The Translational Mixer
The Translational Mixer
Episode 11: William Pao on the hunt for life-changing drugs and a refreshing Hugo spritz
William Pao, CEO of Revelio Therapeutics, and former Chief Development Officer for Pfizer/Head of Roche pRED, sits down with JC and Andy to talk about his new book: 'Breakthrough: The quest for life-changing medicines'. By charting the ups and downs of eight different drugs and the challenges faced by those shepherding them through the complex drug approval process, the book provides a fascinating peek into the hidden world of pharmaceutical discovery and the tireless work of the dedicated R&D professionals who develop life-changing medicines.
INGREDIENTS:
6-8 mint leaves
Bar spoon of water
Ice cubes
1 Oz elderflower liqueur (e.g., St. Germain)
4 Oz Sparkling wine (e.g. Prosecco)
1-2 Oz Club soda.
DIRECTIONS:
Put 6-8 mint leaves and a bar spoon of water in a wine glass and muddle gently. Fill the glass with ice cubes and add the elderflower liqueur, sparkling wine and club soda. Mix gently. Slap a mint sprig to release the aromatic oils and add it as garnish. Enjoy!
The Mixer music “Pour Me Another” courtesy of Smooth Moves!
Andy Marshall: Welcome back to The Mixer everybody. I'm Andy Marshall, your host. I'm here with my buddy and wingman, Juan Carlos Lopez. How are you doing, JC?
Juan Carlos Lopez: I'm doing very well, Andy. Good to be here. Looking forward to our conversation today with an old colleague of mine from my time in pharma, William Pau, who recently wrote a book called 'Breakthrough, The Quest for Life -Changing Medicines'. William has had a very distinguished career both in academia and in pharma, and he is therefore the right person to write about innovation in the pharmaceutical industry. And the book is very nice because it's not an expose or that kind of book. It's really more an attempt at bringing to light how complicated and how human in a way the process of drug discovery actually is. So I really enjoyed the book greatly when I read it and I'm looking forward to learning more about it.
Andy: Yeah, me too. I really enjoyed this book. I felt it really gave you a feeling for how industrial R&D works in these different pharmaceutical organizations, whether it's biotech or pharma, I think it's a really kind of insider's view of what goes on, which the wider world doesn't really get to see. So I'm really excited to talk to William about the book.
JC: Very good. So let's get started then.
Andy: Let's dive in.
---- Music ----
JC: William, it's so nice of you to join us on The Mixer. It's a great pleasure to see you because you and I go back a long time. We first met in person when the two of us worked at Roche. And even before that, you were one of our common reviewers when I was at Nature Medicine. So I knew about you way before I met you. And it was great to work together at Roche and now to reconnect after all these years, particularly in the context of this fantastic book that you recently wrote: 'Breakthrough the Quest for Life-Changing Medicines,' which just came out. It was a very nice read and we would like to talk in detail about what got you to write the book and your experience doing so. But before that it may be useful for our audience to hear a little bit about yourself because your career is the kind of career that a lot of young scientists and even established scientists would really aspire to emulate as a lot of people talk about translation and you certainly have worked the translational path. So it will be great to start with a brief intro about yourself.
William Pao: Sure. So first of all, JC, great to see you again and thanks for the opportunity to you and Andy to be on the Mixer. I'm very excited.
2:56: An illustrious career
William: By way of background, I have an MD-PhD by training, was in the lab of Adrian Hayday (Yale now Kings’ College London/Francis Crick Institute) as a graduate student, worked on gamma delta T cells, and then did an internship and residency at Weil Cornell in internal medicine, and then medical oncology at Memorial Sloan Kettering. So it was there I was in the lab of Harold Varmus, and we and others at that time found the genetic basis for why a new molecule, EGF receptor tyrosine kinase inhibitors, at the time only worked in about 10% of patients, which was basically they had somatic mutations in their tumors in the gene called epidermal growth factor receptor. I ended up staying on faculty at Memorial, had a lab, saw patients help to run trials, doing a lot of translational research at that time, and then eventually got recruited to Vanderbilt where I became the Division Chief of Hematology. I still had a lab, saw patients, help run trials, and during that time, I actually helped other companies develop their medicines.
So then I had a fork in the road in 2014 when I basically got head-hunted to head up oncology, drug discovery for Roche, based in Basel, Switzerland, which is where I eventually worked with you, JC. And that was a big fork in the road because it was like, "Do I stay in academia or do I go to the so -called dark side?" And I personally made the decision that I wanted to go do drug development full -time because I felt that if I developed new medicines for patients I could have a much greater impact worldwide. I'd love seeing patients, I'd love training students and postdocs etc. but you know if you can make a medicine that then hundreds, if not thousands, if not even millions, of people take around the world then you can have a huge impact and so that was the fulfilling part for me.
I would say I was really motivated because my father died when I was age 13 of metastatic colon cancer and at that time I did vow that I really wanted to make a difference for patients like him. I didn't know how I was going to do that but then about 20 years later I started to do that after years of training.
JC: Yeah that's fantastic and then after that you became the head of all of research and development at Roche which I'm sure was a great opportunity and the big excitement.
