Making Rare Disease Treatments A Priority - John Crowley, Executive Chairman at Amicus Therapeutics


It was on a Friday the 13th in late winter 1997 when John Crowley’s life changed forever. John and his wife Aileen had been noticing concerning symptoms in their infant daughter Megan for several months, and after a few rounds of testing she was diagnosed with a rare form of muscular dystrophy known as Pompe disease. Doctors told the Crowleys their daughter likely only had a few years to live, an outlook that ultimately sparked John’s remarkable efforts to find treatments for Megan as well as her younger brother Patrick, who was also struck with Pompe. His family’s amazing journey was the inspiration for the movie Extraordinary Measures starring Brendan Fraser and Harrison Ford. Join host Shiv Gaglani in this captivating and inspiring conversation with Crowley, now the Executive Chairman at Amicus Therapeutics, to learn about how he and his team are shedding light on some of the rarest diseases in the world, the promise of new technology in genetics, and the need for an Operation Warp Speed to develop rare disease treatments. As Crowley puts it, “We can beat nature, we think, in the years and decades ahead. We just oftentimes have to beat time.” Mentioned in this episode: https://amicusrx.com/





Shiv Gaglani: Hi, I'm Shiv Gaglani. We've been fortunate to have several parents of children with rare diseases on Raise the Line recently to learn from and be inspired by their experiences, but none quite so well known as our guest today, John Crowley. Many people in our audience are already familiar with John through the movieExtraordinary Measures starring Brendan Fraser, Keri Russell, and Harrison Ford, and the many years of news coverage and books about their family's challenges dealing with Pompe Disease, a severe neuromuscular disorder. As a consequence of fighting for new treatments for his own children, John entered the world of biotech, forming several successful companies before becoming president and CEO of Amicus Therapeutics, which focuses on rare and orphan diseases. He also wrote a personal memoir, which I really enjoyed reading and recommend to all of you entitled Chasing Miracles: The Crowley Family Journey of Strength, Hope, and Joy co-authored with Ken Kurson. 


I'm really, really looking forward to learning from him about the challenges of drug development for rare diseases and the impact of new technology on the development of treatments and cures, among other topics. So, John, thanks so much for taking the time to be with us today.


John Crowley: Thank you so much for having me. It's a real pleasure and I’m very, very much looking forward to the conversation.


Shiv Gaglani: It's really an honor to have you on and I feel like I know quite a bit about you already, not just from the movie, but the books. We also share Harvard Business School as a place we both attended -- you gave the class day speech in '97, and your 25th reunion is coming up. I was there in 2016, and the CEO of Elsevier was actually there in 2001. So, I know a lot about you, but for our audience's sake do you mind giving us your one or two-minute overview about your professional background and what got you into rare diseases?


John Crowley: Of course, Shiv, and actually the business school degree is a good place to start. Graduating from Harvard with an MBA was something that I had set my set sights on early in life -- with my mom having been a waitress when I was young and my dad a cop -- and to go to the Harvard Business School was a great honor. It was a lot of work, a lot of student loans at the time. But I think if you look back on the day we graduated…if you remember, at HBS, if you've got a child when you graduate, many of us would carry the child on the stage with us and we actually had two. We had John, who was a couple of years old, and Megan, who was six months old or so. So, I had a kid in each arm and everybody kind of laughed with me coming up with two kids. They give you your diploma and I'm kind of reaching for a handshake and then they give you a teddy bear with a little HBS shirt on the teddy bear for each kid. So, I've got to balance two kids, a diploma, and two teddy bears and I almost dropped Megan. There was this big gasp from the audience. Thankfully, I didn't, and I walked off. 


