Hello, everyone. I'm Jay Olson, one of the biotech analysts at Oppenheimer, and it's a pleasure to welcome you to Oppenheimer's 35th Annual Healthcare Conference and our discussion with Bicycle Therapeutics, a company with a versatile peptide platform that's working on a number of applications within oncology, but also has partnerships that extend beyond oncology, and it's a pleasure to introduce Alethia Young, CFO of Bicycle Therapeutics. Thank you for joining us, Alethia. Thanks for having me, Jay a nd also, wow, 35 years, that's incredible a nd congrats to your legacy there as well. Thank you. Thanks. Appreciate that. So maybe just for those in the audience who may be less familiar with the Bicycle story, would you like to kick us off with a short background on the company? Yeah. So, you know, we are a clinical stage company, currently in Phase 2, an oncology-based company. And, you know, the science that we're based on are bicyclic peptides. And that's Nobel Prize-winning science that has evolved, and we've translated it from, obviously, bench to the clinic a nd it was founded by Sir Greg Winter of the science. That's where his Nobel Prize-winning science. So, you know, where we are today is that we are in Phase 2 for our lead asset called Zelenectide, which is in bladder cancer. And it's a Nectin-4 targeted agent. I'm sure you guys have heard about Nectin-4 before. But we have that lead program, and we have some other programs as well behind it with different targets using our chemistry and technology that we have. We also are working in the radionuclide space as well because Bicycles, as being what they are, which are kind of delivery vehicles, smaller, more efficient delivery vehicles, can deliver all sorts of things. They can deliver toxin conjugates. They can deliver radionuclides. They can deliver almost anything you want to attach to it. Sort of like an ADC in a way, but it's different and more powerful. That's smaller and more precise. So there's the opportunity for enhanced safety and potential efficacy advantages as well based on the technology, just because you're potentially able to put those higher, just because the therapeutic window seems to be a bit higher using this platform versus others. You know, we're moving aggressively through our Phase 2, Phase 3 study for Zelenectide, and we also have some very interesting things I'm sure Jay is going to talk about going on that we've talked about outside of bladder cancer with Zelenectide as well. I'm sure we'll touch on 5528 and then also probably on the radionuclide stuff that we've started there, and we'll be heading into the clinic hopefully there in 2026. I'll leave it with you, Jay, to fire away on the questions. Okay. Thank you for that overview. That's super helpful. And yeah, let's jump right in on Zelenectide. You had some initial data at the San Antonio Breast Cancer Conference back in December on the combination with Pembro in first-line, oh, sorry. Yeah, first- line urothelial cancer patients. There may have been some confusion regarding the data, and you recently provided some additional clarification. Can you walk us through the key points in the updated data? Yeah. So what Jay's talking about, we had a 20-person study that we presented in the middle of December. It's a first- line bladder cancer using our drug, Zelenectide, and Pembrolizumab in combination. Obviously, open label, so there's no comparator arm. So, you know, a lot of people, just for context, there's this other therapy that I'm sure everyone's familiar with called Padcev, which is on the market in first- line as well in combination with Pembro. So, you know, that's just the level set where kind of people are thinking about some of these comparisons. But, you know, looking at what we generated, we generated a 50% confirmed response rate in that population. Oh, not 50, sorry. Sorry, 65%, and then confirmed 50 in that population. And then we also showed that the ECOG score was 46%, 40% of people had ECOG score of two. You know, that's kind of the people who are more sick than what, you know, we had seen kind of historically before. That's kind of the beginning of the basis. The safety, obviously, uses Pembrolizumab in combination. That, you know, it's a little bit, you know, you obviously have some, you know, more safety that comes into play when you're using another drug in combination. You know, I think what happened in the first situation in December when it was presented, we had still a fair amount of unconfirmed responses. Because the data cut was in September, and this data were presented in December. You know, I think the market was kind of assumed the worst when they looked at what the unconfirmed were, like thinking that maybe the majority of these would not confirm. So we took the opportunity at JPMorgan this year in January to show actually a data cut in January, so it's effectively about, you know, three and a half, four months later. So more patients had gone through the system, and patients are scanned every other month, so there's also an interval there. So, you know, that's where we were talking about the response rate that I just kind of referenced and saying that, you know, we kind of showed a much, you know, kind of higher confirmed response rate. I think people worried that, like, it would just, you know, none of the responses would confirm that we saw previously. But, you know, the reality is most of the, there's still one response