Trikafta: The Miracle Drug 81 Years In The Making

Ashley holds a box of the miracle drug Trikafta in front of her face. (Courtesy of Ashley Wilson)

ANNA 1: This is True Stories in Sound. I’m Anna Gordon. I’m gonna start this story by introducing you to someone.

ASHLEY 1: My name is Ashley Wilson.

ANNA 2: Ashley’s 23 years old, and there’s a lot of different ways I could describe her.

ASHLEY 2: I am a full-time college student and I’m studying film making.

ANNA 3: She also works part time packaging food at a local small business. And she has big dreams.

ASHLEY 3: All my life I wanted to be a Broadway actress and do theater.

ANNA 4: And on top of that…

ASHLEY 4: I also do youtube and podcasting on the side which feels like a full-time job.

ANNA TAPE 1: How do you manage your time between all those things?

ASHLEY 6: Um… I guess I just learned how to balance everything. Over the years I’ve always been the type of person who’s really busy, like constantly, all the time. I can’t sit still.

ANNA 5: But there’s something that makes Ashley different from your average workaholic.

ASHLEY 7: So the different breathing treatments. That takes about 30-45 minutes twice a day. But if I’m sick then I do that 3-4 times a day depending on how sick I am.

ANNA 6: She was born with Cystic Fibrosis, sometimes referred to as CF for short. It’s a genetic disease that makes sticky mucus build up in her organs over time, especially her lungs. The disease is considered terminal, with an average life expectancy of just 37 years old. It affects more than 30,000 people in the United States. Some cases can be even more severe, with patients passing away in their  teens and 20s.  SO people with CF grow up knowing that life is short, and the clock is ticking.

ASHLEY 8: And I think the reason we kind of do it is because we understand how precious life is. And if we’re going to go all out and live life to the fullest might as well have a jam-packed schedule.

[MUSIC]

ANNA 7: If you want to understand what CF feels like, there’s a game you can play to try to get an idea. You take a straw , put it in your mouth, and then you plug your nose. Now, just try breathing through the straw. If you do this for about 30 seconds, you’ll start to notice your lungs feel tight. Almost like someone is squeezing your lungs and you can’t catch your breath. This is what breathing felt like for Ashley every single day. But she wouldn’t let it stop her. She kept pursuing her passions, singing, acting, and performing in musical shows.

ASHLEY 9: And every time I was in a show my doctors would say Ashley you’re burning the candle at both ends. You have to take a break. And I’m like no it’s ok I can handle it and get IV antibiotics afterwards and then we’re good and just continue on.

ANNA 8: But Cystic Fibrosis is a progressive disease, meaning that the older Ashley got, the more severe her CF would become.

ASHLEY 10: In 2015 I was in the hospital and it was my longest hospital stay at that point. I was there for a month and my life had like flipped upside down. I was diagnosed with CF liver disease and I had to stop doing musical theater because my body just did not have the energy to do it anymore. You know when I closed the door on theater I wouldn’t do that usually. Even when I was at my sickest I would still push through but I was at the point where my body was so tired.

[MUSIC]

ANNA 9: I’ve spoken to a lot of people with CF, and this refusal to give up seems to be a common thread. A lot of CFers I talked with seemed intent on pushing their bodies to the very limit, as if to prove the disease couldn’t stop them.

KEVIN 1: My name is Kevin Dwyer. I’m 48 years old now. I was 6 years old when I got diagnosed with CF.

ANNA 10: Like Ashley, Kevin was always testing the limits of his body.

KEVIN 2: I was a professional ballet dancer which kept me… I was in very good shape.

ANNA 11: In 2012, Kevin ran the New York city marathon and proposed to his then girlfriend, now wife at the finish line. But for someone with cystic fibrosis, this kind of physical exertion came at a price. 

KEVIN 3: After running that marathon, it affected me. And that’s when I started to see a big decline in my health. I ran the marathon at about 50% lung capacity and then through the next few years it just started to dip and dip and dip to about 30%. I felt sick every single day of my life. I was getting tired to fight. Too tired. And um. It got to the point where I was recommended to go on the transplant list.

ANNA 12: Ok, so any transplant is a big deal. A dangerous kind of surgery, where the outcomes are anything but guaranteed. But lungs are among the most difficult organs to transplant. Only 50% of patients are still alive 5 years after the surgery.

And this trajectory… from being a professional dancer and running a marathon to being on a transplant list in less than a decade… That’s what CF does to your health.

But recently, the prognosis for patients like Ashley and Kevin has changed. Dramatically.