In retrospect, it was probably the first sign kind of unbeknownst to us at the time, that Megan wasn't quite as strong as a six-month-old should be and you know, from there, we set out on a journey in life. It's kind of like the old Jewish proverb, ‘we make plans, and God laughs,’ and we made our plans. We moved to California. I took a job with a consulting firm. It was kind of a one-year assignment in California. After we got out there, by that fall of 1997, we realized that Megan wasn't doing the things that an eight, nine, ten-month-old should be doing -- pulling up in the crib and trying to maybe take their first steps, even crawling. Otherwise, she was a perfectly healthy, normal child. 


I'll condense this quite a bit, but we went from blood test to muscle biopsy to, on March 13 -- Friday the 13th -- getting the results in a meeting with a physician and a social worker that Megan had this rare form of muscular dystrophy known as Pompe disease. Aileen and I are silent carriers, so there's no history in our family. Any one of us are silent carriers for maybe, on average, about a dozen or so rare genetic diseases, but it’s not until you have a child with somebody who's also a carrier -- and even then, in a disease like Pompe, only a one in four chance -- that any of our children would actually manifest with the disease itself. 


I remember asking the doctor, “Is it serious?” And he said, “Yes, it's very serious.” He said, “I don't think she'll live to be a couple of years old and there's really no science so enjoy the time you have.” He also said that our son Patrick, who was with us at the appointment -- he was seven days old – had a one in four chance he would have the disease and he should be tested. So obviously, you go through an awful lot of emotions. We tested Patrick shortly thereafter, and he came back positive for the disease. So, in a moment, your life changes and it sets us out on this journey to try to learn everything we could about science, and medicine, try to meet doctors, all the while balancing a young family, working in a consulting firm, and paying off student loans. Life certainly changed in a very short period of time for us.


Shiv Gaglani: Yes, it's quite remarkable and I know even that night you did a lot of research and found that study from Duke about animal trials in birds and how birds can maybe fly again with some enzyme replacement therapies, it seemed. That gave you guys hope that it wasn't necessarily a death sentence, there were things that were being done across the world. You wound up meeting with researchers from the Netherlands. It’s a very similar story to some of the other rare disease parents we've had on the podcast who have taken that step to really learn about the condition, and network with physicians and researchers. How'd you go from that to then starting and selling successful biotech companies? And also, can you give us a sense of how successful now your children are? I think John just had a child, you're now a grandfather, and we were talking about Megan before the podcast started. So yeah, maybe both of those would be very interesting to go into.


John Crowley: Yes, it's amazing, it's a journey in life that's coming up on twenty-five years since the kids' diagnosis. So, if you fast forward through all of that, we were able to find a researcher who had some ideas and we started a small biotech company, really, because back then with a handful of employees and about thirty thousand dollars in seed capital, the best that they could do for a CEO was me. I think for us, personally, we just never wanted to have any regrets. I didn't want to look back years later, and -- regardless of what the outcome could have been for Patrick and Megan -- I didn't want to ever have any regrets that we didn't try, that we didn't leave it all on the field…you know, pick your analogy. So that's what we did. We started that small company and eventually, it sold to Genzyme and I went to Genzyme to run their drug program in Pompe disease and other programs. Finally, thankfully, Megan and Patrick began to be treated with a life-saving enzyme replacement therapy that we had developed on January 9th of 2003 – it would have been my dad's sixty-third birthday -- and within weeks we started to see the change. 


The life-threatening aspect for them at the time Shiv, was their hearts. They were two to three times normal size. Within twelve weeks, Megan's heart returned to normal size and normal function. Patrick took a little bit longer, but his eventually did too, and for a time it made them stronger. Then they kind of plateaued, but what we did with so many people's help was to save their lives from the immediate threat, to give them more quality of life and more time, but also time for us to go back to the drawing board and to think about okay, this isn't a cure. It's not even, we don't think, the best treatment. What else can we do?'


That's what led me to found Amicus in 2005. I'm sure we'll come to Amicus and the science to what we're doing, but there’s good news for the kids. We've got three kids. Our older son John, who's not affected with Pompe, lives with Asperger's -- high functioning autism -- and during quarantine he fell in love with one of Megan's nurses and they got married. This is a young man who never had a girlfriend at age twenty-seven. He fell in love got married, and they just had a baby back in June. So,


Shiv Gaglani: Congratulations!


