#842: The Story Behind EpiPen, The Rise of Food Allergies, and What Doctors Got Wrong

28:33Meanwhile, the recommendations from officials didn't really change. And certainly clinical practice, what parents were being told to do by their pediatricians, that did not really change. The precautionary principle still held sway. And food allergy rates, they continue to rise. And just remember, the fear here, it's very real. In 2001, the Journal of the American Medical Association estimated that between 500 and 1 ,000 people die every year in the U.S. from anaphylaxis. Thankfully, there was something that could help. Should a child or an adult accidentally or inadvertently consume a food they're allergic to, this was a simple device called the EpiPen.

29:20It administered a small but effective dose of epinephrine with a simple stab. happen. The trick was to make sure there was an EpiPen at hand at that moment of need. We'll dig into that after the break.

29:36To set the scene, we're going to run a commercial, but it's not an advertisement for Drug Story. This was a commercial that Mylan Pharmaceuticals, the maker of EpiPen, that they ran in 2016. You'll notice that it doesn't actually mention the EpiPen, not even once. That's because it's what the FDA called a disease awareness ad, which means the ad discusses the condition to raise awareness, but it doesn't make any claims about any one specific product or drug. And again, we can't emphasize enough, this commercial is not an advertisement on Drug Story. Look at your face and your hands. It's still getting worse.

30:16Is it your allergy? There weren't peanuts in the brownies, right? Peanut butter. Oh no, I forgot. What? She asked you. Every six minutes, life-threatening food allergies send someone to the hospital. Always avoid your allergens and talk to your doctor about a prescription treatment you should carry for severe reactions. Learn more at faceyourrisk.com. This is part two, the prescription. So in part one, we heard about the discovery of anaphylaxis, a severe, potentially deadly allergic reaction, and the surprising rise of food allergies in the 1990s and early 2000s. But what about the treatment?

30:55What could treat an anaphylactic reaction before it turns fatal? For that, let's go back. 125 years, 1900. It was actually just a few months before Prince Albert and George Roche and Paul Poitier set off on their voyage to the Azores. And we're going to Philadelphia, Pennsylvania. There, we meet Solomon Salas Cohen. He was a prominent local doctor who was asked to help treat a 22-year-old patient who was wracked with asthma. This poor woman, she was constantly short of breath, with occasional asthma attacks that would have her coughing for hours. She sounded miserable. Dr. Solis tried a few things, and then he gave her an extract of the adrenal gland, known as adrenaline, and sold in tablets.

31:41He gradually upped the dosage to 18 tablets a day. And at that dosage, something seemed to work. Her breathing improved, the spasms stopped. Soon, she was able to go outside and breathe normally. Dr. Solis-Cohen tried adrenaline on several other patients also with severe allergies, typically asthma or hay fever, with similar results. Some required just a pill or two a day. Time and again, it worked with great success. There was one caveat. the tablets were simply an extract of the adrenal gland of animals. They hadn't been purified to just be the active ingredient. In fact, there was no real understanding of what that active ingredient may be.

32:24The result, the good doctor noted, was that, quote, The preparation could give rise to diarrhea with offensive discharges. If we could have the active agent alone, our therapy would be much more definite. Well, okay. This wouldn't be the last time that diarrhea would be noted as the side effect of a drug. But give the doctor credit. His experiments were the first known clinical use of adrenaline to treat allergies. And Dr. Solis Cohen's wish for a more purified preparation, that would soon be granted. Within a couple of years, adrenaline would be chemically isolated and patented. In its synthetic form, it is called epinephrine.

33:06But again, it's basically the same thing as adrenaline. Goodbye, animal extracts. Hello, industrial manufacturing. So, how does epinephrine actually work to control an allergic reaction? Well, remember that the body reacts to an allergen as if it were a poison. It releases histamine, which tightens airways and slows down the heart. There's swelling, difficulty breathing. Worst case, the body slows down so much that people stop breathing, or they go into shock, or they're effectively paralyzed. This is how people die of anaphylaxis. Well, epinephrine, it does just the opposite. It causes the heart rate to increase, circulation to increase, and inflammation goes down.

