#240 Dr. David Fajgenbaum - Can AI Find Cures to Rare Diseases Using Existing Medicine?

20:09Dr. David Fajgenbaum:They were like, well, if your immune system is trying to kill you, maybe we'll try to kill the immune system with some chemo. And so they gave me chemo in this like sort of last ditch effort right around the time I had my last rites read to me. And it just sort of kicked in just in time. And I survived that. But then I would go on to have a bunch of relapses.

20:25Shawn Ryan:What is it? What's going through your head as a 25-year-old man knowing that you're being told that you have a terminal illness? I mean, you're saying goodbye to your family. You got a priest reading your last rites. I mean, how do you handle that? I think about this all the time, if it were to happen to me. Because these things just seem to be more and more. It's like every day, you know, I hear somebody else, my mom got diagnosed with cancer. You know, my, you know, my, my friend who my friends, like all the, it's just, it's like every day you hear somebody else is diagnosed with cancer.

21:06Dr. David Fajgenbaum:That's right. Yeah. I mean, it was, it was heartbreaking. Um, I was devastated. I had this amazing girlfriend, Caitlin, that I wanted to have a life with. Um, I'd made this promise to my mom. I was going to treat all these patients and I was going to discover all these treatments. I wasn't going to be able to follow through on. I just felt like there was just so much that I was never going to experience that I wanted to so badly. And, you know, I didn't have any regrets about what I did in life, but I just had this, like, feeling of regret about things I never would get to do or that I never got to do.

21:34Dr. David Fajgenbaum:And I was just heartbroken. But, you know, I think that I ended up spending about six months in the hospital in critical condition. And I think about, you know, some of the things that you've gone through as a soldier and sort of just, like, fighting, you know, one day at a time. And I think that there's three things that helped me to get through those six months of survival. And I'd love to hear if you've thought about these in the same way. But for me, it was like, for the entire six months, I kept thinking about what I wanted for my future, which I kept visualizing like a family with Caitlin.

22:04Dr. David Fajgenbaum:I kept visualizing like me in the lab trying to find drugs for patients. I had to have this vision for what I was fighting for. So that was the first thing. The second is that I had this like amazing support group around me. my dad, my sisters, Caitlin, like they were literally holding my hand, like giving me strength. Like I could feel their strength from the way they were holding my hands, from their voices, like that, that gave me strength. And then the third thing is that, um, it really was this, like, it's this cliche of like one step at a time or like one breath at a time. But it was, for me, it really was one breath at a time.

22:38Dr. David Fajgenbaum:Like if you told me at the beginning of the six months, like David, you're going to suffer the most horrible pain for the next six months. Every breath you take is going to be horrible. I gained 100 pounds of fluid. You're just going to be in constant agony while your organs are being destroyed by your immune system. There's no way I could have been like, I can do this for six months. But I knew I could do it for like an hour. And then like, all right, I can do it for an hour. Maybe I can do it for two hours. And then those hours just started stacking up. All right, I did it for a day. I can keep doing this.

23:06Dr. David Fajgenbaum:As long as I've got my family around. I couldn't have done it if it was on my own. But as long as I've got them supporting me, I can do this. And all of a sudden they stacked up and then I made it through. Did you ever come to acceptance? Well, I don't know if I would say acceptance, but there was one point where I was ready to give up, where I started slowing down my breathing. And my family was around me and my sister Gina was holding my hand and everyone was saying goodbye. I just had my last rites read to me. And it hurt so bad to take every breath. And it was just like I was fighting. and then I started to slow down and I was going to let go.

23:43Dr. David Fajgenbaum:And I heard my sister Gina and I can picture it, I can hear it. And she said, just breathe, Dave, just breathe. And I heard that, I was like, all right, I can do this. I can do another breath. And I was like, I'm not going to give, I'm not going to slow down. But in my mind, when I was slowing down my breathing and letting go, I was expecting that I was going to be letting go maybe a couple of days of life early. Maybe it's like maybe it's a day of life that I you know a day of suffering basically that I was going to be sort of letting go like you said Wendy she was fighting like you can fight for survival there's that when you're at the end you can keep fighting or you can let go and I was gonna let go I was ready to let go but when she said just breathe Dave just breathe I was like all right I can do that I'm gonna I'm gonna keep doing a couple more breaths and Sean if I'd let go then I would have known that I would be here 15 years later sitting here with you like I like but I took that extra breath i kept fighting and then thankfully the chemotherapy kicked in and you know i'm sitting here with you 15 years later man i mean yeah if she hadn't said keep if she hadn't said just breathe

24:44Shawn Ryan:dave just breathe i'm not here i'm not here so it is i mean i i often think about that i mean what like i said when i was just talking about wendy you know maybe your mom yep you know i mean i I think that you can prolong death. You can at the very end. I mean, how does that, from somebody that faced it, I mean, five times? Yep. I mean, is it just letting go, and then you think it just happens? That's right. You're fighting.

25:14Dr. David Fajgenbaum:You've got adrenaline. You're like at cortisol. You're like literally giving everything you've got to every breath. You're like, you're doing everything you can to stay conscious, to stay there, to keep going. And obviously, you know, I only was sort of prepared to go once and sort of let go once. But, you know, quickly said, no, I'm going to keep fighting because of my sister. But yeah, with each of the, so that was the first one. And then two near-death experiences happened the next few months in that six-month period where my doctors, again, were like, he's not going to make it. And then all the blood work, everything said I wasn't going to make it.

25:50Dr. David Fajgenbaum:But I got more chemo. By the end, they were giving me seven different chemotherapy drugs, like the worst chemos they have at the highest possible doses, thinking like, maybe we can stop this somehow. And thankfully, they would sort of just get me by. But then when I relapsed again a year later, and then relapsed again a year after that, again, both of those times, it wasn't like, this is maybe going to be it. It was like, this is it. Like, you fought really hard. You made it. But for me, each time my doctors told me that I wasn't going to make it after that first one, I was like, yeah, but you told me I was going to make it last.

26:21Dr. David Fajgenbaum:I'm going to keep fighting. I'm not like, I got this amazing girlfriend, Caitlin. I want to get married to her. I don't care. I don't care if I'd, you know, I go shortly. Well, I don't, I didn't want to go shortly after I got married to her, but I wanted to get married to her. I wanted to have this family. I wanted to, um, to do these things. And so I think that there is, there is a real ability, um, to keep fighting. But of course, for me, I, the chemotherapy was necessary. It's not like I could have willed myself into doing this. It was that, you know, chemotherapy, you get my disease is in control and I can keep fighting.

26:49Dr. David Fajgenbaum:Did you think about what would happen after death? I did. I said a lot of prayers.

27:03Dr. David Fajgenbaum:I spent so much of that time when I was on my deathbed sort of sad about the things that I was going to leave behind here that I spent a lot less time forward looking into what was going to happen afterwards. It was a lot more just, you know, sadness about what was behind me.

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28:48Shawn Ryan:TaxAct. Let's get them over with. You know, you'd ask me about, and I haven't gone through anything like that. So I can't, I can't, I cannot relate. You've been in battle and you've, you know. I just, you know, it was, it was different for me. I feared a lot more than I did back then. I mean, back then I figured I had thought that I had reached the pinnacle of my life. I was a Navy SEAL. I was, you know, CIA contractor. Where do I even go from here? You know, yeah, I could have gone maybe and tried out for development group. But, I mean, it was pretty damn close to the pinnacle. And, you know, but, and so I just kind of always, if it got hairy, I kind of always considered myself dead already.

29:34Shawn Ryan:or I just never really expected to come back from any of those deployments.

29:38Dr. David Fajgenbaum:Wow. You know, but I mean, in relation to now, I mean, that was an easy thought.

29:46Shawn Ryan:I had brothers and sisters and parents, you know, but I didn't have kids, a wife, nobody on my radar. You know, all I was doing was that. And so I can't really relate, you know what I mean, to what you were going through. I didn't have a fiance. I didn't have my future was exactly what I was doing at that point in time, which was what I loved. And so it was if I'm going to go, this is a great way to go. But but luckily, I made it through. So you did. But you too.

30:21Dr. David Fajgenbaum:But so let's go. Let's move on. Yeah. So I make it through that six month period somehow, some way. and I got put on an experimental drug, a drug that was going into clinical trials for my disease, my rare disease, this disease called Castleman's with, you know, a thousand patients diagnosed a year in the U.S., like super rare. And we thought it was going to keep me in remission. So I went back to med school. Caitlin moved down to Philly. We're like living together and I'm back on track. You know, I'm still leading this grief support network called AMF, but I'm back on track. You know, I'm going to find treatments for patients.

30:56Dr. David Fajgenbaum:I'm going to finish med school. I'm going to take care of patients. And then I started to relapse on that experimental drug. And Sean, that was so hard mentally and emotionally to go through. Like, this is the drug that's supposed to work. Like, it's working for other patients with my disease. And it just wasn't. I like relapsed right through it, ended up back in the ICU with all my organs shutting down. And mentally to go through that, that was really, really tough. And my doctor explained to me, this is now for the fourth time, you know, David, you know, you're, you're actively dying. This is, it's unlikely you're going to survive this.