John Crowley: Yes. Stella Aileen is three months old now and perfectly healthy. Watching them mature as parents has just been beautiful. Thankfully, now Megan and Patrick continue to thrive in many ways, despite the lifelong challenges of living with a disease like Pompe. They're still in wheelchairs and still require ventilators to breathe. But again, they've had, in many ways, great quality of life. Megan was able to graduate from Notre Dame in 2019, the most physically challenged student ever to go through Our Lady's University. Two years later, she earned a Master's in Social Work from the University of North Carolina Chapel Hill, so she's got a little bit of Tar Heel blue. When she went there, she said, “Dad, don't worry. I still bleed blue and gold like Notre Dame, but the blue just got a little bit lighter on Sunday.” 

Shiv Gaglani: (laughs)

John Crowley: So, there’s a little tar heel in her, and she's just remarkable. Megan began working as a social worker in the Princeton Middle School in New Jersey, working with the same team that supported her many years ago. Very recently, in early September, Megan took a new job as the Assistant Director for Mission Integration at the Make-A-Wish Foundation of New Jersey. So, Megan is going to work on helping to find more eligible children for wishes, making sure their wishes are fulfilled. It involves communications, fundraising, and it's a real passion. Megan was a ‘wish kid’ many years ago, and that's certainly influenced her life. So, she'll continue to work and to give back. Patrick works in a flower store in Princeton, New Jersey called Vaseful Flowers. It's all staffed by people living with physical or cognitive disabilities, so it's a beautiful organization. So, you know, life is a journey, right? If you'd told me many, many years ago that this is where the kids in the family would be, I would have been very pleasantly surprised.


Shiv Gaglani: Well, that's amazing. Congratulations to all of them, and certainly the Make-A- Wish Foundation news. I really enjoyed your commencement speech at Notre Dame where one of the leadership lessons you provided to all the graduates was about how you can start small. Like leadership oftentimes develops starting small. Make-A-Wish Foundation, which I know you were chairman of, started small. That story of that mother who fulfilled her son's wish to become a cop for a day in Arizona. Unfortunately, the son passed away four days later, but had the best day of his life because of that. It's really meaningful, and certainly, you've had that opportunity with your children and many others, I'm sure.


John Crowley: Yeah. When you think about the miracle of the Make-A-Wish Foundation starting with that one child, Chris Greicius, whose wish it was -- when there was no foundation, no 501c3 organization, no board of directors -- it was just a little boy, very much in need, and a couple of people who came together to make his wish come true. Unfortunately, Chris, just a couple of days later, died from his leukemia in 1980. But the legacy that he, his mom, the family, and all the volunteers left began when they came together a couple of weeks later to celebrate Chris's life and to give thanks. They said, “We could do this for other kids.” Make-A-Wish today has now granted, I think, well over 300,000 wishes just in the United States alone, and we have Make-A-Wish International, and that all started by a couple of people just doing good for one child.


Shiv Gaglani: It's amazing. So, that's actually a good segue towards drug development, because we’re coming up on forty years ago -- January 4th, 1983 -- when the Orphan Drug Act was signed. Very similarly, several parents of children with rare diseases came together and said, "How do we incentivize biotechnology and pharma companies to develop these orphan drugs?" Obviously, that's something you're very familiar with at Amicus. Do you mind talking to us a bit about Amicus, what you're focused on, and maybe any lessons you've had over the twenty-five years? What do you see in the next ten years we should be doing to accelerate the development of these drugs as well?


