Andy Plump - Translational Roles & Global Perspectives

Well, thank you Karen. It's fantastic to be here with you. I can't believe it's 20 years ago when we were sitting in that conference room in Merck and you were in clinical pharmacology and I was in the cardiovascular discovery group and I was trying to recruit you over. Remember that conference? Do you remember that conference?

It was great. We've had a long history together and it's really great to be back together again. So, I joined Merck in 2001. Actually, my start date was October 11th, 2001. And I was actually soul-searching that year because I ended up doing something in my postdoc that was very fundamental biology. I was studying axon guidance in the developing central nervous system with Mark Tessier-Lavigne at UCSF and I loved it. But I had felt like I had gone down a bit of a rabbit hole because my interests were not per se in basic fundamental biology. They were really in translational medicine. In my mind I had reasoned that disease is just developmental biology pathways gone awry. So if I could study developmental biology, I could then rapidly translate that to disease biology. And that gap though is massive. So as I started to work more and more on studying neurodevelopment, I started to realize I was moving more and more away from what I really loved. And so I was going through soul-searching and then, as is almost always the case, it was somebody that helped to pull me back. And it was Tino Melon. Oh, do you remember Tino? He was in the INI group with Elise Ryson and Briggs Morrison. Really just an amazing cohort of people. I ran into Tino. We had lost touch. We had worked together in a lab many many years prior. Very similar mindset, similar background and he was at Merck. So he invited me to spend a few days there, meet with, you know, like I must have met with 30 or 35 people. And I got very excited.

When was that?

It was amazing. I remember at the time Merck had this system where employees who worked their lifetimes in the factories could actually apply for chauffeur position. They had four chauffeurs. These are Merck owned cars. Merck owned chauffeur. And there was one very famous chauffeur who was actually written about in books that have been written on Merck. He's quoted in these books. I don't remember his last name. His first name was Guy. And I get into the airport at Newark for this three-day interview. Exactly. To your point, meeting with 30 different people. And I just spend the 30 minutes in the ride listing out everybody that I'm meeting with. And he knew all of them. He was giving me the skinny on all these people. It was very funny.

But you know, I visited and then I reasoned that I needed to expand my horizons. I shouldn't just be interested in Merck. But the reality was I was quite impressed by the people that I had met at Merck and the history of Merck and you know it was for many many years under Roy Vagelos it was not just the best biopharmaceutical company it was the best company to work in across all sectors and I started looking and talking with a lot of people and actually on September 12th the day after 9/11 I was actually supposed to go to BMS for an interview and of course that got cancelled and I basically pulled back from a lot of the soul-searching I was doing because I just loved what I had seen at Merck and so that was my first foray into the biopharmaceutical industry.

Well, so right. So I interviewed in five different groups. The INI clinical group, clinical pharmacology, discovery research. There was a new group that Sean Harper had just started to run which was pharmacogenomics. And then oddly the one I was most interested in was project management. And I remember Mark Hamish Wright who we were just talking about Bill these are physician scientists who were in project management. That's true. And I thought that would be the perfect way to holistically bring my clinical in. So in the end though, I decided clinical pharmacology just the same as you because it just felt like when you train in medicine people always wonder how you eventually decide what subspecialty you want to go into and more often than not you see yourself in the people who are doing that subspecialty and that's what happened with me with clinical pharmacology I saw a group of translational physician scientists who had backgrounds much like I did and who thought a lot like I did.

It was amazing. I learned so much. I mean age 35 when I first started in Clin Pharm and I thought I had learned something over the last 15 years of my training and I came in and I realized I was almost starting afresh.

So, you started in Clin Pharm. I don't know whether you'd already moved on to cardiovascular. Yes, you said it. You were already then in cardiovascular, I think. And we ended up working on a protocol together. I don't know whether we're allowed to say the mechanism.

Yeah so it's interesting because just if I fill in a gap actually so I left Clin Pharm two years into my tenure at Merck to join a new group that was working on pharmacogenomics. Oh, you did too. And we actually were working with decode at the time. Amgen eventually bought them. And so I stepped into that group and learned a lot. We didn't really get a lot done. Just it was a hard time we had a hard time penetrating difficult space and a hard time penetrating the development wall within Merck which was quite outstanding but also quite quite traditional. So then I ended up leaving in I went into a translational role in in cardiovascular which was my sweet spot. I loved it. And if you remember this, but Luciano Rosetti was running kind of the broader group and we was having difficulty bringing in a new development, I'm sorry, a new discovery head to replace Sam Wright who had left and so he asked me if I would be willing to step in and it was one of the most difficult professional decisions I had to make because I loved that translational space and I didn't really have a good sense for what the discovery space would look like. We were scientists, but there's a difference between being a scientist and being a drug hunter, right? And I definitely was not a drug hunter at the time. I was a scientist. And so I took it and it was by far the best move I ever made in my professional career, you know, moving into that space. And so we worked on atherosclerosis, we worked on hypertension, which is a group that you came in to eventually lead, right? And then we worked on thrombosis. And you know it was before things dipped in cardiovascular just everybody left cardiovascular to go into specialty care and into rare diseases and it's now come back. But your question have we have we made the progress that we would that I would have imagined? I think yes. I think we've really realized so much of the opportunity that genetics has provided us in cardiovascular disease. I mean, it's just amazing if you think about it. I think the issues now in cardiovascular disease are around overall health care. It's a little bit less around novel therapeutics, especially in some of the primary indications. And then heart failure, that's the big open space right now.

