All right, good morning. Thank you, everyone, for joining Jefferies Healthcare Conference in London. My name is Clara Dong, one of the biotech analysts here at Jefferies. For this session, it's my pleasure to welcome the Bicycle Therapeutics team. We have the Chief Executive Officer, Kevin Lee. We have the Chief Financial Officer, Alethia Young, and Chief Strategy Officer, Jennifer Perry. Welcome, team. Thank you. Thank you. Before we dive into specifics, could you start by giving us maybe a high-level overview of Bicycle? What have kept you busy for the past year? What is Bicycle's technology platform, and what is really making it differentiated in the oncology space? Sure, thanks, Clara. Before I start, many thanks for the invitation. It's great to be here again, and looking forward to the conversation. At Bicycle, we work on this very novel technology based on bicyclic peptides. These are small peptides which are arranged into two loops around a small molecule central core. The bicyclic nature of them makes them very constrained, so rotationally very fixed in their ability to change conformation. Very high affinity molecules, very high selectivity for the target. The molecules were originated from the work of Sir Greg Winter, who was essentially trying to mimic the antibody paratope. You'll all know that antibody is very large molecules. The business end of the molecule is the paratope, which binds the antigen. There is a large part of the molecule which performs other functions. Sir Greg reasoned that in terms of a delivery system, you do not want the large size of the antibody, which really restricts the ability to penetrate into tissue. You do not want the long circulating half-life of an antibody. You certainly do not want all the off-target activities, which are mediated through the Fc domain. There is actually a family of receptors named after the Fc domain. The concept is that this is a next-generation targeting technology. We can use it to deliver many different types of payloads. We are using it to deliver many different types of payloads. The primary focus we have had over the last couple of years is really focusing on toxin conjugates. With that, our lead molecule, of course, is zelenectide pevedotin, which is a Nectin-4 targeted MMAE drug conjugate. That is really—we spent a lot of time working on zelenectide pevedotin these last few years. We are in a phase II, III pivotal study with that molecule in bladder cancer, as well as exploring it in other types of tumors. We have a very deep pipeline behind that. We have a molecule, BT5528, which targets another tumor antigen called EphA2. Behind that, we have, I think, a very significant effort, both in next-generation drug conjugates and, most excitingly for me, I think, in radio conjugates. That is what we have been doing for the last 12 months. Awesome. We'll make sure we'll talk about all those programs in the discussion here. Maybe let's start with zele, the novel Bicycle Toxin Conjugate targeting Nectin-4. Where do you see this program's value proposition in urothelial cancer, especially as we are all aware of the market where PADVEC actually has a pretty strong presence here? Yeah, maybe I should start, and then I'll let JP jump in on what physicians think. I mean, from our perspective, I think PADCEV is a great drug. I think it validates the concept of a Nectin-4 MMAE conjugate in combination with pembrolizumab. It's obviously made great inroads and a remarkable profile in urothelial cancer. I mean, we're struck also, besides the efficacy, it does come with a lot of toxicity. I mean, we note 70% neuropathy, 70% skin toxicity, a black box warning, fatalities due to skin toxicity, and a 40% withdrawal rate. I think as a community, we have to do better than that, personally. I think that's what we're trying to do with our bicycle molecules, trying to develop molecules that are equally or more efficacious, but without all of this safety overhang, which really is a huge burden for patients. But JP? In our market research, KOLs and academic community physicians, basically, they want something that, number one, more patients can take. Number two, it's more tolerable. Number three, when they're on it, they can stay on it longer. A profile like zelenectide pevedotin that's evolving in our monotherapy in combination trials with pembro could deliver that. Kevin mentioned the skin rash and neuropathy. Those are the number one and number two reasons people have to stop EVP. They always say, if you can solve for those, then you have a winner, especially if you're still bringing the powerful efficacy. You do have some phase I and II data in urothelial cancer. Maybe first, can you talk about those data you've shared in the past? When you talk to physicians, which aspect of those data you've shared in the past actually resonates the most with them? Yeah, the data we've shared to date comes from our phase I studies. Obviously, the phase I escalation is in very late-line patients. More recently, we've shared data in a first-line cohort, but in a phase I unit, where I think the patient's median age was about eight years older than the comparative PADCEV data. Half of the patients had a low performance status compared to only 10% of the patients in the PADCEV cohort. I think what we've shown is comparable efficacy, but very differentiated safety. We don't see these severe