Flagship Dialogues @ JPM: When Biotech Gets Personal with Michelle C. Werner & David Fajgenbaum

Welcome back to our Flagship studios here in San Francisco at the JPMorgan Health conference. I am delighted to introduce David Fajgenbaum, who we met at the Clinton Global Initiative earlier this year. We're inspired by his work and his book, which will be a topic of conversation between David and Alterna CEO Michelle Werner after a presentation by David. Dr. Fajgenbaum, the floor is yours.

We've tried everything, there's nothing more that we can do. I heard those words from my doctors, but I didn't understand until my family came to say their final goodbyes and a priest read me my last rites. I was 25 years old. Six months earlier I was a former college quarterback and medical student. I became critically ill with Castleman disease. In a last-ditch effort, my doctors gave me seven chemotherapies. I survived, but relapsed and nearly died four more times. My only hope was to repurpose an existing drug. I began testing my own samples, and sirolimus emerged. I tested it on myself, and January 5th marked nine years in remission. I married Caitlyn, we had two children, I wrote a book, and joined Penn to chase more cures. We've discovered 10 repurposed drugs for Castleman disease, cancer, and COVID-19. But there are 9,000 diseases without a single FDA-approved therapy. Repurposing is faster and cheaper, but three barriers exist: no centralized database, insufficient incentives, and no organization responsible. We launched Every Cure to build an open-source database. We've received $4 million in donated data and $500,000 in seed funding, unlocking 497 repurposing opportunities. We need $9.4 million more to build an AI-driven engine. We need funding, partnerships with organizations like Flagship, and tech partners to leverage AI. Join us so no one is ever told we've tried everything when a cure sits on the pharmacy shelf.

Oh thank you, Michelle. I'm so happy to be here with you. That might be one of the most well-annotated copies of Chasing My Cure that I've seen. Really excited to chat today.

I'd love that. I'm so devastated by what you and your family have had to go through, but since we've spoken, I've been so inspired by what you are doing, the action that you're taking. Thanks for sharing that with me and with the audience. Excited to chat about the questions you have.

I think it's all relative. There were moments I felt hopeless, but because I believe in the power of science and medicine, I felt there was a one in a million chance. One person may look at that and say you're completely hopeless, but you could also say there's a chance. That little bit of hope drove my action. In the book, we talk about the virtuous cycle of hope and action. You hope a little, that drives you to take action, and success gives you more hope. But what do you think? Is one in a million odds enough to feel hope or is it hopelessness?

I love that. We talked about creating a silver lining. My mother taught me to look for silver linings, but what's even more powerful is to create a silver lining. In the midst of the storm, ask what can I do today to create a silver lining out of this awful thing. You're creating a silver lining not just for your family but for all the other patients and families that could be part of these trials. I love what you're doing.

For me, my mom was diagnosed with cancer while I was in college, and that drove me to go into medicine. Seeing both the promise and limitations of medications made me want to go into clinical oncology and cancer research. I was a third-year med student when I got sick myself. I had to make tough decisions. I decided to dedicate my life to research because I could never help other patients until I figured out a drug that could save my life. That was difficult, but it felt like the right thing. We both resonate with the concept of overtime. I had my last rights read to me at 25, and I consider that the start of my overtime. We're all in overtime, and that can be scary but also clarifying. When you're in overtime, the answer is always clear because the clock is ticking. That's how I feel every day. It sounds like you used that feeling to create clarity about what's important.

I love that. Oncology is a lot further ahead than other fields, but there's still major unmet need. The more we can learn from one another, even between fields, is important. That brings up the next topic: the impact of a fragmented, siloed world. Can you share your observations on why collaboration is so fundamentally important in rare diseases?

Absolutely. Even in Duchenne muscular dystrophy, there are a number of patient groups. They all do great things, but biospecimens are everywhere and they're not sharing. To me, it's one of the things we have to do. In my current role, not just as a mom but as CEO, I wonder if there's a way to incentivize what I call 'coopetition' — cooperate but also compete. If we inspire and incentivize that, can we get the most out of what we have access to and apply it to rare communities? I think so. We've seen it with Every Cure, where companies that compete are making data available for free because they believe it can help patients. We talked about ways for the rarest of rare diseases to de-risk approaches by pooling money and ideas. Whichever idea helps patients, that group gets a bigger cut, but we all de-risk by going in together. I don't know of specific examples, but your comments inspired that idea. It's something that needs to be explored.