that's not confirmed yet. And so, you know, sometime, you know, I'm sure we'll be able to, you know, update on that. But I think people view this data set now as broadly conclusive on the response. We haven't reached a median duration of response yet. And so, you know, I'm sure that will be available at another time. People have gotten some questions about that. You know, I think the safety, the Grade 3 events still look quite low. You know, there's some Grade 1, Grade 2 events, but again, still it's a very small, you know, kind of sample size of people as well. So, you know, that I think kind of rounds out the, you know, the whole thing. And that for us, you know, we were always very confident in the profile of the drug because we've already had this Phase 2, Phase 3 going on in first-line and second-line a nd so I think these results, you know, especially with how high the ECOG status was, meaning the health of these patients, you know, kind of reconfirmed our comfort level with that. Okay, great. And apologies, I may have misspoken about that. The setting of that data, I think I mixed up my December cancer meetings. But I think that's a really important point you raised about the high percentage of patients with ECOG score of two, which is higher than what we saw in EV-302 and EV-103 Cohort K. Can you just talk about how that may have influenced the results and also the tolerability profile of the combo of Padcev with Pembro in that setting? Yeah, no, I think that's a very important call out here. The kind of frame is that, well, you know, I think a lot of us know, you know, have been in the world of cancer for a while, like patients with an ECOG score of two are not functional, you know, pretty much on daily living. You look at, like, our. People make these comparisons, so we have to make them as well. You know, if you look at Avelumab, it was about 13% of people had ECOG two status in that. And so some people have asked us, why do you think the ECOG was so much higher? And do you think there's a read to the Phase 2, Phase 3? I mean, we used very similar Phase 1 sites as well in the study. So I think, you know, we may have gotten a more sick population than what we would perceive in Phase 2, Phase 3. But nonetheless, I mean, it gives us a good degree of comfort. I mean, I know the market sometimes stresses about these things, but it gives us a degree of comfort that the drug is very active in very sick people. And I think that's like one of the key takeaways is that, you know, we showed a very competitive response rate when you boil it down and look at how sick these people were relative. And so that for us, you know, feels very good and is very, you know, very exciting, I would say, you know, heading into like, which I'm sure that you'll talk about, Jay, those selections in the second half of the year potentially. So, you know, we're learning, you know, more, you know, about because we did actually take the cutoff to update, you know, kind of in a pretty speedy way between, you know, kind of the time periods. So, you know, I'm sure when these data become more, you know, presented, hopefully at a medical meeting, we'll get to learn more about the population. But certainly, I think some of the feedback we've heard from, you know, experts have been like, oh, wow, like that's a very, very high, you know, rate or very, very sick set of people that you seemingly, you know, treated in the study, right? I think they found that quite notable because it just is a population that I think when it's all said and done, they, you know, I think investigators and physicians find it different than the typical, you know, kind of, you know, ECOG one and ECOG zero status people. And so I think sometimes that's lost, you know, on people as well, you know, unless you've experienced or had a family member that's gone through this. Great. That's helpful. Another observation that I think a lot of people are excited about is you had a pretty high complete response rate in that study. Yeah. No, that's the confirmed response rate was 20%, right? And that also is a bit higher than what we've seen with Avelumab. Again, you know, it's small numbers, but, you know, the reality is you're going to a population that's like this sick and getting confirmed responses, I think, is also pretty notable. And thinking about, you know, the activity of this drug, I mean, I think, you know, as a company, we feel very confident this drug is very active and still has a differentiated safety profile as well. You know, and so I think, you know, this is these results for us confirms what we saw. Also, I think what you had referenced before a little bit, Jay, was the second- line population in monotherapy where, you know, like we saw a very active monotherapy drug as well with a differentiated safety profile. We think what we saw in combination is very similar to what we saw in monotherapy, which is very competitive, especially on efficacy, but also, you know, I think remains differentiated on safety benefits, which over time, hence why people are so interested in duration response and PFS and things like that, or if people want to see if you are indeed able to take the drug potentially for longer because it's safer, you know, and we know that Nectin-4 is active for sure, you know, what are the real long-term, you know, efficacy benefits? Because a lot, you know, the response rate is still what it is, but it's a marker, right, at a time. But, you