Hello everyone and welcome. My name is Adam Fisher. I'm a Vice President on the Biotech, Healthcare, Investment Banking team. It's my pleasure to introduce Kevin Lee, CEO of Bicycle Therapeutics. I'll turn it over to him. Thank you very much. It's a real pleasure to be here today to tell you a little bit about the work that we're doing at Bicycle. 2024 was a really significant year for Bicycle. I think we made outstanding progress across our entire pipeline and business. Really looking forward to share with you some of the highlights from that year and also give you an overview of what you can expect from us in 2025. I'm conscious this is the first time we've presented at the conference, so what I thought we would do is firstly give you a bit of an overview of the technology, then introduce you to our clinical pipeline focused on our most advanced asset, zelenectide pevedotin. I'll then give you an introduction to some of the work we're doing in radiotherapeutics and finally 2025 expectations. Before I do that, I do need to make you aware we will be making forward-looking statements during the presentation, so at Bicycle, we'll work on the next generation of precision-guided therapeutics based on bicyclic peptides, or bicycles as we call them. We believe this remarkable technology has the potential to deliver virtually any payload to any target in any tissue. To exemplify this, I think we've built a really exciting pipeline of clinical assets in oncology focused on next-generation drug conjugates and radio conjugates. Our most advanced asset, zelenectide pevedotin, we believe has the potential to be the leading therapy for Nectin-4-associated tumors. We've established a number of validating partnerships where we've looked to explore the technology beyond our core area, and suffice to say, I think we have a really experienced leadership team and we're well funded into 2027. So bicycles are actually an evolution of antibody technology. We all know antibodies have transformed the treatment of human disease. They've been used successfully in many different formats. And one of those formats is, of course, the antibody-drug conjugate, or the ADC. Unquestionably, these molecules have made a hugely positive impact to the treatment of cancer. But I do think it's fair to say there does remain some room for improvement, particularly when it comes to tolerability. It was our founder, Sir Greg Winter, and for many, the godfather of antibody therapeutics, who first recognized that the properties of antibodies may not be ideal for a precision-targeted therapeutic. Their large size prohibits effective tissue penetration. Their long circulating half-life, together with their ability to cross-react with multiple cell systems by evolutionary design, is really counterproductive for a precision-targeted technology. Sir Greg rationalized that if you could take the part of the antibody that's involved in antigen recognition, the so-called paratope, which is shown here in magenta, and you can see it's actually quite a small part of the antibody. If you could take that region and reduce it to a minimal active fragment, you may have a more effective targeting system, and Sir Greg went on to show you could do this with bicyclic peptides. We believe that bicyclic peptides, bicycles, really have optimal properties for precision targeting. We call this the bicycle advantage. Their small size, 50 to 100 times smaller than an antibody, allows extensive and effective tissue penetration. The great thing about bicycles is that they have a tunable half-life. So we can optimize the time the bicycle spends in the body, enough time to get to the target, but not so long to undergo off-target, unwanted effects. And bicycles really have a high affinity and, crucially, exquisite selectivity for the target. And we now know that when they're bound to the target in the tissue or the tumor, they're retained for long periods of time. Why does the bicycle advantage matter? Well, we believe that if you minimize the systemic exposure and you minimize off-target activity, then you maximize tolerability. We believe a better tolerated molecule is one that a patient could adhere to more effectively. They can stay on the right dose, the right frequency, all of the time. Fewer dose interruptions, reductions, withdrawals. Also, more tolerated molecules can be combined more effectively with other anti-cancer agents. And through this, we believe you can get longer and deeper responses. But for us, what's most important is not just that patients live longer, but they live well. So with that in mind, we've put together what we believe is a really exciting pipeline of next-generation drug conjugates and radio conjugates. I'm not going to spend much time today talking about our work in EphA2. Remarkable work with 5528. EphA2 being a previously undruggable target, we've now shown 5528 has amazing tolerability, great efficacy. We'll talk about that another time. I'm also not going to be able to talk about the work we're doing with 7480, a Nectin-4-targeted CD137 conjugate. And here we've shown clinically, really, again, great tolerability and really intriguing PKPD. I'll spend some time talking about