Kevin Lee, CEO of Bicycle Therapeutics, shares his thoughts with BioBoss host John Simboli about leadership in biopharma and how Bicycle Therapeutics is working on developing a new class of medicines, called Bicycles, for diseases that are underserved by existing therapeutics.
John Simboli 0:00
Today I'm speaking with Kevin Lee, CEO of bicycle therapeutics, headquartered in Cambridge, UK, with key functions and members of the leadership team located in the Boston, Massachusetts area. Welcome BioBoss, Kevin.
Kevin Lee 0:13
Hi, John. It's really great to be here. Thank you for the opportunity.
John Simboli 0:17
Kevin, how did you find yourself as CEO of Bicycle Therapeutics?
Kevin Lee 0:22
For as long as I can remember, I've always been fascinated with drug discovery, I've always wanted to make medicines. In the early parts of my career, I pursued this through the traditional pharma route, you know, multiple pharmaceutical companies, moving to positions of increased responsibility. And then I was approached about seven years ago about Bicycle, together with a number of opportunities. And I just fell in love with the science that Bicycle are doing, I fell in love with the people in the company and I thought this was a real opportunity to make a difference, both in the discovery of novel medicines, but also in the pursuit of novel scientific understanding.
John Simboli 1:15
As that opportunity presented itself, did it appear, did it feel to you at the time, as you remember, did it feel like, "Oh, yeah, this is a natural progression" or did it feel like, "I'm going to become a leader of a biopharma company? Who'd have guessed?"
Kevin Lee 1:28
I never thought about the consequences of being the leader of the company, There was a moment, I remember it well, it was 2015, the summer of 2015, in Philadelphia, where I met with the, then, CSO of the company. And he described to me in a slide what the company was doing. And I guess the previous 20, or so, years of experience, I had in drug discovery told me, this was something special.
John Simboli 1:59
When that opportunity came along, did it feel like it was the consequence of lots of research you had done looking for an opportunity like this, or did it more appear, and you realized, this is unusual?
Kevin Lee 2:13
I've been at both. The experiences that I'd had in drug discovery, my first job in the industry was in peptide discovery. So I knew quite a lot about the science of peptides. And so I could put two and two together and make the right number. But I also saw the untapped potential in the opportunity, truly novel, truly differentiated. And I think underestimated, actually, I felt that I could make a difference. And you know, if there's one thing you want to do in your career, it's to make a difference. Everything sort of seemed to come together in that one slide. And then obviously, I had to do my diligence and look into the company. And there was a lot of places where I could add value, the strategic direction of the company, the things that needed to focus on. So there were lots of places where I could see the experience that I had in the industry, I could put to good use in this opportunity that I felt was very special,
John Simboli 3:17
What we're hoping to achieve at Bicycle Therapeutics that might not have been possible at someplace else?
Kevin Lee 3:22
I think it comes back to this being consequential by the actions, the work that you do, making a real difference. And sometimes I think that gets lost a little bit in pharma, you become part of a big engine, and you sometimes lose sight of, even as a senior manager. So I felt there was a real opportunity in Bicycle to have a well-defined role. And within that have the responsibility to make a difference. But I also felt that the potential in Bicycle . . . So to sort of step back for a second, I believe that what we do in Bicycle is truly differentiated. There isn't another company on the planet that does what we do. The way I feel about, or felt about at the time, and what I say to people who join the company, is what we do really matters. It may be that the science doesn't work, it may be ultimately that we don't find medicines. But if we don't do it, and there is the potential to find medicines, then that's a huge lost opportunity for society. And so by doing what we're doing, I feel we're doing something really important.