cutaneous adverse reactions that really plague PADCEV. We don't see the profound irreversible neuropathies that often accompany PADCEV. We feel that the drug is going to perform better as we move into that first-line setting into relatively healthier, younger patients. We're really eager and looking forward to sharing those data in due course. JP, anything to add? Yeah, so I think we should talk a little bit about the market. Where does EVP sit? Right now, EVP, and at least in claims data, has a little over half the metastatic first-line bladder cancer market. When you query what are the other 45% of people taking, it's usually single-agent IO and still chemotherapy. When we talk a little bit more with them about, well, why are they not getting EVP because of that great efficacy, they always say these people are usually a little bit too frail or just not good candidates for EVP because of the safety profile. We know from our market research that a 20% or so improvement in all-grade skin rash, all-grade peripheral neuropathy, and an improvement in those SAEs in particular would drive preference for Zele Plus P. In the end, it was about 84% of academic and community physicians in our study said they would select Zele Plus P at time of approval and even switch because of that profile. Again, you're getting that powerful efficacy in the combination of Zele Plus P, but you're improving on those toxicities that make them have to stop EVP. That's very meaningful. Great. You have also started a registration trial in bladder cancer. I think in the past, you have talked about the opportunity for accelerated paths. I know a lot of your focus is on frontline. Maybe just share more details about the study design and how you are thinking about the opportunity for zele in bladder cancer. The study design is quite complicated. It's a seamless phase II, III study, which involves dose optimization followed to potential regulatory approval endpoints. In the first phase, which we've just completed, we're really—and as you say, there is a first-line cohort and a second-line cohort. Let's just focus on first-line. The second-line component is really to understand the contribution of components and to actually enable the first-line process to be seamless. We're essentially taking two doses of zelenectide in combination with a standard dose of pembrolizumab. After 30 patients have been enrolled, we are then taking a cut of the data, looking at the efficacy and the safety. Based on the overall profile, we'll select one dose to continue with. At the same time as we've been recruiting those patients for that dose optimization phase, we've been recruiting patients to our comparator line, which is chemotherapy, followed by a nivolumab. Once we have the dose optimization, we'll continue recruiting. Based on currently, an ORR endpoint will seek accelerated approval, and obviously then do a confirmatory final piece for full approval. That's the design. Coming out of a very recent Q3 update, you shared some updates on zele, particularly around the timeline for dose selection in the pivotal cohort in combination with pembro. Maybe just tell us a little bit more context behind those changes and how are they positioning Bicycle for long-term success? Sure. What you're referencing is that at the last quarter, we set the timeline by which we will update the street around DV-2, kind of effectively the end of phase II will be in the first quarter of 2026. Previously, it had been the fourth quarter of 2025. Not a major change, just to put it in context. Why we thought about this way, number one, we're running a global study. Duravelo-2 is a global study in hundreds of sites around the world. We wanted to, in light of everything that's going on, get feedback not only just from the FDA, but from Europe and the U.K. as well. We also think those are significant and meaningful opportunities and want to make sure there's alignment on the study that we're doing. We decided that it's like you take a little bit of a delay in time to get those answers. But we think taking that time delay is well worth getting those answers and continuing into phase three with the full confidence around the global study. Given that you mentioned you were talking with regulators in different regions, in the U.S., U.K., and Europe as well, do you think there will be any difference in terms of how different regulators perceive your ongoing trial? We would hope not, but it's always good to check and make sure. I think that's a prudent step that we're taking. I think we have consciously accelerated our interactions with EMA and MHRA so that we can get everything to the same time point and then make a holistic decision. I think it was a—I personally think it was a good strategic move to do that. Got it. What could be the possible scenarios after your regulatory discussions next year? Besides the dose selection, what else should we expect after the meeting? Realistically, they are unchanged from what we said in the fourth quarter. Just to make sure everybody's on the same page, we've talked about zelenectide and what type of profile of asset would continue us to move forward. Effectively, we've said our base case has always been with this asset: efficacy as good as and safety better, right? Would enable us to continue forward. Efficacy better and safety better also enables us to move