radiotherapeutics at the end, but what I want to spend most time talking about today is our work in Nectin-4 with our Nectin-4 drug conjugate, Zelenectide pevedotin. And to do that, I'm going to focus on two ongoing clinical trials. The trial we call Duravelo-1, which is a phase one open-label study where we've been exploring Zelenectide across multiple tumor types. I'll also talk about the trial we call Duravelo-2, which is a registrational trial looking at Zelenectide in combination with pembrolizumab in first and second-line bladder cancer. So let me introduce you to Zelenectide. This schematic shows the architecture of the molecule. We have a bicycle with high affinity for Nectin-4 and truly exquisite selectivity for the target, linked via protease cleavable linker to the toxin MMAE. Across a range of preclinical models, we've shown that Zelenectide has superior activity to ADCs. At ESMO last year, we were really pleased to present some data from our own ongoing phase one trial. In that study, we explored Zelenectide as a monotherapy in late-line bladder cancer. And there's three points I want to make in this slide. Firstly, we presented an overall response rate of 45%. We're dealing with a really active molecule. Secondly, the table on the right is the table which lists so-called adverse events of special interest. These are adverse events that have really dogged the ADC field. These are the adverse events that cause patients to have to go on dose interruptions, dose reductions, and heartbreakingly for patients, dose drug withdrawals. What we showed at ESMO was, despite amazing clinical activity, we're seeing a low frequency of these adverse events and a low level of severity. I think this combination of great efficacy, great tolerability then leads to this really exciting duration of response. 11.1 months in this patient population is really very exciting. I think this is the Bicycle advantage starting to show itself. Now, on the basis of these data, we went on to set up our registration study Duravelo-2. This is a schematic showing the structure of the study. It's based on the FDA's Project FrontRunner initiative, and it's a bit complicated. Let me step you through the key points of the trial's design. Firstly, there are two arms to the trial, Cohort One, Cohort Two. Cohort One, we're exploring Zelenectide plus Pembrolizumab in first-line, all-comers, metastatic urothelial cancer. It's about eligible and ineligible patients. In Cohort Two, we're exploring the combination in the late-line setting, second-line plus. If we focus on Cohort One, there are essentially three phases to the study. Phase one, as per FDA's Project Optimus, is a dose optimization. We're exploring two doses, actually two dose regimens. At the end of the dose optimization, the dose selection phase, we take the optimized dose and we compare it with chemotherapy standard of care for potential accelerated approval based on ORR. The final phase of the study is a confirmatory phase. Again, we take the optimized dose, we compare it with chemotherapy standard of care for potential full approval based on PFS. Now, one of the highlights for me of 2024 was the progress we made with this trial. We've seen great enthusiasm and great excitement in the bladder cancer community, which I think is testament to the tolerability profile of the molecule. As of Friday, we have 152 sites active in 21 countries, and we've recruited 188 patients. We're well on track for completing the dose optimization and dose selection phase of the study in the second half of this year. We're also on track to file for potential full approval in 2027. Now, while we await the data from the dose selection phase with some excitement, we've already begun to explore the combination of Zelenectide and Pembrolizumab in first-line bladder cancer patients, albeit in a very different population than the one we're studying in Duravelo-2. That work is part of, again, our phase one study. In that particular study, we're comparing Zelenectide and Pembrolizumab in first-line cisplatin- ineligible patients. We gave an update on the progress we're making with that trial in December. That update was from a data cut that we conducted in September, and I'd like to provide a little bit more color on the progress we're making in the trial today based on a more recent data cut, which was conducted over the last few weeks, so this slide shows the characteristics of the patients that we're studying and the overall tolerability profile. We look at the patients that we've enrolled. We've enrolled 22 cisplatin ineligible patients, and I have to say this is a very frail, fragile population that we've enrolled. They have particularly aged, and 46%, almost half of them, have a performance score of ECOG 2. What does that mean? A performance score ECOG 2 means that these patients spend up to 50% of their time, their normal daily active life, chair or bedbound. So very fragile population. Despite the fragility of the population, despite the fact that we've added in Pembrolizumab, we continue to see a low frequency of adverse events, no maculopapular rash at all, low frequency of adverse events, low severity. We're seeing reversibility of