Kevin Lee 4:39
Anything you do in this in this industry is, I'm a scientist by training, it's an experiment. Sometimes you have to do the big experiments to get answers to the big questions. And the big question we're trying to answer at Bicycle is this very novel drug modality. Six or seven years ago, when I was looking at this opportunity, peptides had gone a little bit out of fashion, there were lots of new technologies coming along and people were getting excited by them. There are lots of drugs with a peptide that can trace back to sort of peptide origins. But I think people have lost a little bit of enthusiasm about that class of drugs. And I thought that the Bicycle approach, which was first conceived by Sir Greg Winter, who has a pretty prestigious career in what he's done in the antibody arena. I thought what he'd conceived in this bicycle platform was truly worth investing a large component of my career in because that big question, and almost the fear, actually, of that opportunity being missed for society, it felt too important not to grab with both hands and pursue,
John Simboli 6:11
Realizing, as you did from your background in peptides, that it was an interesting and powerful potential application which you saw at Bicycle, and realizing that maybe it was of the time to do that, did it cross your mind at all that maybe rather than building a company to do this, I'll take this idea to big pharma, which I am familiar with and make it work that way?
Kevin Lee 6:34
That's a really interesting question. And to be honest, it didn't. And I wonder why it didn't. At the time, the company was five years old, they'd spent a lot of time focusing on developing the technology. At the time, I think there were still a lot of question marks around whether the technology was ever going to be good for primetime. And I think this is the experience that the company had. There were a lot of question marks that maybe pharma would have had, and that's fine, about the technology. And it was probably a little bit too early for a big pharma deal. Looking at it from another lens, it would have been very difficult for pharma to have done a deal with a company that, at the time, didn't have a CEO, even, in place. So it needed the CEO before we could get the deal done, maybe.
John Simboli 7:33
The picture that you had of what it'd be like to build Bicycle Therapeutics, based on your experience and your knowledge of it, looking very exciting. What was that experience like, actually being in and doing that over the last few years, versus what you thought it might be when you came into it?
Kevin Lee 7:50
Oh, I think it was far more challenging than I anticipated. In pharma, I'd had quite a bit of experience with teams that perhaps were not performing as they should, and sort of turning some of those situations around. And I felt that was well, within my grasp and capability. What I didn't kind of account for was the challenge of taking a company, which was five years old, had kind of lost that investor glow, and the momentum that comes with that. And with that perspective, I found that whoever I'd spoken to, had heard about Bicycle, had formed an opinion on Bicycle, and wasn't necessarily looking at the science that was in front of them, was looking at the opinion they'd formed two or three years earlier when the company had a lot of questions that it had to address. One of the challenges we had with Bicycle is it was founded by Sir Greg Winter, who many people would say is responsible for much of the great progress that the industry has made with antibodies, and people have really struggled to understand the difference between what we're dealing with in bicyclic peptides and antibodies. And I think when I joined the company, I wasn't quite sure . . . I knew there was something special in the platform, but I wasn't quite sure, even myself, what it was, and where that sweet spot was. I always felt once we got in and we started doing some work and we brought in some additional smart people with great experience, we would find the sweet spots. That's proven to be the case. But at the time, it was always very challenging to argue the pros of the platform when we hadn't got the data to support it versus, you know, years and years and years of data on antibodies.
Kevin Lee 10:03
And you know, one of the things with the antibody field now is there's a lot of dogma out there that I don't think is necessarily often supported with data. And so it makes it doubly difficult. When we talk about our technology, one of the great things and the thing that people miss about our technology, is we have specificity. We can bind to a target with this similar affinity and similar selectivity as an antibody can. But we're 100 times smaller than an antibody. And, therefore, we penetrate into tissue like a small molecule can. People assume that antibodies go everywhere in the body, which is not the case, they don't penetrate deep into tissue. And so, it took us a bit of time to generate that data to show, well, here's one sweet spot. And what we've developed over the last few years is this idea of Bicycle being a precision guidance system. Yes, they have their own pharmacology and we can use them as standalone pharmacological agents. And we've got molecules in the clinic right now, that are doing very well in that capacity. But using a bicycle attached to, in the case of our most advanced molecules, attached to a toxin and using the bicycle to guide, with precision, that toxin into the tissue of interest, in this case, a solid tumor, I think is very unique. You know, you need the data to support this, initially preclinical and then clinical.
