Barry Ticho - Part 3: Lessons on Drug Development & RNA's Transformative Potential

Intro - 00:00:01: Welcome to The Biotech Startups podcast by Excedr. Join us as we speak with first-time founders, serial entrepreneurs, and experienced investors about the challenges and triumphs of running a biotech startup from pre-seed to IPO with your host, Jon Chee. In our last episode, we spoke with Barry about his time at the University of Chicago, the My Choice program, and his fellowship at Boston Children's and Massachusetts General Hospital, where his zebrafish cardiac research uncovered the complexities of heart formation. Barry also shared lessons from his transition to biopharma, combining clinical care with research to create broader patient impact. If you missed it, be sure to go back and listen to part two. In part three, we continue our conversation with Barry as he reflects on his first industry role at Merck, sharing his insights on the rigorous standards of pharmaceutical research and contrasting them with the academic challenges he's faced. We'll also explore his time at Biogen, where patient-centered research reshaped his approach to medicine and his pivotal role at Moderna in developing the COVID-19 vaccine.

Jon - 00:01:22: Can you talk a little about that first industry experience and kind of how that was for you?

Barry - 00:01:28: Yeah, so once I made the decision that I wanted to... Go into drug development and we can talk a little bit about what does that mean. But then I asked around and I said, where is the best way to learn how to develop? Medicines. And almost uniformly, people at the time said, go to Merck, Merck and Company. That's the place where you really learn how to develop drugs. So that's how I ended up there. It required a sacrifice on my part because that was in Rahway, New Jersey. Which otherwise is only known for the fact that the state penitentiary is there. 

Jon - 00:02:04: Yeah.

Barry - 00:02:07: My family actually stayed in Massachusetts, and I was then commuting back and forth as the initial way to get into industry. And sometimes when you try something new, you really have to endure some discomfort to get in on the ground floor. And for me, to make a change like that and enter a new field. I just decided, well, I have to... I'm going to make this sacrifice. It means being with my family a little bit less for this period of time. But to me, the opportunity that I got out of... Being at Merck and being around all the scientists who... Really, many of them were best in their field. And that's how I truly learned the most rigorous way to make a new medicine. What's the best way to really put together the path to go from something that's still in the very early stages all the way to getting an approved drug? 

Jon - 00:03:07: I realized that the drug discovery process is incredibly complex and nuanced. And, but if you were to distill it down, like that kind of those core principles that, you know, maybe that you carry with you to this day that you learned at Merck, what would you distill it down to?

Barry - 00:03:26: What I realized when I made the switch to industry was that research in industry is actually much more rigorous and reproducible than what goes on in academia. The farm industry is one of the most regulated industries in the world, and everything has to be documented. There has to be a paper trail. And so many of the experiments that we did had to be run in multiple replicates. It's such a highly scrutinized industry that the rigor of the work that comes out of there is unlike others. You know, if you look at, I'm sure you're very familiar with the fact that the estimates are somewhere close to half of research that comes out of academia is not reproducible or even more. And even clinical trials, there was a recent study that showed that more than one quarter of clinical trials, the data are problematic or maybe not, or sometimes even completely made up, but certainly problematic. So even clinical trials that are run out of academia are not as rigorous. So that's the first thing that I learned is that industry actually has the highest quality of research that one can imagine. The other part was, that the lore sort of is, well, if you go into industry, you're sort of giving up your life. You don't have any choices anymore. And you're just doing what the man tells you to do. And I certainly did not find that to be the case at all. In fact, for me, being in industry just opened up so many doors and widened my knowledge base and my experience base so much. But the fact is also that in academia, the research choices are not limitless either. I mean... You're still at the mercy of a granting agency and you have to do the work that sometimes you have to do just to get a grant or just because that's what the granting agency tells you how to do. So I found that being in industry actually, for me, was quite liberating and quite expanding in terms of what I was able to learn and know. 