31:31Dr. David Fajgenbaum:And the drug you were just on is the only drug that anyone is working on for your disease. There are no more leads. Like this is it. The drug you're on that you just relapsed on. This is it. There's nothing else. And, um, I remember, uh, my, my dad and my sisters and Caitlin were around me. And, um, I remember there was like a minute or two of us just like crying our eyes out. Like this is, you know, my, this is the world's expert. This doctor is in Little Rock, Arkansas. He's like the world's expert for Castleman's. And I'd gone to see him just like we're talking about earlier. Like, you know, you go to the expert and he's telling me like, there's nothing else.

32:03Dr. David Fajgenbaum:Like, this is it. We tried everything. And, um, he said, I'm going to give you the chemotherapy that you got in the past, all seven of those chemotherapy drugs. I'm going to give them the highest possible human dose we can give. Let's hope they work. But you're, you're approaching the lifetime maximum of chemotherapy. This one drug called atrium is and we're not gonna be able to keep giving you more and this stuff's gonna stop working so like you just sort of need me to be prepared for that and so we were in balling our eyes out and then um when the doctor left the room you know something sort of clicked the same way that it clicked with my mom and um that's when i told them that i'm gonna dedicate the rest of my life however long that is trying to find a treatment for castleman disease and um i didn't know what that would be.

32:47Dr. David Fajgenbaum:And frankly, I didn't have a billion dollars in 10 years to create a new drug, which is about how much time and money it costs if you want to make a brand new drug. So I didn't have the money and didn't have the time. But I had a really simple and important realization. And that was those seven chemotherapies that I kept getting that kept sort of barely saving my life. None of them were made for Castleman disease. They were all made for cancer of the lymph nodes for lymphoma, but they were saving my life from Castleman. So I was like, wait a minute, you're telling me there's no more drugs for Castleman disease, but you just used seven drugs for lymphoma and those just saved my life.

33:21Dr. David Fajgenbaum:So like, what if there's an eighth drug for lymphoma? Or what if there's a ninth drug for something else that could work for Castleman's? And my doctors were sort of like, well, but there's nothing else that we know of. And I'm like, yeah, but we have, have we tried all 4 ,000 drugs for Castleman disease? And so that became my just total like locked in focus. It was like, I can't develop a new drug from scratch. I want to get married to Caitlin, have a family. I want to develop drugs and treat patients. Like I got to find a drug that already exists for something else. And then I got to try it on me.

33:51Dr. David Fajgenbaum:And that became just my total focus. Where do you start? So to start, I spent a lot of time just sort of researching online. Like, are there any case reports of doctors trying different things? Like it happened in Japan. There was a doctor that was trying these different drugs. And so then when I relapsed and had my fifth deadly flare, I actually started trying those drugs that had been used in other parts of the world. I asked my doctors, would you prescribe this drug? It had been used in Japan. And we tried it and it didn't work at all. And I said, well, can you try this other drug? It was used for a disease like Castleman's.

34:24Dr. David Fajgenbaum:And that drug kind of worked, but I just relapsed right through it, ended up back in the ICU. And I felt so disappointed because I had spent that year thinking about what could be tried. And we tried these two drugs. But the third thing I had done was that I started storing my blood samples every couple weeks in the freezer at a lab at UPenn. Because my belief was if I relapse, and I thought I probably would, that I needed to get those blood samples so I could figure out what was going wrong so that way I could target it. I needed to get like basically some evidence to figure out what to go after.

34:56Dr. David Fajgenbaum:And so thankfully I survived that fifth episode again, again with those seven chemotherapies. and when I got out of the hospital and actually even while I was still in the hospital, I turned to my sisters and to Caitlin and it was like, let's get all the samples we can. All those samples that are in freezers, the lymph nodes that are here and there, get them all to Philly. I'm basically going to go to the lab and I'm not going to leave until I figure something out. And so got back to Philly and then I just worked basically day and night running experiments on, I thawed those blood samples, started measuring proteins in the blood, measuring what those immune cells were doing.

35:29And I eventually identified that a communication line in the

35:33Dr. David Fajgenbaum:immune system, you've got all these immune cells all over your body, and they got to communicate with one another. And I discovered that one of those communication lines was turned into overdrive. Sort of like, to me, I thought of it as like, it seems like maybe the fire alarm is going off in my immune system, even when it shouldn't. It's like a false alarm. And so therefore, it's attacking everything. And what was really important about that discovery, Sean, is that there's a drug that's been around for decades that can turn that communication line off. And it was made for organ transplantation.

35:58Dr. David Fajgenbaum:So like if you were to get a kidney, your immune system would attack your kidney, that new kidney, that transplanted kidney, unless you took this medicine, which would prevent your immune system from attacking that transplanted kidney. And that drug turns this one communication line off. So I went to my doctor, a doctor in DC, and I was like, hey, would you consider prescribing this? And he's like, well, it's never been done before for Castleman's. Like it could cause problems. Like it could turn things in the wrong direction with your immune system. Maybe this could kill you. And I said, well, but I've already died.

36:26Dr. David Fajgenbaum:I almost died five times and I'm out of options. And so he prescribed it. And so I started taking it and it's, Sean, it's now been over 11 and a half years. I've been doing great on this drug. No, no relapses, just full remission. Wow. Do you still have to take it? I take it every day. I took my three pills this morning. And, you know, the moment that that drug, that these drugs are, are these three pills started working for me, Sean, I immediately have gone into this just total focus and obsession, like, holy shit, like how many other drugs are made for other diseases that could treat more diseases?

37:00Dr. David Fajgenbaum:You know, like this drug wasn't made for me and it's saving my life. Are there other drugs that are out there that could treat more diseases? And are there people suffering today that could actually benefit from a drug that's already sitting in their CVS? Because I shouldn't be here. I mean, I'm alive thanks to these, this medicine that I discovered. But if I had died at any point in those previous three and a half years, we wouldn't know that serolimus could treat Castleman's. There's thousands of people around the world that are benefiting from this drug. And it's like, no one would have figured it out.

37:27Dr. David Fajgenbaum:How many more of these hidden cures are just sitting there? Did you, did you ever, I mean, did you talk to the doctor in Arkansas about this?

37:36Shawn Ryan:I mean, what it would, what was that conversation like?

37:39Dr. David Fajgenbaum:Yeah. I talked to him about it. You know, he's, he's, he's incredible. And I'm, I still work closely with him. Yeah. I mean, he, he basically said look david it's never been tried before it's probably not gonna work but there's probably not too much downside or to your point even if there is a downside like i'm already gonna die from this disease so like we should at least give it a shot but there was no data it hadn't been using a human before with castleman so like i can understand the hesitancy because like it could have turned things even worse um but it also it was it was sort of my my last ditch effort to try to stay around.

38:12Dr. David Fajgenbaum:What did he say afterwards? It was sort of a test of time because I started feeling better. My blood results started getting better. It was clearly working early on, but I'd gotten better multiple times before, and then it came back within a year. I sort of wasn't willing to get too excited. I just sort of was like, all right, it's going to be a test of time, cautiously optimistic. I started taking it in January of 2014. Caitlin and I, our wedding day was May 24th, 2014. So it was like, am I going to make it to May 24th? It was sort of this countdown. Wow. And we made it to May 24th and my hair grew back like just in time for wedding day because all the chemo, like it came back just in time and like wedding day, like my hair's back.

38:53Dr. David Fajgenbaum:I made it to May 24th, 2014. And we had the most amazing, like every wedding is amazing. This wedding was like extra special because everyone that was in attendance was like, I can't believe this is happening. Like, I, and I couldn't believe it was happening. Like, and then of course, you know, when you think about you know saying till death do us part it's like it has a whole different meaning when you know that the person you're marrying and for me caitlin that like she was

39:19Shawn Ryan:there with me through everything you we had a little conversation before the interview about how you guys were engaged and you had a question for her could we revisit that absolutely what an

39:29Dr. David Fajgenbaum:amazing woman she's incredible isn't she just with me through everything and so yeah i had the question i had for her was uh right when i finished those six months in the hospital sean You've seen the picture of me. My head's bald from chemo. I've got this huge belly because of my liver and my kidneys aren't working. And actually, I'll tell a story about that in a minute. And Caitlin came down to visit me in North Carolina. That's where I've been hospitalized. And we're sitting on this couch in my sister's house, and I've got my hand over my head. I remember just being like, Caitlin, you know, I've got a terminal illness.

40:05and are you sure you want to be with me?