Kevin Lee 11:31
Another thing that people kind of forget about with antibodies is, people always tell me about antibodies as they're being so specific. I rephrase it and I say they're actually specifically nonspecific. Because you have the parts of the antibody that binds to the antigen, they're very specific in what they do. But these antibodies evolved to talk to the immune system. So you have the Fc component of the molecule, which has multiple pharmacologies. And we see that every day in the long-circulating half-life of an antibody. That's mediated by a bispecific receptor. So, by definition, there are multiple pharmacologies in an antibody. And in some cases, that's a great advantage. In other cases, I think it's a real problem. And it's only when you get something as novel as a bicycle, which doesn't have the Fc, you can actually see the difference and the advantages not having an Fc might bring.
Kevin Lee 12:26
So it's been a fascinating few years. For me, it's been a real eye-opening experience to take some of these dogmas, some of these things that people take for granted or don't think about, and really challenge those ideas. And so not only do I think that at Bicycle we're making great medicines, hopefully, great medicines, potential great medicines. But we're also, I think, helping the entire medical field, think about what is an established modality, and maybe rethink some of these ideas. So, it's a great, great place to be and a great experience to be challenging some of the dogma that exists and asking where the data is.
John Simboli 13:15
When you're talking with someone who's an intelligent and thoughtful person, but from outside our biopharma community, and they say, well, maybe it's your spouse's friend or something. who knows? And they say, Kevin, what do you do for a living? How do you answer that?
Kevin Lee 13:29
Well, honestly, I say, I used to be a scientist, but I'm now in administration. You know, I live breathe, think, Bicycle 24/7.
John Simboli 13:43
As a CEO, have you learned what management style works best for us, is who you are?
Kevin Lee 13:49
When I was younger, I tried to do everything. I tried to be involved in every conversation, directing everything from the front. And then as I think, as you get older, you realize that you're not the best qualified to do everything, there are better people in the company. And if I didn't have people who were better than me, in their respective areas, I wouldn't be doing my job correctly. And, you know, empowerment becomes important, trust in people. recognizing it's a team effort. And actually trying to encourage people to be the best they can and supporting them, I think is absolutely crucial. And then I think as a CEO, you become more of an integrator. A lot of the information comes to you. You need to make sure that the information is shared appropriately across the organization, and that you're supporting people to be the best they can be. And you're not the expert in everything. And I think that's the biggest transition from being a scientist to moving it into leadership. You know, you really want people who are better than you do in the science. And you understand the steps in their respective areas and what your job is, is more to support them, make sure they have what they need to be the best they can be.
Kevin Lee 15:10
And one of the things I've learned, and it's been a really important one is, having the honesty and maybe the humility to admit when you don't know things. And, you know, you know, more than me about this, let's talk it through. Now, that isn't an opportunity to pass on the decision-making. Obviously, every decision has to stop with the CEO, but I think it's important to recognize who the experts are, who the true experts are, and make sure they have a place at the table in these really technical decisions. And listen to what they say, integrate that information into the bigger picture, and then make clear and well-thought-through decisions that, hopefully, everyone supports.
John Simboli 16:03
Can you remember way back to when you were perhaps eight or nine or 10, you pick the time, but that time in life, when we were very eager to be the kind of grown-up that we thought we wanted it to be, usually what we thought our parents wanted us to be, I'm sure, but can you recall that and does it have anything to do with being CEO of a biopharma company?
Kevin Lee 16:24
For as long as I remember, from the day I first started thinking about what I wanted to do with my life, I wanted to make medicines. The difference between then and now is I thought that making a medicine would be taking two test tubes and pouring one into the other. And somehow that was the medicine. Today, I realize that medicines are a very complicated process. And it's not necessarily just pouring one test tube into another that leads to the medicine. There are huge amounts of administration, bureaucracy, technology, and skills from across the board, that lead to the medicine. And so, whilst I've never, in some of the molecules that we now have in the clinic, I could never confess to being the one who poured that one test tube into the other, I think I've touched all the medicines, so I've touched them in a different way, you know?
John Simboli 17:30
I think it's a bit unusual to have been a young boy or a young man and have that as your goal.
