Constantine Theodoropulos: Founder and CEO of Go Therapeutics

May. 16, 2020 Season: 2 Duration: 40:45 Episode: 6

I'm not afraid of the gray area or the darkness that surrounds a few inches in front of your face, which is really what this business is all about." – Constantine Theodorpulos, Founder and CEO of Go Therapeutics

Constantine Theodoropulos: 0:05

I'm not afraid of the gray area or the darkness that's around a few inches in front of your face, which is really what this business is all about.

John Simboli: 0:12

That's the voice of Constantine Theodoropulos, founder and CEO of Cambridge, Massachusetts based Go Therapeutics. Listen in now to hear my conversation with Constantine about leadership in biopharma and his work to develop tumor-specific cancer drug candidates. I'm John Simboli. You're listening to BioBoss. Today. I'm in Cambridge with Constantine Theodoropulos, CEO and co-founder of Go Therapeutics. Constantine. How'd you find yourself here at Go Therapeutics?

Constantine Theodoropulos: 0:44

Well, first of all, good to see you John. It's always an interesting question. So like everything in my life, there was never really a point A to point B type of road traveled. I've been in the life science industry for quite a while , working with all stripe of company from diagnostics to reagents to therapeutic development organizations. Some years ago, maybe seven years on now , I was working to develop a diagnostic test for Lyme disease, which is obviously a big problem in the Northeast, as you're well aware. And so the idea there was to really develop a diagnostic that would be a really rapid test and be able to diagnose the type of infection that a person has that is from a tick-borne vector. And it's through that work that I came across this, what happened to end up being, my cofounders and the company who were researchers in glycobiology. And it was through that interaction that it became apparent to me that there was real substance to the science that suggested that it could really solve a couple of problems that are of extreme importance now in cancer therapies. Which is nothing new, and that is really toxicity. So if you can imagine in cancer therapy,, even today, you got to essentially kill the patient to cure them. And the toxicities involved with chemotherapy, the side effects of radiation. We're all really aware of what they do to a person. And now treating them with all manner of small molecule, large molecule drugs have the same issues. They're really off target toxicities that can cause very severe complications and sometimes death. So it became very apparent through my interactions with with my my partners that O-glycans, or in this case truncated sugars, to put it in a different way, that reside on the cell surface are very cancer specific. And it really was this idea around if you can take advantage of that knowledge, which has been an established fact for 30-40 years in academic literature. If you could take advantage of that and harness it in a therapeutic sense, you could really then make a dent in the toxicity issue for cancer therapies. And that was really the idea at its base, is how can we take advantage of that. And so we put together Go Therapeutics to really leverage the strong understanding around O-glycans and then build a tool set that would be able to, to work with them and really understand where they are in the cell surface. But then more importantly, how to develop an antibody against them. An antibody that would have the required characteristics to be a therapeutic downstream. So, would it be specific, recognize this O-glycan g lycoprotein. So I have to be clear here, we're really targeting a short glycan in association with the protein. So it's a really an epitope that i s mixed. But really working out how heterogeneity plays a part here. Are these really viable as targets therapeutically? Can you develop an antibody against them that would give you a real selective means of targeting or arming an antibody or u se i t as a way to recruit the immune system to kill a tumor. So these things need to be worked out. And so we spent the first years really doing that part. And so over the past five years, five to seven years, frankly, we built this platform that allows us on one end to really understand where these O-glycans are on a given protein, develop an antibody against—an antibody that would have low affinity, is very selective as to that epitope. And then thirdly, d evelop that antibody into a therapeutic so that it could deliver a drug or it can recruit T -cell into killing the tumor i n which these, these O-glycans reside. And so that's really what we're, we've been working on.

John Simboli: 6:02

Do you remember in those early moments when you became aware of some of the ideas in conversation with your co founders? Can you recall it as being either—I've heard this both ways from CEOs and foundersI've worked with—some say, I had to think about it. I was looking for something. I had to weigh a bunch of them that were similar and then others have said this thing, right away. I knew this was the thing I wanted to explore. Does it fall in either of those categories for you?