40:10Dr. David Fajgenbaum:Like you could find so many amazing people, like you're amazing. Like, are you sure you want to be with me? I'm going to be sick and like, I don't know how much longer I have. And I remember she looked at me and she like looked offended. And I was like, wait, what? She was like, of course I do. Like, why would you even question that? Like, absolutely, I want to be with you. And then when I was saying to you, what I was joking about, I was like, once you said that, I was like, I'm not going to ask you anymore. You know, you've told you, you've said it. I've warned you. And you said you want to stick around with me.

40:43Dr. David Fajgenbaum:And so I never asked again. And she's just been amazing. She's just by my side. But I got to tell you the story from just before that conversation, right before I was or about two months before I was discharged from the hospital. It was New Year's Eve 2010. And I was just sort of I just got in chemo. I just sort of like finally well enough to walk around the hospital. And my dad and I decided to do a walk on December 31st, New Year's Eve night, about 8 p.m. And so I've got this huge belly, my head's bald from chemo, I've got my infusion that I'm rolling with. And we pass by the family waiting area on the cancer floor.

41:23Dr. David Fajgenbaum:And there's a guy who's like visibly drunk, he's sort of like, swaying in his chair in this on this unit. And we come by the next time, he's fallen onto the ground. And so my dad runs over to him and helps him back into his chair. And he looks at my dad and I, and he says, thanks so much. Good luck to you and your wife. And we're like, wife, what is he talking about? Then I looked down at my belly and I realized he thinks that I'm my dad's pregnant wife and that we are walking laps to deliver our baby on New Year's Eve. And so I turned to my dad and go, man, you've got an ugly wife. And we just die laughing.

41:56But like, that's

41:57Dr. David Fajgenbaum:what I looked like, Sean, when Caitlin was offended that I was like, are you sure you want to be with me? That tells you how committed she was to me. Wow. That's amazing. Is she a medical professional too? She's not. She used to work in the fashion industry and now she's full-time with our kids. She also helps a lot with Castleman's and every cure in raising awareness. What was the drug that cured you? The drug's called sirolimus. The other name for it's rapamycin. That's a drug that maybe some of your listeners will be familiar with rapamycin is an mTOR inhibitor and actually it's thought to have some anti-aging properties and so sometimes people take low doses of serolimus or rapamycin i take a really high dose like my dose like destroys my immune system damn his have you

42:43Shawn Ryan:has this been if other people with calcium has been treated since then yeah so once it started

42:48Dr. David Fajgenbaum:helping me and once the months and the years started going by um right around the time i Actually, I joined the faculty at the University of Pennsylvania to build a center to do more of this, basically to study the immune system, to figure out are there drugs that already exist that you could repurpose that became my life's mission. So I started that at Penn, and then we started treating Castleman's patients with this medicine. And it actually worked for the first three patients that we treated. And I was sort of like, oh, my gosh, maybe we figured it out. Like, maybe it's going to work for everyone.

43:13Dr. David Fajgenbaum:It turns out that it works for about a quarter of patients. And so there's still more work to be done. But yeah, I mean, the first patient that I saw that we treated was this young boy named Joey, who was in the Children's Hospital of Philadelphia. And I'll never forget, like, seeing him just before treatment was started and then seeing him a couple days later and, like, seeing the blood work and seeing that things were improving. In days. Within days. Within days. He was critically ill in the hospital. Within days, seeing things were starting to stabilize and they started getting better. And I would come by every day and his mom would hand me the lab test and I would look get it.

43:45Dr. David Fajgenbaum:And I was like, oh my gosh, Joey, this is working. And like, for me, that meant so much. He's now a sophomore in college at Temple University in Philadelphia. I just saw Joey a couple of weeks ago. And like, he wouldn't be here if not for this drug that I came across that saved me. And now we've got patients all over the world on it. It just means everything.

44:05Shawn Ryan:I mean, how does that, I mean, if it works 25 % of the time, I mean, that's, I mean, a thousand people a year yeah and in in in the u.s you said that have this 250 that are gonna go on to do greater great things yeah exactly i mean how does that feel to you it feel it's

44:23Dr. David Fajgenbaum:incredible um and you know the feeling and actually the thing that's most incredible sean and i don't know if you'd immediately appreciate this but for me what i found is the most incredible part is when i get to hear about what these people are doing basically in this overtime that they've got So like Joey's a sophomore in college, Kyla, who we've repurposed another drug to save her life. She's now trained to become a nurse. She wants to take care of the other people with illnesses like nurses took care of her. Michael, who has a rare cancer, we repurposed a drug for his cancer. He walked his son down the aisle a year ago, eight years after he was diagnosed with this terminal cancer.

45:04Dr. David Fajgenbaum:and then just last weekend here in Nashville, he walked his daughter down the aisle. And like when I get to see those pictures, when I get to hear about those things that they wouldn't have done, like for me, that's like, it's one thing to be like, oh, months or years, but it's like, oh, I got to walk my daughter down the aisle nine years after I was diagnosed with a terminal cancer. That's just the most incredible thing for me. Man, that has to feel amazing. It's incredible. And it's sort of like, it'll really drive you to want to keep doing it, right? Because it's an experience when you hear about any one of these things where you're like, I just want to do this for more people.

45:39Dr. David Fajgenbaum:And so it's this combination of like, when you can help people like that, that means so much. And of course, in my case, I'm like, every day I breathe, I can remember what it was like. But the other thing is that there's also all this suffering happening right now in the world. And there's people, as you mentioned, getting diagnosed with this disease and that disease. And every day, Sean, I'm hearing from a patient with a horrible condition or many of them. And so you sort of juxtapose like all of the incredible hope that you get from all the people you can help. And then all of the people who are suffering right now from horrible diseases.

46:11Dr. David Fajgenbaum:And that's just driven us to say, like, we've got to make sure that all the drugs that we've got that are, there's about 4 ,000 drugs that are FDA approved. We've got to make sure every one of them is used for every disease they can possibly treat. So that way, these people suffering over here, if there's a drug for them, we got to get it to them. And it's not that I believe, Sean, that every patient with every disease could be treated with an existing drug. I don't believe that's the case. But I do believe that if there's a drug that could treat some of them or a fraction of them that's already at our CVS, we got to find it.

46:41Shawn Ryan:Yeah. I don't know how often this happens, but just two examples off the top of my head. I mean, Viagra was originally a blood pressure medicine, correct? Now people are getting busy in their 80s and hopefully I'll be one of them. But, you know, and then the other one that comes to mind is, and I've never used it, but ivermectin, you know, with COVID. I mean, we've, a lot of people, Joe Rogan, you know, swears by ivermectin, you know, to fight COVID-19. And so how many other of these drugs are there?

47:16Dr. David Fajgenbaum:There are a lot of drugs that can be used in multiple ways. You know, Viagra is a funny one because not only, as you mentioned, to go from heart disease to erectile dysfunction, but it actually is also used for this rare pediatric lung disease called pulmonary otillar hypertension. Kids were dying because they weren't getting enough blood flow to their lungs. And a random doctor thought to themselves, huh, if this can increase blood flow for these older men, could it maybe increase blood flow to the lungs of these little kids? And then it was tried and it worked. And for me, those sorts of examples where like you would never think of pulmonary hypertension in little kids as being similar at all to erectile dysfunction, right?

47:54Dr. David Fajgenbaum:Like, and it's because even though the conditions appear very different, they share the same underlying problem, which is limited blood flow. And so there's a lot of examples in medicine. And there's another drug you've probably heard of called thalidomide. It caused all these horrible birth defects back in like the fifties. That drug can treat leprosy and also this rare cancer or this blood cancer called myeloma. And And leprosy and myeloma, again, they seem so different, but they share the same underlying problem. And so it turns out that just like you said, there are drugs that can do one thing in the body that can actually have an effect across multiple diseases.

48:27Dr. David Fajgenbaum:And typically, this is discovered through sort of random chance. Like this doctor I mentioned in Houston who was like, huh, I wonder if Viagra could be useful for these kids. It happens sort of randomly. And there isn't like a system that exists. There's never been an entity, whether it's in the government or within industry, that's just been focused on saying, okay, among the 4 ,000 drugs that are approved, that are available, what are all the other diseases they can treat? And because it hasn't been done systematically, I could discover a drug like serolimus could save my life. And, you know, drugs can be found like tocilizumab could be used in all these different ways.

48:59So there's all these drugs out there and

49:03Dr. David Fajgenbaum:there's just never been an entity to say like, we're going to match into everything we can.

49:08Shawn Ryan:so how do you i mean how many drugs have you how many drugs have you personally found the treat

49:15Dr. David Fajgenbaum:we've advanced 14 drugs for 14 for diseases they weren't intended for 14 drugs yeah 14 is that incredible and that's in the last just 11 years you know since you know serolimus of course being one of them and that's primarily from my lab at penn where we're focused on just a few rare cancers and inflammatory diseases. And so about three years ago, I'm sitting here thinking, okay, in our small lab at UPenn, we're advancing at that stage, it had been over 10 drugs for diseases they weren't intended for. It's like, how many more are there out there? And what was so important that this came up about three or four years ago is that one of my really close friends from medical school, Grant Mitchell, was really pioneering the use of artificial intelligence to use medical record data to try to figure out subtypes of patients that could benefit from one drug or another drug.