33:52It also makes people anxious and excited. Remember, it's just synthetic adrenaline. But the important thing is it works very well to stop anaphylaxis and to prevent anaphylactic shock. By 1918, an injection of epinephrine was specifically recommended for use by doctors and pharmacists to treat anaphylactic shock. And it was cheap to make. But there was relatively limited demand. By the 1940s and 1950s, other drugs had been discovered that treated asthma, including ephedrine and isopreniline, and even cigarettes laced with belladonna. Yes, they actually once prescribed poison cigarettes for asthma.

34:33For many people, though, these worked better, and they were easier to tolerate than epinephrine injections. But another use case for epinephrine emerged in these years, the years after World War II, during the so-called Cold War. The United States was concerned about reports that the Soviet Union was developing a new kind of nerve gas that could be used on battlefields. They brought in an engineer named Sheldon Kaplan. He had just the right qualifications. He had recently worked for NASA, developing emergency medical kits for the Apollo missions. Kaplan invented something called the combo pen.

35:11It was meant for military troops to administer an antidote to nerve gas in the field. Soon, Kaplan realized that his invention also had an application for consumers with allergies. Instead of filling the pen with nerve gas antidote, it could be filled with epinephrine for the emergency treatment of anaphylaxis. Kaplan and Survival Technology Inc., that was the name of the company that hired him, they were awarded a patent for his invention in 1977. And the EpiPen was approved by the FDA as a drug device combination in 1987. For years, the EpiPen wasn't actually used very much. It wasn't until 1990 that the New York Times first mentioned the device, and a story that mentioned how a Brown University student with a peanut allergy had died a few years earlier after eating chili that had peanut butter in it.

36:02And the EpiPen did make a big difference for a lot of people with food allergies. It saved a lot of lives. So, eight years old, going camping in Huntsville State Park, which is this really beautiful, lush, piney woods forest north of Houston. This is Lauren. My name is Lauren Gilmer. I am 33 years old. I currently live in Nashville, Tennessee. So I went to the nature center, looked around, and right outside of the nature center, they had a collection of bird feeders. Poisted up a plinth style with a pole in the center, and I wanted to see if there were any birds, and climbed up, looked inside, put my hands on the edge of it, didn't see anything, popped down, walked with my family to the trailhead, bent over a water fountain, took a drink.

36:53And when I straightened back up, I had a sneezing fit, which sounds kind of silly. But when I say sneezing fit, I sneezed maybe for a minute and a half straight. I couldn't stop sneezing. And my mom was bewildered. I straightened up and looked at her probably to try and gain some perspective. Like, is this normal? My mom realized, okay, we should probably pull out the big guns. At this point, I had developed hives on my neck, like the capillary rich areas, the backs of my hands on the tops of my feet. I was extremely itchy. I could feel my face swelling and it was getting harder to see, harder to breathe.

37:34Oh my God. And this is all in like 10 minutes after the bird feeder or how long? Yeah, a max of 10 minutes, I would say. And my mom looked at me and was like, your lips are turning blue. And I knew what that meant because I'd had anaphylactic reactions in the past. And I said out loud, I think I need my shot. I was having a really hard time breathing. And I felt this panic rising up in me as it became harder and harder to breathe. And even for someone that had had asthma attacks and for whom that was a pretty normal aspect of life, I mean, this was an entirely different level of air hunger. So her mom busts out the EpiPen and jams it into Lauren's leg.

38:19I remember not even feeling the needle because I was kind of out of it at that point and focused on breathing. And you're eight years old. Yeah. And there is a small hospital in Huntsville, but it was like, I want to say 20 minutes away. So without the EpiPen, I doubt if I would have made it there. And once I arrived, I needed more epinephrine. Stories like Lauren's were becoming more and more common, and the EpiPen was in more and more homes and cars and schools. The EpiPen was turning into a very good business. From 2003 to 2007, revenue from EpiPen grew by nearly 50%, with sales at around$200 million a year.

39:01That sounds like a lot of money, and it was, but it's still puny compared to massive blockbuster drugs like Lipitor, which made$16 billion in 2005. And then in 2007, Mylan Pharmaceuticals spent almost$7 billion to acquire EpiPen. Now, things were getting interesting. This quiet little drug delivery product made for emergencies would become a very big and very controversial thing. That's coming up. But first, a commercial. One more gem from the advertising archives. an ad for EpiPen from 2013.