adverse events. True testament to the tolerability of the drug. We've had no discontinuations whatsoever due to a Zelenectide-related adverse event. And to put that into context, in trials with some ADCs, we've seen 40-plus discontinuation rates, 40-plus% discontinuation rates in arguably fitter patients. I think this data is really quite remarkable for this patient population. What about efficacy? Of the 22 patients we enrolled, 20 of them were efficacy evaluable, and their individual responses are shown here in the waterfall plot. What's amazing for me, again, despite the fragility of these patients, so far, 65% of them have shown some form of response. There are 12 patients still ongoing. This data may change. Still a long way to go in this particular study, but I think that's really exciting. Really, really active combination. The most exciting thing is the durability profile, as you can see here in the spider plots. The arrows indicate patients who are still on therapy. And again, we're already seeing patients staying on therapy for 12 months. Really remarkable, again, considering the fragility of the population. So I think this is really exciting data for the bladder cancer community. I think it's a really promising piece of data, and I think it bodes well, incredibly well for what we might see on Duravelo-2. But for us, Zelenectide in bladder cancer is just the start. We think Zelenectide has a huge opportunity, not just in bladder cancer, but also beyond bladder cancer in other Nectin-4-expressing cancers. And with that in mind, a few years ago, we identified that the Nectin-4 gene was amplified in a range of different tumors. We've carried on that work with our collaborators. Some of that is shown in this slide. So on the left-hand side, what we have is the frequency of Nectin-4 amplification across a range of different tumor types. What you can see is the Nectin-4 gene is amplified in a number of really difficult-to-treat important tumors, such as triple-negative breast cancer, lung cancer. In fact, the frequency of Nectin-4 amplification in triple-negative breast cancer is greater than that of HER2. Our collaborators have gone on to look at this in more detail. What they've shown is in triple-negative breast cancer, for example, the Nectin-4 amplification, if I can find the pointer, is associated with increased membrane expression of the Nectin-4 tumor antigen. This leads us to postulate that maybe these Nectin-4 amplified patients have greater sensitivity to Zelenectide. To explore this, what we did is we went back to our phase one study where we've already looked at Zelenectide in late-line breast and lung cancer. We went back and looked at the data to understand the relationship between Zelenectide activity and Nectin-4 amplification. I think the results are really quite remarkable. What we have here for triple-negative breast cancer, late-line, and non-small cell lung cancer, and these are patients who've exhausted all lines of therapy. We have the overall response rate to Zelenectide analyzed by all-comers response, non-amplified, and Nectin-4 amplified. In triple-negative breast cancer, for example, the all-comers response is 13%. In the amplified population, it's almost 60% with 100% disease control. Similarly, in non-small cell lung cancer, the all-comers response rate is around 10%. In Nectin-4 amplified population, it's 40% with 100% disease control. Why is this important? Well, if you think about the number of patients who can derive benefit from Zelenectide, if we think about the bladder cancer population, the number of newly diagnosed metastatic urothelial cancer patients in the U.S. each year is around 25,000. If we think about the number of patients who are Nectin-4 amplification newly diagnosed across a range of other different tumor types, we increase the number of patients who can benefit from Zelenectide potentially sixfold, another 150,000 patients, so in view of this, we've now established a comprehensive suite of studies to explore this in more detail, and I'm really pleased that in addition to the Fast Track designation, we've previously been awarded by the FDA for our work in bladder cancer. We've recently also got Fast Track designation for our work in Nectin-4 triple-negative breast cancer and Nectin-4 non-small cell lung cancer. As of today, we've dosed Zelenectide in more than 400 patients. I think we have a molecule that's incredibly active, that's incredibly well tolerated, and I think it's really exciting for the cancer community as a whole. But for us, that's just the start. We're doubling down on our drug conjugate pipeline. We have 5528 already in the clinic. And what we've done is we've taken our learnings from this work, and we've applied it into our next generation of drug conjugates. We have new linker systems, which we believe are going to be even more tolerable and therefore even more effective. So it's really exciting. But remember, I said, we believe this technology can deliver virtually any payload to any target in any tissue. An obvious place to apply that in oncology is radiotherapeutics. The properties that make bicycles so good to deliver toxins to tumors also make them really good to