William: Yeah, so then after four years, I was then asked when my boss left to take over the whole unit. This is Roche Pharma Research Early Development (pRED), global unit based in Switzerland, but also with seven sites around the globe. And that was in charge of early discovery for neuroscience, ophthalmology, rare disease, immunology, infectious disease, and oncology. Got a lot of medicines over to late stage, and the early discovery unit, as you may know, was responsible for showing proof of concept in the clinic and then handing it over to their late-stage colleagues. And multiple molecules have been approved by now, which has been very fulfilling. And then after that, I was recruited to be the Chief Development Officer at Pfizer, where I got 13 approvals in the US and EU. And then after leaving there, I became the CEO of my own biotech, actually here based in New York.
05:56: Why a book on innovative drug discovery?
JC: To start discussing the book, it's quite remarkable because being chief development officer of Pfizer, even when you were already approached and you started working on this book, surely, it's very time-consuming and it's something that requires a lot of attention. So why don't you tell us a little bit what got you motivated and interested in writing the book in the first place?
William: Yeah. Well, I wrote the book mainly for three reasons. The first was having been both in academia and in and in industry, I knew that there were a lot of unsung heroes behind the new medicines that were being made. They're completely invisible to the public, and whether they're in academia or industry, or in biotech, they're working hard every day to make breakthrough medicines for patients. They're not necessarily motivated by money or fame, but really just for really trying to make a difference for patients. And as you might know, behind every molecule, there's probably not one, not two scientists, but sometimes even like 3 ,000 people that contributed to that molecules development. And I really wanted to bring to life behind the scenes people who dedicate their careers to making a difference. And that could be like biologists, protein engineers, toxicologists, clinicians, and so on.
The second reason I wrote the book was because there's very few books about innovation and drug discovery, actually. So, I was reading a lot at the time when I was the head of Roche Period about innovation and you can read about going to the moon, you can read about electric cars, you can read about iPhones, computers, etc. But there's very few about drug discovery and I think there's just as much innovation if not more going on in drug discovery because unlike an iPhone, which you can put in your pocket but not in your mouth, you have to put a medicine in your mouth and it has to go in and try to help you and not kill you at the same time. So that's the second reason.
And then the third reason was really to inspire the next generation of scientists to make breakthroughs where we still need breakthroughs, not necessarily in medicine, but in all aspects of life.
Andy: So why do you think there haven't been more books written about that process of innovating in drug discovery?
William: Andy, that's a great question. I think one is obviously the science can be complicated. I tried as much as I could to try to explain some scientific concepts in as lay terms as possible, but I think you do need to have some fundamental understanding or curiosity about biology and medicine. The second thing is, you know, we like to tell stories and most people like to hear stories and remember stories about one or two people. But in drug discovery, as I mentioned, thousands of people can contribute to the development of a molecule, and sometimes it happens over decades. So you might have a discovery in 1910, and then no progress, despite people working on it until 1950, which is a whole other generation of people, and then no progress until 1970, and so on. And so then it becomes hard to track the arc of what happened over time and remember all that. And then the third thing is, you know, I think most people don't actually want to be on medicines or taking medicines, and they have very complicated names that are hard to remember. And so maybe people don't necessarily think about all the innovation that goes into the pill that they take when they're taking it, as opposed to being enamored by their iPhone and opening all those apps and stuff like that.
JC: Another thing that I would add to that is that drug discovery quite often is about trying to prove yourself wrong, but you do a lot of experiments to show that actually this drug may not work. Let's try to kill it in as many ways as possible, and then at the end, "Oh, I couldn't kill it, so this must be a medicine." So it's more than trying to create something and say, "I'm going to defend this, I'm going to get it through the finish It's more I'm gonna have to really work hard to convince myself that this is actually true." And so because of that it's like almost antithetical to a hero story
William: That's true. You're right. But I think there are a lot of heroes because there's a lot of failure so to speak or a lot of dead ends that people run into and the heroes are the ones that really pick themselves off their feet get around the failure and figure out how to keep going.
10:08: Innovative molecules
JC: Yeah, and in fact in the book you are very good at bringing that to life. So how some people were so tenacious that even though they failed several times, they said, "No, no, no, there must be something going on here." They persevered and eventually met with success. So that's quite inspiring. In that regard, the book is very interesting because you have different medicines and some of them are in different therapeutic modalities and not all of them are new and all of them are from different companies. So why don't you tell us a little about your process, choosing what to cover?
William: Sure. So to dial back in time a little bit, you know, I did start this project during COVID. I was originally traveling about a third of the time for my job. And as you can imagine with COVID, I was all of a sudden having some time on my hands. But the other thing that was happening was that a molecule from Roche, risdiplam, for a rare disease called spinal muscular atrophy was coming out from our group and it's really cool science and I wanted to highlight the scientists that had developed that and so ended up writing a chapter. We knew that the molecule was about to get approved so we wrote that chapter to try to highlight them and it included you know the academic discoveries followed by what happened in biotech followed by ultimately what happened in the company. So then I thought because people liked it, I would write another chapter about a different molecule, but I didn't want to write about all molecules from the same company, particularly because if it ended up being a book, then people would think I was just advertising for that one company.