We’re going to get to that later, but first, it’s important to understand the history and science behind this disease and its treatment. Because that life changing discovery was eighty years in the making.

[MUSIC]

Let’s start here.

Scientists believe that cystic fibrosis has plagued humanity for at least 5,000 years, but it wasn’t until 1938 when a woman by the name of Dorothy Andersen began to notice the peculiar set of symptoms that marked the disease.

BIJAL 1: So Dorothy Andersen, she was this tough lady, and she wanted to have a career in medicine.

ANNA 13: That’s Bijal Trivedi, a science writer who wrote a book called Breath from Salt, that chronicles the history of Cystic Fibrosis.

BIJAL 2: Back in the 1930’s only about 5% of physicians were women. Women physicians were sort of relegated to the realm of babies and home hygiene.

ANNA 14: But Dr. Andersen was never interested in that. So instead-

BIJAL 3: She went and got her PhD in pathology. So she was an MD-PHD in the 1930s.

ANNA 15: As a pathologist, Dr. Andersen studied tissues of the human body inside a lab. It was perfect for her because she didn’t have to interact with patients, who were often hesitant to see a female doctor. Instead, she spent most of her time in the basement of the Columbia University hospital doing autopsies. And one day-

BIJAL 4: She got the body of this little girl. And this little girl was diagnosed as having died from celiac disease which we now know today as an allergy to gluten.

ANNA 16: Both celiac disease and cystic fibrosis present with some similar symptoms. A big distended stomach, and severe malnourishment. In pictures of children with both diseases, you’ll notice bones protruding, as if these kids were starving despite eating thousands of calories a day. But when Dr. Andersen started doing the autopsy of this little girl, she noticed some things that didn’t seem normal for a celiac patient.

BIJAL 5: The most shocking thing was that her pancreas was completely abnormal. It was shrunken, it was white. It should be soft and squishy. And when she cut into it, it felt gritty, and hard. And when she opened it up, she could see that none of the regular cells were there anymore. This organ had been completely obliterated and filled with hard, tough, cysts.

ANNA 17: Dr. Andersen began looking in medical journals to see if anyone had ever encountered anything like this before. And after careful research, she saw that other doctors had also found similar cystic, scarred, pancreases and organs in children who had been classified as celiac patients. She requested tissue samples from these other doctors, and collected the patients’ medical histories. She began to notice that in many families where one child had the disease, other siblings seemed to die of mysterious causes as well. Dr. Anderson published a paper describing her findings titled “Cystic Fibrosis of the Pancreas.” With this article she named the condition and showed the medical world that it was indeed a separate disease. Word of her discovery quickly spread, both to other doctors, and parents of sick children.

BIJAL 6: As soon as the disease was categorized she got this flood of patients coming into her. But there was still nothing to be done. You could diagnose them but there was no treatment. 

ANNA 18:Dr. Anderson put together a team to help manage the caseload of new CF patients at her hospital. And it was there, on a hot summer day in 1949, that they noticed something odd when a bunch of children with CF were admitted with heat exhaustion.

BIJAL 7: All the kids coming in with heat exhaustion were leaving salty fingerprints on their glasses and they must have some kind of salt imbalance.

ANNA 19: It turns out that people with cystic fibrosis have extremely salty sweat because the disease fundamentally has to do with a problem in how salt is transmitted in and out of their cells. Because their sweat is so salty, it makes people with CF more susceptible to heat stroke. And, in the lungs, this salt imbalance makes the mucus extremely sticky and dry.

BIJAL 8: And the the result of that is that you have bacteria that like to live in that mucus in the lungs. And the the patients cannot cough out the mucus because it’s so thick. It just stays in their lungs, and it ultimately destroys the lungs.

[Melancholy music]

[beat of silence]

ANNA 20: But then came the 1950s. WWII had ended with a resounding victory, the American economy was expanding at an unprecedented pace, and there was a sense that any problem could be overcome. In public health, in particular, this optimism was pretty well-founded.

ARCHIVAL 1: 1955. A year of anxiety and triumph. A major medical hurdle was crossed with the discovery by Doctor Jonas Salk of the anti-polio vaccine, which was to spread a mantle of protection over millions of American children.

ANNA 21: This was a generation that had seen first hand the power of science to save lives. It was in this context, that a few CF parents came together to found a non-profit, in the hopes that, with the right support, scientists could do for CF what Dr. Salk and his team had done for polio. They knew, even back then, that scientific research was the only way they were going to put a stop to this disease.