Kevin Lee 17:38
I mean, just to give you a bit more insight into that, I come from a railway town, very working-class town in the northwest of England, and most of my family, generations, worked in the railways. It would be very aspirational and virtually unheard of. Around about 40 miles away from where I lived, there was a pharmaceutical company, and that was kind of, I really aspired to try and go there. And that's what got me interested what does this company do? What's it about? And then I read into it, and then I just became fascinated, absolutely enthralled with the idea that there were these things that you can't see that somehow, you know, the lock and key, you know, they bind in this specific way. And something that you cannot see, can actually have such a profound effect on human physiology. And I was hooked, and it's still, one of the most exciting things for me, these days, is structural biology. And you're seeing how our molecules fit into the receptor. I don't confess to being an expert or understanding it, but it's one of the most fascinating and exciting things that I get to touch in my job.
John Simboli 19:17
When people ask who is Bicycle Therapeutics, how do you like to answer?
Kevin Lee 19:21
I say we're a company that's working on a very novel technology that has some of the beneficial attributes of classical small molecules and some of the beneficial attributes of large molecules. And we create these molecules with unique properties. I think they have very broad applicability across many therapeutic areas. They're not a replacement for biologics or for small molecules, but there are certain aspects about this technology that I think make it a superior approach for certain applications across many therapeutic areas.
John Simboli 20:00
To people who follow the field, they ask the question, isn't that a bit like? . . . and then you name it, the company? Do you have to get that question? Or is yours differentiated enough?
Kevin Lee 20:11
What we work on are what we call constrained peptides. So one of the problems with peptides is they are, classically, every amino acid in a peptide is free to rotate. So everything is moving and the peptide adopts many conformations. What's very clever about this technology, there are a number of things clever, but one of the fascinating things is, what we do is we take a peptide, and we essentially wrap it around a small molecule. So, schematically, like a pretzel, it's a bicyclic molecule, it has two cycles, two loops, hence, the name Bicycle. And when you do that, to a peptide of this size, it massively constrains the rotational freedom of the individual amino acids. So you get a molecule which is kind of locked into its preferential conformation for target engagement. So you get very selective, very high-affinity molecules. And that is a complete differentiation. the bicycle structure. And I'm not aware of any other company that works on bicyclic peptides.
John Simboli 21:23
In my experience, a CEO will often be at a presentation, at a conference, perhaps an investor conference where they can quickly, after their presentation, see who might want to talk further. Some people are a good fit, some people are not a good fit, that's fine. And there's another group where it seems like there could be a good fit, but then when there's the follow-up conversation, there's a realization. well, they actually heard something different from what I intended. So now I need to re-clarify. So if that happens with you, what do people tend to hear that you say, well, that's actually not it, it's this?
Kevin Lee 21:58
People confuse what we're doing with antibodies. I've actually had follow-up meetings with people. and it's interesting, you get that moment where it just dawns on them. It's fascinating that these things are 100 times smaller than an antibody. I've even said it, and then I've had the person, you know, two minutes later, say "So they're that's small?" Because that just opens up a whole manner of new possibilities. And, you know, there's a number of features about the technology, but I think the size is really important. They're fully synthetic because they're small, they penetrate into tissue. They're renally eliminated, so we don't deal with any of the vagaries of liver metabolism, liver recirculation. And something that's really, really cool about what we do, and this is very technical, John, so forgive me, if I go too technical, but the very, very clever thing that Sir Greg, conceived when he thought about bicycles, was the manner in which we find bicycles. So we use a technical phage display. So we use bacteria phage, to present the bicycles on the surface. Every phage presents a different bicycle. So we have these huge libraries. Successive drug discovery is a function of the size and diversity of the library you start from. So we have this mind-bogglingly large library of bicycles that we can screen very quickly. But the really cool thing is, the bicycles we find when we screen, there's actually an added advantage to what we do. So the first thing is, when we screen, we basically take this phage library and combine it with the target of interest. And then we wash everything that doesn't bind away. So we find, in that process molecules which bind to the target with high affinity. Now, the kind of unforeseen upside of this is not only do we find bicycles which bind to the target with high affinity but, by definition, these are bicycles that are tolerant to conjugation because they're attached to the phage. It sounds small, but it's huge because, for us, it's very simple for us then to attach anything to the bicycle, because there's nothing we can attach to a bicycle that's going to be bigger than a phage. And so, in small molecule drug discovery, you have a molecule and you might change a me-file group for an e-file group and you'll lose activity. So it's very difficult to conjugate onto a classic small molecule a toxin, or another molecule. In biologics, yes, you can attach, but it's quite complex biological engineering. It's complicated. It takes time.