So I did then email some colleagues and friends, heads of R&D around the industry, and asked them, "Hey, would you be willing to contribute a molecule for my book about innovation and drug discovery?" And as you know the be very competitive. So usually people across pharmas may not be in the best mood to collaborate. And so I thought that they would just say no. But to my surprise, many of them or most of them said yes. And then so we ended up with eight different molecules from eight different companies. The criteria really had to be cool science, impactful patients, and there had to be stories about resilience, and determination, and what was going on in the innovation that happened to make those ultimately successful. There is one molecule, paracetamol, as you mentioned, a very old molecule that's Tylenol. I did write about that one because the accidental discovery of that molecule was pretty remarkable. And so I just found it fascinating.
Andy: I think that's also for our audience, just reading up about some of these molecules that everybody uses is completely fascinating, especially molecules discovered at the turn of the century, very different historical development compared with the drugs of today, yeah?
William: Well, as you know, the story is that there was a patient in France who had intestinal worms and went to the local pharmacy after he'd seen a couple of doctors and was prescribed naphthalene, which is the chemical in mothballs, and thought he got naphthalene, ended up taking it. His intestinal worms didn't go away, but he had fever and that fever went away. And the astute clinicians had never seen a fever go away with a medicine. So they really wanted to find out more about what happened. And they went back to the pharmacy and it turned out that he didn't even get naphthalene as it was an accident. He got a different drug [acetanilide].
Andy: That kind of speaks, William, I think to another part of this is that the genesis of a rationale for therapeutic intervention can start in all kinds of different ways, can't it?
William: For sure. I mean, we all like to think that, you know, we're all brilliant and we can come up with these great ideas. And I would say a lot of times in science, as you know, serendipity is actually what makes the difference. But it's really the person who is the serendipity that can do something about it. As Pasteur liked to say, "Chance favors the prepared mind." But yes, new discoveries and you'll see in the book often come from left field. People can be working within a field really hard and not make any progress. And then some other experts in some totally different area even accidentally or intentionally find something. That's what leads to the next breakthrough. So the lesson there really is you have to keep an open mind and really be open to new ideas and understanding what's going on around you also because those breakthroughs may help you ultimately in the end.
Andy: One of the drugs that I kind of wish you'd done the treatment on is Solvaldi, which is the hepatitis C drug that has really changed the face of treatment for hundreds of thousands of people who suffer from that condition. So an interesting question here is like where do you draw the barriers [line] as to what you cover. One of the things that I was wondering is whether you steered away from drugs that maybe people had talked about a lot. But then when I looked at Solvaldi, I mean, it's all about the price of it and how it costs so much. That's where the popular books are, but they're not really about the process of discovery and what an amazing breakthrough that was.
William: Yeah, I agree. One of the biggest breakthroughs for that was just being able to culture hepatitis C in the laboratory, I think, which was done by
Andy: Charlie Rice
William: Right, at the Rockefeller. Yeah, I mean, I think for the general public, it might be, again, hard to explain all of that versus just the scandal of high prices, which I understand is why pharma gets a challenging reputation. For the selection of the molecules in 'Breakthrough', which included risdiplam (Evrysdi) for spinal muscular atrophy, I have two molecules for cancer, one for hemophilia A, one for COVID, the antiviral pill, the gene editing molecule for sickle cell, and then one for HIV. I did try to pick more contemporary molecules that had more been recently approved, really trying to show the cutting edge science that's happening today. Some of the technologies now get into some inside baseball, right? But you have to understand like bispecific antibodies or small molecule splicing modifiers or gene editing. Some of these are really cutting-edge new medicines and I think just a glimpse of what's yet to come in the future. But you're right. I think behind every transformational medicine. There is probably a book or story to be told.
I did also want to be able to interview scientists who were still available for that. So for the book, I interviewed almost 100 people and again got access to inside the companies. So not only was able to talk to academics and the people who'd made some key observations in the laboratory or the clinic, but then I think what's unique about the book is the access that I got to the scientists inside because it really gives you a glimpse of what happens with the chemist who's really trying to make the molecule or the protein engineer who's facing the setback or a lot of the different challenges, you know, even in toxicology, for example, meaning that there might be an unexpected side effect in an animal study that puts the whole setback to the program and then people have to go back to the drawing board and so on. So, I think a lot of that people don't see even in other stories or textbooks about drug development.
Andy: To me, what's interesting is when you're telling a story, it's really humanizing the story. So as you said, and I think it's absolutely correct, drug discovery is a team sport, and we never really hear very often about the teams that are in companies that do this activity. And it's a very different activity from what the people who are doing it work in academic labs who end up getting Nobel Prizes that we do hear about. Yeah?
William. Yeah.
17:39: The people behind drugs
Andy: So I think that's a really important niche that you're fulfilling there. But the other part of this that I found really compelling in many of the stories you found a way to do this. And I think it really brings home why this is so important is giving examples of patients, how they experience the disease and why this type of work is so transformational. One thing that has always struck me about people working in R&D in pharma or biotech is that they're doing it because they want to make a difference in people's lives.
William: Yeah. Yeah. I think a very common theme when I tried to depict the various humans, you know, the scientists who are doing the work, is many of them are motivated personally by either a direct family member that's affected by cancer or some disease or a relative, and that's what really got them motivated to work on it in the first place. So I did, yeah, I did really try to humanize the scientists because sometimes, you know, they get a different, a certain caricature, I think, in life. And then also, ultimately, obviously, the patients are critically important. And so, yeah, there's many descriptions of patients, in particular, like in one chapter, really going through the life of a child, well, she's now an adult, but who had spinal muscular atrophy and what she was going through at the same time that the scientists were trying to develop the medicines. And ultimately, she ended up getting risdiplam but did have a lot of suffering along the way. And I'm really grateful for her to share her story, Aria Singh, who had spinal muscular atrophy. She just got married, by the way.