[MUSIC]

But CF proved to be more complicated for scientists than polio. Nobody could figure out how to fix the salt imbalance.

[FADE]

For decades, scientists remained stumped.

ARCHIVAL 2: The race is on. For Kathy it’s a race against time. Because she suffers from cystic fibrosis, an incurable lung disease.

ANNA 22: This Cystic Fibrosis Foundation ad, for example, is from 1971,

ARCHIVAL 3: You can help her and 5 million children with lung damaging diseases. Support the cystic fibrosis research foundation.

ANNA 23: More than 30 years after Dr. Andersen had discovered the disease, there was still little progress to show for all that research. Kevin, we met him earlier… The marathon runner and dancer… When he was born in the 70s, life expectancy for a child diagnosed with CF still hovered somewhere around the early teenage years.

Doctors, parents, and patients alike felt frustrated with the lack of progress. But little did they know, a revolution was about to take place in the scientific world that would dramatically shift our understanding of the human body, and prove especially promising for those with rare, genetic diseases.

BIJAL 8: In the 80s, there was a lot of work going on with what’s known as gene therapy.

ARCHIVAL 4

It holds amazing promise. A way to cure diseases that have been incurable. A revolutionary treatment to actually replace defective genes that cause disease with healthy genes.   

BIJAL 9

So the idea is that if you have a broken gene in your body, if there’s a way to get a healthy version of that gene into the body, then you can basically override the malfunctioning copy.

ANNA 24: All they had to do was figure out where the gene for cystic fibrosis was located. Not easy, it turns out.

BIJAL 10: Finding the gene was sort of a Herculean task, because you didn’t have the human genome printed out in front of you, you know, you didn’t know where the genes were, you didn’t know what the genes were, you didn’t know how many there were in the genome.

ANNA 25: It took almost a decade of searching. And then in 1989

ARCHIVAL: A researcher called the news the most exciting event since the disease was first described in medical literature 50 years ago. Medical researchers say they have discovered the gene that is responsible for cystic fibrosis. It is only a step towards eventual treatment, but it is a significant one.

ANNA 26: Hope was in the air. People seemed convinced that a cure was just around the corner. Now they knew exactly what caused the disease. And 90% of CF patients carried at least one copy of the same exact mutation. That meant that all they had to do was find a way to insert a healthy copy of this gene into patients. And nature already has a natural way of inserting DNA into our cells all the time, through viruses.

This is a little hard to understand, but Bijal explained it to me this way.

BIJAL 12: With viruses, they’re like tennis balls. They’re hollow inside. Normally they have the genetic material of the virus. But you could pull that out, put in the gene that you want, and send that tennis ball virus into the lungs. But as we all know, and we know this from covid, when you inhale something into the lungs, your immune system goes crazy.

ANNA 27: Everytime they would try to insert the virus with the healthy gene inside, the patient’s immune system would destroy both the virus and the gene together.

BIJAL 13: And this was devastating because everybody thought that you get the gene, you can do gene therapy and it would be straight forward. But getting genes into lung cells is one of the most difficult things you can do. Because the lungs evolved to keep stuff out.

ANNA 28: Gene therapy, it turned out, was more difficult than scientists had expected. Then, to make matters worse, in 1999, an 18 year old patient who was being treated with gene therapy for another disease, passed away unexpectedly, casting even more doubt on this area of research.

It was in this context of dashed hopes and failed dreams, that a start up called Vertex Pharmaceuticals attempted a radical new approach to treating CF.

BIJAL 14: Chemists across the board were laughing at scientists at Vertex for even proposing this. I mean they were just branded the crazy people.

ANNA 31: Ok. So I wanna take a moment to explain the science behind what Vertex was trying to do. Bear with me, because this approach ends up becoming really important.

Remember how we said that CF is caused by a faulty gene? So what this gene is supposed to do in a healthy person, is it gives the cell instructions to build a protein and  a doorway. The protein helps pull this molecule called chloride out from deep inside the cell, up to the surface. And once it’s on the surface, the doorway allows the chloride to pass in and out of the cell.

If any part of the protein or doorway malfunctions, you would have a salt imbalance and you would be diagnosed with cystic fibrosis.

So now, instead of trying to fix the gene that causes CF, scientists at Vertex thought maybe they could try fixing the broken protein and doorway directly. If they could just give patients the right molecule, the right drug, maybe they could fix the problem at the source.

It sounds like a smart idea, right? Well, there was only one problem

BIJAL 15: Nobody ever thought that you could fix a broken protein in the cell of a living person.

ANNA 32: In other words, it had never been done before.   

