Everyone. My name is Kevin Lee. I am the CEO at Bicycle Therapeutics, and it's my absolute pleasure to welcome you all today to this, our first R&D Day. I hope you find the day interesting, informative. Most of all, I hope you leave today as excited about Bicycle as we are. Let's start with our forward-looking statements. So our aim today is to provide you with an update on the progress we're making across our entire clinical portfolio. We have three wholly owned programs on the clinical investigation. We're very excited about what we're seeing. We also want to tell you about our next generation of molecules and our forward-looking strategy. But before we do that, I want to start by making a few opening remarks. Before I joined Bicycle, I was an SVP of research at Pfizer, and in that role, I, I worked on, I reviewed, I invested in a very, very broad range of different therapeutic modalities. And then one day, someone came to me and told me about the Bicycle opportunity, and they told me, "This is a company that works on a completely new, differentiated, unique therapeutic modality based on bicyclic peptides, co-founded by someone widely believed to be the godfather of antibody therapeutics, who themselves believed this was a step change in technology." Now, I found that intriguing, and so I went and investigated the opportunity in more detail. What I saw was a company... A company at an early stage, but a company that I truly believed had the opportunity to address one of the key challenges that faces many of the modalities of today, the concept of precision targeting. Now, we believe that the Bicycle, Bicycles can, can influence, can be used in a very broad range of different therapeutic areas, but you have to start somewhere, and we chose oncology to start. Every cent of every investor dollar that we've obtained, we've invested in our oncology pipeline. But we care passionately about getting this technology into as many therapeutic areas as possible. So we've used non-dilutive sources of cash to fund our exploration into these other therapeutic areas. As we've been successful, we've generated revenues which we can invest back into our oncology pipeline. So today, you're gonna hear about our first three programs. Three programs that are at a relatively early stage, still in Phase I escalation expansion studies. But I think the data is convincing, and I think it's becoming increasingly more difficult to, for people to argue that this technology is not offering a step change, a fundamental change in tolerability profile. We think we can offer patients the opportunity not just to live longer, but to live well. Now, to understand the full Bicycle story, it's important to understand its origin. And to do that, there's no better person than the co-founder of Bicycle Therapeutics, the godfather of antibody therapeutics, the Nobel Prize-winning scientist, Sir Greg Winter. So I'm delighted that Sir Greg made a short video to share today, just a couple of days ago. So I'm going to hand you over to Sir Greg. I'm Sir Greg Winter, one of the scientific founders of Bicycle Therapeutics. My main claim to fame is as an inventor of technologies for making human and humanized antibodies. These include the humanized antibody, Keytruda, currently the world's top-selling pharmaceutical drug, and the human antibody, Humira, which until recently was number one. There is that share of the Nobel Prize in Chemistry for the development of phage display of peptides and antibodies. This is the technology that was responsible for Humira and that now underpins Bicycle Therapeutics. Antibodies have proved very successful pharmaceutical drugs, but they do have some limitations. In particular, their large protein molecules do not penetrate as well as small chemical drugs deep into tissues and solid tumors. For many purposes, it would be ideal if they could be much smaller. But how can this be done? The solution came from an unexpected direction. There's a theory that proteins were generated in evolution from smaller peptide segments by exon shuffling, in which the peptides collapse on each other to form a stable structure. We'd been trying to mimic this process in the laboratory and discovered that one of our stable primordial proteins was bright red, having folded up around a heme group. The heme was helping to stabilize the protein. This led us to the idea of making small protein mimics by wrapping a polypeptide chain around the chemical core. To keep it in place, we anchored it to the core with covalent bonds. Three covalent bonds generates two peptide loops anchored to the scaffold, essentially a bicyclic peptide. In this form, it's structurally analogous to the architecture of antibodies, which consists of a large protein scaffold surmounted by six loops. With Bicycles, we have a tiny chemical scaffold with two loops, 100 times smaller than an antibody. Despite their small size, we can make Bicycles with potent binding activities to targets of pharmaceutical interest using phage display technology... By linking Bicycles together, we could also create molecules that would take immune effector cells or a toxin to a tumor. In this way, we can mimic the activity of antibodies. But there are also differences when compared to antibodies, and potentially advantages. Unlike antibodies, we can synthesize and chemically modify them. Unlike antibodies, they penetrate quickly into tissues and are excreted through the kidneys rather than the liver. Furthermore, they're much cleaner than antibodies in that they don't bind to cells and receptors other than those intended, unlike antibodies, which bind to a whole range of cells, some unintended. This sits at the heart of what the company calls the Bicycle Advantage. In essence, we've created a modality