It's been an incredible journey and having been through three companies, you know, one of each basically in terms of culture. The learnings have and continue to be just amazing and I've grown so much as a human being and as a leader and I continue to grow. You can't stereotype a company per se but Merck had this incredible discipline and scientific excellence and there was the Merck way of doing things and it was pretty good. It didn't it was both enabling and created a barrier. It was enabling because it was a recipe for success particularly around small molecules. It challenged Merck's ability to move from small molecule chemistry to other modalities because the mindset shift was a difficult one for Merck to make. Sanofi was an interesting transition. It was funny because when I left Merck, nobody at Merck could understand how I could leave Merck and then they started to realize, oh, Andy will move to Paris. And so Paris they could understand not so much the company shift but Sanofi had Sanofi was a really young company. Merck was founded in the 19th century and Sanofi was a mid-20th century company so it was a young company that was incredibly successful that was trying to still find its way. And as with many companies at the time, this is 2012, there was a transition away from small molecules to other modalities and had just bought Genzyme. So I learned a lot at Sanofi. I learned a lot about being a global company. I learned a lot about being open to new ways of thinking in some respects different from Merck. And then rare disease and specialty disease. Merck had been very much a primary care focused company. And then of course the third transition which was I didn't spend enough time at Sanofi because this opportunity at Takeda came around in 2014 and so this last opportunity working in a Japanese company you know when I joined in 2014-2015 the board meetings were 100% in Japanese. There were 13 board meetings a year all in Japan. 50% of our business, 50% of our employee base was in Japan. And so truly a Japanese company, but a Japanese company that was primed to globalize based on decisions that the prior CEO Yasu Asaga had made and that Christophe Weber, our current CEO, was brought in to help to catalyze. So I came in. I think I'm one of my intrinsic I'm a middle child of five. So intrinsically I like to bring people together and having that entrenched in the global company that I was in in Sanofi helped me then step into this job at Takeda and bring those cultural sensitivities and understanding as we started to then expand Takeda into a global company.

Yeah, I will. And then I'm curious in your thoughts on culture because I'm sure you've in your experience at Merck and now at Schrodinger you have similarly learned an immense amount.

I mean, have you seen this?

It's too bad we're on a podcast and we don't have video because I have a huge smile on my face, Karen, just listening to the story. It's great and it's been fantastic to watch you develop and contribute to our mission. It's been wonderful. And as I've gotten older, I've learned to balance some of my tendencies even, you know, because it is great to come in and want to try to drive change and try to be dynamic. You know what I've learned is that organizations will naturally try to block that. If they're not if that's not the kind of foundation of those organizations and most biopharmaceutical companies are not like that. They're not most biopharmaceutical companies by definition are not progressive. We're not like the tech industry, right? Our life cycle is not months, it's years. Yes, it's very difficult to change the direction, but you can. You have to be consistent, right? You have to be repetitive at some level. You have to we were just talking earlier, you have to be optimistic. Yes. Or you can't get stressed. You can't get beaten down. But you also need to deliver. And I think what I've learned in my infectious enthusiasm and exuberance to make things happen and do things differently. What I've learned through failures is that it's not just about doing something differently. And of course, this is obvious, but it's about doing it differently and being successful. Indeed, that's what you have to figure out is how you thread that needle. And coming back to the talent piece, that's been the balance that I've learned. In the current job, one of the things I feel perhaps most proud about, maybe in the same way that you might given what you just described, is bringing people on who are a little bit more junior, who have all of the potential. You have to be really careful when you do that. You have to have a lot of conviction. And you have to be willing to invest in their development. But those are the people that will change the world, right? But then you need to surround them with some people who are experts in their domain. Exactly. Right. That aren't going to necessarily change the world, but that will ensure that we're able to execute, deliver and take informed risk. Right. I think that's where that juxtaposition is helpful is when you've seen enough failure, you know that there are things you can see and there are things you can't see. And sometimes I guess when you're early career you don't have that experience but bringing those two worlds together I think is often quite powerful.