John Crowley: When we started Amicus, we had a really big vision. We said we wanted to build a company and we wanted it to be enduring and lasting and we wanted to be a global leader in making medicines for people living with rare diseases. It’s a very clear mission. We knew back then that there were more than 7,000 rare diseases that taken together affect, in just the United States, more than thirty million people and nearly a half a billion people around the world. So, taken together, not very rare at all. Some of them are well-known diseases like Duchenne Muscular Dystrophy or Cystic Fibrosis. But the vast, vast majority…not only has the general public, not ever heard of them, most people in the medical profession haven’t either. I remember -- when I had never heard about Pompe and when I was first talking about it -- I remember my friends who were just finished medical school said "Oh, yeah, I think I know that. It was a trick question on a cardiology exam or a pediatrics exam.” 


When you think about the unmet need, the Orphan Drug Act has been essential to ensuring a market-based environment for proper incentives for companies to invest in R&D to make medicines for rare diseases, otherwise, there is no business model that would work. But even then, we only have approved therapies for a couple of hundred of those now more than 8,000 known rare diseases, and really only a couple of approved gene therapies or real cures. We've got a long, long way to go. So, that's the difficult news.


The good news is that I really believe we are on the cusp of this golden age of medicine, in genetics. We're able to much better diagnose these diseases, oftentimes through newborn screening in utero, and increasingly to have a range of options to think about how can we treat these. Now some of those options may not have yet translated to medicines. They may not have even translated to molecules. But when you think about the range of technologies…whether it was the older generation enzyme replacement therapies, if it's small molecule oligonucleotides, if it's gene therapy, or gene editing. 


Maybe we could talk about a little bit because I really think that has such remarkable promise when you put all that together. I really am hopeful that over the next decade, maybe two decades, we can really, truly start to develop medicines for hundreds, maybe thousands of these rare diseases, and increasingly have very, very safe and effective treatments and many, many cures. So, it's super exciting. There are a lot of barriers to get there, but it's an exciting time. It's never enough and it's never fast enough, though, when you or your child has one of these diseases, that's for sure. And that's part of our battle, Shiv. We can beat nature, we think, in the years and decades ahead, we just oftentimes have to beat time. That sense of urgency, the same mindset that we brought to the development of vaccines and medicines and COVID -- great science -- we need to bring that to the rare diseases. Frankly, we need an Operation Warp Speed for rare diseases.


Shiv Gaglani: That's a great point. I enjoyed the talk you gave at Goldman Sachs last year in which you make that exact point…how medicine is capable of solving these issues. Clearly, the vaccine for COVID was predicted to take three to five years, and was made in a year and now it’s helped us return for the most part to a state of normalcy without masks and social distancing. Let's actually go into some of those therapies. You mentioned gene editing. One of the rare disease parents we had recently on the podcast is named Akiva Zablocki. He helped start the Hyper IgM Foundation. It’s a one-in-a-million disease, which, in aggregate means there are about seventy thousand people worldwide who have it. That's a condition where, right now, bone marrow transplantation is the state of the art for curing it. But for actual gene editing purposes, I think it’s a single nucleotide that goes wrong in Hyper IgM. Can you talk about those therapies you mentioned when you're talking about gene editing?


John Crowley: Yes, gene editing is very exciting. This is a chance actually to kind of correct the mistakes of Nature by using these tools that have been invented by some of the world's greatest scientists, including scientists like Jennifer Doudna, and her colleagues. You know, Jennifer just recently earned the Nobel Prize for her work in CRISPR therapies. There are a lot of ways that we can think about gene or genome editing, but at its core, you can think about it in a couple of different ways.


There are some diseases where you have a gain of function, essentially, of a gene…something turned on that needs to be turned off. It is kind of a toxic gain of function. Right now, the technology is much better at turning off genes, cutting out some of the bad parts of the genetic material, and using the technology to turn off bad genes. All of this is all in vivo -- within the body gene editing. What we also now need to be doing -- and increasingly science is leading us there -- is to cut out the bad part of the gene or even sections of the gene using something like base editing, and actually then insert the sequence for making a protein if there's a deficient protein. You would do that in cases where there’s a toxic loss of function, we might call it. 