Constantine Theodoropulos: 6:27

Yeah, great question. By the way, I've always wanted to have the same thought with other entrepreneurs. Is it "aha" moment or does it just osmosis that come to you? In this case, it really was a profound for me simply because I had been working with a variety of companies and I recall going for years, now to different conferences in both oncology related conferences but more general biotech conferences. And you know, in every oncology panel, I mean, the problem is the problem—no targets And with the advent of some of these really exciting , modalities in cancers such as CAR-T or even ADCs, antibody drug conjugates, or T-cell bi-specifics, , they offer such great promise. But they're severely limited by two things.

: 7:23

One, are are they going to be efficacious? Will they hit this target number one? And if you do, to what extent is that target exhibited or expressed on unhealthy cells, which will then lead to off target effects. And that's really the big problem. So at every meeting it became clear as day what, to me, was a big roadblock to really being able to push this field forward to take advantage of targeted therapies or even immunotherapies and the combination thereof. And so when I came across what ended up becoming Go Therapeutics, it hit me like a bolt of lightning. It's like, well, if these really are specific to a cancer cell and the data suggests , or at least some experiments had suggested you can develop an antibody to it, that would be very selective to that antigen, then the rest is engineering., Then this is worthwhile. This could open up a whole new biology for cancer therapies. So for me it was really like you see in a TV movie, like POW, there it is, I'm doing that! And so, yeah, I mean for me it was a Eureka moment.

John Simboli: 8:49

I sounds like you had explored the territory enough that it must have occurred to you that, "I could take this idea and I could explore this with an existing biopharma company that would have some of the infrastructure built in, or I can do it the hard way and I can build something from scratch." How did you work through that?

Constantine Theodoropulos: 9:11

Also a good question. It's really combination of both. I think, at the beginning you just have to assume it's going to be the hard slog. You just have to go into it. It's going to be a long, hard campaign. It's going to be a constant battle. Every day is going to be a slog. You just have to go in with that mindset. At the same point in time, our initial strategy, which I'm happy to say worked, was that we really need to work with a big pharma here to really accelerate the translation of the science. And by virtue of doing that, we will both be able to validate what we're doing at a large scale, but also in terms of the company, but simultaneously really be able to advance the science in a far quicker capacity than if we were just to continue to take one step forward, two steps back as a small company. So we took that strategy and we ended up having a deal with with Roche around the development of a T-cell bi-specific that took advantage of one of our first antibodies that we made into to a target. I'm happy to say that it's progressing quite nicely. But moving forward, I think as a small company you have to take advantage of the need within the marketplace, within the big companies. And if there is a synergy on that level, you have to take advantage of it. And for us it was really a key strategic stepping stone, being able to bite off more and more of the development process, which is what we're doing now. So as we sit today, rather than rely wholly on a partner to take on the burden of developing what we produce, i.e these antibodies that are very specific to these cancer-specific epitopes, we are actually developing them ourselves in the context of a CAR-T, to really generate some functional data, in v ivo data, and ultimately take it to a patient. It has occurred to us, at least, that in order to really drive the science to where we ultimately want to take it, which is to get it to a patient, we have to take on more of that process, more o f that development process. Because after all, nobody cares about it as much as we do. And although our pharma partner h as been great, , and we hope to do more with them, at the end of the day we have to be responsible for moving iit ourselves.

John Simboli: 11:58

What were you hoping to achieve that you could do here, that you said yourself, I can't do this any other place?

Constantine Theodoropulos: 12:05

Well, for me it wasn't necessarily that kind of option. It wasn't, I can't do it here. I can do it here. It was, there was no choice, frankly. Because it's a new area of science, at least as far as the application in cancer is concerned, I think it comes with a lot of risks, inherent risks from a business standpoint, obviously. So you can't do it at another place really. You really have to build a team around the idea that is really there to de-risk, scientifically, the premise and surround yourselves with a small team of experts and t he capabilities to be able to weed those out. But it also comes with having financial partners that are also willing to accommodate that level of risk. And that rules out a big swath of potential places where you could do it. So it's a natural fit, to actually start a small company around doing it. So for us it really wasn't even an option. We just said, this is the way we have to do it. This is the only way we're going to be able to really translate this in a way it will be done right. Because nobody knows the science like we do. Obviously, that's why we exist.

John Simboli: 13:32

Can you remember when you were a kid, what your image of, when I grow up, this is what I'm going to be?