Andy: I think if you're gonna write a book that's gonna appeal to a broad audience, people need to know why this is kind of life-changing stuff. And it is the life-changing stuff, but the kind of technical depth of understanding it often, I feel, gets in the way of this appealing to that broad audience.
William: Right. Again, the science can be pretty complex in some of the molecules that I describe, but I think I really did try to write the book for the curious reader, particularly the one who's interested in innovation. I don't think you need to understand every last detail of the science and I did try to put in a lot of analogies also so that people could understand. But it's really about the determination, the resilience, and a lot of the other elements that go into innovation, I think. And also trying to humanize the stories about how people had particular self-interest or hobbies or other things, or sometimes they were constantly working just to develop new medicines for patients. I think in one of the stories, he didn't see his wife, one of the heads of R&D or discovery, he didn't see his wife for three years. At least that's what he said. I mean, at least the drug came to the market, so that...Well, I still owe my wife a vacation to Hawaii. I was working on it in one of the molecules on a sort of a race, I guess, against some competition in academia, and then ended up getting scooped. So I did have to hunker down and work incredibly hard for a long period of time, which included skipping a vacation, which my wife, I will take her there eventually someday.
21:05 Lego bridges and the Hudson river
JC: I hope that she's not a listener of the Mixer. So you were referring to the analogies that you put in the book and it's true that you have a lot of them and many of which very interesting. But the one that stuck with me is, I don't remember who said it, it's this analogy of when you cure a disease in the lab, it's like building a bridge out of Lego, but now to really take it to the market, you need to build a bridge across the Hudson River. And I thought that was very perceptive, because it is indeed the case that a lot of discoveries in academia are very promising. They look like we have cured cancer many times over in the animal model, and as you know better than most people, the reality of translation is very different. So I wonder if by writing the book, do you get any new insights on that interaction between academic science and industry science, and what can we do to make sure that people start speaking a common language?
William. Yeah. So that quote comes from David Altshuler, who's at It was previously in academia as well, and he was referring to work done by Stu Orkin and others in terms of curing animal models with sickle cell disease by gene editing of a gene called BCL11A. Certainly the work done in academia is incredibly important and actually leads to fundamental new breakthrough discoveries, but what he was referring to is then to make a drug that's available to people around the world takes a whole different set of skills and knowledge and processes and that's the part about building a bridge with lego and then trying to span the Hudson. So just remember a molecule that's approved has to be given around the world and hopefully every patient that takes it has the same quality medicine no matter where they are and every time they take that medicine and that's a totally different set of skills. Yeah, so I think the Even among academia and industry is incredibly important. A lot of big fundamental breakthroughs comes from curiosity -driven research. And curiosity-driven research, meaning a lot of times academics and myself haven't been there previously, you know, are just curious about why certain things happen in nature. They're not necessarily interested in developing a drug. This was at least also many years ago, maybe now people are more savvy about their potential for translation once they have a discovery, but it's certainly critical for drug development that you have academics working on fundamental problems and making new breakthroughs. The best example of that is, you know, Jennifer Doudna and Emanuel Charpentier working on bacteriophages and understanding CRISPR and gene editing that came out that ultimately was used in the molecule for sickle cell disease.
You know, I think one of the lessons that I learned was really that every molecule that ever makes it to approval has to achieve this sweet spot of biological understanding, clinical understanding, and technological advancement. And by that, I mean, you need a key biological understanding of the target that you're going after. And oftentimes that comes from academia, the clinical understanding of the disease and how relevant that target is in that disease. And that also often comes from academics or conditions who are in the frontline seeing patients and then technological advancement, meaning do you actually have a molecule that can hit the target that you want. Now that can come from pharma, sometimes may come from academia, but you know you really need all three of those elements to come together in order to make a launchable drug. You can certainly do biological research, clinical research and technological research you know without getting that sweet spot but you won't get a drug.
24:18 Technology fixation
Andy: I think you come back to emphasize that in the Afterword of the book. And from my standpoint, I was at a journal that covered all of these new technologies that intersected with biology over the past two decades or so. So I'm kind of interested as to, I completely agree with the insight that you needed advances in all of these areas. In some ways though, it seems to me that perhaps the technology world moves fastest, the biology world moves a bit slower than that. And then the clinical world, it's like this glacial pace that everybody's trying to move forward as fast as we can. I think this is something that we should explore in a bit more detail, William, because it'd be nice to talk about the clinical aspect.
But you know, maybe we could start with technology. I remember when you were talking about the PI3 kinase inhibitors, you mentioned SAGE. And I was like, Oh my God, I had almost completely forgotten about SAGE. Yeah. Serial analysis of gene expression. Yeah, that was in the early 2000s. And it was really important in rapidly identifying all these mutations in the gene. And yet, today, everybody's forgotten about SAGE, yeah? And everybody uses RNA-seq or whatever. But it's interesting that we've added all of these technologies. And I think in the world of biotechnology, one of my observations would be people, especially investors, make this mistake time and time again, is that the new technological advance is kind of heralded and people say this is going to change everything and my response to that and is it's very powerful; It usually allows you to do something faster or more cost effectively but overall it's usually adds to the cost of R &D itself. And unless it's married to the biology and the clinical advances, it doesn't get you any further. It just makes everything more expensive. Do you think that's fair?