That's all a very high-level description of that incredibly complex scientific field. But we've seen it happening. I'm on the board of Intellia Therapeutics, another company who have been making substantial progress now in human clinical studies. Only in the last couple of years have we introduced this technology into human studies. Obviously, safety is incredibly important and these companies, the innovators, the physicians, the regulators are hyper-focused on safety as they need to be, and the appropriate measures of efficacy. I think it'll be a number of years until we see this become the standard of care in medicine, but you're seeing more and more success, and that's really exciting.


I mean, look, when our kids were diagnosed and the docs said ‘I'm sorry, there's nothing that can be done’…in the next couple of years with the range and the power of the technologies we have, that's just not going to be acceptable anymore. It should be, "Your child has this disease. We have a range of tools to address it. Here's what we think is the best-customized approach for this disease and for your child's genetic background, and here's the plan.” That's kind of the dream for many of us in the field that we want to get to. We always had that ambition and the goal, we just never had the technology. Now we increasingly have the technology in our grasp and, frankly, we just need to make sure we don't screw it up. It's an exciting time. But again, it's never enough and never fast enough. So, that's where we're so focused: how many of these diseases can we address and how fast can we safely address them?


Shiv Gaglani: It's very, very exciting. There's this whole diagnostic odyssey for rare disease patients where often it takes four to nine years on average to get diagnosed. You were talking about your friends who were finishing med school and how it was like a trick question to learn about Pompe Disease. I was in medical school at Johns Hopkins -- I'm technically still a medical student -- and one of the first things we learned is ‘when you hear hoofbeats think horses, not zebras’ which is great advice for value-based medicine. But at the same time, that never really sat well with me because I was actually born in Namibia, and in Africa when you hear hoofbeats you think zebras, not horses. 


So, for the nearly half a billion people who have one of eight thousand zebras, or rare diseases, we want to shorten how long it takes them to get the diagnosis. Then once they get the diagnosis, to get care, some of which will be new therapies like what you've developed at Amicus and Novazyme, and etc., but some of which will be repurposed therapies. One of our other guests is David Fajgenbaum, who...



John Crowley:David is great, what a hero.


Shiv Gaglani: He's awesome. I'll see him next week at the Clinton Global Initiative because Chelsea Clinton, who was also on the podcast, she and Bill Clinton have taken a real interest in rare diseases. So, it's an exciting time, I think, and hopefully, we get that operation warp speed together. 


Our audience comprises millions of current and future healthcare professionals, one of which now is your daughter. She's a social worker, so she's a healthcare professional. What advice did you give your daughter and/or what advice would you give to our audience about meeting the challenges of this moment in history and beyond?


John Crowley: My daughter Megan is a social worker. We have other family members involved in the healthcare field, a lot of nurses in the family who have come up, and one, Maggie, graduating medical school here in a few months. What I try to tell all of them is, you know, we say in our companies that we are patient-focused -- and many of us increasingly are in the industry -- but you have to think about what does that mean? At Amicus, I've tried to lead a company where every one of us thinks, 'Okay, if you had this disease, or you were the mom or dad of a child with the disease, how would you make a decision? Where would you invest your capital? Where would you build a facility? What type of person would you hire?”


It's a different mindset and I think anybody involved in the field of healthcare has to think about that. If you're a caregiver, if you're a medical technician, a physician, a nurse -- whatever it may be, whatever role you play, in this virtuous circle of delivering healing therapies to people in need – you have to think about what if this was you? Or what if this was your child? What would you do? How would you think? Where would you go? What questions would you ask? So, constantly trying to put yourself in other people's shoes. 