that can get into the patient, do the job required, and then get out. We have built a precision-guided transport mechanism. This is a completely novel modality, potentially best in class. I've no doubt that Bicycles will work across multiple therapeutic areas. You'll hear about some of this later today. We don't underestimate how challenging it is to introduce a new modality to the healthcare system. The team's job is to make this happen. I'm going to hand you back to them to explain just how we're going to do that. Many thanks to Greg for sharing that with us, and on a personal level, many thanks for all the help and support you've given me over the years. Greg talked about this concept that we talk a lot about in Bicycle, the Bicycle Advantage. What is the Bicycle Advantage? Well, I'm going to show you what I think is the Bicycle Advantage in the next slide. So what you see here, this is a time-lapse video recording taken in five-minute frames over the course of one hour. Now, what we've done is we've taken a Bicycle with a high affinity for a specific tumor antigen. We've conjugated it to a radio imaging agent, and we've injected it into a xenograft model. So at the start of the experiment, we've got this here, we're five minutes in, and due to the small size of the Bicycle, 100 times smaller than the antibody, that sea of red shows that the small molecule nature enables the Bicycle to rapidly and extensively penetrate into all the tissues, including, in this case, the tumor. Now, we can tune the PK of our Bicycles. We can generate Bicycles that have a long half-life or a short half-life, and when you're delivering a cytotoxic agent, we choose a short half-life agent. So as you can see over the course of the hour, after initially penetrating all tissues, the agent is rapidly eliminated from all the tissue beds, apart from the tumor. The high affinity of the Bicycle means that it's bound to its target in the tumor, and we now know that it's retained in the tumor for several days. We think that's the Bicycle Advantage. Why do we think that's the Bicycle Advantage? Well, for us, it stands to reason that if you limit the systemic exposure of any drug, you're gonna minimize the systemic toxicity, and even more amplified in the case of cytotoxic agents. If you limit the systemic exposure, you limit the toxicity. If you limit the toxicity, you maximize the tolerability. If you have a more tolerable agent, you can give that agent at the optimal dose, in the optimal way, the optimal regime, for the maximum period of time, and through this enhanced tolerability, we think it enables us to potentially generate longer therapeutic responses. Again, I think it stands to reason that if you have a more tolerable agent, it's going to be more combinable with other drugs. And through enhanced combinability, I think it's possible to get deeper and broader responses. So the idea of increased tolerability leading to longer responses, leading to improved combinability and greater and deeper responses, I think that's the Bicycle Advantage. This idea that it's possible to enable patients to potentially live longer but also live well. Now, I'm very proud of what we've achieved at Bicycle since our IPO. We've industrialized this Nobel Prize-winning science. We have a phenomenal success rate in our screening platform. I think best in industry, particularly when you think about many of the targets have been very challenging to drug. We have three wholly owned molecules under clinical investigation. We've established five partnerships with some of the top biopharma companies on the planet. We care a lot about ESG, and I'm really proud of the fact that we're one of the top-ranked companies for ESG across the whole of pharma. We've raised $628 million in equity financing. Now, if you think in our last quarterly update, we had $570 million in cash, I think we've been incredibly thoughtful and productive in the use of our investor dollars. We've raised $213 million in non-dilutive financing, which we've invested back into our oncology pipeline, as well as exploring a range of other therapeutic areas such as neurology, neuromuscular, and others. So where do we go from here? Hopefully, you're as excited about the molecules as we are, the ones we showed you today. It's gonna be imperative that we execute well on those molecules, and through executing well on those molecules, we believe we're gonna become a leader in the next-generation therapeutics for solid tumors. You're also going to hear that we've taken the learnings from our clinical programs, and we've applied those learnings to our next generation of molecules, and we're even more excited about what's coming through. And we're going to use those molecules to expand our footprint and enhance our leadership in the oncology field. And we're also going to continue to build ever more innovative collaborations and partnerships, both in oncology and outside of oncology, to ensure that we get this incredible science into as many hands as possible to maximize patient benefit. We're very committed to making sure maximum number of patients benefit from these technologies. All of this is only possible if you work with a very dedicated and talented team of colleagues. I'm absolutely delighted that some of those colleagues are here today and will be our speakers, taking us through the agenda. I'd like to introduce Nick Keen, our Chief Scientific Officer, Santiago Arroyo, our Chief Development Officer, Jennifer Perry, our Head of Commercial, Mike Skinner, our Chief Technology Officer. This is the agenda we plan to run through today. We're going to spend the first hour or so talking about Nectin-4. Now, for us, Nectin-4 is a very high-value target, very highly and broadly expressed across many tumor