Jon - 00:05:38: Very cool. And I've never kind of had the ability to juxtapose those two. You know, and the stat is pretty staggering that most my wife used to work at a plus one at the academic journal. And I think a lot of the the reproducibility kind of chats were always just like, oh, my God, like some of these are just what a mess. And there's obviously the whole project to try and check all the previous studies to see like, does this stand the test of time and reproducibility? But it's also cool to hear that in industry you get that level of rigor and it makes a lot of sense. Like if you're going to create a medicine that's going to, you know, people are taking worldwide. You better make sure that this thing is airtight all the way from soup to nuts. So it makes a lot of sense.

Barry - 00:06:30: Exactly. And that's part of the process. You were asking about the process. The process of drug development itself... Really has four parts to it. There's the discovery part, then there's preclinical part, there's the clinical development part, and then there's the approval part. But as you said, the end product is a medicine that's going to go into people. And sometimes thousands, or in the cases we'll talk about at Moderna, billions of people. So the research and the evidence that came along the way to allow that to get into people has to be as close to airtight as possible, because you don't want to take people's lives to chance, and you don't want to take a chance that once a medicine gets approved and is being used, that there's something there that was wrong in the early stages that could have been prevented.

Jon - 00:07:25: Yeah, and it's kind of what you mentioned earlier is the ability to have massive impact, but impact can go both ways. Whereas you can have massive positive impact, we can also have massive negative impact. And people are trying to not have the latter. So it makes a lot of sense. And I know after Merck, you ended up at Biogen. Can you talk a little bit how that opportunity came about?

Barry - 00:07:51: Yeah, part of it was, that I had to choose between living in New Jersey and Boston. And my family said, we're not moving to New Jersey. So that sort of made the decision easy for me. 

Jon - 00:08:06: I had no decision here.

Barry - 00:08:07: But again, along the lines of... Being drawn to something, Biogen was just starting. To develop a cardiology portfolio. And they were looking for somebody with cardiology experience and pharma experience. And so I fit the bill perfectly there. So that was an opportunity for me to join in what turned out to be a very important company in my life.

Jon - 00:08:37: And I know you were heading up clinical development at Biogen. We talked about the phases of drug development, and this is kind of more in the latter part of the drug development process. Just a level set for everyone out there. Can you just set the table? What exactly goes into clinical development? And can you talk a little bit about that discipline for the listeners out there?

Barry - 00:09:05: Certainly. So what precedes clinical development is the discovery and the preclinical stages. And in the later preclinical stages, once a drug candidate has been identified that has all the right pharmacology and has proven some degree of efficacy in an animal model, then there is a series of toxicology studies that have to be done. But then it gets to the point where it's ready to file in the U.S., it's called an IND or clinical trial application in Europe, for instance. All of the supporting evidence that this that this medicine is, first of all, safe to test in people. Are there, but also some indication that there is a benefit to people to take this medicine. So once you have that established, then there are several phases of clinical testing, phase one, two, and three. Phase one tends to be, by nature, the very earliest stages, the first in human testing, where the most part there's a testing of safety. Is this medicine going to be tolerated in people? Are there any unexpected safety issues that arise that would prevent this from being a medicine that can be used in a larger number of people? Then phase two is where that medicine starts to get tested in patients and in a larger number of people overall. And there one is starting to look. Still looking for safety and to some degree looking at the distribution and the metabolism of the drug, but also some early hints for a clinical effect or a clinical benefit. And if we see that in phase two, and we have now out of phase two an idea of what's the right dose to administer to people and what's the right interval, and are there any safety issues that have to be monitored in the clinic, then we would go to phase three, which is a larger number of patients. And frequently those are controlled studies where there is either a placebo or some other control arm where the medicine is tested against. And there, there's a primary clinical endpoint that has to be proven statistically significantly different from the control group. And you have all that together, that's when one would file an application for approval. And that's sort of the goal of clinical development is to get a drug approved. Now that what's been changing a little bit in medicine, in clinical development right now is that in addition to getting approval, there also has to be access that's worked in there. So we've had to adapt our processes in the course of developing medicines to also develop a data set. That will convince payers to pay for this medicine. And that's now an increasingly important part of developing a medicine is not just to get the approval, but to get a better guarantee of access for patients through reimbursement from payers. 