Kevin Lee 24:58
For us It's one kind of procedure, it's very quick. So we can use this for all manner of things. In fact, our lead molecules are conjugates. Here, we're conjugating a high potency toxin to the bicycle, using the precision guidance system of the bicycle to deliver the toxin. But we can take two pharmacologically distinct bicycles, one is designed to home into the tissue, and the other could activate the immune system or some other functionality. So I think this is a step-change in drug discovery. For years, people have talked about precision medicines. And when we talk about precision medicines, we often talk about a small molecule which binds selectively to a mutant kinase. That's one way of achieving precision. Another way, which I don't think we've really honed in on and managed to realize is by having one entity which guides an agent, which might not, in itself, have that precision targeting system, but drives it into the locality of the tissue where it needs to work. I think that opens up so many opportunities. When I started, at Bicycle, I thought, there's going to be really exciting opportunities, I'm not quite sure what they're going to be, I think this is truly one of those really exciting opportunities.
John Simboli 26:33
What sort of partners are a good fit?
Kevin Lee 26:35
Bicycle is a high-science company. And we want it to remain a high-science company. I want it to be a company where we have the best scientists, doing the best work, innovating in the best way, coupled with the best clinical function that we can possibly attain. The nature of our technology is very high science. So, collaborators, whether they're academic or commercial, I think, really need to be of very strong scientific caliber. I think, when you start working with the Bicycle technology, the possibilities are endless in the right people's hands. I think it's really good for our scientists to sort of riff off of other scientists' ideas, and then what I have to do, and my colleagues have to do is then, we have to overlay some discipline and some focus. Because one of the problems with Bicycle being the only company on the planet that has this technology, and the technology being so broad, is there are almost too many things to do so. So from a partnering perspective, I like imaginative, strong scientists, who are very collaborative, able, and willing to pursue areas that they didn't first imagine that they would, but also have the sort of commercial acumen to realize you can't do everything. And we need some discipline in the process as well.
John Simboli 28:20
What kind of people thrive at Bicycle Therapeutics?
Kevin Lee 28:23
Myself and my colleagues, we're trying to build the most scientifically strong organization we possibly can. We're blessed to be in the two Cambridges, the two ecosystems. So I think people who are scientifically strong, driven, disciplined, and importantly, team players. We've got a really strong team culture here. The technology is so novel. I would argue that in some of the more modular technologies, you can just think in one dimension, well, I've just got to go after this target. and I've got to, follow the footsteps of 100 people before and to optimize in this molecule to get to the biological, small molecule to get it to be fit for purpose. Bicycle is a bit different. Every experiment we do, potentially, is the first time that experiment has ever been done. You know, what if we take three bicycles and put them together? What if we put two bicycles and something else together? This is groundbreaking stuff. And so we need people who have the imagination and the curiosity to be able to cope with that, frankly.
John Simboli 29:38
Kevin, what's new at Bicycle Therapeutics?
Kevin Lee 29:41
Every day, there's something new and exciting. That's the beauty of having four molecules of our own in the clinic, one partnered molecule in the clinic and progressing new Horizons. So, you know, very excited by the emerging clinical data. And, actually, the translation of that data and the interpretation of that data, and putting it into context around what we know about more traditional approaches, I think it's truly, truly exciting to be seeing the emergence of some of the things that we've long hypothesized might be true. And then the actual real-life manifestation of it, I think, is very exciting. Our screening platform continues to reward us and fascinate us and deliver things that we never expected it to. We get a lot of interest from potential partners and existing partners, and it's great because they bring new ideas into the mix. So, Bicycle is a really, fascinating and exciting place to be.