types. For us, for a long time now, we thought about a multifaceted approach. We talk about our portfolio of Nectin-4 molecules, and we're going to tell you about the advances we've made here and how we think about the future of these molecules. Then we'll have Q&A. We'll take a break, and then we're going to come back and tell you about another target, and this target is slightly different. So Nectin-4, of course, is a precedented target, but it's a target that has encountered some tolerability issues. In the second session, we're going to tell you about another high-value, highly expressed target across many tumor types. But this is a target, Ephrin A2, that to date, has proven impossible to drug with any other therapeutic approach. And we're very excited about what we've seen to date with our Ephrin A2 molecules, and we'll tell you about that. Then we'll take some Q&A, and then in our third session, we're going to tell you about our next generation of molecules and how we're going to bring those forward. We'll take a short Q&A, and then I'll come back to provide a summary and close the meeting. So on that note, once again, many thanks for being here. Really appreciate the support, and let me hand over to Nick. Thank you, Kevin. Thank you. My name's Nicholas Keen. I'm the Chief Scientific Officer at Bicycle. It's an absolute privilege to be here today. Thank you. So, before we jump into the data and slides, I thought I would just give you a brief overview of why I joined the company. So I come from a family of cancer survivors. My mother has had cancer twice. She's still around and still keeps me in line. But I've seen what this disease does to both the to individuals and to families, and I've spent my whole career working in oncology research and oncology drug discovery. I've had the fortune in that time, the good fortune in that time to work on many different modalities, to work on antibodies and small molecules, and even on cell therapies. What I saw in the Bicycle platform, I felt represented a really unique opportunity to address underlying biology in cancer in a way that I couldn't tackle with those types of modalities. And I'm extremely excited and very proud of what our teams have delivered, and I'm going to walk you through some of that today. So let's start off with Nectin-4. I've no doubt that you're very familiar with Nectin-4, as a target in bladder cancer. But we've done a lot of work inside the company to really understand the biology of Nectin-4-expressing tumors, and we believe the opportunity is much broader than just bladder. If we turn first to just the pure expression of Nectin-4, it's expressed very highly, not just in bladder cancer, but in many other tumors. When we overlay that with sensitivity to MMAE, we observe that there are actually a lot of opportunities outside of bladder, including non-small cell lung cancer, ovarian, triple-negative breast cancer, and others, and you'll hear more about that from Santiago later on. In addition, what we've observed in Nectin-4 positive tumors, that these tumors are actually home to multiple immune cell populations. We've considered an alternative approach to direct toxin delivery, which to activate or reactivate the immune system in Nectin-4-expressing tumors. So we're essentially taking two orthogonal approaches. One is to deliver high-potency toxins to tumor cells that we know are sensitive to MMAE and to directly kill them, and the second is an indirect approach, which is to activate resident immune cell populations in the tumor using a completely unique mechanism, and we'll talk about that more in a few minutes. We have two molecules in this space or two approaches in this space. One is BT8009, which is a Nectin-4 targeted Bicycle toxin conjugate to pursue that first approach, a precise delivery of payload of toxin payloads into tumors. The second is BT7480, which is a pretty unique molecule. It's quite simple in structure, and we'll talk to that again later on. This is a molecule that's designed to activate a key receptor in the immune system, but only where it's needed in tumors. It's a Nectin-4-dependent CD137 agonist. Again, we'll walk through this later on.... Let's dive a little bit deeper into BT8009. I think this is a very elegant molecule, actually. It's very simple in structure. It carries a highly selective binding Bicycle that binds to Nectin-4, and that's coupled via a protease cleavable linker system to the cytotoxin MMAE. Now, this is a fully synthetic molecule. It's made using chemistry, not using biology. It's very small. It's only about 3.8 kilodaltons versus 150 kilodaltons for an antibody, and that's very important for tumor penetration. And what I'm gonna walk through in a minute is that we see really differentiated preclinical performance of this molecule. So I can tell you right now, it's much more selective than any comparator antibody drug conjugate. In preclinical studies, it reduces skin and eye toxicity, and I will show you data to support that. It has very distinct PK properties, so the exposure to parent molecule is greatly reduced as compared to antibody drug conjugates. We believe that's important to avoid distribution and delivery of toxin to non-target tissues, and it has excellent anti-tumor activity in preclinical studies as well. A lot of this work is actually outlined in the publication at the bottom here, so if you want to go and see how we really discovered the molecule and the full chemistry behind it, you can go and read that later. Bicycle toxin conjugates have a unique mechanism of action. If you cast your mind back to the video that Kevin showed you, once injected, these molecules extravasate very rapidly. They come out of the blood vessels, and they fully penetrate solid tissues really