Constantine Theodoropulos: 13:37

So I know people who've actually had real clear vision of what it is that they want to do at an early age, really wanted to be. I really have to confess, I had no such clarity as a child. I think when a lot of people my age—professional baseball player, something like that. But it became clearer as you go down the line, what your personality is fit for, how you work, the people who you like to work with, the kinds of situations where you tend to thrive. And, for me, those things got worked out over a relatively long career as a consultant and working in some companies. There's no easy way, but you learn to put yourself in the context where you can deliver the most value, so to speak, and for me it became really clear that it's in a startup environment, it's where you really are flying blind a lot of the time. Some people really don't like that. I don't seem to have a problem with that. But it's not for everybody, but for me it really works. I really enjoy it. And I like discovering things and I like problem solving and I'm not really all that deterred from, from the lack of a real safety net. I'm not the most introspective person, but my wife always tells me that, she just says, look, you're, you're just not built for that. And I've been around people who just saying, wow, you should, you should do that because that's way risky. Like, you didn't have a problem with that. I'm not afraid of the gray area or the darkness that's around a few inches in front of your face, which is really what this business is all about. I have to tell you that this biotech business is really not for the faint of heart because failures happen all the time. The successes are far too few. It's always several steps forward, many steps back on a daily basis And you're really working in a realm that, at the end of the day, we just don't know a lot about. Information, learning more and more every day. But it's still a big mystery, especially in oncology. So you just have to be really aware of that kind of environment. And it's really not for everyone. This is an industry where time really is the key factor. Right now in the age that we're in, in biotech and even from our small vantage point, we're really working on engineering problems. The basic science around our biology, you know, we're working it out, we're learning. I think we got a lot of it figured out, there's still big gaps, but nonetheless. Now translating that into therapeutics is really an engineering problem. And engineering just takes time and smart people and money.

John Simboli: 16:56

Lots of opportunities to find what doesn't work?

Constantine Theodoropulos: 17:01

Correct. So that's really it. So it's really time and you just need to be around. You have to ensure that you're going to be around in the timeframe it's going to take for you to really get to the end, which is a therapeutic that's going to help somebody. And that's a long timeframe It's going to take a lot of money for sure. But thankfully we live in an environment now where those things are available. The risk capital is there, the networks are there to help you along. It's not like it was 20 years ago, even10 years ago. I mean, it's really kind of an interesting landscape now.

John Simboli: 17:40

Because you're operating on these many different levels, with many different skills and all happening simultaneously, I imagine from time to time, people that you don't know approach you—family, friends, whatever, and say, what do you do? And that's probably not an easy thing to answer, but how do you answer that?

Constantine Theodoropulos: 18:00

Well, I certainly don't talk to them about glyco biology, that's for sure. So simply, we're really into targeted therapeutics. We're trying to develop a new class of oncology therapeutics So therapeutics that will exclusively target the tumor, be able to kill the tumor without killing the rest of you, in the process. That's really what we're trying to achieve here. And our biology that we're exploiting gives us a chance to do that. We're working that out now. But the data suggests that it's not a pipe dream, that in fact, we can do this. And the rest is engineering.

John Simboli: 18:51

How about a little kid, extended family, someone who doesn't really know you've been , knows your family, says, well, what do you, do? You personally, you could say, I'm a big shot, I'm a CEO, but how would you answer something like that?

Constantine Theodoropulos: 19:02

I tell them I work with really smart people who are really trying to develop new medicines. That's really what I do. And frankly that is my job. I mean, it's really my job in this current context to be of service. I'm not the guy at the bench. I'm not the CSO. I don't have the bright ideas around how to make the science work. But I'm there to help put it all together. I'm there to make sure they have everything they need to perform and really be of service to the ultimate mission. And that's really the way I view myself now. But at the end of the day, I would tell somebody, a young person w ho asks me now that I h appen to be working with some of the most incredibly smart people on the face of the planet, working on the most fascinating and most interesting topic in the world, which is solving some very deadly diseases.

John Simboli: 20:07

And with the potential to help people in the most profound way. In setting, what have you learned about your management style that works best? It may be similar to what worked before, maybe different.