deliver radionuclides to tumors. But it's more than that. Our technology allows us to find novel bicycle binders to any target, whether it's previously been drugged or not. And so our ambition here is to develop radiotherapeutics to completely novel targets, to move away from the focus of the radiotherapeutics field on PSMA and somatostatin and start to introduce new antigens in essence to bring more value, more benefits to an even broader population of patients. And with that in mind, I was really pleased last year that we presented our first data, clinical imaging data to a bicycle binder to a completely novel tumor antigen, MT1-MMP. Some of that data is shown here. Really clean profile, really precise tumor targeting. We're building a pipeline of radiotherapeutics, radio imaging agents to completely novel, previously undrugged targets. And we expect our first radiotherapeutic to be in the clinic in 2026. If we look now to what you can expect from us in 2025, it's going to be another pivotal year for the company. For Zelenectide, we have a lot to do. We have a lot of studies to get rolling. And we have data updates from our ongoing phase one studies looking at Zelenectide monotherapy in late-line bladder cancer, Zelenectide combination with Pembrolizumab in that first-line cisplatin ineligible population. And of course, that data from that dose selection phase of the Duravelo-2 potential registrational study. In the radioconjugate space, expect additional data from us from our MT1-MMP imaging work and a second imaging agent targeted EphA2, that novel previously undrugged target. In the drug conjugate space, you expect more data from us looking at BT5528 now in combination with checkpoint inhibitor and for BT7480 likewise combination with checkpoint inhibitor. Big picture, where are we going? So we talked about our near-term aspirations. Long-term, it's our ambition, and I believe it's our obligation to get this remarkable technology into as many molecules as possible to maximize the potential of the technology, and importantly, to help patients live longer, but most importantly, to allow them to live well. So on that note, I'm going to draw the presentation to a close. Very grateful for your attention and very happy to take any questions. Thank you. Thank you very much, Kevin. So from on his left to our right is Jennifer Perry, Chief Strategy Officer and Head of Commercial, Santiago Arroyo, Chief Development Officer, and Michael Skynner, Chief Technology Officer. So I'll start off with a few questions, and then we'll turn it to the audience. So tell us a little bit more about your strategy. It looks like your platform is mostly focused on oncology at this point, but how else could you use your platform technology? That's a great question. I think I said at the start, the technology we believe is applicable across multiple therapeutic areas. We've chosen we have a core focus in oncology, but we're very excited about the potential beyond. With that in mind, we've set up a number of partnerships to explore in neuroscience across anti-infectives. We've got collaborations looking in immunology and inflammation. So it's our desire, it's our ambition to get bicycles as broad as possible, maximize patient benefit. Okay. Yeah. It sounds like your platform has broad applicability across. So you presented monotherapy and combination data in metastatic urothelial cancer. Put these data in context, what does that tell us about Zelenectide's potential as a treatment for metastatic urothelial cancer? And how do these data inform expectations for your ongoing registrational trial? JP, do you want to take that one? Sure. So I think the metastatic bladder setting is something that's really important to kind of drill into just a little bit because to understand that market is to understand that it's also complex and evolving very quickly. So obviously, everyone's very familiar with Padcev plus pembro in the first-line setting and how they've had their full approval now since December of 2023. But also, there's other agents moving very quickly into earlier settings like MIBC and NMIBC, as well as new Nectin-4 ADCs and HER2 ADCs. I bring that all up because usually the question is, how can you compete? What perspective can you put that into? Three key things that come to mind for me. One is ADCs have been plagued, as Kevin said, with some toxicity that does limit treatment. The first thing I always like to start with is that Zelenectide is not an ADC. It's not an antibody drug conjugate, as Kevin described. Why is that important? It's an elegantly designed molecule that was developed to really limit the liabilities that really plague ADCs and stop patients from either being able to get on the drug because of the profile or stay on the drug. So first things first is you have this opportunity now to have people treated for a long time, more people getting treated, unlocking that addressable opportunity, and hopefully having a better treatment experience both for the clinician and for the patient. The second thing is they're doing that with maintaining that strong efficacy. Next, in our market research, people wonder, can a drug compete on a tolerability platform