Jon - 00:12:20: And I love that overview because I think it makes you realize that like getting something approved and now we're talking about access to it's like, it's like a miracle. It's like a, not just a little miracle. It's a massive miracle that it gets all the way through. And I can imagine, again, we talked about how heavily regulated it is. Like when you start dosing people, the stakes get really, really high. And. As you're kind of thinking about your experience at Biogen, maybe up to now, has clinical development gone easier? Has it gotten harder? Are there like, in your mind, any big bottlenecks that perhaps, not just you to solve, but like kind of like the healthcare life science, you know, community needs to solve in order to make this a more, I don't want, for me, I'm like, I wish the medicines, like impactful medicines weren't a miracle. I wish we could actually have this more kind of prevalent. But is there anything that's like, really, you think when you think about clinical development, that's really, we need to solve in order to kind of have that unlock? 

Barry - 00:13:23: Yeah, I'd say overall, it has gotten more difficult to get medicines approved and used. I mean, we still, the core is still determining the benefit risk and making sure that the benefit of the medicine outweighs the risk. But how we get there in the end has gotten more difficult for a variety of reasons. First of all, overall. Biology is complex. And the more we learn about biology, the more we learn how complex it is. So it's not so much that the complexity of biology is changing, but we're also understanding more about what it is that we want to make a medicine do. And as we learn more about the complexities of biology, we have more demands on what that medicine can do. And we're also trying to tailor the treatments more. We're trying to make much more, this term that you may hear about, precision medicine, making the right drug for the right person. And that requires a... Certainly a much more challenging way to develop medicines because that individualized approach requires understanding what makes the medicine the right medicine for a person, but also what are all the different aspects of a person that have to be taken into account when we're trying to make a medicine just for that person. And all of that has sort of made clinical trials more complex in general. There are more endpoints that we're trying to assess. There are more ways that we're trying to figure out, is this the right medicine for that patient? So that complexity definitely adds to the challenges of making medicine. And then we also have regulatory issues. And for the most part, the regulatory agencies, they have an important job. They have to make sure that medicines are safe and that they're effective. And I still see them as collaborators. It's an important way to approach working with regulatory agencies, is to see them as partners rather than adversaries. But despite that, there are still more and more complex rules that get established that have to be followed in order to get a medicine approved. As an aside, there are also intellectual property issues, which we don't have to get into. But the amount of information that we have and the number of patents that are being filed is... Make it more and more difficult for companies to have property or intellectual property that they can maintain as their own. So that also makes it more difficult to develop new medicines. And unfortunately, the failure rate of clinical trials has not gotten any better. The fact of the matter is still that when we take a medicine that's starting in the clinic, first phase one that we were talking about, there's still only a 10% chance that that medicine, starting in humans, is actually going to end up to be an approved drug. So that's a 90% failure rate, which is still high, quite high. And all that adds up to the fact that it's taking longer and costing more. So the average drug can still take 10 years. Over a billion dollars to get approved. And that hasn't changed. In fact, it's even gotten a little bit longer. So all in all, things have gotten more difficult, I have to say. 

Jon - 00:16:52: Yeah, yeah, yeah. And it sounds like there's a lot of work to be done. There's a lot of work to be done. And I'm going to imagine, as you said, it's not that biology has gotten more complex, but it almost feels like the kind of low-hanging fruit has been picked. And now we're going to like harder and harder problems that are more complex than the previous ones. Like the mechanism of action is like not as clear as like the other, you know, earlier kind of approvals and drugs out on the market. So, and then, you know, we don't need to solve this issue immediately, but I think it's probably something that we eventually do need to solve. And, you know, while at Biogen, can you talk a little bit about just like, were there any mentors that took you under their wing that kind of helped you cut your teeth in clinical development and learn all of this? 