50:03Dr. David Fajgenbaum:And we came together and we said, what if we could utilize artificial intelligence to scan across every drug and every disease? Like my lab works on a few diseases and a few drugs. What if we could actually scale what we're doing for these few, but to all, like, what if we could use AI to look across all of the world's knowledge to come up with how likely every drug, all 4 ,000 of them are to treat every disease, all 18 ,000 diseases. And if AI can help us to figure out what looks most promising, then we can do the hard work afterwards. We can work in the lab. We can do the clinical trials. We can do what's needed to prove it.

50:34Dr. David Fajgenbaum:But let's actually start by using AI to make these matches. And so Grant and I co-founded a nonprofit called Every Cure, along with Tracy Sikora, our other co-founder, which is on this mission, which is to save and improve lives with the drugs we already have. And we start out by using AI to scan everything, the world's knowledge of everything versus everything, to find out the very best opportunities to take forward.

50:56Shawn Ryan:My day kicks off with a refreshing Celsius energy drink, then straight to the gym. Pre-K pickup, back home to meal prep. Time for my fire station shift. One more Celsius, got to keep the lights on. When the three alarm hits, I'm ready. Celsius. Live, fit, go. Grab a cold refreshing Celsius at your local retailer or locate now at Celsius.com. Wow. I want to get into that more in depth, going back a little bit. I mean, you're researching. I mean, how many drugs are there? There's 4 ,000. 4 ,000 drugs. I mean, there's a lot of conspiracies around pharmaceutical industry and that they don't want to cure cancer.

51:39Shawn Ryan:They don't want to cure these drugs. They just want to prolong, you know, and basically what I'm getting at is they just want to make money. They don't really give a shit about people's lives. I don't know if that's true or not. um you know a lot of conspiracies running wild in the world today but but one question i you know i have is i mean when you find a drug like this especially uh the one that you were just talking about that was kind of a sleeper back that they were using in the 50s birth defects i mean i don't know what company developed that but i mean do these when you're taking a drug that's you know it's a Pfizer drug or whatever.

52:16Shawn Ryan:Are these companies helping you do the research? Are they funding it? I mean, because they stand to make a lot of money if you repurpose the drug and you do the research, correct?

52:26Dr. David Fajgenbaum:It's a great question. And it ends up that it's like such, it's so much more complicated than it should be. And the reason it's complicated is that once a drug gets approved for one disease, it has about an eight to 12 year lifetime before it goes off patent and becomes generic. So basically drug companies, when they develop a drug for one disease or a couple diseases, they've got an 8 to 12 year clock before it becomes generic. And once it becomes generic, then anyone can make a copy of that exact same drug. And they all make, there might be 10 people making the same drug and the price plummets because it's all the identical drug.

52:57Dr. David Fajgenbaum:And so drug companies stop making money once their drug becomes generic. So they have to think in those 8 to 12 years, what are the diseases that are most profitable? And so they tend to go after the most severe diseases because the most severe in the most common diseases because that's typically where they're going to be able to charge the most amount of money. So how common is it and how severe is it? That's usually where they go. But they can't typically go after a lot of different diseases because they want to really focus on maximizing profit for the few they can. So it's not that they're avoiding diseases.

53:29Dr. David Fajgenbaum:And again, this is partly my opinion, but I'm saying it as someone who lost my mom to cancer and who personally has battled these horrible diseases. If I was seeing things like people hiding cures, I'd be the first person to talk about it. I don't see that. What I see is that drug companies focus their drugs on whatever diseases they can make the most money on in those 8 to 12 years because they're businesses. And the moment that drug goes off patent, all research stops. So what that means is that we've got 4 ,000 drugs. Well, 80 % of them are already generic. So there's no drug company that has any interest at all in selling more doses of that drug because there's 10 manufacturers and they all sell them for a penny a pill.

54:11Dr. David Fajgenbaum:And so the problem is that, in my opinion, the problem is not that drug companies are not pursuing these additional uses. The problem is that if I discover that ruxolitinib can be useful for a new condition after ruxolitinib goes off patent, I got to figure out a way to drive forward the science for it. I got to figure out a way to get, whether it's the government or philanthropists or individuals to donate to do the research because the drug company is like, hey, I made it like a few years ago, but like 10 other people are making it right now. And I don't make any money off of that drug. I'm on to another drug now.

54:44Dr. David Fajgenbaum:And so I think that that's a problem in our system is that 80 % of our drugs are not profitable to find new uses for them. So that means someone's got to stand up and do the work, right? It's like, whether it's the government or some entity. And so that's where we at EveryCure said, like, we figured someone else was doing it. Like when I got into something, there's got to be someone who's doing that and it's like, oh wow, there's no one who's picking these things up once they're generic and finding more uses for them because no one's incentivized to do it. So we've taken that up.

55:12Shawn Ryan:I mean, how do you fix this at scale? I mean, I have a feeling you're going to say AI, but I mean, and maybe that is the answer. Is there a better answer? Is there, would it be, I mean, I'm just curious, you know, let's say the US government gets involved, you know, and they start to incentivize the drug companies to continue their research. Maybe they grant the patent for another 10 years, or maybe they subsidize it. And I mean, what is your answer?

55:42Dr. David Fajgenbaum:I think what you just described, I think that's the only way you can do it is that if you want to do this fully at scale, I think what you have to do is you have to incentivize these companies to say like, yeah, you get more patent life or maybe your drug that's off patent, you can get a patent back on it. The thing is, is that if you do that, you're going to end up saving a lot of lives because that's going to drive a lot of cures. You're also going to increase the cost of health care because those cheap drugs that are generic, it's good for the health care system for them to be cheap. Like that means that they go from being thousands of dollars or tens of thousands of dollars a dose to like tens of dollars or hundreds of dollars a dose.

56:16Dr. David Fajgenbaum:That's good for cost of our health care system. So it's going to increase costs. It's going to increase cures. And so like that's where the that's where the challenge is, is that if you incentivize that, you're going to increase pharmaceutical costs. Now, I would make a pretty strong argument that even though you're going to pay more for drugs, you're going to end up saving the health care system in the long run because people are going to spend less time in the hospital. they're going to have less other issues, less comorbidities because you're going to be treating the actual diseases and they're not with the drugs we already have.

56:46Dr. David Fajgenbaum:So it ends up becoming probably, I think, close to a wash or a cost saver. I mean, what I think is needed is for the federal government to also just rather, one is you can incentivize the drug company to do it, or you can just spend on proving these things work and then use the cheap version of it, you know, use the drug that's already out there. And that's basically what we're doing right now. Now, at EveryCure, we actually have a federal contract with a U.S. agency called ARPA-H, where they are actually funding a lot of the work that we're doing. And we're finding new uses for medicines that will end up saving money to the healthcare system without actually creating these sort of incentives that maybe aren't aligned.

57:25Dr. David Fajgenbaum:How big is your team? We're about 50 people. 50 people? Yeah. Is that enough? I mean, I think that when you think about the world we're in, which is we got 4 ,000 FDA approved drugs and they're approved about 4 ,000 diseases, but there's 14 ,000 more diseases that don't have any approved drugs. That's a crazy stat, right, Sean? You know, a lot of those 14 ,000 are very rare diseases, but they collectively, we're talking tens of millions of people have these 14 ,000 diseases with no treatments. And so there's a huge opportunity to match these 4 ,000 drugs to these 14 ,000 diseases that, yeah, a 15-member team is not going to be able to do.

57:59Dr. David Fajgenbaum:So, you know, I think that at some point we're going to need an effort, whether it's ours or another's, that's as big as the Pfizer's and the Merck's of the world that are like doing the non-profitable drug development. I mean, we joke that every cure is, it's a non-profit drug company, basically. You know, we're just looking for the non-profitable stuff to help people. You know, we don't care what the drug was made for. We don't, you know, care how common the disease is. We just want to relieve suffering with the drugs we already have. But we joke that we're both like the biggest drug company of all time because we'll use any drug out there that can help people.

58:33Dr. David Fajgenbaum:But we're also the smallest drug company because we don't own any drugs. We're just using the things that are already out there. But I think that proving out the impact of what we're doing and using AI to focus us in on the right opportunities, I think, is important. And then as we help more and more people, I hope that that'll lead to more support, whether it's from individuals who care about someone with a horrible disease or whether it's philanthropists or the federal government. I hope it's going to lead to more opportunities here. Because like I said earlier, I'm alive because of a drug that wasn't made for my disease.

59:01Dr. David Fajgenbaum:And there's a lot of people suffering today that could benefit from a drug we already have.

59:05Shawn Ryan:And so it's government funding in conjunction with donations. That's right. Philanthropy as well.