know, ultimately when you have, you know, sick loved ones and people in your life, you're looking at survival and progression-free survival and things like that. So that data will begin to emerge, you know, hopefully, you know, over the coming course of time for us as well. I think that'll help to continue to differentiate the medicine. Okay, great. And then I guess looking ahead to additional updates in the second half of the year, you mentioned dose selection, longer-term follow-up from monotherapy in second line bladder cancer, as well as the additional Pembro combination data in first line bladder cancer. Can you just walk us through what the key focus will be for these updates? Yeah, I think you caught most of them. I'll just name all the kind of updates and things to look forward. I said with Zelenectide, you talked about the study called Duravelo-2, which is the Phase 2, 3 study in first line and second line bladder cancer. And so we've said in the second half of this year that we'll be at kind of the end of the Phase 2 portion, this dose selection that people are talking, which is effectively there's a five milligrams and a six and a half milligram dose as they're being studied. And the active comparator is chemo and Avelumab here. And so, you know, we'll hopefully be able in a place to kind of characterize, number one, what dose we're using. You know, potentially those kind of interactions have some, you know, with the FDA and agency as well, which I think people will be looking forward to see if, you know, everything, you know, remains intact with this study, which we remain confident as such. Sometimes we still get questions from investors that, you know, in light of, you know, Avelumab being where it is in the market, like does the chemo Avelumab, you know, comparator still hold water? But like, you know, the reality is that, you know, that's probably an important moment that we'll see at the inflection as well. I think the last piece of it is like, you know, we're keeping it pretty broad on other things that we might show or we just have to think about how that plays out because the way some of the dose selection works is that we will have confirmed responses in some patients, but unconfirmed because the FDA is comfortable with reviewing the data with some unconfirmed as well. And so like we, in light of what's been going on in the market, I think we have to be very mindful about what we choose to show, right? And hope that when we, if that data is shown, it'd be very conclusive so people understand what they're getting. You know, nonetheless, there will be, you know, a commentary around the dose that's being selected, which I think is informative because one is that, you know, people have talked about the weekly versus like the every other week, you know, kind of being a little bit more, you know, these intervals or three and one on week on off. I think, you know, a less frequent dosing interval like the six and a half may show, you know, could be encouraging as well. It continues to, you know, improve and enhance upon patient convenience. That's what we framed. We're kind of keeping it pretty broad for right now in the dose selection part. We've also said, you know, the study that I just talked about technically, which is a Duravelo-1 study, first-line bladder in the 20 people, you know, we will be presenting data in the second half of the year as well, hopefully in a medical meeting, and that's our aspiration, you know, to try to get there. The data cut will be probably somewhat similar to what you've seen in the timeframe just because, like, the timeframes for some of these medical meetings work out to be about the same as when the data were cut in January, and so we'll look to do that, and, you know, over time, you know, we'll hopefully continue to be presenting the data as they mature. The second line, Duravelo-1, which is our second-line part of the study that was presented most recently at ESMO in 2024, we hope to be at PFS at that point to have some conclusion there to help people kind of see, you know, how to think about that. We've gotten some questions because that would be the first time that we'd presented that kind of data. Again, I guess to my point, you know, that we're talking about with like trying to see in how safety really is, how that safety thesis plays out on longer-term efficacy outcomes. You know, we've also talked about in the radionuclide space, which is exciting as well, that we will have some more imaging data for the MT1-MMP, which is the first tumor antigen target that we're going in and getting images. We'll have more patients with our collaborators, DKFZ as well on that. And then the second half of the year for the next target, which is EphA2, we will have some more early imaging data as well. And we can talk about the importance of what imaging data tells us and how it informs moving the radionuclide program overall and, you know, kind of to the clinic. So I mean, those are, you know, I would say the very notable. We have some smaller, like with 5528 combinations, like small cohort studies that may help to inform, you know, the path forward as well there. So those are kind of the main things to look forward to. The one thing that people ask about sometimes that we did not call out here is that we are going to be starting some prospectively defined Zelenectide gene amplification studies outside of bladder, which are going to be very exciting. We