Barry - 00:17:44: I'll start by saying that what Biogen does so well is to really focus on the patient. And that's something that I learned as an everlasting lesson there is to make sure that whatever we're working on, it's to do something that will benefit patients and always keep the patients in mind. And that's something that I've continued to hold dear as I continue my career. And even now, part of what my job really is, is to maintain that focus on the patient. First, to make sure that patient safety is being maintained, but also that we talk to patients and find out what's important to them as part of their disease. What do they want to have a change? And that's something that's definitely changed in the industry, is to bring in much more of that patient input to the point right now where when we develop a new medicine, we talk to patients and say, what would be the ideal medicine for your disease? And then when we develop a clinical trial, we tell them this is what we're planning to do. What do you think about that? What possibly should we change? What are we missing here? So that focus on the patients is something that I really learned initially at Biogen. But Biogen is also very much a data-driven company. So the decisions that were made there... In terms of how to develop a drug and where to put resources were primarily made based on what do the patient data, what do the data from our labs and from our clinical trials tell us. And it was less about how can we make money off of this or how can we sell this. It was more, what is the science telling us about how we should proceed here? And then the other thing that Biogen focused on quite a bit were severe diseases. So it was a company that developed medicines for multiple sclerosis, developed medicines for Alzheimer's disease, really focused even now on diseases like ALS. The focus there was, and this is also part of what I have as a philosophy, as you were just saying, it takes a lot to make a medicine. There's so much time and effort that goes in. If we're going to put all that time and effort into something, let's do it something that has a big impact. And that's almost a philosophy you can have throughout life, not just in medicine, but in almost any aspect. If you're going to put the effort into something... It might as well be something that's going to be impactful. And Biogen really did that in terms of the diseases they selected and how much... A medicine in that disease could change the entire course of a patient's life. 

Jon - 00:20:48: That's amazing. And those are like some really, really important pillars. I think I can, I can see it's just like, well, exactly. You're right. You're like one, let's not settle for incrementalism here. Like it's kind of just like, especially if you're just putting so much blood, sweat and tears into something, just like, yeah, we're just like, you know, we're just going to hit a single here. Like, let's not do that. That's going to be a monumental waste of time and everyone's effort. So I love is just like, if we're going to, if we're going to put so much work into this swing for the fences and actually try to get a massive, like have massive impact. And I love hearing that. And I also, love the having the patient input. It reminds me, you know, outside of just the life sciences, when, you know, people are, let's say a software company is trying to design a product, but they never actually talk to the end user. And then they launch the product and there's like, this market doesn't even exist.

Barry - 00:21:46: A big thud.

Jon - 00:21:47: Yeah, a big thud. You're just like... Well, we just like we're in, you know, we were just in kind of like the dungeon here, like toiling away on something that we probably would have behooved us to have this conversation. I love how. In that process of drug development, you're looping in the patients. Like, I love just like, so what would you want? Like, tell us, like, cause that is what we're shooting for here. But I love how close the, that feedback loop is. And, you know, I can imagine you, you get really, really great feedback when they're like, oh, they're trying to, you know, kind of customize this to me. And, you know, as you were wrapping up your time at Biogen and you, it sounds like you learned an incredible amount. When did you know it was time to leave and move on to your next role? 

Barry - 00:22:35: Part of it was I had a great opportunity to work on very wonderful drugs there, including Tysabri, which is probably still the best medicine for multiple sclerosis. And also I had the opportunity to start to do some of the early work on Alzheimer's, which now, as you know, has come out of Biogen with several new medicines for the treatment of Alzheimer's. But it had taken me away from the cardiovascular focus. So after 13 years at Biogen and many great learnings there and great colleagues that I'd worked with, I decided that I wanted to do a little bit more back in the cardiovascular space and knew that Pfizer was one of the, it certainly has always been and continues to be one of the leading companies working on cardiovascular treatment. So I decided, to me, it was almost a little bit of a sabbatical and actually work more on the business development side, actually. So I joined the cardiovascular metabolic research unit, but in the group that was doing search and evaluation for new outside opportunities to bring into the pipeline. To Pfizer. And I was fortunate to work with the internal colleagues there. To help, they would tell me what they were looking for and I would go out and find it, especially focused on treatments for heart failure, for obesity. For what was then called NASH is now called MASH, which was also part of the cardiovascular metabolic. Portfolio that Pfizer was working on. And there... Brought in 11 new programs into Pfizer there, and I learned a tremendous amount. One of the things that I came out of my experience with Pfizer, I looked at probably a thousand, if I added it up, a thousand different drug programs overall. And I developed my own sort of internal algorithm for how to evaluate. Drug program, but this also works for how to develop a new company that you might be thinking about going to. And I called it FITT. Is it a good fit? F-I-T-T. The F was, when you're looking at a new company is, and we looked at Pfizer, we looked at a lot of companies as potential acquisitions. The F is the finances. The I is the IP. The first T is the team. And the... And the fourth letter, the T, is the technology. So those all have to be in place in order for a company to be a place that one would want to work at or potentially acquire. But then out of my work at Pfizer, that's where I developed an interest in RNA as a medicine. Part of it came out of a collaboration that I started with a company called Wave Biosciences. Which was working on RNA treatments. And that taught me a little bit about this whole field of RNA. And it was ironic because if you remember, I started way, way back even when I was in college. Already starting to work on RNA. And my graduate work was on RNA polymerase. And my postdoc in zebrafish was on transcriptional regulation, and cardiac development. So I had this thread of RNA. And I'd be lying to you if I said, well, when I started in college, I knew that I was going to focus on RNA my whole life.