quickly, well, probably within a few minutes. Once they've penetrated solid tissue, and particularly once they've penetrated a tumor, those highly specific binding Bicycles recognize that specific tumor antigen expressed on the tumor cell surface. And depending on the biology of those targets, they can either be internalized, where that linker system is processed to release payload, or they can be cleaved in the tumor microenvironment by proteases that are present in the tumor microenvironment. The payload that we use, MMAE, is cell permeable. We consider this an important advantage of the molecules. Cell-permeable payloads allow killing of adjacent tumor cells, which are target negative. And actually, almost all human tumors are highly heterogeneous for target expression. It's rare that they're homogeneous for target expression, and we see really excellent activity of this molecule in preclinical studies looking at patient-derived xenografts that are heterogeneous for target expression. So quite a different mechanism of action as compared to a classic antibody drug conjugate. Now, we've used the term selectivity a lot. Selectivity is really important if you're trying to deliver toxins or activate the immune system. And what we're showing you here is a study where we took BT8009, and we took enfortumab vedotin, and we ran these molecules across an array of approximately 5,500 membrane proteins, and we looked to see what these molecules bind. And you can see that for BT8009, it only recognizes its biological target in that array. The only signal we got was Nectin-4. If we compare that to an antibody drug conjugate, in this case, enfortumab vedotin, you can see that it binds to multiple Fc receptors. These are normal receptors for antibodies. Antibodies, of course, evolve to interact with other receptors and systems in the immune system. But that's probably not a great thing because that means that an ADC will typically deliver its payload to Fc receptor-expressing tissues, as well as your tumor target. In addition, for enfortumab vedotin, we also observed an off-target SLC16A2, again, suggesting that antibody drug conjugates may deliver their payloads where you don't want them. So we know that our Bicycles are really very selective for their intended target, and we believe that this may decrease toxicity to non-target organs, potentially increasing the duration of response of our drugs and better enabling combinations with other molecules, for example, IO agents. So let's dive in a little bit deeper on that. So this is a, a really interesting experiment. So what we did here is to take normal human tissue and then treat this normal human tissue in vitro. So we took human skin, and actually, we reconstructed human cornea in vitro. So we took human corneal epithelial cells, got them to grow on a basement membrane, and then we treated them either with a Bicycle Toxin Conjugate directed to Nectin-4 or enfortumab vedotin. And what we observed, I think, is really interesting. For enfortumab vedotin, we observed in the skin studies, separation of the dermal epidermal junction, which is reminiscent of some of the pathology or histology that's observed in the skin adverse events of enfortumab vedotin, and we also observed very significant thinning of the corneal epithelium. In contrast, we did not observe these for a Nectin-4-targeted Bicycle toxin conjugate. And I think this is really quite clear demonstration that selectivity counts and selectivity matters. And as you'll see when Santiago talks later on, we're hopeful that this is now translating into a significant difference in adverse event profiles clinically. So just to round out briefly on this section, we really have a different class of molecules on our hands here. These molecules are engineered, tailor-made, and designed to be highly selective, minimizing off-target toxicity. We know that they penetrate human tumors rapidly. The image that's inset here is from an independent academic group, who took a Nectin-4-binding Bicycle and coupled it to a radiolabel imaging agent. They dosed that to patients with bladder cancer and observed rapid accumulation and selective accumulation in Nectin-4-positive tumors in humans. Indeed, they saw accumulation within 15 minutes of dosing. We believe this offers a new modality with advantageous properties that might increase the duration of response and be far more combinable, particularly with IO agents that carry toxicities of their own. At this point, I'm now going to hand over to Santiago, our Chief Development Officer, who will walk you through the clinical experience with BT8009. Thank you, Santiago. Thank you, Nick. Good morning. I am Santiago Arroyo. I'm Chief Development Officer for Bicycle. Thank you for being here. As you may know, I joined the company a few months ago, last April. My excitement for joining the company was my conversation with Sir Greg Winter. I mean, you have heard him. He's very engaging and truly he can communicate what is this technology about, which is about highly penetrant targeted therapies that promise to be a better tolerated type of therapeutic, especially compared with ADCs. But the second thing that attracted me to the company was AT09. The challenge of how to develop a drug in a quite busy landscape and evolving landscape in metastatic urothelial cancer, and also with an evolving and complex regulatory pathway. So we, we took that challenge, and I think that we got through, and I will talk today about our data in AT09, about how we communicated that with the agency, with the FDA. And how we got alignment to develop this compound for first line and second line in metastatic urothelial cancer. Our strategy has been three-pronged to execute in metastatic urothelial cancer. I will show you data