40:36We'll be right back.

40:39This is part three, side effects. In 2007, EpiPen was a quiet but reliable moneymaker. It brought in$200 million a year. But after Mylan acquired the rights to the EpiPen that year, the company began to raise the price. Over the next five years, the price of EpiPen more than doubled, from about$109 each to about$230 in 2013. And all the while, even as prices climbed, people kept buying the devices for a couple reasons. First, the epinephrine inside the EpiPen, well, it had an expiration date on it. They generally are good for one year. And second, Mylan began to spend a lot more money on lobbying to Congress and states with great success.

41:30In 2010, the FDA adjusted its guidance to allow two EpiPen devices to be sold in a package instead of one. The idea made sense in theory. Sometimes one EpiPen wasn't enough, so a second dose would be needed to avoid anaphylaxis. It happened rarely, but just like that, parents were now buying two packs instead of single EpiPens. States started passing laws requiring public schools to have EpiPens on hand. At the same time, Mylan began to create training programs at schools, where they would instruct teachers and nurses free of charge on how to administer the EpiPen. So they were getting trained on the EpiPen devices.

42:09Now, there was an alternative device, the Adrenoclick, and that was even cheaper. But it worked a little differently than the EpiPen. And since teachers and nurses weren't trained on those devices, schools required parents to purchase EpiPens. This is what economists call lock-in. And if that wasn't enough, in 2012, Mylan started its EpiPen for Schools program, providing free and discounted EpiPens to schools that agreed not to purchase competing products. That's even more lock-in, a captive market. And still, prices continued to climb. By 2016, a pack of two EpiPen devices had a list price of over$600.

42:53for$300 apiece. That's more than three times in less than a decade. Annual sales now topped$1 billion. It was officially a blockbuster drug, more than a century after epinephrine was first synthesized. But by now, people had noticed. The soaring cost of prescription drugs had become a national scandal. And myelin found itself standing out as a prime example of pharma greed. The company had been just so consistent in raising prices and so good at playing the game. The headlines, news reports, they were full of outrage. And sometimes tragic stories of parents who were now unable to afford the EpiPen for their children.

43:40As the Fuhrer grew in August 2016, Mylan tried to diffuse the controversy by announcing that it would begin offering a generic version of EpiPen at half the price. Now$300 for a two-pack instead of$600. But that gesture didn't quell the outrage. On September 21, 2016, the CEO of Milan, Heather Bresch, found herself in front of the U.S. Congress, testifying before a House committee investigating drug prices. Do you think you were charging too much at$600? Sir, we believe it was a fair price, and we've just now lowered that price by half. Why'd you lower it by half if you thought it was fair? If you thought it was fair, leave it where it's at.

44:23Because we wanted to make sure we're addressing the patients out there that are facing higher out-of-pocket cost and paying the wholesale acquisition cost, which was not intended. The system wasn't intended for people to pay the wholesale acquisition cost. And that's what's happening at an alarmingly rising rate, which is we took the unprecedented step of putting the generic in to sidestep that and be able to lower the cost. You're doing everyone a favor by charging three times what you acquired the drug for as a generic. Eric, you're trying to make us feel good about that. I just don't. I mean, I'm not buying your argument.

44:56And, sir, do you have a guilty conscience about any of this? Over that period of time, putting it in public places, giving free 700 ,000 free EpiPens to 66 ,000 schools and wanting to get it into all of the public schools across America. Well, if it costs 20 bucks, they could afford to buy their own. You wouldn't have to give them to them. But instead, you chose to jack the prices up and then somehow make everyone want to feel good about you by saying how much you do. So patients could get a two-pack of the official EpiPen for$600, or a generic version, basically the same thing, but not called EpiPen, for$300.

45:30And sure enough, over the next few months, more people started to fill their prescriptions for the generic version rather than the full-price EpiPen. Although here's the thing, because of the odd economics of drug prices, even the generic version would still earn the company massive amounts of profit per device. By some calculations, almost the same amount of profit, as it turns out. Okay, so prices still high, rates of allergies still high, and still the official guidance to pediatricians told parents, avoid feeding peanuts to young babies. Avoid foods that are potentially allergic. Here's where Gideon Lack re-enters our story.