Brilliant. So you've been doing this for how many years now? Yes, 30ish. It's a long time.

Yeah. Well, so I'll give you the answer, but I'll tell you the my first experience in 2001 when I came into the industry a week after I had joined. So I told you I joined October 11th, 2001. This is October 18th, 2001. And I'm entering an office. I'll throw out the names. I don't know if people will know them, but Barry Gertz is leading our clinical group. Paul Deutsch is my my mentor in Boston, clinical pharmacology. And Gary Herman. Gary is is presenting his first study. It's a phase two study of a PDE4 inhibitor in asthma. And Paul brought me into the office. So, it's the four of us and I'm a fly on the wall. And Barry was a very intimidating figure as you you'll remember. And Gary presents the study and it's like I've never seen a cleaner negative result than what he had in the study. It was so obviously negative. And I'm thinking, oh man, this doesn't end well. And he finishes presenting and Barry gets up and stretches his hand across the table and shakes Gary's hand and says, 'Congratulations. You just made a no-go decision.' Awesome. And it was at that moment I realized in our business, of course, we need to see success, but success is not just a positive result. Success is an ability to make a clear decision and move on. So that's a mantra that's really stuck with me is when you run an experiment, ensure that you have clear criteria and then you're able to make a decision at the end. We don't always end in that space, but that is our recipe for success. Absolutely. But my favorite program is one that we're still working on right now at Takeda. It's an orexin 2 receptor agonist program for type 1 narcolepsy but also for probably more than type 1 narcolepsy probably for a range of sleep-wake cycle disorders. And I say this because the science is driven by genetics. Type 1 narcolepsy is a genetically predisposed disease. The pathophysiology is so clear. The approach is very obvious. The way you get there is really difficult. And we've been working on this program since before I arrived at Takeda. So it's a program that's been ongoing for 15 years. I've been a part of the last 10 or 11. And when I came it was somewhat of a twinkle in the eye of our discovery colleagues and I got very interested in it because scientifically it was quite exciting. And the scientist in Japan who had started the program, it wasn't kind of on a big strategy slide. He was in his own lab working on it because he had a friend with type one narcolepsy. I see. And Merck had developed an orexin 2 receptor antagonist for sleep. And so now of course a centrally acting agonist is a bit more complex. And he had gotten one hit out of the screen. So there was no in silico approach at the time. It was all wet lab. And he got one hit which is absurd to start an optimization program on a hit and he did and we were able to bring it forward and it's actually we're now actually on our fourth molecule. So not uncommonly you have learnings and failures along the way. We had a very big safety issue with one of our oral molecules and now we're on our fourth molecule. We're in phase three. That study should read out in a few months and the phase 2 data looked transformative for these patients. So it's the combination of really extraordinary validation based on human genetics incredibly rigorous and difficult path through discovery and development. And then knock on wood I think it's going to work. We'll see in a few months the potential to fundamentally transform this disease for patients and you don't get too many of those in your career.

Yeah it's interesting that you point to the example where Gary presented. So as you know I came from the discovery world and for me the idea of following a molecule into the clinic and watching what could happen it's about learning. And one of my favorite programs is not necessarily one where there was a powerful result although Keytruda as you recall we were fortunate to be at Merck when the Keytruda moment happened and you know you just saw the power of that mechanism unfold and I remember a story of one of the patients who was almost at the last stage of his life came on the trial and ultimately ended up being cured. And had a license plate made for his car that was Keytruda. Wow. I mean, that's the power of someone who was writing wills and saying goodbye and being able to bring that person back to have a full and healthy life. Those are the amazing moments that inspire us to continue doing this despite the failures. But I will say that from a learning perspective, the trial that I was on, it was an asthma trial where we had seen beautiful PKPD. Everything looked as if it was going great and then in phase two the signal wasn't strong enough. Not only was the signal not strong enough when you looked at standard of care that was already available. It wasn't going to have the kind of impact that we wanted. So we ended up terminating the program. Now why is that important? Because it's easy to get very excited about the biology, the genetics, the PKPD correlations, but at the end of the day, it's all about that efficacy and the complexity of where our science then goes as it relates to patient population, marketplace, physicians, payers, and regulators. Even the most terrific science can get lost almost as it starts to transition through those real world situations. And so that was an interesting learning for me that even though we had an amazing package, it wasn't enough.

Absolutely. It's almost like your high change, low change, bringing those two people together. Absolutely. At least listening to each other. In this case, listening to the payer perspective, the patient perspective, the physician perspective as you're sort of working up these programs, I think can give you amazing insight. And I encourage also that on my teams that even though you're thinking about the molecule, you've got to think about the patient, the outcomes day. Yeah. If you can not start a program versus carry one forward for eight years only to stop it because you don't have a commercial path forward. I mean, think about that opportunity cost.