on, on dose, on how we understand the dose, how we believe that our compound differentiates from ADCs, and how we believe this compound could be a first treatment and a treatment of choice, in bladder cancer. But we are also expanding to other, tumors, and I will show you data today in ovarian, non-small cell lung cancer, and triple-negative breast cancer. We are also putting together the initial plans to go to earlier stages of bladder cancer. Finally, we are obviously investigating combinations, as Nick was saying and Kevin was saying. These type of compounds are really ideal for combining with other compounds, with checkpoint inhibitors, for example. So we will be doing that and also investigating alternative routes for dosing. The BT8009 DURAVELO 1 study, the Phase 1/2 initial study, is here in this slide. We have already talked in the past about our dose escalation from doses of 2.5 milligrams per square meter every week, up to doses of 10 milligrams per square meter every two weeks. We have already completed some expansion cohorts in EV naive patients with urothelial carcinoma, ovarian, triple-negative breast cancer, non-small cell lung cancer, a small cohort in combination with pembrolizumab. And we are currently enrolling patients in the EV exposed urothelial cancer, renal insufficiency, and also expanding further in EV naive, triple-negative lung and a combo with pembrolizumab in first line. The data that I'm going to show you today is pretty complex. I will go fast. You will have the slide, the deck posted, so don't worry. I know that many of you are very detail-oriented. You will have all the details, but I will just point you to the main highlights of the data here today. On the efficacy, I will present the data on the EV naive urothelial cancer at 5 milligrams, which is 26 patients. Then the three cohorts in ovarian, triple-negative breast cancer, and non-small cell lung cancer. On the safety, I'm going to present three populations, so three different cuts of the data, all of them at 5 milligrams per square meter every week. The first one in monotherapy, which is 113 patients. The second one is an EV-naïve in urothelial cancer, which is 34 patients. And the third one is the combo small cohort, seven patients, with pembrolizumab. We'll obviously do adverse events of special interest analysis to give you some data so that one can compare, if you allow that word, to current ADCs. The baseline characteristics of our EV-naïve patients, which is 34 patients, are typical of a Phase 1/2 study. The ECOG was 1 in 62% of the patients, and the median lines of therapy was 2.5. Again, most of the patients have visceral disease and obviously metastasis, and most common metastasis were in the lung. This is the response data in EV-naive patients. We had one complete response, nine partial responses, and seven patients with a stable disease. The ORR was 38% and the CVR 58%, with a median duration of treatment of 11 weeks and the median duration of response of 11.1 months. I believe that this efficacy is in itself remarkable and very similar to what we have seen at this stage of development with ADCs. If we saw the data in a spider plot, I think it's even more clear that something that is most interesting of this type of compounds is the long duration of response. This long duration of response, we believe, is probably mostly due to the safety of the compounds. You see that there were some patients that have stayed in the draft for over a year and a half, and the median duration of response, again, is 11.1 months, with still 5 patients ongoing. So that duration of response in this cohort of patients will be even more prolonged. As you know, the duration of response obviously depends on the response and is in a sense related to the progression-free survival, right? So longer duration of response will likely be allow this compound to have a longer progression-free survival. The first cohort in other cancers, and this is new, I believe that the other ADCs haven't presented data of Nectin-4 in triple-negative breast cancer. It's a relatively small cohort, but we see 3 responses, several patients with a stable disease, an ORR of 20%, CVR of 27%, with a mean duration of response of 4.2. The next cohort is the ovarian cancer. We see 2 responses with, again, an ORR of 20% and a mean duration of response of 1.8 months. Most of the patients in this cohort, they are at 5 milligrams per per square meter per week, except for those that have an asterisk, which is at a different dose. The final cohort is in non-small cell lung cancer. We saw so two responses, which makes it into an ORR of 13%. Again, the idea on this cohorts is that we we are actually currently expanding in two of them and considering the expansion in ovarian, because the ovarian data is relatively new. Next to the expansion, we will likely do combination therapy. So we we we believe that we are starting with a 20% or so ORR, and from there, with combination, we could get into something possibly pretty dramatic. At least that is - that's our expectation. Let's go now to the safety, and I will start with all the population across different tumors treated at 5 mg/m² every week, which is 113 patients. The population, again, very typical of this early patient population, with a median lines of therapy of 3, an ECOG of 1 in 65% of the patients, and the median duration of treatment was 8 weeks. The overall safety and tolerability profile, we consider adequate or more than adequate. If you this is a busy slide again, but if you focus, for example, in the related grade 3 severe adverse event, it was 25% of the patients. Again, related SAEs in 12% of the patients, and very rarely a patient had to be discontinued due to intolerability. Only 4 patients had to be withdrawn