Constantine Theodoropulos: 20:20

So number one, I think given the type of company we are, the size of the company or the problems we're truly trying to solve and figure out that you really have to create an a really safe environment. But you also have to give a lot of power over. You have to really empower the heck out of everybody who's there from the most junior person to the most experienced. I really to reinforce the fact that we're all essentially equals here. We cannot achieve what we're trying to achieve in a top down hierarchical organization. As obscene as that is for a company that is under 10 people. But I've seen that before. I think here it really is a jazz ensemble that everybody has a big contribution to make no matter how big or small because that's the only way we're going to really move this forward. I mean this is not insurmountable and it's going to take a huge effort from a lot of people with a lot of diverse skills and we're going to need all of it. And so, I really try to create an environment whereby people feel, A, safe in what they're doing, to take risks, be able to self manage, do the things that they think need to get done, within reason, obviously, and really problem solve, which obviously takes the mindset of taking risks to some degree but also also requires some level of confidence in what you're doing. And ultimately, if you're working with us, we have confidence in you, so do it. The companies that I've seen and I've worked in that have been able to really do great things on a small scale, even large scale, is create an environment where they're essentially working for each other. And I think it's tough to create. You have to really care about their coworker, have a relationship there and, I think that's really what you have to try to encourage and create.

John Simboli: 22:45

Companies that when they're getting started are often five or 10 or 12 people. And I was thinking how, I remember reading about someone who said that the reason that platoon is 12 men or women is that if it's any bigger you don't have that same cohesion where the person cares deeply about the person next to him.

Constantine Theodoropulos: 23:02

I think there's probably a ton of truth in that. I mean, it's no secret that's what every company is trying to do, however large, they're trying to break it down to smaller and smaller functional groups. And that's just the way human nature is. But that's also the way you advance problems. Especially when you start out with big ones, you just need a really tight team that is going to put a lot of effort in and it's going to require a lot of trust in one another to go ahead and take the risks that you need to take along the way to solve it. I think that's ultimately what it's about. You try to create an environment where you can encourage that and sustain it.and hope you never lose it. But at the same point in time, it also has to be open to evolution because the problems change. Therefore, the people need to change and their skill set needs to change. It's part of the way it goes. And I find myself having to remind the people that work at Go of what we're in this for. You get so focused on a particular thing that you lose sight of what the end goal is. I try to make reminders. , I don't encourage it, but I do suggest visiting an oncology ward, if you can. You want to see what we're in this for? Go there. I've been there and when you're there, you really get it. That this is not about a small thing, that the mission here is worthwhile but certainly worth the sacrifices you're making along the way.

John Simboli: 24:57

It must be really a test to be in the moment. So focused on the details and yet have that perspective to keep reminding yourself these details add up to something potentially life- changing.

Constantine Theodoropulos: 25:10

But it's around you. You just have to open your eyes. You can see it. So it's a tough thing to do. It's my personal belief that in this industry, as I said , it's possible to lose that connection. And I think it's always worth that reminder.

John Simboli: 25:35

I think that the bigger that the bigger the entity, the bigger that is.

Constantine Theodoropulos: 25:39

It becomes very abstract. So what we're working on becomes extraordinarily abstract. In our case it's going to be in a vial. And you lose the connection, where that goes, where it ends up and what it's going to do. For a lot of people, I mean that's not for everybody, but certainly, especially for a preclinical organization that's not working with patients yet or testing in patients, then it's definitely worth that kind of a reminder. And somehow our society does a really good job of masking it. Like you just don't see it. It's remarkable. You just don't see it.

John Simboli: 26:22

Constantine, what's new at Go Therapeutics?

Constantine Theodoropulos: 26:26

A lot of very interesting things. So the most exciting thing that I think that we're doing now is developing CAR-Ts from our antibodies. And so we are now engaged in animal studies to evaluate the efficacy and obviously toxicity. That is very exciting for us. But that's of course layers on top of what I'm most impressed by and most excited about is the fact that we're able to, on a consistent basis, generate quality antibodies to these novel cancer-specific epitopes. So I think we really cracked the nut there. That was the big problem, certainly in this field. But now we are consistently developing high affinity quality antibodies that are selective t o epitopes that are very specific to tumors and that really opens up the doors to a lot of potential. So w e a re now translating some of these antibodies in the context of a CAR-T to further demonstrate how they w ould work as a therapeutic. And then I believe w e'll probably advance one or two of those ourselves downstream into the clinic.