presented that data, the early data, you know, from retrospective at San Antonio. And I think it kind of got lost in the shuffle that, you know, we were able to use gene amplification and significantly increase, you know, not significant by statistical terms, but by numerical terms, you know, increase the efficacy that's been seen in, you know, patients who had, you know, breast and lung cancer. And so, you know, I think starting those studies and we have some more retrospective work going on where we've opened up Duravelo-1 breast and lung as well that we can talk about, Jay. And so, I think that we haven't said when that data are coming, you know, and then specifying that's coming in 2025, but I think that's something else just to kind of keep on in the hopper, you know, as you kind of think about the Bicycle story because that's definitely something that's a priority. We just, we wanted to get some of these studies underway and going before we provide, you know, kind of a guidance on when to think about that. And we also want to watch how many people we want to kind of really have before we go and communicate to the street. Okay, super helpful. Thanks for walking us through all those key data readouts. And I want to follow up on the work that you mentioned in Nectin-4 amplification, really innovative research you guys are doing. Can you just talk about the rationale behind using Nectin-4 amplification as a biomarker? And is Nectin-4 amplification correlated with a poor prognosis? And any update you can give us on the Nectin-4 assay? Yeah. I mean, you know, I think the way I think about it is that protein expression to some degree here isn't going to be the best predictor in like trying to figure out kind of to tease out what happens as patients progress through their experience, you know, with these different cancers that are associated with Nectin-4. So we, you know, kind of the gene copy or gene amplification seems to be an important signature and especially more important as like metastasis occurs. And so it's distinguishably different, right? It's from some work with, you know, Niklas Klümper and his teams in Germany as well that we've been collaborating with where we saw, you know, you would look at the population as a whole, like all-comers, like we had Duravelo-1, we had breast and lung populations, and we showed that data, you know. I would say we had an R&D day in 2023 and we had kind of talked about it over 2024, and this is in the whole population. You see the teens of a response rate. Then, you know, you go and you look at other companies that have generated all-comers, breast and lung data, and they're in the teens too. And so then, you know, a lot and some people have done the work with protein expression to see that it doesn't really, it seems not to be, doesn't really enhance the response rate. The potential like gene copies that you have, gene amplification seems to, because when we went back and looked retrospectively in light of some of the work that Niklas Klümper and his teams are doing, you know, and again, it's retrospective because you're taking a data set that was like, you know, 20 people, and then you're trying to find the amplification signal. But when you looked at it, you know, you would see in small cohorts, and this is what we presented at San Antonio Breast, that you're talking two, three times the response rate. Like in the breast cancer in the retrospective look, if they were amplified, the response rate was in the, you know, in the low 60s. In lung, it was probably, you know, somewhere like again, like two times, you know, increased as well. So you're seeing something that's like people are seeing responses 50%-60%, you know, in these two kind of very, I think, you know, very, very high unmet need still types of cancers. You know, as much as we have lung and breast cancer medicines, there's always need for more. And there's always need for kind of linking, you know, the personalized genetic signature of these things. So I think that really comes into play that seemingly this becomes more of a factor as the patient metastasizes, that the amplification signal is like something that is teasing out people who, you know, tend to seemingly respond. Like, you know, their response is almost like a PD-1 positive if you thought about something like that, whereas like these people, if the signature comes into play and the gene copies increase, then they seem to be more, you know, selected or able to like respond using a Nectin medicine. But the problem is, is that you need to find the gene signature. And that's where you're talking about with the diagnostic, because if you don't, you would have the same thing. And if you looked at classical like protein or IHC, you probably would not see this. You wouldn't see this, you know, pronounced of a difference. And so I think what we're talking, you know, what we're really focused on this year is we've started, we've opened up Duravelo-1 again in breast and lung to enroll more patients because we need a safety cohort. Again, that's all comers. But also it helps us, you know, understand what the signal is, like meaning the gene, how many percentage of people, because roughly it's, you know, kind of 25%-30% of people have amp signal, so I think, you know, we want to go back and look and see now that we're enrolling it again, all comers is at the same signal that we'll see, and then we've also started, you know, prospectively