John Simboli 30:57
When you're contemplating this fascinating puzzle, let's call it, for a moment and how you're forming it and shaping it and putting the pieces together on it. Do you at that stage get to step back, ever, and say, you know, if this works out the way I hope it, will we're actually going to really do some good in people's lives? Obviously, that's where you want to go, but is that something you address later on, after the puzzle pieces come together?
Kevin Lee 31:25
You know, I think it's kind of part of my role to actually explain to the Bicycle team, and try and translate what I think we're seeing and what they could potentially mean. It behooves me to take that step back, and lay out the sheer enormity of the potential opportunity. So, I think it's something I try and do quite a lot, actually. Because this is a big beast of a company. And we really need to reflect on that, and understand that and handle it in the correct way,
John Simboli 32:03
When you're trying to explain to your colleagues and to others what the potential benefit is for patients. how do you describe that, given the complexity of the science that you're working with?
Kevin Lee 32:13
I would say a couple of years ago, that was challenging. The great thing is now, I don't have to do that anymore. Because we're in the clinic, and we're already seeing the advantages. It's really exciting and rewarding for the staff. It's also, actually, very illuminating for investors and potential partners. Because you've got to remember, what we're doing has never been done before. But to be the first people ever to put these molecules in and to see that, to a large extent, they're behaving as we anticipated, they would. Already, it's bringing benefits to patients. Handfuls of patients right now, but, you know, the early signs are really promising. And much of what we predicted, has proven to be correct. So now, once you get that data, people really believe.
John Simboli 33:08
How does the Bicycle Therapeutics pipeline express your vision for the company?
Kevin Lee 33:13
That's a really interesting question. Because the modality is so novel, I think about each approach that we're taking as an experiment, an unvalidated experiment. Our initial hypothesis was these very small bicycles could precision guide high-potency toxins into solid tumors. And we actually took three molecules into the clinic, one to an unprecedented target, one to a target—a conventional approach that has failed against, and a target where the conventional approaches had worked. And what we're trying to address there is one, does the technology, actually do what we wanted it to? Does it precision guide the toxin into the tissue? And does that generate benefit? And then, if it does, how broad is the applicability of the target? So does it work against unprecedented targets? Does it work against targets that have failed conventional approaches, and targets that have been successfully drugged. We're trying, in a very novel technology to address important questions about the technology in a logical, kind of gated manner. I think the pipeline does represent the way we think about the technology and how we want to apply it. So, having done that experiment, we're only halfway through the experiment, we have emerging clinical data, which looks I think, pretty good. We're now gated to say, well, let's double down on that investment.
Kevin Lee 35:00
So we have that. And then we have this other approach where we're really trying to bring a next generation of Immuno-oncology molecules. One of the fascinating things about Immuno-oncology is one approach to immuno-oncology is you use bispecific antibodies where one arm of the antibody binds to a tumor cell, and the other arm binds to an immune effector cell. And the idea is that the antibody brings the two together, and the immune cell can then kill the tumor cell. And you see these really nice cartoons where there are these two cells, in juxtaposition, this tiny antibody, which fits perfectly in between the two. The only place that exists is in the cartoon. The fact of the matter is the distance between the antigen-binding parts of the antibodies is quite large. I guess they're close, but they're not in the normal immune synapse. And because our molecules are so much smaller, we actually can bridge a tumor cell and an immune cell within a normal immune synapse. So we have the experiment going on at the moment in the clinic, does that afford better efficacy? What was the tolerability of that look like? And then, if that works, then we'll double down on that. Because this is a new technology, we can't go charging in any one area. And I think that would be a bad investment. So we do staged investment, asking logical questions. And then based on what we see, we're then making decisions on further investment. And we'll continue to do that with the technology. So I think it does represent the way we think about the world.
John Simboli 36:42
Kevin, thanks for speaking with me today.
Kevin Lee 36:44
John. It's been an absolute pleasure. I really enjoyed it, and hopefully, we get the chance to talk again.