William: Yeah, I think there's lots of different kinds of technologies. I think there's, it's great that we always have breakthroughs in technologies. When I mentioned technology, I'm specifically talking about technologies that make the undruggable, druggable. And by that, I mean, if you have, say, a target that you want to go after, it could be totally impossible to hit that target today. But then all of a and say, next week, a scientist figured out a way to hit that target. That's the technological breakthrough that's needed. There's a lot of other technology breakthroughs like SAGE and RNA-seq and stuff that might help you do more of the translational research and understand the disease biology and maybe identify a target, but really for medicine, you need that technological breakthrough to make an undruggable target -druggable.
Andy: Right, so that's more about modalities then, like a new therapeutic modality in a way.
William: But even there, I think you're right. I mean, usually when a new breakthrough comes out, everyone's like, oh, this is going to be applicable to everything. And then often what happens, particularly in big pharma is you buy a platform or a platform company and then you're like, oh, yeah, we're going to cure this disease and then probably 10 others and stuff like that. But I think in reality, you usually only get like one medicine out of that platform. But the most important thing is you apply that new technology to the right target. One of the lessons I had at the end was a big mistake, I think, is to apply the technology just to a disease because you're working on it already or because you have a strategy in that but you don't have a strategy in another area. That's a recipe for disaster. Every target that you go after should have a fit for purpose modality that's specifically going after that particular target.
JC: And that's very interesting because just the same thing in academia, right, that people come up with a new technology and then everybody uses that technology. For example, in neuroscience, when people invented optogenetics, everybody started doing optogenetics. For whatever question you were trying to answer in the brain, optogenetics. Sure, I mean, I'm sure that some questions require that technology, but not every question, and yet everybody needed somebody who knew the technologies so that you could say that you were at the cutting edge.
William: Right. But if you really want to be, you know, making insightful discoveries, you got to just tailor whatever technology to the right. It's all about answering the right question, right?
29:00: Innovation precedes understanding
JC: Yeah, those lessons that you include in the last chapter of the book are very interesting. And I was quite mystified by one heading in that section where you write that ‘innovation precedes understanding’. And I was wondering if you would like to elaborate a little bit on that because I agree with what you say. And in fact, some of these things that we're discussing are relevant to that point. But I wanted to see if you want to talk a little bit more about it in detail.
William: Yeah. I mean, innovation precedes understanding might be a little paradoxical. You'd think like, "Hey, maybe you'd have the idea and you'd know exactly what you want to do, and then in a linear way you'd be able to achieve what you want to achieve." But as you know so much of what we do, we just don't have a full understanding, particularly in biology. Weve gotten great advances in our knowledge there, but still there's a lot we don't understand. But if you wanted to understand everything before you ever started a drug discovery program, I think you would probably only be working on the same hundred targets that we've known for a long time. So anytime there's a new target that comes out, you know, we have enough of an understanding that we want to think that that's a relevant target to go make a molecule against and there's a disease for which it's important. But oftentimes we can be proven wrong once you're in the clinic. You know, one example is the molecules I was talking about before it, epidermal growth act receptor tyrosine kinase inhibitors. You know, there was a lot of research on the target EGFR for about 30 years since its discovery.
And then finally, there were molecules coming into clinic. And the understanding at that time was that this particular gene was overexpressed, meaning that there was too many copies of it in a lot of different cancers. And so the idea was that, "Oh, this molecule is going to cure a lot of patients with cancers that have overexpression of EGFR." So people who were developing that brought the molecule in the clinic, tested it in hundreds, thousands of patients, but it only really worked in 10 % of lung cancer patients. And then when they looked more closely, it turned out to be a unique subset of lung cancer patients. Basically people who never smoked, they never smoked cigarettes, but they still got lung cancer. And often they were female and of Asian background. And then it turned out the genetics showed that they had a particular mutation. That was something that was not known at the time that the drugs were developed. And that's what I mean by innovation precedes understanding. You can be working on something using all the knowledge you have, but still once you get into human beings with a new medicine, you're always going to be learning something new. And there's just many, many examples of that. The challenge for us right now is we don't have any human model systems that are completely predictive of what actually happens in a human body. We have animal models, we have in vitro culture systems, but there's no system now that can predict what will happen, and so we do ultimately have to do clinical trials to test our new molecules in patients, and very often we're surprised once we get in there. And it's not for You know, trying to be safe or anything, it's just there's just too many variables right now. that we don't understand still.
JC: That's right. And that's very humbling. That's very humbling because the number of trials that go wrong, even though you crossed every T and dotted every I, and you still got it wrong, it's humbling.
William: Yeah. The important thing is what I also mentioned, this concept of emergent learning, which is basically learning as you go, right? Often in school, particularly in high school, you know, you're taught to have rote memorization. But really, for innovation, you need to be able to learn on the fly. You need to have that knowledge, fundamental knowledge. But then, if you're faced with new pieces of information every week, you know, how do you absorb that information, digest it, pivot, and then figure out what needs to be done next? That's critical. Yeah. How do you accept that what you thought you knew might be wrong because of what you're learning now.