John Simboli: 28:00

When you have the opportunity to tell the Go Therapeutic story, sometimes in very tight little windows of 15 minutes perhaps to investors, and you get done you think, I've made it pretty clear and then they come up afterwards over coffee. Some will say, here's what I heard and you'll say, great, I made it clear. Others will say, here's what I heard. You'll think , no , that's not what I intended. When that happens, when you get the "that's not what I intended," what are the misunderstandings people tend to have? And then how do you go about helping with that?

Constantine Theodoropulos: 28:28

What they do ask or what they may misinterpret is that we are not a CAR-T company. We're not a cell therapy company. We are not an ADC company. What we are is really a platform company that is able to produce antibodies to these novel class of antigens, which then allows either a partner or ourselves to have the option of developing them into multiple different modalities. Not to say that we would do multiple modalities, but it gives you the option because what we have delivered, what we've created, allows you to do that. It really gives you a cancer-specific antibody that will give you a nice therapeutic window for you to really address in the context of a variety of different modalities. We happen to produce CAR-Ts around them, but really there's nothing stopping a partner or ourselves to doing it as a T-cell, bi-specific or an ADC . Those are engineering problems because the technologies are there. But, really, I think it's that clarity we constantly have get across. Everybody's got an opinion about "platform company.", We're really proud to be a platform company because it allows us to routinely develop assets. So we're not a one and done company and a lot of companies are.

John Simboli: 29:57

So when you give that explanation, which makes sense to me, although I'm not an investor. Do some of those folks who weren't following it , saying , Oh, I get it or to, so do they just filter it out and say, Oh, I'm not interested in a platform company.

Constantine Theodoropulos: 30:11

Sometimes that happens, sometimes they just don't want to do a platform company. But I think t hen when t hey understand really what we're presenting here, it is not necessarily the platform company, which they might be thinking about. So we're definitely a company that's focused on assets, but we also have a platform able to produce those assets. So replenish our pipeline. We don't have to go out and scour the earth for new assets to develop. But here we really have a way to rationally go ahead and develop these targets. We've been really successful in doing that with, now, seven, So we'll keep adding to it, mostly for IP reasons, but it really gives the opportunity to address multiple different cancers in multiple different ways.

John Simboli: 31:02

What kind of partners are a good fit to Go Therapeutics?

Constantine Theodoropulos: 31:05

I'm a firm believer in partnerships. I think in the business that we're in, the problems we're solving, it really does—the vernacular, it really does take a village, I mean you have to do it in partnership with multiple different partners. Just due to sophistication, the level of complexity and what's required to get from idea to drug, to patient, to market. It's just a huge undertaking. So with that said, the partnerships that we find valuable and that we look for, have tried to develop and have developed, are certainly with academic institutions where that science is continually being worked out. So we have that Large pharma comes in very handy. Because they really know how to develop drugs. They can actually develop a drug and more importantly, they know how to get into the clinic and move it through and then ultimately market it. So obviously I think for any company in our shoes, having a strategic pharma partnership is a huge help. Thirdly for our case, there is a whole constellation of smaller companies that you really need to work with. For our case, for example, we have three different partnerships around antibody development. So the type of antibody that you want , what kind of system you want to use to generate antibody . So, we've got a variety of partnerships around just the building blocks to getting to where we need to go on a scientific basis. And then of course, we have downstream implications as well. So, we work with a variety of companies that are thinking through now with us how to advance the company down to a clinical pathway. And that's also buttressed by partnerships which we are also looking into around the different types of modalities. So for example, if we wanted to develop a T-cell bi-specific, there are a number of companies that have really great platforms for that. And so we would look to partner with them. Similarly if we have a target which is really suitable for antibody drug conjugate, we would similarly look to partner with that type of company that has that focus. So in a nutshell, partnerships are just key. I mean, as a small company they n eed to be core to your business.

John Simboli: 33:48

So to keep your channels of communication open with so many things in ferment around here, Cambridge, what organizations can you tap into and then tap back out of and get involved with and not get involved with what, how do you share your ideas? How do you get new ones ?

