutical executives, look at what I got here. I got this peptide that actually has these great effects in diabetic mice for an extended period of time, you should license this. Most of them said, no, what are you talking about? It's a lizard venom.

I'm not going to inject that in humans, that sounds crazy, but one pharmaceutical executive at one of these conferences looks it his poster and says, that's interesting. Maybe this is the key to turning this GLP-1 stuff into a drug and so he licensed it. Then the real hard work begins. Then it was a nine-year process of developing it clinical trials and in 2005, you get a drug called Byetta, the generic term is called exenatide. That was the first GLP-1 receptor agonist that came out and it was derived from the Gila monster venom. It's interesting to the story of today's drugs not because they are derived from Gila monster venom. Those guys Novo Nordisk and Eli Lilly solve the problem in different ways. But what some of those folks will tell you in this world is look, that drug demonstrated that this could be done, that you actually could come up with a GLP-1 mimicking drug that lasted in the body for a sufficient period of time that it could be sold as a drug. Then you get the pharmaceutical companies kicking it into high gear, the research and development budgets and sure enough, you get the drugs we have today, which are leading to phenomenal weight loss.

Ricky Mulvey: We'll give the Anglerfish 100% credit in developing these drugs and perhaps the Gila monster partial credit. Because the venom is not a part of the current drugs that are being made today.

Rolfe Winkler: Correct. Exenatide when it came out was, and by the way, all of these drugs really started as treatments for diabetics. That's what that started as. It had positive effects for diabetics, but you had to inject it twice a day. It's better than an IV infusion but it's still not. By the way, the needle they were using for the injection, the gauge of the needle was larger. It was not super comfortable. If you've used those epic and we'll go over your Mounjaro, today's drugs I haven't but people who tell me it's basically a painless needle, tiny little thing. But bigger needle twice a day, you're not going to get a blend, and by the way, you didn't get any blockbuster weight loss out of it. It wasn't itself going to be a blockbuster drug. But then Novo Nordisk comes out with its drug called liraglutide. Well, you know it as Victoza. That was a bigger drug. It was a once daily injection, also a smaller needle and better effects. By the way, they showed that it had cardiovascular benefits. One of the things that diabetics really suffer from is basically cardiovascular trouble, heart trouble. This drug they demonstrated it protected the heart as well as helping control the diabetes. But since then it's just been a steady advance. After that, the next drug from there was Trulicity from Eli Lilly which had a similar impact as liraglutide and controlling things, but it was a once-weekly injection. Then you have Novo Nordisk comes back with Ozempic approved in 2017 and other once-weekly, which has even more benefits. What they discovered was this incredible weight loss of an average of 15% over a period of just over a year on people who are using the drug, which is now you're starting to talk real numbers. When you have somebody who's obese, 15% of their body weight can be large number, and there's more coming behind it that show the data is even better.

Ricky Mulvey: Promise only one more Gila monster question, but this is a burning question I've had since reading your article. You feature a dentist Mark Seward because when you're studying Gila monsters, you got to find him. He is a dentist in Colorado Springs. This guy has 100 Gila monsters in his basement. Did you find out why he had so many of these very specific lizards.

Rolfe Winkler: Mark Seward has today, that this is by the way, when he is part of that story that was around 2000 and they were developing the drug. Really, you know what, they don't need to find Gila monsters because you can get powdered venom to study and you go to places like Miami Serpentarium, that's its own interesting story. [laughs] Where the guy who ran that probably handled millions of snakes in his life and survived 170 poisonous snake bites. But that's where they got it. But during the course of studying it, the small company that had licensed this Gila monster venom do this compound to turn it into a drug, they just wanted to know more about what does this thing even do in the Gila monsters this compound, we need to study it. How do you do that? They find this guy. He was a dentist in Colorado whose hobby was raising Gila monsters in his basement. He had at the time over 100, he told me. Now he's got probably over 60. He still does this. He's retired from dentistry and it's actually not very hard to keep these Gila monsters because really they live most of their life below ground. They come out, they eat a few meals a year, and then they store the fat in their tails and slowly digest it. It's not too hard to basically keep a bunch in your basement because that's not unlike how they live in the wild anyway.