Do you have a favorite?

Yeah. So, it's such a good question. I haven't. It's almost like asking of your kids, do you have a favorite? Yeah. And maybe at any one moment you do. No, I think they all have their own special elements to them. I wouldn't say that I do. I mean Paris is it's a museum it's the most beautiful city in the world. The hard part of living in Paris in our business is Paris like a museum doesn't change. Right. And when I was at Sanofi, I used to bounce back and forth between Paris and Boston and Boston is just so dynamic and it's the epicenter of biotechnology and so that's so exciting. I don't have a favorite.

That's very interesting. I mean this is a global endeavor in a way right we work even if a company is based in one city biopharmaceutical research is really a global endeavor there's collaborations either on the biotech industry side or academia that's something I recall working with you at Merck we had a lot of collaborations even if you're not necessarily from a sort of diverse background in terms of where you've lived and worked. I think by default our industry sort of forces us to be in this sort of mode of working in a global sense.

I'm on the transform side of the spectrum. Okay. I think I don't think even the skeptics I don't live in their minds actually, so I don't know their level of skepticism. I sense they react to some of the extreme places that certain people go. And I agree with you that I don't ever see a time certainly not in our lifetimes but probably beyond where wet lab science and running clinical trials in human subjects is not going to be a fundamental part of what we do. But in both discovery and in development there's so many inefficiencies that are primed for advanced technologies to help us with. I mean just automation if you look at generative AI all of the document work that we have to do and all of the repetitive activities that we have to do if you just look at a clinical trial and you look at the dossier from the trial and the investigator brochure to the CSR and all of the documents that come out of those three. I mean that's your whole regulatory filing essentially. And if we could do more to automate that process it will help us with insights. But it will certainly speed up significantly and reduce the amount of cost it takes to generate. So that's just operational. I think there are massive changes operationally. And then of course discovery is more challenging because biology doesn't always follow logic and laws in the same way that physics does. But I still think that there's a and we've seen this play out. There's a huge opportunity to simplify discovery, reduce cycle times, and reduce costs. So, I think I'm in the transformative camp. And to me, it's just a question of how long, not if.

So, what about you as a person? Are there things that we don't know about you? Music, sports, things that motivate you beyond trying to cure disease.

So, I had a boss, Elliot Hoon at Sanofi and he gave a convocation address at MIT a number of years ago and his theme I think was a brilliant theme it was a 50/50 theme, 50% of life do A, 50% of life do Y and he talks about reading and learning and he said to make yourself the best that you can be in whatever job you're doing, 50% of your reading should be about that technical subject matter and 50% should be about everything else and you're able to then integrate different worlds with one another. Brilliant. And in this day and age where I feel like the next generation perhaps doesn't read as much, I worry about that because I love reading. In fact, I'm scolded often to get into bed because I want to read. I have to do it every single night. All sorts of things. To your point, I also love history. Unfortunately, I don't have as much time to read about history as I would like. I'm often reading papers about targets and diseases, but I feel as if the next generation perhaps isn't as immersed in that serendipitous learning that you get from reading. Do you agree with that?

You know, one question that you sent to me in advance of this podcast that you asked me to think about is is there one book or something that I've read or song that's been particularly meaningful to me. And I've thought a lot about it and I struggled with it because there's so many pieces. But there is one actually. It was an op-ed piece that was written by David Brooks maybe 12 or 13 years ago that I was combing through the New York Times and I landed on it and it was about I can't remember the name of it maybe it was about your eulogy CV. So there was your professional resume which is of course everything that you've done where you've gone to school the jobs you've had the accomplishments professionally. And then there was your eulogy CV, which is what people really remember. It's not so much what you've done, but how you've made them feel and how you've treated them and the person that you are. And I remember that so well because I read it and reread it. In the world that we live in today, there's so much happening because it talks so much about us as people and how important it is for us to be human and to treat people as humans. And I went back to it recently because in the world that we live in where there's just so much polarization that's not really reflecting who we are as people and the differences that exist across political parties across the world. They're not as great as they are made out to be. In the end, as people, we are much more similar than dissimilar. And I was reminded of that in this David Brooks piece. I really encourage you to go back and read it. It's incredibly inspiring. I am going to find it. I'll send it to you. Yes, please. And I think that's one of the things about travel and working in different places. We have an office in Hyderabad in India and when you go to these different places, you are reminded that we are much more similar than we are different. People tend to think about something they don't know or understand or haven't experienced as different and problematic. But actually there's so much beauty in the similarities and also the small differences that we have.

Thank you very much, Karen.