[MUSIC]

SABINE 1: In spring 2002, when I did my first job interview at vertex in San Diego, is when I actually learned about the underlying cause of CF.

ANNA 33: This is Sabine Hadida, who ended up leading the team working on this approach. And in spite of the doubts, and even the ridicule, they went ahead anyway. They started by looking through the company’s chemical libraries, testing thousands of molecules to see if any of them could help with the doorway. And then, once they found a molecule, they’d try to rebuild it from scratch and tweak it to make its effect stronger. A process they’d repeat thousands of times.

SABINE 2: Over the course of the years, we made over 40,000 molecules one by one.

ANNA 34: And eventually, they landed on one that seemed to work. This molecule, called ivacaftor, was supposed to open up the doorway. It went through clinical trials in 2007 and they tested the drug in a group of people who had a rare mutation that only affected the doorway. So if the drug worked as it was supposed to, it would be easier to see in these patients. Sabine still remembers exactly where she was when she heard the results.

SABINE 3: I was in my office. Just working. It was an afternoon. My boss at the time came and said Sabine, Paul Negulescu, who is our site head, wants to talk to us. And I thought Oh my god we are in the biggest trouble ever. And when I got to the office there was a page on the table. With the clinical results. And it was like, in one second we got right away what was going on. 

[SUSPENSFUL MUSIC]

ANNA 35: It was a spectacular success. It hit every metric they could have dreamed of. After just two week the salt in patients’ sweat had dropped to normal levels. They wouldn’t even come up positive on a diagnostic test for the disease.  Patients gained weight, and best of all, lung function increased by an average of 12%.

SABINE 4: We all hug each other and started crying and laughing.

ANNA  36: News of the new drug took the scientific world by storm. The results were so conclusive, that it was one of the fastest drugs to ever be approved by the FDA.

BIJAL 16: It was completely paradigm shifting. I know that we’re not supposed to use the word “paradigm shifting” in science journalism anymore, but it was.

ANNA 37: But as much as this drug felt like a big deal, for more than 90% of CF patients, people like Kevin and Ashley, it still wasn’t enough.

KEVIN 4: It was kind of keeping me stable but not really. I was still in and out of the hospital doing lots of IVs.

ANNA 38: And there was a reason for that. Remember how we said earlier that in most CF patients the gene causes two problems. A broken doorway and a broken protein. Well, if you remember, the protein’s job is to bring the chloride from deep inside the cell, up to the surface. So if this drug only fixes the doorway, but the chloride is still stuck deep in your cells, it can’t really help that much. So Sabine and her team knew their work was far from over.

SABINE 5: We knew that drug only had the potential to treat a very small percent of the patient population. And we knew we needed to do it for everyone. We had a lot of work to do.

ANNA 39: In the next decade, Sabine and her team would keep working to build more molecules. And Ashley and Kevin would keep fighting, both dealing with multiple hospital stays and health scares. During that time, Ashley posted this song to her youtube channel.

ASHLEY SINGING:

When you treat me like that, when you treat me like that,

You’re pushing me harder, pushing me harder.

When you break my back, when you break my back,

I only get stronger. I only get stronger.

I should’ve walked away one year ago

When you said I wouldn’t make it out alive.

When you treat me like that, when you treat me like that,

I only get stronger. I only get stronger

 When you treat me like that.

ASHLEY 11: My very first friend slash CF mentor. She did pass away in 2018.

KEVIN 5: You fight and you fight and you fight.

ASHLEY 12: So that definitely shook my world. And it’s hard every time you see someone go downhill. And you know that there’s no cure.

KEVIN 6: It’s mentally draining to do that over and over again.

ANNA 40: 2018 was a brutal year for both Kevin and Ashley. This disease had just taken so much from them  Ashley had watched mentor pass away from the same disease she had. And for Kevin, his health had declined so much that even walking a few blocks could leave him winded. But all the while, Sabine and her team were still working hard, and in October 2019, 81 years after Dr. Anderson had discovered the disease- they finally had their breakthrough.

ARCHIVAL 7: Experts Call it a game changer. The FDA has approved a new breakthrough treatment for Cystic Fibrosis. It is the first therapy able to treat 90% of patients with the rare life-threatening disease.

ANNA 41: The scientists had done it. They had figured out a way to fix both the doorway, and the broken protein at the same time. The new drug is called Trikafta, and all patients would have to do is take one pill in the morning, and one pill at night for the rest of their lives.