Jon - 00:26:33: Yeah, yeah, yeah.

Barry - 00:26:35: But it just sort of all came together. My background in RNA from a molecular biology and scientific perspective. And my realization that there's this little niche right now that RNA medicine has started to fill. That is definitely growing based on few new technologies that are coming, antisense technologies and RNA editing and splicing modulation, all of which we can talk about. But that's where I started to see that there was this untapped resource of RNA as a medicine coming. And that's what actually got me to Moderna next. And, you know, Stéphane Bancel. Recruited me into the company to run the cardiovascular metabolic. And rare disease clinical development there. But that was all based on the fact that I had a sense already that RNA in medicine had tremendous potential.

Jon - 00:27:35: It almost feels like a homecoming.

Barry - 00:27:38: You could put it that way, exactly. 

Jon - 00:27:40: Yeah, it feels almost like a homecoming. And I'm thinking about the previous experiences at Pfizer, Merck, and Biogen, larger companies, I would imagine, than Moderna. Was this kind of where the startup bug, the spark for entrepreneurship and startup energy came from? 

Barry - 00:27:59: Very much so. I'd say that... My experience at the larger pharma was the resources there are great and there were, for the most part, very great experiences there, but they are slow-moving machines. That's part of what I learned. Is that in a company those sizes, even a single person can slow things down. And there are so many people there, many of them are very bright and are just trying to do their job. But a single person can slow up the works. And so decision making is quite... Quite slow there. And what attracted me to the smaller companies was the fact that, you know, I could, I'm sitting in the chair next to the CEO of the company, I can turn and say, should we do this? And he or in other cases, it would be a she would say, yes, we should do that. And off we were. And there wasn't a requirement to go through five or six committees for decision making before we could get an answer on something.

Jon - 00:29:04: I think about like larger organizations. Where you kind of it just becomes kind of almost like politicking. You have to like socialize a lot of ideas with like many, many different stakeholders. And I could just imagine how slow that just slows everything down. And it must've been a breath of fresh air to just be able to be like. Sound good to you? Sounds good to me. Let's go kick this off. So can you talk a little bit more about, you know, the initiatives you kicked off at, you know, Moderna and just kind of overall how that experience was for you and what were some key takeaways?

Barry - 00:29:41: Well, part of what I learned was big thinking. And this comes from Stéphane. It comes from... Flagship is, and it's along the lines of what we were saying before, if you're going to do it, go big, go big or go home. And that certainly was the philosophy at Moderna is that we can take messenger RNA and use it for many, many, many diseases. And that was a message that was inculcated from the top and was present in all the mission statements and thinking that went on at almost every level in the company. It did give me the opportunity to work on the lipid nanoparticle that ended up being the basis for the vaccine, the COVID vaccine. So that was a great opportunity. And those learnings with the lipid nanoparticle helped me when I was starting a new company called Verve, which we can talk about. The other things that I learned is that... Sometimes technology is not always. Fit for purpose. And you have to realize that. And so for some of the diseases that we were trying to treat, the lipid nanoparticle mRNA combination... Had some challenges in terms of its ability to be used, especially chronically. And so the learning there was to know when to pivot or to make a change. So for me, I came away from Moderna with... With great respect for mRNA and its potential as well, but also realizing some of the potential. Drawbacks to using that approach.