59:12Dr. David Fajgenbaum:Where do people donate? So you can go to everycur.org slash donate, and you can donate along. We're a nonprofit organization, and we put every one of these dollars towards making sure that the drugs we have help the people who can benefit.

59:23Shawn Ryan:Man, that's amazing. Thank you. I'm donating. I love it. Thank you. Donate. I love what you're doing. Thank you. So let's talk about some of the other successes that you've had. Sure.

59:33Dr. David Fajgenbaum:So I shared a little bit about, maybe I'll share a couple of these patients. So one of them is Michael. He was diagnosed with a horrible form of cancer called metastatic angiosarcoma. And that's where basically this cancer is in multiple places in your body. And no one lives past a year with metastatic angiosarcoma. This is 2016, and we found a study from 2013. It was just a laboratory study. It wasn't done in patients and clinical trials by any means, but it was a lab study. But in that lab study from 2013, it indicated that this one marker was up called PD-L1 in a few people's tumors from angiosarcoma patients.

1:00:18Dr. David Fajgenbaum:And what was important about that is that there's a drug that's really good at inhibiting PD-1 that already existed for other cancers. It was approved for melanoma at the time and also approved for lung cancer. And so we saw that result in this paper and thought, well, maybe his tumor also has increased PD-L1 and maybe that drug could work for it. It had never been used before for his form of cancer. But he was told by his doctor that they were out of options, that there was nothing else that could be done. The chemo that they had tried wasn't working. And so we actually ended up getting that test done.

1:00:51Dr. David Fajgenbaum:And it came back that it was very positive for the thing that we thought it would be from that paper. And we were able to get Michael on this drug called Pembrolizumab. It was the first patient ever with angiosarcoma. And as I mentioned, a year ago, he walked his son down the aisle on his wedding day eight years later. And just last weekend here in Nashville, last weekend, he walked his daughter down the aisle on her wedding day. And this is amazing. I mean, this drug was always there. No one had ever tried it before. what's important is that this drug is also now used for other patients the angiosarcoma unfortunately it only works in the number it's about 18 of patients and so it's not you know when it worked for michael we're like oh my gosh we saw angiosarcoma got so excited and it doesn't doesn't turn out that it works for everyone but for those 18 of patients it's everything right

1:01:38Shawn Ryan:um you know if it works for you it is a life changer i mean if it's just one life exactly

1:01:43Dr. David Fajgenbaum:Exactly.

1:01:44Shawn Ryan:It's a success in my life.

1:01:45Dr. David Fajgenbaum:Because the drug was already there. It's not like you had to create a new drug. It's already there. You just had to give it to someone. So that, to me, means the world. And that was the first time that we went into a disease outside of Castleman's or related to Castleman's. It was sort of the first time I was like, oh my gosh, we can do this outside of the diseases that we're focused on, which was so important for us to want to keep pushing this mission forward. Another one is a young girl named Kyla who has castles. She has the same subtype of castles as me, the really deadly one. And she spent about a year in the hospital.

1:02:21Dr. David Fajgenbaum:Nothing was working at Chicago, Lurie Children's Hospital, and nothing was working. And one day her doctor called me late. I remember during the pandemic, it was like 8 p.m. one night, and said, you know, we've been trying things for a year. Nothing's working. The drug that I'm on, serolimus, didn't work. Chemotherapy wasn't even working for her. You know, is there anything you can try? And just a couple weeks before, a couple members of my lab had discovered that this one part of the immune system was an overdrive, not mTOR, but something called JAK. And I recommended, you know, it's early days, but like you could try a JAK inhibitor in Kyla.

1:02:53Dr. David Fajgenbaum:You know, we've shown this stuff in the lab. Maybe it'll work. And so Kyla became the first patient ever with Castleman's to be treated with a JAK inhibitor. And she responded so well, Sean. And she is doing so well today. I mentioned she's training to become a nurse now. And like, it's just incredible. that like this drug was always there. We actually have just opened up a clinical trial of that drug. We're going to study it in more Caswell's patients because when you do these, they're called like N of ones, where you try a drug off-label in one patient and it works, that's great. But you really want to get more data to prove that it works.

1:03:25Dr. David Fajgenbaum:That way you can get more patients on and you can really figure out who's it going to work for. So we have a trial that we just opened up for that. How many test subjects do you need for a successful trial? It's a great question. So it really depends on a couple of things. The more effective the drug is, the fewer test subjects you need in the trial. Because if it's clearly effective, like you could have a trial of just 20 people. But if like the 10 people that got the drug all do better and survive and the 10 people don't get the drug, none of them survive. That's sort of, you know, night and day.

1:03:56Dr. David Fajgenbaum:So it's one part is how effective is it? Like what's the effect size? And the other one is how common is a disease? Because really rare diseases, sometimes you're forced to like have very small numbers. But if it's a common disease, you know, the bigger, the better in terms of how confident you are in the result.

1:04:12Shawn Ryan:And how did, so when you find, when you repurpose these drugs, I mean, how does the word get disseminated across the world, across the country and the world, you know, on how to cure these diseases? You know what I mean? I mean, for the everyday, I guess I shouldn't say everyday professional, because I'm sure they're very specific, trained doctors for that specific disease. But I mean, how does the word, how do you get that out? How does it happen?

1:04:43Dr. David Fajgenbaum:This is so important. I mean, honestly, right now it happens very randomly and sporadically. Like you publish a paper in a journal and you hope a doctor reads that journal or you give a talk at a conference and hope the doctors are there. It's very sporadic, but we're trying to fix that with every cure. And I'll share an example that's that is actually also got a Nashville connection. An amazing doctor named Chip Chambers had two kids born with a rare condition called data two syndrome. Data two causes kids to start having strokes at very young ages and they usually pass away in their teenage years because they've had hundreds of strokes.

1:05:15Dr. David Fajgenbaum:It's horrible. And about 15, almost 20 years ago, a doctor sort of randomly tried a drug in one of his patients with data too, because he thought the patient's profile looked similar to another disease. He was like, oh, I'll try this drug that I use in this disease for this one because nothing's working for these kids. And it worked really well for that first kid. That kid stopped having strokes. And the doctor gave it to a few more of his kids with this condition. And he helped. He was great with the patients he took care of, but the word never spread. And so then Chip Chambers comes around. He has two kids with data too.

1:05:48Dr. David Fajgenbaum:And he learns about this doctor who's doing that. And he's like, oh my God, this is amazing. I'm going to get my kids on it. Chip starts a foundation called the Data2 Foundation. He starts reaching out to every doctor around the world. He's sending emails. He's tweeting. And now everyone, well, and another important step, we published a paper with guidelines. Okay, this is how you treat Data2. So it's out there for the world. And then he started telling everyone he could. So now every kid in the world that's diagnosed with Data2, they get this drug, they stop having strokes, and they live full lives.

1:06:14Dr. David Fajgenbaum:But there were a lot of years between that first doctor doing it. And he did his job. He was helping his patients. He did, I mean, he was brilliant to think of that. But to your point, you got to disseminate it. You can't just treat your patients. But the thing is, it's not a doctor's job to like be a PR marketing for how to treat patients, right? Like their job, like take care of their patients. He did a brilliant job. But that's where I think every cure has to come in. And honestly, that's why being on a podcast with you like this, I think is so important because when we find these drugs, we got to get the word out to people and being able to work with people like you and others to get it out is literally a tweet.

1:06:49Dr. David Fajgenbaum:A social media post can be the difference between life and death for someone. Man, I mean, isn't there some type of a, I mean, like I said, I have no insight into the healthcare industry other than through the podcast.

1:07:00Shawn Ryan:But isn't there some kind of a database that all physicians use and they can type in a specific disease or treatment for anything? And it's these drugs right here.

1:07:13Dr. David Fajgenbaum:These are what we do. The closest to that is a website called UpToDate. And the idea is that the world's expert for every disease enters that in and keeps up to date. That's what it's called up to date. So that's sort of the theoretical place. However, sometimes when you use a drug like they were using data to for that rare condition or using that TNF network for data to if it's just happening in one part of the country, one part of the world, it may not get into that database for up to date. It may be that there's sort of debate. OK, well, it's only been using a couple of people like are we sure there hasn't been a trial done yet.

1:07:47Dr. David Fajgenbaum:And so it's not perfect. UpToDate's a really good place. It's not perfect. And then the other issue is that, you know, it's updated by individual experts. And so they might miss things that are here or there. And it's also not widely available. Not everyone has access to UpToDate. And so like we at EveryCure feel that we got to make sure that UpToDate pages are UpToDate. And we also got to make sure that we get the word out to people that don't have access to it.