Constantine Theodoropulos: 34:08

I'm a big believer in direct contact. So they're here and I think we have something to show. We have something to say. We have something that's really interesting. So we've never have had a problem accessing people, the right people in the right organizations. So we're doing that. I'm a big believer in networking generally, I don't exclusively do it here. I take a really broad global view. I'll do a name drop here, so EBD group, for example, a fantastic organization who puts on these partner events around the world that I've been involved with for a long time, have really created a very significant, powerful community that is focused on partnerships and sharing ideas. And I think if you tap into that, you really have the ability to expand your network, but also see what's available beyond the three miles of Boston, Cambridge. It's a big wide world out there. And to be clear, our science comes out of Copenhagen, Denmark. Our CSO is in Copenhagen, Denmark.So ideas can happen anywhere. Good science happens all over and you don't have to be here to find it. And that if you have that, that flexibility and open mind, you're probably better off for it.

John Simboli: 35:49

You're sharply focused on running the business day to day and making sure all the data are comprehensible and can be shared and just all the little things that one has to do in the kind of business that you're in. But you also, from our conversation, I can tell that you're also thinking at times, I could do some real good in the world if this works out the way I hope it will. So when you allow yourself to do that and I'm, sure you can't do it too often, but what goes through your mind?

Constantine Theodoropulos: 36:20

For me, this is very a very personal business. I don't have the luxury of not thinking about this on a daily basis, at least that aspect. So I don't talk about this often, but my six year old daughter passed away this past year from Ewing sarcoma. So very rare cancer. And it happened very quickly. And prior to then it was very abstract, what I was doing. But I think the situation and experience that my wife and I had around the passing of our daughter and the way she went and the cancer that she had and our experience around that, which is so unbelievably profound in so many ways, that it really puts into stark relief a lot of things, but certainly the way you spend your days. And so here and with Go, it has taken on a completely different relevance in our lives. At least, my life certainly. Because ironically, we're working on cancers that had affected my daughter and we have, potentially, a therapeutic in the making that could have addressed maybe some of her tumor. But here, I think for me there's really no escape. I can't really not make the connection at all between the purpose of what we're doing on a high level and what I do on a daily basis. I wish it wasn't the case sometimes, frankly. But here, as long as I run this company, it's definitely mission centric. Because it can't be anything but that. And in our context, I also have a partner that shares that. He's an MD and so he didn't get into this game for a financial reason. It was really, let's try to take advantage of what we have in terms of the science to develop a better therapeutic that will address some really nasty, nasty cancers. So, that's, that's kind of the way I view it.

John Simboli: 38:44

Constantine, thanks for spending time with me today.

Constantine Theodoropulos: 38:46

Thank you. I appreciate it.

John Simboli: 38:49

When listening to Constantine's thoughts about leadership, three qualities come through again and again—his courage to confront the unknownl his vision for targeting cancer tumors; and his humility when facing the emperor of all maladies. For Constantine, courage starts with equanimity. As he says, "Launching a biopharma company is not for the faint of heart. You're flying blind a lot of the time and some people don't like that." But Constantine likes to discover things, which is one reason he's able to move forward without the kind of safety net found in some other fields. As Constantine says, "I'm not afraid of the gray area or the darkness that's around a few inches in front of your face, which is really what this business is all about." Another driver for Constantine is his dedication to helping patients with cancer. His vision for Go Therapeutics is to develop a new class of oncology therapeutics, which will exclusively target the tumor and kill the tumor without killing the rest of the patient. Like several of the biopharma founders and CEOs I've spoken with, Constantine had an " Aha" moment. He remembered it as "It hit me like a bolt of lightning. If you can develop an antibody that would be very selective to a specific antigen— and the rest is engineering. This could open up a whole new biology for cancer therapies. So for me, it's like you see on TV or in a movie like, POW!. There it is." And Constantine has the humility to see cancer as an elusive foe in the longest running war in human history. He understands that while he has a vision for attacking tumors, we're all in this together. He likes to say Go Therapeutics is a jazz ensemble where everybody has a big contribution to make, where his job is to make sure his team has everything they need to be of service to the ultimate mission. I'm John Simboli. You're listening to BioBoss.