I think the COVID pandemic gave all of us a sense of what rare disease patients feel every day. When you have a disease like Castleman or Duchenne, you need a drug yesterday. We all felt that with COVID. It created a sense of urgency that we've always had in the rare disease space. The big question is how to bring that feeling to everything we do. Living in overtime can be terrifying, but it can also be clarifying. If we can use that sense of urgency to hone in on what we should focus on, it could make a major difference. One specific is the FDA's emergency use authorization, which allows promising treatments to be tried quickly. A similar process outside of an emergency would be great because there is an emergency for Duchenne and for Castleman patients who don't respond to current drugs. And the other is repurposing.

You have both an urgency to find drugs and at the same time you have drugs that are in the pharmacy that might be within walking distance if you or someone you love, and it's right there, and we just don't yet know that it could be a treatment for you or someone you love. To me, that feels like an emergency too: the fact that the treatment could be right there and we just haven't done the work to make the link, or maybe someone has done the work but we haven't lifted it up and done the clinical trial to prove it. I think both of those allow you to really accelerate progress.

I agree. I really like the word responsibility for this because up until now, repurposing has been considered an opportunity: if we can do the right work to figure out that this drug could work for that disease, that would be great. But in my opinion, it's almost the inverse. It's not that wouldn't it be great if we could find one new use among the 3,000; I think it should be that we have a responsibility as a society, not even just the medical field, to unlock the full potential of every drug. I really don't believe that anyone should suffer when there's a drug at their pharmacy. In the same way that there have been global efforts to say no one should suffer because they can't afford medication or because that part of the world doesn't have access, we have overcome mountains to make sure that's not the case. It feels like the same sort of equity issue here: the drug is there, but the work just hasn't been done to connect this drug to this disease.

Exactly. I couldn't agree with you more. One thing I tell my team at Penn — I run a center at Penn — I tell them all the time that all the scientific questions we're exploring are going to be answered at some point, maybe 100 years or a thousand years, but it's a matter of time. The best thing we can do is answer them as quickly as we possibly can, because it's not can we answer it; humankind will answer all these questions. But we need to answer them now so that your son can get a drug in a year. It's all about time.

I think it's a situation you don't ever want to be in, but there were a lot of aspects that led me to say, 'Let's try this drug.' First off, I've told you about my wife Caitlyn. One thing I never could understand was how confident she was that I was going to find a drug to save my life. I wished I had her confidence. She had this unwavering confidence. That was helpful. I think there are three things that have helped during really difficult times. One: you need a really good vision for your future that you're working towards. In my case, we had a wedding date — May 24, 2014 — and I dreamed of a family with Caitlyn. I also wanted to keep searching for treatments for patients; I felt I had unfinished business if I couldn't find more drugs in my mom's memory. So one: the long-term picture. Two: I really believe in the power of support from the people you love. When I was struggling to breathe in the ICU or making decisions about taking this drug, I always had my sisters, my dad, and Caitlyn by my side. I receive strength from them. Three: taking things day by day or even hour by hour. When I was on my deathbed, if you told me I'd have six more months of pain, I couldn't have kept fighting. But I could fight for an hour or a day at a time. That formula — vision for the future, strength by your side, focus one hour one day at a time — had been refined because I nearly died five times. I knew what my disease could do. I had a wedding date I wanted to make it to. I thought this drug could work. I had okay amounts of data — probably a 10 or 15 percent likelihood realistically that it would work. But I had a vision for the future and knew I wasn't going to make it unless I tried something. We talked about hope and action; for me, it was time to take action. I started taking it. I can't even put into words — January 5th, nine years. I never could have imagined.