because of that. Actually, the median relative dose intensity was 90%. The adverse event profile that we see in this compound, and you will see a theme here because all of our Bicycle compounds really behave with a type of similar general adverse events, nausea, fatigue, diarrhea, vomiting, decreased appetite, so some GI, some general, complaints. In general, relatively low incidence and quite low severity. It's the severe adverse events, grade 3 and over, are relatively infrequent. We did an analysis for this adverse event of interest that even though they were not adverse events of special interest for our compound, because we didn't believe, we didn't see any data on this in the preclinical world, we thought it would be important to do this analysis because the high frequency that ADCs have of ocular disorders, peripheral neuropathy, and skin reactions. As you can see, we didn't see a lot of incidence of that. Ocular disorders, 5%, peripheral neuropathy, 22%, skin reactions, 10%. We'd rarely seen any severe. Actually, the only severe peripheral neuropathy, grade 3 peripheral neuropathy, was in 1 patient that entered in a study. This was a previously treated EV patient and entered into the study with a grade 1 neuropathy and evolved during the treatment. We saw a couple of patients with hyperglycemia, Grade 3, and 6 patients with neutropenia, Grade 3, that was manageable with dose reductions, most of the cases. We did a further analysis on those 25 patients, 22%, with peripheral neuropathy. 8 of those patients had sensory neuropathy, most of them Grade 1. Maybe what is more interesting here is that the median time of onset of peripheral neuropathy was 1.7 months. The peripheral neuropathy resolve or improve, basically went to either to 0 or to Grade 1 in 44% of the patients, with a median time of resolution that was relatively quick, 2.6 weeks. In addition, only 11% of the patients with a baseline history. You know, in this study, we accepted patients with Grade 1 neuropathy, and that was 25% of the patients. About 25% of the patients came with neuropathy, but only 11% of those that came in with peripheral neuropathy had a worsening during the treatment. And actually, in two-thirds of the cases, the peripheral neuropathy got into a complete resolution. So let me go now to the second safety population, which is the patients treated with 5 milligrams per square meter every week with urothelial metastatic urothelial cancer. These were 34 patients. Overall, the safety data is very similar to the whole population, and this is going to be a little bit repetitive because it's basically the same, but it's worth to go over it. Grade 3, Grade 3 treatment-related adverse events, we see it in 15% of the patients, related SAEs, we see in 9% of the patients. Again, rarely we saw patients that had to discontinue the compound due to intolerability, and the median relative dose intensity was 80%. Adverse event profile, as I was presenting before, is pretty general. Some GI complaints, myalgia, decreased appetite, a few cases of anemia and vomiting. Again, the severity is low. Most-- You see the column, it's mostly zeros. There is no-- There is very few patients with severe adverse events. We did a further analysis on those special interest adverse event, ocular disorders, peripheral neuropathy, skin reactions, no Grade 3 and other adverse events in those three. Finally, the last population, the safety population, is a combination population. This is a small safety cohort, only 7 patients, but it was important for us to have that experience with the combination of pembrolizumab and AT09 and understand if there were any potentiation of adverse events with the combination. That actually had been seen with ADC, so we wanted to make sure that hopefully we'll not see that. And actually, as you can see in the slide, we see a profile that is very similar to the profile that we've seen in monotherapy, even though the medium pre-prior lines of therapy was high. We actually shared this information with the FDA because it was important, as you will see in our Phase 2-3 study. We are going to do a fair amount of use of the combination therapy. The adverse event profile in this combination population was fairly similar to what I have just presented, with rarely severe cases, Grade 3 or over, of adverse events. The case, the anemia case is related to pembrolizumab. And similarly, when we do the assessment of a special interest adverse events, we don't see a lot of severity there in ocular disorders, peripheral neuropathy. Skin reactions are relatively higher incidence of those. This is the efficacy data in this, again, very small cohort. We had 2 responders, patient responders. Those were actually second-line patients. Both have been treated with chemotherapy and one with a checkpoint inhibitor. We saw another patient that did not quite meet the criteria for a response. It went to 28%, not 30%, and that patient had received two prior lines of therapy. The other three patients had a stable disease, and the patients had had four, five and six lines of therapy. They were very late patients, very advanced patients. Overall, this efficacy data, again, is a small cohort, but it tells us that the drug is doing what it's supposed to be doing, and the drug, in combination with pembrolizumab, will most likely have the efficacy that we expect in this second or first line, although this was second and very late line. As Nick was mentioning before, and actually as Greg Winter was mentioning, this AT09 has a very unique PK profile that is adequate or absolutely good to be able to be in and out and not have any broad on a specific tissue distribution. As you see in the orange line, this is the conjugate, AT09 compound, and in the green dotted line is an