Ashley began to see her social media flood with stories about the miracle drug. But as she waited for her doctor to give her the OK to go ahead and take it, she couldn’t help but feel-

ASHLEY 11: Skeptical. That’s a good word to put it. I was skeptical. Even my nurse knew that. And I know that a few people were having trouble understanding why I was so skeptical. They were like, you know, this is here, it’s great. But I’m like, yeah but what if it doesn’t work for me? Let’s not get our hopes up.

ANNA 42: And she’s right. Trikafta doesn’t work for everyone. About 1 in 10 patients have rare mutations that render the drug useless. And then there’s the people who tried Trikafta but had to get off of it. It’s uncommon, but it happens. A couple of Ashley’s friends had severe enough side effects that they went off the drug after just a few months. She remembers her first dose like it was yesterday.

ASHLEY 12: The night before I was going to take it, I was really nervous. Really anxious  because I’m just like I don’t know how this will affect my life. Will it change my life? How much am I gonna put my bets on this drug?

ANNA TAPE: And would you say it changed your life?

ASHLEY 13: Oh yeah, definitely.

ANNA 43: Ashley took her first pill on the morning of December 15th, 2019. And within a few hours-

ASHLEY 14: I was coughing a lot. Like some of those were kind of crazy where I felt like I was gonna throw up. Like they were like these coughed that I had never experienced.

ANNA 44: And Ashley wasn’t the only one going through this. Across the country, Kevin was experiencing the same exact thing.

KEVIN 6: The first few days it’s like the great purge where I just coughed and coughed everything up. Just so much junk coming out of my lungs.

ANNA 45: It was scary and uncomfortable. But after a few days –

KEVIN 7: My coughing stopped. And since then, I do not cough. I literally do not cough at all.

ASHLEY 15: To this day I don’t cough. I rarely cough which is crazy.

KEVIN 8: Every once in a while my wife will comment and be like you never cough anymore. Do you know how much you used to cough before? And I know I used to cough a lot but it was such second nature to me that I didn’t even notice it a lot of the time.

ANNA 46: And just like that, the disease that had turned both Kevin and Ashley’s lives upside down, the disease that had plagued them from the moments they were born, suddenly seemed manageable. Within days, Trikafta had changed their bodies at a fundamental level. Once on Trikafta, most patients won’t even register as positive on the diagnostic sweat test for the disease.

DIMANGO 1: This group of drugs, modulators,  it’s not a cure, but it really gets to the cellular defect in the lungs and in other parts of the body.

ANNA 47: That’s Dr. Emily DiMango. She’s a pulmonologist who treats CF patients. 

ANNA TAPE: So potentially, if this works, it could give patients with CF something close to a normal life expectancy? Is that correct?

DIMANGO 2: I would say yes. That’s very very possible. We don’t know yet but I would say yes it’s possible. And the other thing to keep in mind is if you introduce these drugs in patients very early in life before they have even developed significant lung disease. The question remains can we prevent lung disease or can we keep lung disease in CF to such a minimum that it’s really not disruptive to quality of life or longevity. All of these questions remain to be answered but we’re very optimistic that we’ll see benefits like that.

[MUSIC]

ANNA 48: And it’s not just people with CF who can benefit from this approach.

ANNA TAPE: Do you think this could have the potential to change things for other genetic diseases too?

DIMANGO 3: I do. I think in many ways CF has been the groundbreaker for precision medicine.

ANNA 49: And Bijal agrees.

BIJAL 17: Alzheimer’s is a problem with a misshapen protein. Alzheimer’s affects 10s of millions of people throughout the world. So you know we’ve got a lot of big diseases that can be helped by this principle of refolding or fixing a broken protein. 

ANNA 50: Only time will tell what the future holds, but for patients like Kevin and Ashley, everything has changed.

ASHLEY 16: Yeah it’s definitely been life changing and I’m thankful for that. But it’s also bittersweet because I know people that I love aren’t able to be on it. Also when you think of a few of your CF friends and mentors who have passed before you and just thinking about how life changing this would have been for them.           

KEVIN 9: I didn’t realize how sick I really was until I started feeling better. And you know there was a couple days this summer where we were on the beach. And I just was sitting there watching like… my daughter and my wife playing. And I was so thankful to the scientists who created this drug.

ANNA 51: This story was produced as my master’s project for the Columbia graduate school of journalism. It was edited by Daniel Alarcón and Lucy Soucek. A special thanks to Bijal Trivedi, who’s book Breath From Salt helped provide me with important historical context. The music for this story comes from Blue Dot Sessions, Pixabay, and Bensound.com.

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