1:08:10Shawn Ryan:damn i wish there was a better way than that i know right i wish there was a better way i mean that would just that would that would jet launch it we would and that's what and that's what we're

1:08:19Dr. David Fajgenbaum:hoping to do with every cure and i'd love any ideas you have for how to how to get it out i mean that's like that's all we care about it's like the drugs we got should treat all the patients who could benefit from the drugs and it's like we got to just figure out how to make that match

1:08:31Shawn Ryan:more podcasts exactly podcasts it'd be great if the media the mainstream would jump on this and it would be great if i mean if they had the the database of them i mean it sounds like they do but i mean something that's it just seems like there should be something that the that the world can tap into and it lists out every possible drug and scenario yeah that they can read it should i

1:08:54Dr. David Fajgenbaum:totally agree how does that not exist yeah it's it's sort of the kind of thing that we all think someone must have done or there must be something like that and then you sort of sit around and then And all of a sudden you realize like, if no one else is going to do it, I guess we have to do it. You know, it's like, I guess somehow these things just, everyone's got their lane, right? And it's like sort of, oftentimes we lose track and there isn't someone who's taking that big picture look. Man, man.

1:09:18Shawn Ryan:Let's move into the AI stuff. So you're utilizing AI to basically do the initial research. That's right. How do you do that? Sure.

1:09:29Dr. David Fajgenbaum:So we use something called a biomedical knowledge graph, which is basically like if you took every drug, disease, gene, protein, everything you can imagine that's related to medicine and bioscience and just put it on the wall, like mapped it up. And then you put connections between every one of those things. So we know that interleukin-6 is elevated in Castleman disease. And you'd put that onto your map. You'd map every single concept and then the relationship between everyone. You'd create a map that basically represents what we know about all of medicine. like every drug, every disease, every gene, every relationship between all of them.

1:10:01Dr. David Fajgenbaum:So now you've got sort of a map of what we know about all of medicine. And then we train machine learning algorithms on treatments that we know work. Like we say, so Tuximab treats Castleman disease. Sirolimus is effective for organ transplant rejection. We train the algorithm over and over again on all the known treatments. And it gets really good at picking up the pattern of connections. Okay, if that drug treats that disease and that drug treats that disease. And then we say, okay, now that you know what a good treatment looks like in this map of knowledge, now give me a score from zero to one for how likely every other drug is to treat every other disease.

1:10:36Dr. David Fajgenbaum:There's 4 ,000 drugs. There's 18 ,000 diseases. We're basically asking it to calculate 75 million times, the 4 ,000 drugs against 18 ,000 diseases, 75 million times how likely every drug is to treat every disease. And it's between zero and one. And so then our medical team, we look at the things at the very top and say, what are the 0.99s? What's machine learning, artificial intelligence saying is the highest, most likely drug to treat a disease? And that's where we start. Wow. So it sifts through everything. Sifts through everything. It goes through the world's knowledge. And actually, when we ran it for the first time, Sean, we built the nonprofit three years ago, spent a lot of our first year fundraising.

1:11:13Dr. David Fajgenbaum:But we finally hired our first data scientist. We finally ran the algorithm for the first time about two and a half years ago. And it took 100 days to run the algorithm, to like literally scan everything the world knows about everything, 100 days. And we're like, for 100 days, and we didn't know it would take 100 days, but like just every day, it's like slow. And we don't have the results back. Finally, the results 100 days. Sean, now it takes 17 hours to scan the world's knowledge of everything to get a score. 75 million scores in 17 hours, which the reason that's really important is because then you can actually improve the algorithm and say, that's actually not the way to do it.

1:11:46Dr. David Fajgenbaum:We want to do it more like this. You can run experiments and see like, what's the best way to get the best results. And if it's a 17 hour turnaround time, you can just keep doing it.

1:11:53Shawn Ryan:Wow. Wow. I mean, would it be, would it be a possibility that that AI database could, could be the answer to what we were just talking about? I think so.

1:12:04Dr. David Fajgenbaum:A part of it could be. So, you know, when we score every drug against every disease, you now in that database, you now would have a bunch of drugs for diseases that score poorly or that are middle level And so there's parts of it that maybe would be not that helpful, but the things at the top, absolutely. The things at the top very much can be, so, you know, at the very top for, let's say, for a horrible disease, let's say like ALS, there's two drugs that are FDA approved for ALS. They don't work very well, but there are two drugs that are FDA approved. That's got to be at the very top of the list.

1:12:36Dr. David Fajgenbaum:And then right below those two FDA approved drugs, there are some drugs that are sometimes tried where there's early data. That should be next in the list. and then you should get into like these sort of AI predictions of like, well, what's AI telling us? But what I wouldn't want is for people to sort of skip the things at the top where there's like good data and just go to like what AI is predicting. Because for us, like at every cure, when we make these predictions, we look at the things at the very top, but we don't automatically say whatever score is number one, we're going to give to patients.

1:13:04Dr. David Fajgenbaum:It's like whatever score is number one, we're going to look really deeply into it. We're going going to study in the lab. We're going to do clinical trials and we're going to figure out, is it the right thing for patients? But not necessarily, we don't trust fully in AI is basically what I'm saying. It's like AI for us is a great starting point, but there's still more work to be done.

1:13:22Shawn Ryan:Gotcha. Let's take a quick break. Sure. And when we come back, I want to, I want to talk about some of the diseases that you're targeting nowadays. Sounds great.

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1:15:07Shawn Ryan:is a prescription medicine used to treat adults and children 12 years of age and older who weigh at least 88 pounds or 40 kilograms with moderate to severe eczema. Also called atopic dermatitis that is not well controlled with prescription therapies used on the skin or topicals or who cannot use topical therapies. EBCLIS can be used with or without topical corticosteroids. Don't use if you're allergic to EBCLIS. Allergic reactions can occur that can be severe. Eye problems can occur. Tell your doctor if you have new or worsening eye problems. You should not receive a live vaccine when treated with EBCLIS.

1:15:33Shawn Ryan:Before starting EBCLIS, tell your doctor if you have a parasitic infection. Ask your doctor about EBCLIS and visit ebglis.lily.com or call 1-800-LILY-RX or 1-800-545-5979.

1:15:47Shawn Ryan:All right, Dave, we're back from the break. And, you know, we're talking about all these horrific, rare diseases, some of them not so rare. I mean, are you looking at any preventatives specifically, you know, specifically for cancer? Yeah.

1:16:03Dr. David Fajgenbaum:So there's one of our programs. So we've got six active programs at every cure. So different drugs that we're repurposing for diseases. And one of them is around the numbing medicine lidocaine. So, you know, when you go to the dentist, you get an injection of lidocaine and the role that it can play in preventing recurrence of breast cancer. So actually, if you inject lidocaine around a breast cancer tumor, there's really compelling evidence from a big clinical trial that was done in India that you're going to reduce recurrence of breast cancer and also reduce mortality from breast cancer. Now, this is an example where it's not total prevention, because it's not like it's preventing the breast cancer in the first place, but it's preventing the breast cancer from coming back, which of course is so important because that's oftentimes what's so deadly about breast cancer.

1:16:42Dr. David Fajgenbaum:And it's an example where lidocaine is this really cheap old substance where unless a nonprofit like ours or another nonprofit comes in, the work's just not going to be done to push it forward. And so we're really optimistic about that. And we're actually also studying the role that lidocaine might play in other cancers as well.

1:16:59Shawn Ryan:Are you studying or do you have any insight onto what causes cancer? Yeah.

1:17:07Dr. David Fajgenbaum:So the breakthroughs over the last 10 or 15 years really indicate that cancer occurs when mutations occur in the genomes of those specific cells. And so they're called somatic mutations basically means like we're all born with our own genetic makeup, but within the cells, let's say in your pancreas, a mutation occurs. And that could be because of exposure to UV light, or it could be from exposure to carcinogens in the environment, what you eat. And those genetic changes, if they happen in a part of the genome that isn't that important, that cell just dies and you never even knew the mutation happened.

1:17:47Dr. David Fajgenbaum:But if that mutation happens to happen in a part of the genome that's important for, say, cells to replicate or maybe to grow blood vessels, then that cell now has an advantage and then it accumulates more mutations and all of a sudden you have cancer. And so it's sort of this random set of things that have to happen for you then to develop cancer. And of course, you can do things in your life to reduce your risk of cancer by, you know, eating well and exercise and doing all the right stuff because that's going to reduce the amount of those somatic mutations that occur to your cells. But it is sort of this very much random thing, which is tough because that's why sometimes young kids get horrible cancers.

1:18:26Dr. David Fajgenbaum:And it's also why you see cancers emerging in older years because basically more of these mutations have occurred over the course of life.

1:18:34Shawn Ryan:I mean, is there anything to, I've heard a lot that inflammation can cause cancer, sugar can cause cancer. I mean, is there anything to that?

1:18:42Dr. David Fajgenbaum:Yeah, so the inflammation for sure, you know, the more you proliferate, the more your cells are proliferating, which often occurs in the setting of inflammation, the more chances there are for genetic mistakes and basically mutations to occur because of the increased proliferation. So, so absolutely sugar. I think there's, there's a lot of data that sugar plays a really important role in cancer development and progression. Like once it starts, I haven't seen as much on it, like sort of causing it to start in the first place. but it's also really hard to keep track of all the research because there's just like so much

1:19:14Shawn Ryan:work being done and then you know I've I've all I've also heard that a lot of these diseases uh and I might I might rattle a couple off that this is not true about but you know cancer Alzheimer's a lot of these I mean I've read things and interviewed people that said none of these are actually organic diseases. They are potentially a product of our filthy environment. Is there truth to that?