33:08: Clinical innovation
Andy: Exactly. Yeah. I would like to explore from the case studies that you've presented in the book, William, and just more generally, talking about technology, biology and the clinic. So in the pastiche about EGF receptor, you talk about some of the innovations that happened in the clinical world, making the clinical community start to think about mutation profiling, there was innovation in clinical development where this kind of concept of expansion cohorts was explored. You also talk about this kind of intersection of technology in terms of liquid biopsies and how they can accelerate patient recruitment. So I'd really love to hear from you what are the things that you're most excited about in terms of innovation and clinical development and how you see us making clinical trials faster and perhaps reducing the cost of the trials that we do?
William: Yeah, so I'm very optimistic about the pace of new innovation coming out in drug discovery. Many people call this the biological century and I really think that is true in the sense that we're just making, we meaning the community, new and new breakthroughs every day based on, you know, the new science, the new technologies that are coming. And if you think about the way the chapters show how things happened over hundreds of years or a hundred years, I think that's all going to accelerate, right? Because you can imagine initially a lot of the diseases originally had to be characterized in the first place. And so through humankind, we've basically done that for the past centuries. But now we're understanding the biology. And then hopefully now we're coming up with new technologies and on top of that if you look in the past hundred years You know, it's taken sort of a haphazard path in terms of how to even develop clinical trials. You know, it really wasn't even formalized till after World War II and you know The Nuremberg trials and things like that in terms of setting up how should we actually even do trials ethically, etc. But now we're much more able to do these trials faster and more efficiently and maybe using surrogate means of testing and measuring the impact of our molecules.
But I think, you know, I don't talk about this particularly in the book, except that, you know, just imagine the pace of advancement for COVID, particularly the vaccines, right? But in the book, I do talk about Paxlovid and how that antiviral medicine was developed in record time against the virus. And it could only have been developed in record time because of all the fundamental knowledge or a biology that came before that. And so I do think that the pace of development is gonna only accelerate and it's gonna be very, very exciting century and beyond of lots of new innovation
Andy:- But are there particular areas in clinical trial innovation that you think are gonna be really transformative?
William: Yeah, so that's a very interesting question. I think in particular areas will be a lot faster. You know, we'll be able to identify patients a lot faster through AI or machine learning will be able to enroll them much much faster. I think in cancer we're going to come with surrogate measures for example instead of having to measure exactly the tumor size and get scans you know we're going to be able to measure what amount of circulating tumor DNA they have in their blood and so on so I think that all of these new ways of measuring someone's disease type will help us do trials a lot faster. I think some of the other areas though, where we still don't have drugs, for example, like in Alzheimer's or in a lot of psychiatric disorders, we have new medicines, but there's still a lot to be understood. We still may have to use some of the more conventional methods. But ultimately, as you know, a medicine is approved if we can improve how someone functions, feels, or survives. Those are the three categories that regulatory agencies use. So the more surrogates we can have on how someone functions, feels, or survives, then the faster we'll have clinical trials.
36:31: Triangulating take aways
JC: Let's talk a little bit about the audience for this book. I like a lot what you said at the end of your three reasons why you wrote the book; that there being this interest in helping the next generation of physician scientists getting to through discovery. I think it's very clear. I personally think that that's the the core audience for this book, people who understand enough with the biology to be riveted by your description and who are really wondering what it's like to be on the discovery side of a new medicine. I think that those people are really going to enjoy the book quite a lot. And so I'm wondering if from your learnings after writing this book, if there's anything that either you would advise the next generation of scientists, this is the way that I think you should go about it or something that you would advise your younger self as in, you know, if you're going to get into drug discovery, do these as opposed to these other thing I did?
William: Yeah, that's a great question. So first, I do think hopefully that the audience will be wider than just the physician scientists. As I mentioned, I tried to write it for the curious reader interested in innovation. But in particular, yes, those who are contemplating a career in drug development may find this book particularly enlightening. I would say it really comes down to that sweet spot that we talked about. Every drug that's ever been developed has to get to the sweet spot of biological understanding, clinical understanding, and technological advancement. And the reason I bring that up is because the art of drug discovery within your own lifetime is knowing how close you are to that sweet spot. You can work on a new target X, but If you don't have enough biological understanding or clinical understanding or if you don't have the technological advancement, you'll never make a drug. So you could be working on that thing for 20 years and still not be successful. If you work on a completely validated target, clinically validated target, that might not be as exciting unless you really have a huge breakthrough in terms of the efficacy, for example. So I think these are all things that people have to consider when they take on a project. Certainly you want to be breaking new ground and new biology and new clinical understanding, et cetera. But to be successful, you're going to have to be as close to that sweet spot and then ultimately get to that sweet spot in your lifetime if you want to.
JC: That's very interesting. And very profound, actually. I haven't thought about it that way. Think about it in terms of that delta that there is between where you are in the question that you're trying to answer and that sweet spot. There's a biological delta, a clinical delta, and a technological delta, And you need to triangulate so that you calculate the smallest distance between where you are and that's what spot It's very profound that insight.
William: I like the way you characterize it; I should have borrowed that language. The important part of that also is all of your activities should really be thinking about how close am I to that and how can I get there?