forward. If the profile were indeed on efficacy, like less good, and we haven't said what that number or how to think about it, we probably wouldn't move forward. The reason why we did this is because we're going to issue a top-line press release. This remains unchanged as well. Except now it's in the first quarter, and the top-line press release would go something like this. It's like, here's the dose we've selected. Because if you remember in Duravelo-2, there were two doses. We would probably just say, hey, we're moving into the phase three portion of the study. Also, data for Duravelo-2 will be at a medical meeting somewhere in 2026, right? We get the question a lot from investors, like, well, if you're going to put that not a lot of information in, then how do we know is it good or bad? We've tried to just make the clear assertion that if the data on efficacy were not good enough, we would not move forward, right? Now, basically, we are well capitalized. We have $648 million as of September. There's no need for us to particularly show a couple of pieces of information in a press release. As a company over, obviously, 2025, we prefer to show things at medical meetings and its completion. You can look at it and assess for yourself. In a press release, if it did come out and said that, you should interpret what we're saying, right? I mean, that's kind of the case, right? We've tried to bridge that so people have some context around a top-line press release, but also kind of know that we wouldn't take a profile that we think is inherently inferior against the kind of—because we know there's this other drug called PADCEV on the market. I think that's what we're trying to kind of put people to. This is an unchanged dialogue throughout the entire year. I think as many times as we've said it. Just the fact that it's now in the first quarter versus the fourth quarter. Those selection data at a medical meeting next year. What is the scope of data we should expect to see there? I mean, as much as we have, right? I mean, that's the whole point, right? It's not going to be like, oh, here's the response in this. It's like, as much as we have and the maturity will allow, it will be showed in whatever format it comes in. We're accepted, right? We have to be accepted. You should accept it. Oh, you would see probably all the efficacy information we have. You still can't show things that are particularly immature. Sometimes it's not helpful, right? You would see safety. I mean, at this point, the safety is probably relatively mature if you think about it that way. I mean, we'll show as much as we possibly can. In addition to that, we've talked a lot about not only would we show that, we are thinking about packaging kind of data at medical meetings next year. We have a program. We have two targets of focus that we talk a lot about: EphA2 and Nectin. You would think maybe we would also be showing all the information related to the Nectin program in addition beyond Duravelo-2 in that format as well. I think what we're trying to do is create a holistic profile for each program to the targets that we have so that people can understand kind of the totality of what we're doing. We're now just almost like we're close to slightly under 600 people. We want to show things in a very full way rather than like, oh, here's a piece here and here's there. We do not want to show things that are inherently immature because we all know that that comes with a lot of debate and controversy about how it matures. Why not just let it mature? That's fair. I definitely want to touch on EphA2 shortly, but I want to briefly touch on the other opportunities for zele. I mean, you've presented some post-hoc analysis of zele in non-small cell lung cancer and asthma. What are the key takeaways there? How do those findings kind of inform zele's potential in Nectin-4 amplified solid tumor overall? We're super excited about the opportunity in Nectin-4 amplified tumors. We actually discovered the amplification ourselves. You see the gene is amplified in somewhere between 20%-30% of all bladder patients, all breast patients, all lung patients. We presented some data from our phase one study where we did retrospective analysis, and we can change the response rates in breast and lung from being in the teens, so 15%, 16%, 18% to between 40%-60% when you select for Nectin-4. We spent a lot of the first part of this year really establishing the assays, getting FDA clearance on the assays, setting up the study. Studies are now actively enrolling, progressing very well. I think that really provides a really good sort of blue sky opportunity for zelenectide in an area where there is, I think, a real urgency to finding new drugs, particularly in breast and this post-Topo kind of setting. I think zelenectide really has an opportunity to do very well there. We are really excited about those studies and look forward to sharing data. Maybe let's pivot to radio pharma here a little bit. Maybe remind the audience here, what's Bicycle's approach in Radio Farm? What really sets it apart in this space here? I mean, Bicycle has been exploring radio pharma in, I would guess, in stealth mode for at least 10 years. We were publishing in this area before anybody was excited about it. I think what makes it—our approach is, I guess, slightly different in that we are isotope agnostic. We do not think