defined studies. We're going to start them, Duravelo-3, 4, and 5, which are Duravelo-3 is breast, Duravelo-4 is lung, and Duravelo-5 is pan-tumor. They're going to start over this year with the first one being in breast, and so that would use a diagnostic. So that's what we've been, you know, up to. I would say over the past, you know, months is really getting these studies standing up and setting up a situation if we are to see a signal that is similar to what we saw in the, you know, the information at San Antonio, that we would be able to move pretty aggressively into kind of later stage development because, you know, now it's still, this is Zelenectide, so it's the same drug that we're using in bladder. So you're starting to get, you know, you have an ample amount of people that have been treated with this medicine now at this point, we're in the 400s, you know, if you go back and think about it that way. You know, we're trying to set ourselves up in gene amp to be able to move hopefully potentially very fast if we are able to see something that is similar to what we've seen before. Okay, great. It sounds like the work that you're doing with the Nectin-4 amplification is really opening up the possibility for patients to benefit from Zelenectide outside of bladder cancer. When do you suppose we might see data for Zelenectide in breast and non-small cell lung cancer? Yeah, we have a set. But, you know, I think, and that's kind of what I was getting at in the prior walking through timelines is that we want to get these studies up and going, and then we want to, you know, kind of think about what, how many people do you need before people find it very conclusive, right? Because I do think we believe that we are in a market where people, you know, want to see enough people and enough time that they're able to make heads or tails. I think we're not in an era where people, you know, look at data and say, "Oh, that might be okay," or that, you know, or those three people maybe, that's okay. No, it's like the bar has certainly increased, I think, across biotech in general, and so we have to, you know, move with that. So we, to be frankly, just wanted to get the studies up and running. And because like once you say give guidance on timelines, you can't really take it back. So we left it open-ended, but I can certainly say, you know, as an organization, this is like one of our top priorities, you know, besides, you know, the enrollment of Duravelo-2. But this is, you know, high, high up the food chain because we understand the potential opportunity that could be much more white space for us. And the ability that if we're able to see such a tremendous enhanced response, the ability to potentially move fast. So, you know, like the great thing is you can take guidance away, but you can put it out there if something changes. So I think that's how we're kind of thinking about it, is that we're moving fast. We want to see though how, you know, some of the, you know, timelines get going with this, and then, you know, we might think about when we would say and help people understand. Because certainly people are, you know, excited about it, but they want to see the information and we're very cognizant of that. Okay, got it. Well, we will look forward to that. And maybe just from a competitive perspective, is this innovative work that you're doing on Nectin-4 amplification something that your competitors can replicate, or does this effectively build a sort of a differentiated barrier around Zelenectide in the Nectin-4 space? I mean, certainly I hope. I mean, we have, you know, we've done a lot of work with the IP and different things on this, and we're trying to ring-fence things as much as one can, and that's also why urgency, you know, moving fast is very important. Because we do think we're onto something that, you know, others haven't quite clicked into yet because of our work with Dr. Klümper and his teams, and so we just have, now we want to see if that really plays out. Because I think it could be, it could be incredible for patients, you know, to get that dramatic of an enhanced response rate, and we all know Nectin-4 is, you know, expressed in many different tumor types beyond bladder. I think there's been a challenge in how to crack the code. So this might, you know, I mean, this is how we hypothesize that one might crack the code, so we're really excited about it, I mean, and trying to move as fast as we possibly can and create the protections and things around it that would enable this to be, you know, something for us that we think we could be potentially first in class, and, you know, obviously, hopefully best in class. All right. Excellent. That's super helpful. And I want to make sure we talk about your radiopharma franchise. You mentioned some of the key catalysts there. Can you just talk about your strategy? You have some programs that are partnered. You have an innovative new program that's wholly owned. What's, I guess, what's the sort of strategy in radio? You know, I think for us, you know, we had the collaborations we did with Novartis and Bayer. But those were in, you know, 2023 or so when we did that. But our view is when we want to build, you know, our own radiopharm capability, I think learning from people who are experts in the area, it never hurts, right? And I would say both of those players are experts in the area. But also, you know, as we've gotten more capital and we've gotten more