Absolutely. Sirolimus has been around for decades, approved for kidney transplantation. It had never been used for Castleman's, but we know how it works: it blocks a part of the immune system called mTOR. I discovered that mTOR was highly active in my immune cells, and we've now found that's the case across Castleman disease. Unfortunately, the drug only works in about 15 to 20 percent of patients, but we find increased activation of this pathway uniformly. We knew how it worked, it had good safety data. There's a newer version, temsirolimus, but I liked the idea of the older version with decades of data. To your point, there was a real risk it could push me over the edge. If a part of your immune system is highly activated in a disease where your immune system attacks your vital organs, it could be a compensatory mechanism. The last thing you'd want to do is turn it off. But with a horrible disease and a vision for the future, and a drug that was safe and old, it was the right formula for me to start testing it.

I like that you use the word hero. I agree with you completely.

Oh, it's incredible. That's so special and so touching. Thank you for sharing that with all of us. I think there are these incredibly courageous individuals who take a drug for the first time ever, and the incredibly courageous individuals who develop those drugs and get them to patients. We're in this ecosystem where we've all got to work together. Was it collaboration? Cooperation? I think we've got to figure out ways to all work together because what you shared about this gene therapy in your son's case, and sadly the patient before your son — this is why we go into medicine, to help these patients. Yet sometimes we get lost worrying about who's the first author on the paper, things that just don't matter. I thank you so much for sharing that story. All of us that are part of companies like Flagship, Penn, Every Cure, and beyond — this is why we're doing this.

Absolutely. Going back to COVID, some of the risk shifting that occurred with the federal government led to things moving more quickly. In drug development, it's a lot of risk-benefit and risk-reward calculus. When you think about drug repurposing, drugs at your pharmacy might be helpful for your disease, and the only thing between you and that drug is a prescription pad. I made the discovery about mTOR being activated in Castleman disease about two weeks before I was on a medication that hits mTOR. A lot of doctors would hesitate, but in my case there were no other options and I had decent data. When that's the case, there's an incredible opportunity: the drug is in the pharmacy, and all the doctor does is write a prescription. But there's also risk: the drug might not help and might cause harm. We need some ability within the system to restrain desires to try a harmful drug, but we also must not be so paternalistic to think that my doctor always knows the right risk-benefit ratio for me. My risk-benefit ratio might be different from my doctor's perception or your family's perception.

It makes me think about what we're doing with Every Cure and drug repurposing. One part is utilizing existing data to find connections between drugs and diseases. Another part is working directly with companies to understand what assets or drugs they have that they couldn't pursue. If you make tough decisions, the quote I heard today was, 'You can do anything, but you can't do everything.' There are diseases you just can't pursue that drug in, and that's okay. But what's missing is a way to share that insight with a central broker, a Switzerland. We want Every Cure to be that Switzerland where anyone can share insight. 'I really thought sirolimus could be useful for this disease, we never pursued it, but you guys can.' It goes into our database, available to the world. We might say, 'That's worth a $5 million clinical trial; let's get philanthropic dollars together and do the trial that wasn't done initially.' That resonates as we think about risk. One company may say it's too risky, but another may like it. One company's trash is our treasure.

When I started the CDCN, I brought together doctors and researchers from around the world. I didn't want to tell them I had Castleman disease because I was worried they would treat me differently and see me as biased. I think some of the stereotypes in our system are that we in the health profession think of patients in a different category. I didn't want my colleagues to think of me differently, so I didn't share for the first year and a half. Then I relapsed, lost my hair from chemo, came into a meeting and couldn't hide it anymore. I said, 'Yeah, I have this disease.' They had asked me for years why I was so interested in Castleman. Once I started sharing with my colleagues and classmates in business school, it felt liberating to just say, 'Yes, I have this horrible disease, I'm working on it.' It doesn't make me a better or worse scientist, but certainly more obsessed. Being able to share openly has been really helpful. I know you said that's been helpful for you too, as part of your grieving process.

I love it. I think what you also realize is that all of us have our own things we're dealing with. Certainly different in many ways, but we're all dealing with challenges. When you can be authentic and open and share yours, it can make them feel more able to share their challenges as well.

Thank you.