ADC, so that we can compare the PK behavior.... So the half-life of our compound is very short compared with an ADC, and the actual exposure, the BTAT09 exposure, is much lower, while the MMA exposure is slightly higher than an MMA. So all of them are good properties. We have done already a fair amount of analysis, because our compound is renally cleared, and we don't need to do any adjustment of those with the creatinine clearance is over 30 milligrams per minute. And we are currently starting to enroll in a further renal cohort to try to understand what will happen at more severe renal impairment situations. So the key takeaways of this part of the presentation is that we have a, what we believe, a very differentiated safety profile. We have efficacy that is on par what we have seen before with ADCs, but we have substantially longer mean duration of response, probably related to the safety of the compound. We have encouraging data in three other tumors, and we are obviously already enrolling and exploring the possibility of efficacy in these tumors and the combination. We have initial data to support that the combination with pembrolizumab is safe and well tolerated. So let me go now to the kind of second part of this presentation, and is the FDA interactions. We started the year with good news. The FDA granted us the Fast Track designation for late-line metastatic urothelial cancer, and since then, we have had several interactions with the agency. During those interactions, and as you know, there was a new guidance issued last March on the development of oncology drugs for accelerated approval. The landscape, the regulatory landscape, has changed, and what you're going to see here today is a novel trial design. But I believe that this type of trial design will be seen more often in the future because that's what we believe, but not only we believe, I mean, the FDA is aligned with that, is what the FDA wants to see in the future. More type of Phase II, III adaptive design with dose exploration. So we have alignment on the overall study design, the populations, the endpoints. We have alignment on the control arm, which is chemotherapy plus Avelumab, which is the standard of care now, and we believe is going to be the standard of care for a while. The FDA aligned with us on considering accelerated approval both for first line and second plus line in urothelial cancer based on overall risk benefit. Finally, we got alignment on the doses to be selected. Finally, we ended well the year because the FDA also granted in last September our program to be a part of the CMC Development and Readiness Pilot Program, and that is a program that the FDA has pioneered. We are one of the first companies that is going to do that, that will allow us expedited preparation, CMC preparations for commercial manufacturing. So that ability to have a lot of interaction with the FDA on CMC will, you know, likely help our compound to streamline the process to market. So this is the study design for the DURAVELO 2. It's a little bit complex. I'm going to try to go part by part as quickly as possible. It has 2 cohorts, first line and cohort 2 is second line plus. Basically, most patients with metastatic urothelial cancer can enter into this study, if obviously they comply with the inclusion, exclusion criteria. Patients in cohort 1, which is untreated patients, will be randomized to 3 arms. 2 combination arms, AT09 with pembrolizumab at 5 milligrams per square meter every week, and at 6 milligrams per square meter, 2 weeks on, 1 week off. The third arm will be chemotherapy plus avelumab maintenance when indicated. After 30 patients are included in each cohort, the first interim analysis will be done for dose selection. The dose selected will be carryover, which will be optimal dose of AT09 plus pembrolizumab, and the chemotherapy arm will carry over. A second interim analysis will be done for potential accelerated approval, and the endpoint will be ORR. And here, the bar, the FDA has raised the bar of what they want to see for accelerated approval. They want to ask to compare AT09 plus pembro to chemotherapy. So in the past, as you know, the idea of the accelerated approval was comparing to historical control. In this case, we actually have to do a direct comparison with our arm. So it's a full interim analysis. In addition, the FDA, in the conversations that we have with them and the interactions that we have with them, align that we will need to show reasonable clinical benefit. Meaning, not just the ORR, a differentiated safety profile and a differentiated duration of response. Finally, we'll continue the study to seek full approval, and the primary endpoint for the full approval will be PFS. That is different from what has been agreed in the past. I think it makes a lot of sense, and the FDA actually has approved other drugs with primary endpoint on PFS, especially when you believe that your OS is going to be very prolonged, more than two years. It starts not to make a lot of sense to have OS, and PFS is probably a better endpoint. Obviously, we will measure OS, will be the key secondary, and OS is fully powered. The total number of patients in this cohort one will be 566 patients. The second cohort, cohort two, previously treated patients, will initially randomize patients in monotherapy, this time to 5 milligrams per square meter every week and 6 milligrams per square meter, 2 weeks on, 1 week off. After 30 patients, the optimal dose in monotherapy will be selected, and we will start another arm, and we'll re-randomize the patients between optimal dose in monotherapy and combination therapy with that with pembrolizumab and with that optimal dose. The study will continue until we do the final analysis, which will be for ORR, and