46:10You'll recall that back in 2008, he published his observational study that suggested a link between early peanut exposure and no allergies, or the opposite, a lack of exposure and a higher rate of peanut allergies. But that study, it didn't change the mainstream practice or recommendations by doctors. It wasn't strong enough evidence to meaningfully shift the guidelines or to shift what most pediatricians were telling parents. To actually prove that early exposure was beneficial and not, in fact, dangerous, well, to prove that, well, you would need the gold standard of evidence. And that would be a randomized control trial, or an RCT.

46:51In an RCT, you would take a group of children and randomly assign them to one of two groups. Some of them would be given a treatment, in this case, early exposure to peanuts. And others would be given the placebo, a fake supplement with no potential allergens. And the study should be what's called double-blind. neither the children or parents or the researchers would know who was in which group to avoid bias. And then several years would have to go by, and then several years later, you'd see if there's a difference in allergy rates. But all that would take years. Dr. Lack and his colleagues started this other study.

47:29They called it the Learning Early About Peanut Allergy, or the LEAP study. They recruited 640 children between 4 and 11 months old, and the plan was to carefully expose half of them to peanuts regularly and consistently until they turned five, and then to compare the rates of allergies between the two groups of children. Talking to Dr. Lack, though, I was curious. How exactly did they convince 640 parents to enroll their babies in this study? A lot of resources went into screening and talking to the families and explaining to the parents what the situation was. People respond to data and common sense and realized that the guidelines were not working and that there was a significant chance that by doing nothing, the baby would develop peanut allergy anyway.

48:24Here was the possibility of an intervention that would actually reduce peanut allergy. And so five years of careful experiment go by, and finally they have their results. It was published in the New England Journal of Medicine, the most prestigious journal in medicine, in February 2015. Here's what it found. At five years of age, the rate of allergies in the children who had avoided peanuts was nearly 14%, about what it was in the general population. But in the group that had been consistently consuming peanuts since those first few months, the rate of allergies was just 1.9%. 1.9 % compared to 14%.

49:02That's a huge difference. Exposing babies early, as early as four months, was clearly and profoundly beneficial. This prevented food allergies. Well, I was really astonished that it would be that high. We were powered statistically, I believe, to look for a 50 % reduction, not an 86 % reduction in the rate of allergies. So that's at a level of very successful vaccines in terms of protection. It was a massive finding. And of course, it directly contradicted the prevailing guidelines at the time. But the evidence was solid. And within two years, in 2017, the National Institute of Allergy and Infectious Diseases announced a new recommendation.

49:51Instead of avoiding exposure, the new guidance was to expose children to peanuts and other potentially allergic foods early and often. When you give by mouth, expose it through the gastrointestinal tract, an antigen early on before the child's immune system is fully developed, that you, what we call, tolerize the child to not make a bad response against the peanuts. they become, quote, tolerant to the peanut. That voice might be familiar. That was Dr. Anthony Fauci. Yes, that same Dr. Fauci announcing the new recommendation. So there we have it. After a generation of children had been raised with exactly the wrong recommendation, we finally had a new evidence-based recommendation to expose children early and often.

50:44That would be the best way to avoid food allergies later in life. This was quite the U-turn. But Dr. Lack, he's fairly modest about his discovery. You know that famous line, there's nothing to fear but fear itself, which couldn't be more appropriate in the case of food allergy, where your fear of your baby developing the disease leads to avoiding the food, leads to causing the baby to have the disease. And undoing that way of thinking is very difficult. Yeah, it's just striking to me that it was the kind of medical establishment. I mean, it was the official recommendation of NHS and NIH that avoidance was the best course of action.

51:27And that, in some ways, ended up, well, I guess it goes to causality, but it certainly ended up, if not creating the epidemic of food allergies, exacerbating the epidemic. Look, we don't hold all the answers. And very often we get it wrong before we get it right. And I got it wrong. You know, if I were to criticize my colleagues, I would equally have to criticize myself. And people change their minds. I think it's important to change one's mind when new evidence comes about. So is that all it took? New science, new recommendation, and presto, no more food allergies. Well, not quite. In fact, despite the change in guidance, food allergies are not going down.