with similar efficacy? And the answer is yes. We've just finished market research with 150 oncologists in the U.S., and basically that profile for Zelenectide plus Pembro outperforms being selected 20 times more often than Padcev plus Pembro. And so for us, that's extremely encouraging because what they see is SAEs, serious toxicities do matter to them. People cannot stay on the drug. And so something that solves for that is very desirable. And then last but not least, many people have heard me tell the story of can drugs come several years behind a market leader and actually compete? And the answer is yes. I've talked about Calquence versus ibrutinib in hematology. I've talked about Cabometyx and Inlyta in the renal cell carcinoma space. These were drugs that solved for those toxicities where people couldn't keep people on the drugs. Clinicians couldn't keep patients on. As a result, if you solve for those, suddenly you can become the market leader, taking a lot of new patient share within the first year, like those two drugs did. And so we're very ambitious and very excited about the fact that this is a drug that's strong on efficacy, comparable, and can win on a tolerability platform. Excellent. Extremely exciting. Does anyone in the audience have a question for the team? Don't be shy. I'll pass the mic to you. Anyone? All right. Well, I can ask a question that bankers love to ask, which is cash balance and runway. How do you guys plan that? I think in our last update, we have $890 million in cash, and we believe we can achieve all our milestones between now and well into 2027. Into 2027. Okay. Any questions? Going once, going twice. I'll keep going. How are you viewing the Nectin-4 competitive landscape, and where do all of those competitors sit in terms of stage of development as well as modality? I think, you know, I mean, to take a step back, I think in the bladder cancer arena, obviously Padcev is on the market. There's a number of molecules, ADC molecules behind us targeting bladder cancer in various indications. When we think about this Nectin- 4 amplification strategy, we think we're leaders in that. I think we have significant IP in the space. We have a really good position there. So I think we're in a really strong position to be, as I said at the start, leadership in treatment of Nectin- 4 associated tumors. Anything to add, JP or Santiago? How are physicians viewing the data? When you guys have presented it? Santiago. How do physicians view the data? Oh, the physicians. Physicians, yes. The support that we've had from physicians has been pretty significant. I will repeat the numbers that Kevin has given you. We have recruited since April of last year until now, 188 patients, and we have 26 countries open for business and 152 sites. There is a lot of interest in this trial. It's a trial that is complex, as Kevin was saying, but at the same time, it's very friendly to investigator sites because basically most patients with metastatic bladder cancer can enter into one or the other cohort. We are expecting to have results soon on the interim analysis and continue the study. I think just to add a little bit of color to that, I think the physicians that we've spoken to, the KOLs, are really excited by that tolerability profile, and I think it's testament to that that we're recruiting so quickly, so a lot of excitement. That's great. Anyone in the audience have any questions at this point? You touched on your radiopharmaceutical efforts a little bit, which is, of course, as we know, a really hot space right now. Why are you excited about working in that space? If we move away from what activity we've seen in terms of M&A and licensing, and then how is it different from your approaches? And then lastly, what is your strategy in radioligand targeting therapeutics? First question, why are we excited by it? Yeah. Why are you excited about it? I think our technology is made for precision delivery, and I think the opportunity to bring benefit to patients and to move away from PSMA and somatostatins is just so important for the patient community. I think it's just we have to do it. We have to do it, and Mike, do you want to take the other? Yeah. I mean, why are we excited? I mean, if you look at approved drugs in radiopharmaceuticals, they are based on peptides. PSMA, Pluvicto, and Lutathera are both derivatives of peptides. So it teaches that peptides have the relevant properties to be successful in this area. I think our platform is a platform that allows us to find novel peptidic agents to targets that don't have pre-existing ligands that can be derivatized. So for us, it's the ability to build this potentially first-in-class portfolio of drugs to take forward and not, as Kevin says, to pursue incremental changes to existing targets. Yeah. So to touch on that point a little bit, why did you target those as your novel ligands for your first few efforts in radiopharma? Why do we target the targets Kevin talked about? Yes. A number of reasons. I mean, those targets are well known to us. EphA2 is a target, for example, that only we seem to be able to prosecute on a toxin conjugate background. There are also targets that are widely expressed in