JC: Yeah, you have to reduce the delta, absolutely.
William: Right, if you focus your activities on that, hopefully you'll get closer. But if you start to meander and ask different questions, if you're in biology, you may ask purely biological curiosity questions, but that's not gonna get you closer to the drug. So I would say, steer all your activities to try to close the deltas in those three areas.
JC: Yeah, I think that that's a very good piece of advice. I'm sure that our listeners will appreciate that.
Andy: It's interesting to me because over the past 20 or so years, I think there's been this change in terms of, we joked at the beginning and you said kind of going over to the dark side, yeah? I would suggest today for most young scientists, it's no longer the dark side, yeah? It's just another path. And the academic track, you know, has its own difficulties and frustrations and so I'm really interested William and I think it would be really helpful for our listeners, people who are thinking about this, you know, is academia the place for me or should I go to industry? The differences you experienced in academia and in industry, the ways of working, how science is practiced and how success is measured and what are your takeaways from this path that you've been on?
William: Yeah, I mean, I think each of them has their own merits, but also each of them has their own drawbacks. So there's no one perfect one. So everyone has to choose for themselves. Obviously in academia, I think you have more freedom to do pure, as I talked about before, curiosity driven research, as long as you can get funded. You have a lot of freedom to do whatever you want, working on what you want, publishing, collaborate with who you want, and so on. I think for the clinicians and also other folks in lab, one of the things that might be underappreciated is you can work with multiple different companies on different molecules, but obviously once you're in a company, you can only work on that company's molecules, right? Within pharma or biotech, I would say one big difference is the amount of collaboration that goes on. In academia, obviously the number of people on papers has increased over time. But still, you have an individual lab, you have a particular person's project and so on. But every project in pharma or biotech, multiple people are working on. And so you really need to have a lot of collaboration and teamwork. There's that for sure. And everyone has to be rowing in the same direction, so to speak. I would say from some things that are the same. I do think the science now is cutting edge on both sides. I think many decades ago, maybe in oncology, there was a divide between the companies that were just making chemotherapies versus the molecular biologists. But now, I don't think you could make oncology drugs without a full understanding of not only the molecular signaling pathways, but also the immunology behind it and so on and so on. So I think the science is cutting edge technology. All that stuff are similarly being used on both sides, but you would have less academic freedom in pharma. You're doing more applied research and really trying to obviously make a medicine because it is a business. Ultimately, and if you're not successful, you know you could potentially lose your job Not because of a bad work that you did but just because the company may go in a different direction or some of that. You know so that that wouldn't happen in academia so to speak. So, you know, there's pros and cons of each.
I would say the other difference is one underappreciated one is obviously in academia, you have peer review, which is usually anonymous both for your grants and your papers; in pharma or in companies, you go to review committees. It's always the same people. You actually know them outside of the review committees. And so it's just a different interaction. And then now I'm in, you know, with a biotech and now interacting with venture capitals for funding, and that's a totally different interaction as well.
43:15: Company cultures
Andy: That's for sure, that's for sure. It's also probably important to emphasize that industry is not this [monolith], you know, every company has its own culture, has its own way of doing things with them.
William: Oh, yeah, for sure. Some I would say are euphemistically more commercially driven, some more science driven, and you know, the culture will be very different in that aspect.
JC: Did you get that impression while writing the book and interacting with different companies or is this more for other interactions you've had with people? Because I think that the fact that you got to look a little bit under the hood, it gives you a better perspective on that question. Did you really get the feeling that different companies have markedly different cultures?
Andy: But JC, just think about Chugai and Hemlibra. Would that kind of antibody program progress everywhere? I mean, it's an incredible story. And I'm not sure outside of a Japanese pharma company whether it would have gone ahead, I don't know. William, what do you think?
William: Yeah, I would say that's a particular one that molecules for, it's a bispecific molecule for hemophilia A, really groundbreaking, and was in preclinical discovery for 10 years and almost got killed several times. But ultimately, I think the challenging part of that, as you probably remember, is the scientists screened like 44 ,000 bispecific molecules to ultimately come up with the one. I'm not sure that would happen in a lot of other places. That's true.
JC: Although you also have the example of the HIV drug, right? That inhibits the structure of the virus. And with that one they showed a lot of patience with the team.
William: Yeah. In a lot of other places, it would have been killed, that program, and yet they persevered and got the result. Yeah. I would say from my book, I can't glean the different cultures, because as I mentioned, one of my criteria was cool science and impactful medicine. So all of those companies in the book did fit those criteria. But I would say, when I say commercially driven, it's sort of like, hey, we have a franchise in, say, this disease, so everybody needs to be working on this disease and then sometimes you can bend the science to try to work in that disease and that's not a recipe for failure but for success, right?
45:22: A Hugo spritz
JC: Yeah, so we're coming to the end of our time and it's been very informative. I certainly enjoyed our conversation as much as I enjoyed the book, I'm sure Andy did too, but before we finish as you know we always ask our guests Is there a go -to drink when they finish writing a book or when they finish a very exciting program when they get on a drug approval? All of these things that happen all the time. What is your go-to drink so that you join the ranks of the Mixer?
William: Sure. So, you know, I lived in Switzerland for eight years, and so living in Switzerland got exposed to Aperol Spritz and Hugo Spritz, but I would say my favorite one is Hugo Spritz because it's less bitter. It's a really refreshing drink with prosecco. I think it has elderberry in it and mint. Yes, is my go-to drink having lived in Switzerland.