1:19:45Dr. David Fajgenbaum:I think that our filthy environment contributes and probably increases risk and increase the numbers. I think all the conditions you mentioned have happened as long as we've been around. They're in textbooks from the 1700s, but they maybe weren't as common. One reason why they might not be as common, I think, is exactly what you said. There's things in our environment that are making them more common. The other is that we're thankfully living a lot longer. You know, we're not dying from, you know, infections from bacteria, you know, that's in our water, for example. So we're living longer, which means there's more opportunity for these other diseases to sort of emerge.

1:20:20Dr. David Fajgenbaum:So I think that my experience with a lot of these things is that I think that there is definitely a lot of truth and data backing up the idea that our environment is playing a really important role in increasing the number of these cancers and conditions. But oftentimes it's a lot more complicated than just like, it's just the environment. Because, you know, these things have been in textbooks for a lot longer than a lot of these chemicals have even been around.

1:20:44Shawn Ryan:And another thing, I mean, there's a lot of, ever since COVID, it's really caught fire after COVID. I mean, there's a lot of hesitation with vaccines. There's a lot of hesitation to pharmaceuticals, you know, and there's this massive movement on, I don't know, kind of holistic type medicine. I mean, what are your thoughts on that? I mean, I think it could be, you know, I mean, I don't know. I don't really know much in this sector. But, I mean, it seems, my fear is that we demonize all of the progress that we've made with medicine due to, you know, due to conspiratorial claims. And so I'm just curious.

1:21:27Shawn Ryan:I mean, I think there's got to be a healthy balance here. I mean. There has to be. Yeah, I mean, my feeling is that I and we just want to help patients with the medicines that are available.

1:21:39Dr. David Fajgenbaum:And if it's from a holistic doctor or if it's from sort of traditional Western medicine or if it's from pharmaceutical companies, you know, the drug that I'm on, Sirolimus, it actually was discovered in the soil on the island of Rapa Nui in the Pacific. Like it literally was discovered in the soil and then a drug company figured out ways to manufacture it. And so like my drug is about as natural of a drug as you could ever take, but it's a pharmaceutical drug and it's used for transplant rejection and it destroys your immune system. And so there's, we like to oftentimes think of things as very black and white.

1:22:12Dr. David Fajgenbaum:There's like, there's the natural stuff and then there's the pharmaceutical stuff. Well, my pharmaceutical stuff was natural. We just figured out how to make, make the exact same thing over and over again. And so it's a lot grayer than I think that it's easy to wrap our heads around. And I think that, um, we've just got to follow the data and like, what's the, what are the drugs that can help people? And is there data to suggest that it can help people? If so, like we should put people on them. And I think try to get less caught up on, you know, is it from a drug company or, you know, what's the source of it?

1:22:41Dr. David Fajgenbaum:But I think just really just, just actually track, like, you know, is there good data here? And to your point earlier, like when I was dying from my Castleman disease, there was no data for serolimus to save my life. I had lab data that made me think it might, but sometimes you do follow the things that don't have much data because the alternative is that you're going to die. And you just, you do that. But if you do have data on drugs, like, you know, what sort of breaks my heart is when I hear about people with terminal cancer that say, I'm not going to take this medicine because it's a pharmaceutical product.

1:23:08Dr. David Fajgenbaum:I'm going to take something else. And then you hear about them passing away and you just think to yourself, like, I wish they had given themselves a shot with the traditional pharma stuff. And who knows if the pharma stuff would have worked, but we have a lot of data to show that it does work in some people. And we talked about earlier, 18 % of people and 20 % and 25, and these things don't work in everyone. But if they work in you and they could work in you, I really want to make sure that we try it in you because the work's been done to prove that it can help some people.

1:23:38Shawn Ryan:What about, I mean, what are some of the diseases that you are targeting nowadays? What are you going after? I mean, we had a brief discussion about Alzheimer's on the break here. I mean, that that's another massive fear of mine that it's it seems to just be happening more and more and more and more it's frightening and um so i mean yeah so the you know as we shared earlier this

1:24:01Dr. David Fajgenbaum:sort of way that uh that our ai platform works is we look across every drug and every disease and basically see what matches score the highest um and so we start from there so we we don't pick a disease a priority it's ever going to work on it we you know let the algorithm point us towards a match. And then our team looks into it and we spend lots of time reviewing through them. Our team has now reviewed over 6 ,000 of the top matches. It's out of 75 million. So we've got a ways to go, but 6 ,000 brilliant MDs, PhDs reviewing through them, looking for treatments that are hiding in plain sight.

1:24:32Dr. David Fajgenbaum:And out of the ones we've looked through, we currently have six active programs. We're actually just getting ready to add three more. So we'll have nine active programs in the next month or so that look across conditions that I mentioned earlier, the example of breast cancer is one of them. That's one of the more common cancers. We've got another program in a condition called Bachman-Bopp syndrome where it's only been described in about 20 kids ever where kids are born with this horrible rare condition where they basically, they're hypotonic, which means their muscles don't work. So they're on feeding tubes and they're basically bed bound and they would be bed bound their whole lives.

1:25:08Dr. David Fajgenbaum:but there's a drug called DFMO that's been around for a long time that wasn't made for this condition and it actually is really effective. So the kids that have been started on DFMO early in life, um, are standing up, sitting up. Some of them are even walking the kids that are started later on in life. Maybe they're feeding tubes out, but they're not quite at the same level they would have been if they were, um, if they were a typical child. Um, this is why we started this organization is like maybe only a couple dozen kids are going to benefit in the short term, but maybe a couple hundred are going to benefit in the longer term.

1:25:41Dr. David Fajgenbaum:And they're going to benefit like, you know, walk into school and like, you know, running with their siblings and doing things that they wouldn't have been able to do with a drug that wasn't made for their condition. And so those are the kinds of things that that's just not going to, in our industry, a couple dozen kids, no one's going to take a cheap old drug, you know, and work on a couple dozen. And it's not that they're not going to work on it. I take that back because I should really emphasize that there's been amazing work done because the condition is called Bachman-Bopp and that's after two doctors, Dr.

1:26:10Dr. David Fajgenbaum:Bachman and Dr. Bopp, who have done just the most outstanding work in the world to advance treatments for this condition. But the point being that like typically that's where it would stop with like, you know, this doctor and that doctor, they're doing the best they can for these kids. But us at EveryCure, we're trying to find as many of these as we can. So that way, to your point, we get the word out. So if you're a child in some other part of the world and you've got this condition let's get you diagnosed and let's get you on the medicine

1:26:34Shawn Ryan:you know when you're when you're sifting through the the the ai program that you guys have i mean how do you i mean it's still i mean you said i think you said 14 000 diseases have no treatments have no oh that's only that has that's and then another 4 000 have treatment so it's a total of 18 000 diseases that 18 000 diseases how many drugs 4 000 4 000 drugs i mean that's that is a even with ai sifting through all that i mean that's a lot of stuff to sift through and so i mean how how does the how does the program kind of notify you i mean is there is there a like a tier ranking that's that says like hey this this drug we've you know the ai has found may work for a spider web of diseases and i mean do they rank them to how do you guys sift through

1:27:23Dr. David Fajgenbaum:all of that yeah so we get a score from zero to one for each every drug against every disease so So like DFMO for Bachman-Bopp gets a score and DFMO for breast cancer gets a score. And that's probably a low score because it's probably not going to work in breast cancer. But you get a score for every match. And then you look at the things at the very top. So you rank order the less and you say, well, what are the 0.99s? Which basically the algorithm is saying this is like there's some heat here, right? Like there's probably something here. Maybe it's this drug. And DFMO Bachman-Bopp is an example where like there's too much of this thing and this drug inhibits that thing.

1:27:56Dr. David Fajgenbaum:And so it's like the match is being made even at that simple of a level. Like in my case, there was too much of mTOR, that signaling pathway, and serolimus inhibits mTOR. And so it's like it's looking for the – and most of the time it's not that simple, but it's looking for matches like that. And it's going to give a high score if there's something clear like that. And then the other thing is we also generate a separate score. We call it our unmet medical need score, which is basically how bad is the disease. So we score also, the higher the score, the worse the disease, lower the score, less bad the disease, because we want to be going after good matches for really bad diseases.

1:28:29Dr. David Fajgenbaum:As you said before, we're a 50-member team with limited resources. When you can go after any drug and any disease, there's a lot of opportunities. But if we're going to spend our time on earth going after the really bad diseases with the really good matches, and so we use both scores to get us started. So do you actually sift through each drug?