there is one isotope which is going to fit all indications and all settings. We have access to a range of isotopes. The other thing is that we have a very large bank of Bicycles to a range of tumor targets. We do not need to chase after yet another PSMA or some other statins. We are going into very blue sky targets with multiple agents bearing multiple isotopes, and we will select the best molecule to go forward. I think the radio isotope space really lends itself to the small molecule, short, rapid tumor penetration, and short systemic half-life that Bicycles have. We really think this is a big opportunity for the company. Maybe let's talk about EphA2. I mean, what makes this target compelling from a scientific and clinical perspective? EphA2 has been a very high value target for the industry for many years, but there are no EphA2 molecules because you can't develop an ADC, or nobody has been successful in developing an ADC to EphA2 for reasons we don't fully understand. All the ADCs have had this very extreme, peculiar coagulopathy where patients just bleed. The only molecule—and that can be seen in actually the preclinical models—the only molecule that was taken into patients was the MEDI molecule MEDI-547, which in the first six patients at the lowest dose, they saw the bleeding events. We've now dosed over 160 patients, and we don't see bleeding. We see—I said it a couple of years ago at Jefferies—we see a safety profile for that molecule, which is better than any ADC. The more patients we put it in, the better it looks, I think. We think this is a big molecule, a big opportunity. Everyone's focused on zelenectide. We just moved this molecule forward carefully, thoughtfully, given the safety events that have happened with ADCs. I think next year is going to be quite an important year for BT5528. You've also recently shared some first-in-human imaging data in pancreatic cancer. Maybe just tell us, what do those images tell you, and then when should we expect more data from them? One of the beautiful things about the Bicycle platform is it's so versatile. You can put any payload on it. We've shown we can do it with small molecules, cells, antisense, nanoparticles, you name it. The Bicycles can drive the cell activity. We think that lends itself to a next-generation type of drug development whereby you can use an imaging agent. Historically, if you think about it, you have a target, and then you rely on historical legacy IHCs, which are taken from small biopsies of the tumor, which might have been taken five years ago and no reflection of what's happening in that patient at the current time. Imagine a world where you can take the same agent with just a different payload and give that to a patient, not only to show that the target's expressed, but the actual therapeutic binds to it. I think what we showed—we've shown it a couple of times now with our MT1 program. We've shared data this year, and very recently, we've shared it with our EphA2 program. We've known that EphA2 is highly expressed in pancreatic cancer. About 80% of patients are believed to express EphA2. The question then becomes, does the drug get to its site of action? Can it actually get in there, and can it bind? I think what that data shows very early, very preliminary, is that indeed it can. That obviously opens up a whole range of horizons for that molecule. You're also exploring ovarian cancer and bladder cancer as well? We've explored across a range of different tumor types. Got it. When should we expect next update for? We've guided that we'll provide a very significant update on BT5528 in a medical conference in the first half of 2026. There'll be more images for EphA2, right? We shifted, as you know, the BT5528 study, which is a safety study. We'll be packaging that hopefully into an update. Hopefully, we'll be talking about the planned future, right? I think that's what we mean when we say significant. Just kind of helping people understand what's the next pathway for BT5528, where we're going, and why we have evidence to support that as such. That's helpful. Lastly, maybe just want to talk about the balance sheet, the cash runway, and any milestones investors should watch for the next six to 12 months? I mean, we have cash into the first quarter of 2028. We reported $648 million as of September. I mean, we're well funded to do the things that we need to do, including complete the Duravelo-2 study out to the end of phase III. Obviously, many of the things we've talked about here, achieving proof of concept, hopefully for BT5528 and for radio pharmaceuticals as well. I think if we do not include also in that assumption anything around any potential partnerships or deals. I mean, we feel very good about the capital we have. We know the environment we're in. We want to be as judicious as possible though as well. We really do try to hold the programs to a high standard and move programs that are the best programs forward, right? That is always going to be the case because we have a platform that can do a lot. We do not have to hold on to one thing if it is not hitting the bar that we think will get us to the best outcome for patients, to be honest. Great. That is very helpful. That concludes our session here. Thank you, Kevin, Alethia, and Jennifer. Thank you to the audience for joining us here. Enjoy the rest of the conference. Thanks, everyone.