high-value tumors, and there are targets that are often expressed when tumors are at advanced stages of metastasis, so in severe ends of the oncology market. So that's the reason why we pursue those, and to reiterate, the first-in-class potential. First-in-class potential. And what isotopes do you plan on using in those? Bicycle is not a payload company. We have the luxury of being payload agnostic. We believe that different tumors and different tumor antigens may require the use of a different payload, a different isotope, depending on how that antigen is expressed in the tumor over time. We believe that the best approach is to choose the right isotope and match it to the tumor indication. I don't want to ask all the questions. There you go. So on the Nectin enrichment strategy you're pursuing, is the ultimate goal there to get some kind of tumor-agnostic indication? And do you have any sense of the resources that would be required from a regulatory perspective, the studies you'd have to run, the timelines at this point, or is it just too early to say? And I guess the other question is, why wouldn't Seagen or Pfizer have pursued such a strategy for Nectin? Yeah, I think it's very early to talk about tumor-agnostic. Obviously, that's a consideration, but it's very early. We will be doing three exploratory studies starting this year in lung, breast, and a basket study, and depending on the results, we'll move from there, but we haven't started really to dig into what we'll be doing in the future. Seattle, Pfizer, why they might be doing it, I don't know. We believe that we identified the amplification. We've a very, very comprehensive patent estate around it. I think it's going to be quite difficult for people to navigate through that. So we feel we're in a really advantageous position to win in that space. Just in terms of your long-term strategy, you've got a lot of cash on the balance sheet. Does that give you enough firepower to kind of hold onto your assets for longer and perhaps mature into a pharmaceutical company rather than exit too early? Our ambition is to bring the best medicines to the most patients and do that as an independent company. Any other questions for the team? Hi, thank you, Amanda. And I have a simple question about the Nectin-4 program. And we know that Nectin-4 is not only expressed in the breast cancer and the lung cancer, also including other like ovarian cancer and other types. But I wonder that when you choose the patients and you said you validated the expression, now the expression, that's my question, I think. You are saying the Nectin-4 application is important for the outcome, but why not the protein expression level? I think you're the basic structure may be more related to the structure of the receptor or the protein level. I mean, due to the CDC or the ADCC, the structure base. So why not the protein level, but you choose to amplify? Why do we use an amplification strategy for selection rather than a protein IHC type strategy? So the breast cancer data, I think, is really illuminating. When you look at Nectin-4 protein expression in non-amplified tissue, you see that it's heavily in the cytoplasm. In the amplified patients, you get much greater on the cell surface, which has to be on the cell surface to target. So that's where I think the others have shown that if you look at IHC broadly and the correlation with activity, there isn't a correlation because largely it's in the cytoplasm. But in the amplified patients, it all seems to go to the surface and therefore is targetable. Okay, thank you. Pleasure. I see. Yeah. Thank you. I guess it's a question that's kind of similar or related to the previous questions. I hear I'm an ambassador, so I know little about the scientific part, but I hear some scientist friends say the Nectin-4 ADC probably is very confined to the UC indication. Do you see data that's supporting maybe otherwise? I think data speaks a lot, right? We know that whether it's Zelenectide or it's Padcev, if you go into the frontline bladder cancer patient setting and you combine with Pembrolizumab, you're getting a 60-ish% response rate, all comers. If you go into the Nectin-4 amplified in triple-negative breast cancer as a monotherapy, we're seeing a small data set, but 60% response rate. I think in bladder cancer, an all comers approach makes sense. I think in some of these other tumor settings, I think an amplification strategy makes more sense. It's really back to the FrontRunner, what are they doing and what's showing up? I mean, as far as we can tell, I'm not aware. I don't know what other companies do. I know that we have a very comprehensive patent estate around the concept. I know we've got trials initiating. We've got our assays in place. So I think we're well positioned to be very competitive in this space. What's your research strategy in terms of kind of geographic locations and spread and activity, perhaps in different locations? We're a transatlantic company. Most of our discovery is based in the U.K. Most of our clinical and translational work is based in the U.S. Okay. I think we can wrap up here. So thank you very much. Thank you very much. Thank you, everyone, for coming.