validation around our platform, our linker platform in general, that we really think this is now the time to strike. Because I think when you think about specificity and small, precise, you know, kind of conjugation vehicles, for lack of a better word, that they're only like way, way, way more important with delivering an isotope, you know, versus a toxin. So we think that our, you know, our platform is uniquely positioned for that. And also we think that we are able to deliver more different tumor antigen targets beyond, you know, PSMA and somatostatin. So that's why we're going after MT1-MMP, and then EphA2, both we know a lot about the biology. And I think we also have the ambition to be isotope agnostic, right? Like, I mean, I think we want to try our linkers with, I mean, all the isotopes. But, you know, I think, you know, and we'll see maybe one might be better than the other. But I think we want to make, we want to try to really be a, you know, a next generation radionuclide player and build upon, you know, kind of the successes that have been seen here. Because I think, I think this modality is here to stay for now. But I do think, you know, there are some limiting factors as it relates to, you know, kind of the therapeutic windows with some of these and the limitation and just antigen targets that you can go after. So we're really trying to broaden that aperture. And so the imaging studies are important because not only are they important for radionuclides, but imaging is important potentially for our toxin conjugates. Because if it shows that, I mean, obviously if the tumor is being delivered, you know, if we're delivering to the right place and images show that, that's a powerful tool in validating, you know, first-in-class novel targets, stuff like that. And so that could really open up, you know, like I said, for not only just radio, but just for toxin as well, be a way to really help us understand, you know, and have a greater confidence interval going into it. But, you know, we're obviously doing those imaging studies and that work. And we're encouraged by what we're seeing. And, you know, we're looking to kind of, you know, but you also have to do the work to get to the clinic. So we're doing that work, you know, in parallel to really be able to position, hopefully to have our first Bicycle-sponsored therapeutic. Because the current work we're doing is in collaboration with DKFZ in Germany, who many other people have used. But, you know, our goal is to build our own, you know, independent capability. We think obviously time is right. We think we have, you know, we could responsibly allocate capital to this. We think this is like a high value for patients and potentially for shareholders as well to really broaden out this modality, which I think, like I said before, is here to stay. Okay, great, and you guys have a lot of experience with your BTC programs, obviously Zelenectide, BT5528 and now your TiCA program also in the clinic. How can you leverage some of the lessons learned from your BTCs and other programs for your BRC programs? I mean, I think when you look at the BRCs that we're going, I mean, or the programs that we've talked about, tumor antigen targets, there are two that we have a lot of biological experience with from the toxin conjugate world. And so we know that these, even though they're kind of, you know, first in class and that it's been harder for some, you know, ADCs, I think, to target some of these, is that, well, like for example, with EphA2, we've had quite clean safety with our toxin conjugate. We've dosed 100+ people easy with that right now. You know, that gives you a little bit more flexibility. You could do, maybe you do toxin conjugate in one indication, maybe you do radionuclides in the other. So that's something. And then when you have the imaging, you know that you're going to the right place. And so there's like a way that like you start to meld all this together to like kind of unlock more power in our platform, more precision as far as like efficiency and being able to kind of know this is the modality to use, this is the tumor antigen to use, and this is how we're going to use it. I think being able to figure it out as fast as possible is like kind of the power of being a true kind of next generation also precision medicine-based company as well. Okay, great. We're just about out of time. But is there anything else you'd like our audience to know about Bicycle Therapeutics? No, I think we've covered all. We have a, you know, exciting second half of the year with a lot of the catalysts and events there, and I think, you know, we have a lot of things that are starting to build beyond, you know, first line bladder, second line bladder, which, you know, a lot of people focus on, but we are very focused as a company on, you know, continuing to evolve opportunities, finding different ways to leverage the platform, finding places where we can be first in class, so these are all things that we're doing, they're like certainly percolating, so I would say stay tuned on some of the things that we've discussed today, and of course, Jay, it's always a pleasure to chat with you. Likewise. Well, thank you so much, Alethia. I really appreciate the opportunity to learn more about all the impressive work you're doing on behalf of patients. And look forward to future updates. Awesome. All right. Thank you, Jay. Thanks, Alethia. Thanks to everybody for joining us.