JC: Very good. Yeah, it's actually a drink that the origin is unclear, but some people say that it originated from the northern part of Italy or from Austria and Switzerland. That corner there of Austria, Switzerland and northern Italy, that's where it seems to have originated. It has elderflower liquor. Here in the US you can make it with Saint Germain, but I'm sure that in Switzerland they must have some artisanal liqueurs that, you know, just thinking about it, I think it would be very nice to have an opportunity to try them. For you, Andy, it would be nice because as you're partial to the mojito, you can think about this one as the rich man's mojito. The rich man's mojito. This is the rich man's mojito.
Andy: You know, actually, a drink that Delphine really likes is, and I don't know if you've tried this, William, is the Lille Spiritz.
William: No, I haven't tried it.
Andy: So that's a spirit that's in the south of France. I can't remember that. It's a village close to Bordeaux, maybe 50, 100 miles away. And the factory is still there, but they're still making it the way that they used to make it. But they have the Rosso version and they have the White version, JC, yeah?
JC: Yeah, and Red as well, yeah. Well, as you know, Andy, one of my favorite drinks is the White Negroni, right? Williams, as I told you before the recording started, we know one or two things about drinks over here.
William: I see that.
JC: William, it's been wonderful to have an opportunity to chat with you about the book and about your thoughts on translational research and on innovation. It's been very informative, and I'm really glad you accept our invitation. –
William: Well, I'm really grateful, JC and Andy, for the opportunity, and thanks so much.
Andy: Thanks a lot, William. It's been great.
48:08: Parting thoughts
Andy: So this was a really interesting conversation we had with William. It's really nice to have this insider's view of a drug discovery and development program within a pharmaceutical or biotech company. So what were your takeaways from what we heard, JC?
JC: Yeah, first of all, I think William deserves all kinds of recognition for the amount of work that he put into writing this book, right, interviewing over 100 people people to get all the facts. He didn't say these during the recording, but I know that he had to get legal clearance from all the companies so that he could include the stories in the book. So that was a huge amount of work and he deserves all kinds of recognition for doing it.
In terms of the conversation, to me the highlight was this idea that medical innovation takes place in the sweet spot at the intersection of medical understanding, biological understanding, and technological advancement. To me that is a very useful piece of information because as we said during the recording there's is a delta between where you are in the process that you're studying and that sweet spot. And so if you try hard to reduce that delta, your chances of meeting with success will increase. So anybody interested in getting into drug discovery would do well paying attention to that piece of advice. So I think it's very profound.
Andy: Yeah, I completely agree. I think this idea, you put it in the terms of kind of triangulating between technological innovation, biological understanding and clinical implementation, I think is a key takeaway from our conversation. And the way I think about it, as somebody who's kind of intimately aware of the way in which different waves of technology are kind of introduced into the realm of biotechnology is that you have these three areas and for a successful drug program you need all of those three areas to be in perfect alignment and in many cases they're not. And what I have seen at a journal that focuses on technology is that there's this emphasis on technology because technological innovation is gathering pace and is happening at a much faster cadence than advances in perhaps biological understanding. And then the clinical realm is the slowest moving realm.
But to me, one of the problems with drug discovery and development is that there is an overemphasis on new technological breakthroughs. There's a kind of allure; people embrace those new technologies and think that they're going to have a greater impact. But what happens is, is that they are important, they give us new information, they may accelerate the way in which we can gather information. But unless you have at the same time, the biological insight and the means to, to do the clinical implementation, they're not going to get you to that drug. They're just going to add to the cost of R&D and that's what we've seen as R&D costs have increased as we've had technology on technology on technology.
And then the other, the second, point that really strikes home for me from what William said is there's enormous opportunity here for the intersection between technology and the clinical realm and the ways in which we can use technology either in selecting patients for trials, measuring different surrogates of clinical outcome whether it's proteins or metabolites, those types of biomarker assays, liquid biopsies that have been so important in the oncology realm but could be adapted across the whole of drug discovery and development so to me the most exciting part of this is that we can bring down the cost and time of drug development by starting to apply those technologies in clinical development.
But this is the Mixer, so I'm interested JC what you thought about his favorite cocktail what about this Hugo Spritz?
JC: It's a very refreshing drink; much more appropriate for the summer than for now the middle of the winter but if you want one Andy, I won't stop you. I know that you like mint so maybe you want to go and have one later today. It's a very nice drink in the sense that if you don't have any tools at home to make it; if you don't have a shaker, or a mixing glass you don't need them because you build the cocktail directly on a wine glass, you can just mix it with a straw and enjoy. So it's the ideal beginner's drink if you want to get your feet wet in the world of cocktails. So we thank William for that insight because I think all the cocktails that we've had in the past have been more involved.
Andy: It's a new cocktail as well, JC, yeah?
JC: Yeah, apparently it was invented early this century. So that's, that's good. There's innovation in cocktails as well, as you can see!
Andy: That's great. Well, thanks for the conversation, JC. Thanks to William for sharing some of his insights into drug discovery and development. And thank you for joining us. We look forward to seeing you next time.
JC: Cheers, Andy.
Andy: Cheers, JC.