1:28:46Shawn Ryan:It's not each disease, it's each drug.

1:28:48Dr. David Fajgenbaum:And it's actually not even each drug or each disease. It's actually each drug disease match. Like if you look in this spreadsheet, it's like DFMO for Bachman Bup, lidocaine for breast cancer, serolimus for Castleman's. Like that's what the row is. Like the row is actually the match. And then there's a score next to the match. And then like you might not see breast cancer again until number 10 ,000. Like the second best for breast cancer might be way below the first best, but it's actually the match that gets the score. How many matches are there? 75 million. because there's 4 ,000 drugs and 18 ,000 diseases.

1:29:20Dr. David Fajgenbaum:So if you multiply 4 ,000 times 18 ,500, you get 75 million because you try every... So basically we're asking the algorithm is like simulate how likely each one of these 4 ,000 drugs would be to treat each one of these 18 ,000 diseases. That is a lot of information to sift through. It's insane. Yeah, and so like, yeah, our team of 50, we're working really hard.

1:29:40Shawn Ryan:Man, how many... I mean, how many... I'm just curious. How many have you been able to go through so far?

1:29:45Dr. David Fajgenbaum:So the team of 50, we've now gone through the top 6 000 um and that's like deep review like you know reviewing through to understand what data exists and why it might score well um out of those top 6 000 um we've identified about i think it's about 60 or 70 right now that have gotten what we call a deep dive where um an md or a phd or an md phd trained person will really try to understand what are all the data for or against like why would this drug likely work or not work and then out of those 60 or so we've done deep dives about 15 of those have then basically taken down to where like we have a good plan.

1:30:22Dr. David Fajgenbaum:Like we think that if we do this clinical trial, we're going to be able to unlock this drug helping a lot of kids or adults. And then out of those, I mentioned now like the nine active programs that we're moving forward. And we've only, so we started as a non-private three years ago. We spent most of our first year doing fundraising, most of our second year really building on our infrastructure. it's really only been about one year where we've had the team working hard going through all these scores. And so the opportunities I think are so huge. How do you find the patients to do the studies on?

1:30:56Dr. David Fajgenbaum:Yeah. So once we find a match that we think looks really promising, the next thing we do is find out who are the disease experts and who are the doctors that see the most patients? Is there a disease group? Like for a lot of these diseases, there's a parent of a kid with a disease where they've like rallied around and created a nonprofit for that disease. We want to get in touch with them and understand their disease more. We want to understand, you know, what's missing? Could this drug really make a difference? And when we connect with them, it's like, we want to help your kids' condition or your condition.

1:31:22Dr. David Fajgenbaum:You know, will you work with us? You know, we've raised money from the U.S. government and from philanthropists and foundations. You know, we're going to bring some money into here. You know, do you want to work with us on this? And not surprisingly, there's a lot of enthusiasm because, I mean, you think about something like Bachman Bopp. Those kids, like the couple dozen that have ever been found, their parents probably weren't expecting that there would be sort of a full-blown effort for their condition. And, again, thankful to Dr. Bocco and Dr. Bopp for all the work they've done and we're excited to work with them.

1:31:52Shawn Ryan:Wow. That's incredible, man. Thank you. I love, love, love what you're doing. Thank you. you know what do you think about and this is a little off the main subject here but I've got a really good friend here his name's Rich and he's done very well for himself and his whole family multi-generational live with him and it was his grandpa and his grandpa had like his legs were purple you know i don't think he had any feeling in his toes you know nothing in his feet and he was going to a local um doctor here in nashville and this guy told him to go to argentina and i think it was i think i believe it was stem cell and he went down to do the stem cell somewhere in argentina grandpa does a stem cell all the color comes back into his legs within like 12 hours they're on the plane ride back home and he's telling he's telling rich he's like my feet are fucking killing me like i i he's like this is this is horrific pain oh no and rich is rich is like hey you know are you are you okay and he goes yeah i feel amazing he's like i haven't felt any pain in my legs in 25 years or what some i mean so you know in your opinion i mean why why do we have to go to argentina for things like that why do we have to go to mexico for for you know better stem cell yeah like what what is holding the u.s behind on this stuff it's a

1:33:40Dr. David Fajgenbaum:great question because you know in the u.s and i've wondered this too like in the u.s we do what are called autologous stem cell transplants for people with cancer all the time. That cancer I mentioned, multiple myeloma, you oftentimes treat people with their own stem cells. Like you, like, you basically take their stem cells out, you give them chemo, and then you give them their stem cells back. We do that. We do what's called an allogeneic stem cell transplant. We get someone else's stem cells, like their bone marrow stem cells, and that can sometimes be curative for leukemia and for lymphomas.

1:34:09Dr. David Fajgenbaum:Like, so we're doing it already in some settings, but I'm not sure why some of these other settings it hasn't come forward because some of that the stem cell work with autologous and allogeneic stem cells it's been 20 years that we've been doing that in the U.S. so I'm not sure why because what that tells me is that like the U.S. FDA is willing and they're open when these sorts of stem cells are effective in certain ways maybe it's for cancer maybe there's a different sort of risk profile because there's a big there's a big risk when you do these stem cell transplants for cancer like you have like a 10 chance of death within that year from the treatment, you had a 90 % chance that you might be not 90 % cured, but you have a high chance you might be cured, but you got a 10 % chance you're going to die from the stem cell transplant.

1:34:51Dr. David Fajgenbaum:And so it might be that the FDA is willing to sort of put a stamp on that sort of a risk when like you've got a deadly leukemia and maybe less willing to like put that sort of a risk if it's not as deadly. And again, that's not from any data that I have, but that's the only way I can wrap my head around it is like, why do we do it here, but we don't do it over there?

1:35:11Shawn Ryan:Thank you for answering that. I don't know the full answer, though. Well, Dave, is there anything I should be asking you that I haven't asked yet?

1:35:18Dr. David Fajgenbaum:You know, there's one thing you were asking me about my mom earlier, and you asked about the last conversation that I had with her. And she actually left a message for me, even after she was gone. A couple weeks after she passed away, and I actually would love to read this to your audience if it's okay. A couple weeks after she passed away, my dad and I were cleaning out her purse, and I came across this newspaper clipping that I keep in my wallet.

1:35:53Dr. David Fajgenbaum:And to me, this is like, it just embodies my mom because, I don't know if you can see it, but this is basically like on a piece of cardboard, probably from some cereal box, and it's like, you know, got some tape on it. This is just like who my mom was. And it's got a quote that, as you can tell, I take it everywhere with me. It's now been 21 years. It says, Pope John Paul said it best in his address to the use in Kamigai. Dear young people, whether you are believers or not, accept the call to be virtuous. This means being strong within, having a big heart, being rich in the highest sentiments, bold in the truth, courageous in freedom, constant in responsibility, generous in love, invincible in hope.

1:36:33Dr. David Fajgenbaum:and like I said I found this two weeks after she died and um I remember reading it and just thinking to myself like this is her message to me about how I need to live bold in the truth courageous in freedom constant in responsibility generous in love invincible in hope and these are words that like I just I just take with me everywhere I go and I love the idea of of your listeners and your audience taking this taking this with them as well man thank you for sharing

1:37:02Shawn Ryan:that. Thank you for sharing that. And I just want you to know, it was an honor to interview you, and you're changing, you are changing lives, literally saving lives, and I mean, just bettering the world. So thank you for what you're doing.

1:37:22Dr. David Fajgenbaum:It's an honor to be with you. You're a true warrior, and we're fighting hard. We're fighting a battle. Like we said, 4 ,000 drugs, 4 ,000 diseases have treatments, but 14 ,000 don't. So like, we've all got to take this up. It can't just be, you know, one group here or one group there. Like we've got to take this opportunity to make a difference. And there's a lot of drugs out there that can help people. So we're going to keep fighting. And actually, you know, I was telling you during the break about, about how we've sort of turned the castle man into this like warrior here. And this is like our, you know, our castle man warrior.

1:37:53Dr. David Fajgenbaum:And I've been wearing this, excuse me, I've been wearing this pin for, for the last about 12 years. And so I want to, I want to give this warrior pin to you, my friend. You're an ultimate warrior. I appreciate you. Thank you. Thank you. No, absolutely. Absolutely. Oh, man.

1:38:11Shawn Ryan:It's going right here in the studio. And man, thank you.

1:38:15Dr. David Fajgenbaum:You're a warrior, and I appreciate you giving me the opportunity to share about our work because we've got a lot of work to do. And it's actually going to be raising the word, raising awareness through things like

1:38:25Shawn Ryan:this that are going to help a lot of people. Well, I'm going to tell all my friends about this, and they'll be listening to it anyways. but I hope this, I hope this podcast helps and, and I would love to see again, hopefully on good terms. I'd love that. Yes, exactly. Yeah, but seriously, it was an honor. Thank you. Thank you so much.

1:38:43Dr. David Fajgenbaum:Thanks, sir. That's awesome.

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