Jon - 00:31:27: I was going to say, I love those lessons, mostly because I'm like in my head, I'm like, yeah, like I need to like continue to like remind myself of that because I can sometimes get wedded to ideas. And exactly, we said, we put all this work in. It's kind of that sunk cost fallacy. 

Barry - 00:31:41: Exactly.

Jon - 00:31:42: Where you're like, but sometimes you got to be like, it's not working. Like it's, and that's okay. And we should probably just like reallocate the resources to another kind of experiment bet where it actually is fit for purpose and not just like feeling so wedded and just like stuck to this thing. It's like, well, we have to see it through. That's kind of the crux of the sunk cost fallacy. You're just like, oh, I put so much into this. So I have to, but didn't mean to interrupt you.

Barry - 00:32:09: No, that's exactly part of the point was that Moderna was able to pivot. They happened to be in exactly the right time with the exact right technology. But there also has to be the mindset to go on to take on what was then a Herculean effort to develop the vaccines that everyone knows, the impact that those had. But the important lesson there is having that agility and being able to pivot. And not having sort of what sometimes gets called the ossification of ideas where they're just set in bone or set in stone and you can't turn. So that agility is a very important skill to have. Throughout life, but certainly in our industry, you have to have that agility and the ability. That agility, it comes from in many different ways. First of all, you have to be ready for change, but To be able to be ready to make that change, whether it's an individual or a company, there are a few things that have to be in place. First of all, you have to have some degree of financial stability. And as an individual, it means you do have to save your money or use your money wisely. As a company, you do as well. You have to have that sort of rainy day money or at least know to keep some money aside if you want to make a change to have that available and not spend all your money in another area. And just on an individual level, I found that for me, agility also means staying healthy and having the right mindset. And part of that requires being fit and eating well. But you mentioned sleep before, but sleep is such an important part of staying healthy. And sometimes we glorify people who say, well, I only need two hours of sleep. But that's not really the right way to function. We know, as humans, we require a certain amount of sleep in seven to eight hours is probably what we need. But I'm getting way off on a tangent. 

Jon - 00:34:21: That's spot on. Spot on.

Barry - 00:34:24: Trying to make sure that you stay agile means that you have to have certain practices in place.

Jon - 00:34:30: Yeah. And I think what I'm hearing here, and I agree, is like the importance of like resilience, whether it be your health or the financial well-being. And just like kind of burning the candle at both ends is not resilience. It doesn't afford you the ability to make that pivot. And I think the one thing I would add to it, too, and I see it a lot in during like in academia, but it's also in business, too. It's like sometimes the pivot can be held up by like pride and ego, where it's like, this is my baby. Like, I can't be wrong. And sometimes you have to swallow your pride and be like and just be okay. I'm wrong. And kind of letting go that quickly enables us to freeze everyone up to just be able to make that quick agility. That's the part of it. And so you were able to learn these critical startup lessons at Moderna.

Outro - 00:35:34: That's all for this episode of The Biotech Startups podcast. We hope you enjoyed our discussion with Barry Ticho. Tune into part four of our conversation to learn more about his journey. If you enjoyed this episode, please subscribe, leave us a review and share it with your friends. Thanks for listening and we look forward to having you join us again on The Biotech Startups podcast for part four of Barry's story. The Biotech Startups podcast is produced by Excedr. Don't want to miss an episode? Search for The Biotech Startups podcast wherever you get your podcasts and click subscribe. Excedr provides research labs with equipment leases on founder-friendly terms to support paths to exceptional outcomes. To learn more, visit our website, www.excedr.com. On behalf of the team here at Excedr, thanks for listening. The Biotech Startups podcast provides general insights into the life science sector through the experiences of its guests. The use of information on this podcast or materials linked from the podcast is at the user's own risk. The views expressed by the participants are their own and are not the views of Excedr or sponsors. No reference to any product, service or company in the podcast is an endorsement by Excedr or its guests.