52:12Even after the guidance shifted in 2017, rates of food allergies among children have continued to increase. And they have also increased in adults as well. Which is confounding, but maybe not too surprising. When you think about it, there's probably a couple things still going on. First, many parents are probably just still not okay with the idea of exposing their babies to these foods in those early months and years. The precautionary principle is still holding us back. What's more, the belief in hygiene and sterility, it hasn't gone away. Many parents are probably still bathing their infants too much.

52:51And so food allergies and other sensitivities, they're still common and prevalent, meaning there is still a very big market for the EpiPen. And the EpiPen is still a huge moneymaker. In 2023, the EpiPen and the generic, they brought in nearly$2 billion in revenue. Yes, that's double the amount from 2016. And the price of a two-pack, it's now about$700. That's 15 % higher than when the Milan CEO was called in to testify in front of Congress. Since the controversy and congressional hearings back in 2016, there have been many efforts to control drug prices. Price controls, more generic competition, and lots and lots of talk in Washington.

53:39But nothing has changed the direction of prices. Nothing has really stuck. Drug pricing is a very confusing, very convoluted subject. And it's one we will return to again in other episodes. But the bottom line is, manufacturers have huge leeway to set prices as they see fit. And the U.S. government has shown very little appetite for stepping in with price controls. So many drugs stay expensive, and people still want and need those drugs. And so the cost of health care, it creeps a little higher every year. And for many people, that means deciding between medicines they need and the other things they need, like clothes or food or school.

54:21This is still a very, very big problem. Oh, and in 2019, Mylan Pharmaceuticals announced that it was merging with a unit of Pfizer and would become a new company called Fiatris, a name that must have been designed just to be easy to forget. Fiatris. Meanwhile, for all those millions of people who still suffer with food allergies, there are some signs of hope. Maybe this idea of exposure could be used to help people who already have an allergy. Dr. Lack explains. While the LEAP trial was being constructed, designed, carried out, people also started to explore the notion that, well, if you have a food allergy, you're told to avoid the food, and we still give that advice.

55:11That's correct. But maybe low-level, regular supervised exposure in an allergic child might be a better thing than avoidance. And we're now at a phase where we do have new products to treat peanut allergy, but also people are doing this to multiple food allergies, starting at milligram quantities of food protein, tiny amounts and increasing it. and showing that you don't reverse or cure the disease, but you get these children to be able to tolerate significant amounts. This is called allergen immunotherapy or exposure therapy. It can work wonders. In fact, in 2020, the FDA approved a prescription treatment for people with food allergies, a product called Palvorzia, which exposes people with peanut allergies to tiny amounts of protein, with some proven benefit in reducing the risk of anaphylaxis.

56:07And for new parents, there are foods, besides, you know, plain old peanut butter, that are designed to help them introduce peanuts and other potential allergens into the diet early. One of them, Mission Mighty Meat, is from a company co-founded by none other than Dr. Gideon Black.

56:34Drug Story was created, written, and hosted by me, Thomas Getz. Molly Warner is our research director. From Reasonable Volume, Rachel Swaby produced and sound designed this episode with assistance from Audrey Ngo. Elise Hu was the editor. Mark Bush is our engineer. Voice acting by Colin Borden. Drug Story was produced with support from the University of California, Berkeley, School of Public Health. Special thanks to Claudia Williams and Dean Michael Liu. Thanks also to Alexander Haju, Lauren Gilmer, and Dr. Gideon Black. For an annotated list of our sources for this episode, visit drugstory.co.

57:13Drug Story is an independent production. There's no tech company or big media conglomerate behind us. If you would like to support our work, contact us at drugstory.co. You can also subscribe to our sub stack there and be notified when new episodes come out. And if you like this episode, please tell your friends, rate us on Apple or Spotify. The more people who download and like Drug Story, the closer we get to doing a season two. Seriously, help us spread the word. Next up on Drug Story, we're going to look at Lipitor and heart disease and ask if millions of people are taking a drug every day for the rest of their lives with no real benefit.

57:57We'll see you next time.

58:01listening to this episode of drug story may cause you to feel itchy dizzy woozy or even a bit wheezy we advise you to watch what you eat take your medicine as prescribed and avoid exposure to people who don't appreciate who you are and why you are so awesome

58:31Thank you.