Some small pharmaceutical company finds this guy who has a bunch of Gila monsters in his basement and say we want to find out what this hormone is doing inside the Gila monsters so we need you to do blood tests on the Gila monster. He had to feed them and then take blood, stick a needle in their tail and take out blood samples at specific intervals. He told me that in all of his years raising Gila monsters he really does Gila monster husbandry. He's really just breeding them. They're an endangered species and he's breeding them. Adding to the population. Call him the Elon Musk of the Gila monster. He had this restraint, he said an all these years, the only time he's ever been bitten by Gila monster was when he was doing these experiments. He's got one of the Gila monsters in one of these restraints he's built and he's sticking the needle in the tail and one of the Gila monster said, fuck you and slipped it's restraint, turned around and just snapped onto his palm. He said, it's like a wasp sting but a lot worse. You go to the hospital? He said no, I had to keep doing more blood draws and 15 minutes I walked over to sink and I washed it out a lot.

Ricky Mulvey: He didn't call a sick day after getting bitten by a Gila monster. I feel better knowing there's a conservation angle to this and that he's not just keeping dozens, if not 100 Gila monsters in his basement.

Rolfe Winkler: He doesn't go, and from the wild and bring them as far as I know. He doesn't go catch them and bring them into his house.

Ricky Mulvey: Good. 

Rolfe Winkler: He's breeding them.

Ricky Mulvey: Jumping to today, one of the incredible things about this drug is that like Ozempic may not just help with weight loss, but it might help with alcoholism and drug addictions because apparently it reduces the brains reward system to dopamine. Are we seeing any of the side effect issues from the early research? Are there any clues from the early research on these weight loss drugs that are showing up today in the side effect issues besides the nausea and the vomiting.

Rolfe Winkler: Really bad. The early research well, there's a whole bunch of stuff there depending on what time you got. Another fun element of the story is when they were first studying GLP-1 and they were doing these IV studies, where they're infusing people with various doses. There were at least two different studies where I spoke to people and they said when they turned up the dose, people just vomited, they got sick. Then they learned the way to take these drugs is to titrate them up. You started a low dose and your system builds a tolerance and you work up to the therapeutic dose. That was certainly foreshadowed. There was a scare related to these drugs circa 2009, 2010, when a couple of doctors came out really hard arguing that they caused pancreatitis and that was something that for a time threatened the drug class. There was pressure on the FDA to pull the drugs. The FDA not only didn't pull the drugs, they in fact rescued them because there was a paper in The New England Journal of Medicine, I think this is 2015, was 2014 or 2015 that basically said these fears about pancreatitis, we don't see it in the data. It's nice, but it's not there according to the FDA. That put out the fire as it were. But that was when it comes to side effects, I think there's, in terms of long-term treatment, on the one hand, this drug class has been around, remember since 2005, since that first drug, the Gila monster drug, that one came out in 2005 so you do have some long-term data on the use of these medications. The same time, Ozempic and Wegovy and Mounjaro are being used by a population of people that is so much larger than any of the other prior drugs that there, I think scientists are on guard for, are there going to be other things that pop up. Recently, the European Medical Association, God is that, its the EMA, I forget what the acronym actually stands for, but their FDA has had reports of people who are having suicidal ideation, depression, they say come from these drugs. They're investigating those reports. I think that's something you'll see whenever you put a drug into so many people, you may end up seeing effects that you didn't encounter during the clinical trials.

Ricky Mulvey: You have a larger sample base.

Rolfe Winkler: The n is an order, and order is a magnitude larger. You were tell talking instead of a few thousands of people that are testing these things, we're talking millions. People are saying that there could be tens of millions of people if the price comes down. There's hundreds of millions of people worldwide with obesity. Never mind Type 2 diabetes. This is going to be applicable to a very very wide population of people and the drug companies account on that.

Ricky Mulvey: Be interesting to see how this story continues to develop. Story is called monster diet drugs like Ozempic started with actual monsters, it's in the Wall Street Journal. Rolfe, that was one of my favorite business stories I've read in a while. I appreciate your work on it and appreciate your time on Motley Fool Money.

Rolfe Winkler: Thanks, Ricky. Yeah, happy to be here.

Mary Long: As always, people on the program they have interest in the stocks they talk about. The Motley Fool may have formal recommendations for or against, so don't buy yourselves stocks based solely on what you hear. I'm Mary Long, thanks for listening. We'll see you tomorrow.