You mentioned, Shiv, such an important aspect of this is the diagnostic odyssey in rare diseases. We're getting better at it. We need to get much better at expanding newborn screening. It's a very disparate system now, across all fifty states here in the United States. And in many parts of the world, there is no such thing as newborn screening. What a tragedy it would be in the years ahead if we have therapies and we miss children. Right now, the way this system is set up, we would miss most of them. You think about fatal brain diseases…diseases we work in like Batten disease. You can have the greatest gene therapy, gene editing -- pick your technology -- but you get to points of irreversible damage in brain disease and many neuromuscular diseases. So that's, again, that sense of urgency…finding people soon, and bringing that mindset to your practice of medicine, to your involvement in healthcare in any way. 

Maybe the last lesson is one of persistence. You just gotta keep trying in whatever you're doing. Because, you know, what we do is really, really hard and this is a really hard business. A really hard field.


Shiv Gaglani: That's really wonderful advice. I know we're coming up on time, but I had one and a half last questions for you, if that's okay,


John Crowley: I'll give you at least one answer (laughs)


Shiv Gaglani: (laughs) Well, the first is I also enjoyed your podcast episode with Tim Ferriss, where he calls you the real-life Captain America. I dug more into that. You've served in Afghanistan. You've obviously served on the board of Make-A-Wish. A lot of your life has been dedicated to service and faith. I'm just curious if you have any words of wisdom to people? I think the last few years have been very difficult for people in general -- with the war in Ukraine, what happened in Afghanistan recently, with the COVID pandemic -- any advice for people who may be feeling a little lost out there? And what gives you that real sense of service, of duty, that hopefully, we can bottle up to be therapy for people?


John Crowley: Yes, Shiv. You mentioned that podcast I did a number of years ago with my friend, Tim. He asked me at the end -- and I think it's very much the same question that you're asking in terms of motivation and centering -- where do you find that ‘true north?’ My answer is whatever you're struggling with, whatever you're working on, whatever field, whatever effort you're putting in, just to know that it's bigger than you. It really is. So, to think about that. 


In my commencement talk at Notre Dame I talk about leadership and the notion that the world is in urgent need of great leaders, so become one of them. It doesn't mean you need to be President or king of the world or whatever. Just again, go back to start with one mission, one organization, one team, one life -- maybe it's a family member, a friend. If each of us does that, and maybe we developed some economies of scale…and think about that notion of servant leadership. I lived it in my time, in my career in the military. It's something that we do in biotech, and maybe in biotechnology we have an unfair advantage because our mission and our purpose is very clear. I think for me, it really comes down to that bigger picture issue. Maybe it's trite, but we all are going to be on this earth for a remarkably short period of time. Think about years from now…what would you be proud of? What did you accomplish? You know, what we did for our kids I did because we had to, and I think any parent similarly situated would want to or have to do that. So, in many regards, it wasn't very special. We just were blessed to have a lot of great people help us and frankly, a little bit of luck, and maybe a little divine intervention along the way, too. I'll take all the above.


Shiv Gaglani: That's wonderful. So, is there anything else you want to share with our audience while you have them about biotech about you, your family, anything?



John Crowley: Look, this is an incredibly exciting field. Biotech is, again, it's a really tough job. Almost everything we do, everything we try, doesn't work and yet still, we persist. Because what we do is simply too important. But when it does work -- and I think this is true broadly about healthcare -- when it does work, when you do save a life, when you do improve a life, you help somebody…I still think it's the best job you can have. So, thanks for bringing all this to your listeners too. It’s incredibly important.


Shiv Gaglani: Of course. My hope is many of them will go on and follow in your footsteps and either provide the therapies that you and Amicus are working on, or help develop them as well. So, with that, John, thanks so much for taking the time to be with us today and being such a positive force and inspiration for many of us.


John Crowley: That's very kind, Shiv. Thank you so much, and have a great day.


Shiv Gaglani: And with that, I'm Shiv Gaglani, thank you to our audience for checking out today's show and remember to do your part to Raise the Line and strengthen our health care system. We're all in this together. Take care