we'll be seeking accelerated approval in second-plus line, either in monotherapy and/or add-on therapy, combination therapy. The agency will request, and we know that we will need to do a confirmatory study, and the confirmatory study will be—we are working already on, on how that confirmatory study will look like for second-plus line. The total number of patients in this cohort two will be 240. So let me finalize this part of the presentation and just restating that we are excited. We, we are seeing this compound working, working reasonably well, very on the efficacy side, very comparatively what we've seen with ADCs. On the safety side, very, very different from what we've seen with ADCs, and we believe with a better safety and tolerability. We have alignment with the FDA on, on the clinical trial, Phase II/III trial, and we have emerging data in other tumors. So all of that is very exciting. So next year, you will see the study, the Phase II/III study, starting on the Q1. We are currently recruiting sites, and things are moving forward. We also will be having data in the second half of the year on monotherapy in late line, combination therapy in first line, and also data in monotherapy in other tumors. Plus, you know, we'll initiate other work in combination therapy in other tumors. So let me pass now again to Nick King, who is going to talk about our second Nectin-4 asset, and then I will follow with some clinical data. Thank you, Santiago. So I want to talk now about, as Santiago said, our second program in our Nectin-4 portfolio. And as I outlined in that figure at the start, this is an orthogonal approach. You've heard that we're very effectively delivering cytotoxic payloads to Nectin-4 positive tumors. This is an immune oncology approach, and I think a very original approach. And it's really quite different than anything else that's out there. So what we want to do, in essence, is to wake up or reinvigorate those resident immune cells in tumors. And we're trying to do that by targeting a positive activation signal, so a gas pedal for the immune system, or if you're from the UK, an accelerator pedal for the immune system. The receptor that we're targeting is CD137. This is a co-stimulatory receptor. It's expressed actually not just on T cells, but also on NK cells and dendritic cells. So importantly, it's expressed in the innate immune system as well as in the adaptive immune system. Now, the problem with targeting co-stimulatory receptors is that global agonism of a co-stimulatory receptor can be very toxic. I'm sure you're all familiar with the checkered history of CD137. The superagonist antibody, urelumab, for example, did show some clinical responses but produced pretty profound liver toxicities. And I'm sure you've also heard about CD28 agonism as well. So what we've chosen to do in the design of these molecules, and I'll show you how we did it in a minute, is something I think that is really very different. We are designing molecules that only activate these receptors in the presence of tumor cells that express Nectin-4. And the platform enables us to do this, and it also enables multiple other facets that I think are really unique and be very hard to achieve with a traditional biologics platform. The first of which is that the molecule I'll show you is very small. If you can't get into a tumor, you cannot activate the cells that are there. So these are small, fully tumor penetrant molecules. The molecule is actually an incredibly potent agonist of CD137. It's a 30 picomolar agonist of CD137, but only when bound to tumor cells expressing Nectin-4. It has enhanced selectivity, so it doesn't bind to any other receptor that we know of. That's really important. Again, if you're a biologic that switches on the immune system, and you're bound to an Fc receptor in the liver or elsewhere, that's not great for those tissues. This is less obvious. It has fast on and fast off kinetics. In this field, you want a molecule that can turn these receptors on quickly and then allow them to turn off. These are a bit like a light bulb. You don't want to turn them on and burn out the light bulb. You want it on and off, and in fact, for CD137, we know that prolonged agonism leads to downregulation of, and internalization of CD137, thus removing the ability to target it again. And what we're seeing is a completely unique phenotype. We're seeing a reprogramming of the tumor microenvironment with a unique mechanism of action that's revealed by this type of molecule. So how are we doing this? Well, the receptor in nature is activated by the CD137 ligand that's presented by an antigen-presenting cell, and that clusters the receptor, and clustering leads to activation. So using the platform, and it's a huge advantage of this platform, we were able to engineer molecules to mimic this. So what we did was to take a binding Bicycle to a specific tumor antigen, in this case, Nectin-4, and to couple that to a CD137-binding Bicycle. What that does is it coats the tumor antigens on the surface of a tumor cell with an artificial version of the ligand. So essentially, you're now turning a feature of the tumor cell into an activating signal to the immune system, providing context-dependent activation. So this is the molecule itself on the left-hand side. It's about 30 times smaller than any other agonist that we know of. It actually carries two CD137-engaging Bicycles and one Nectin-4-engaging Bicycle. It's completely selective, again, in this Retrogenix panel of 5,500 membrane proteins. The only things it binds to are CD137 and Nectin-4. When we take this molecule into in vitro assays, as you can see on the right-hand side, it's a super agonist of CD137 only when presented with cells that express Nectin-4. When presented with Nectin-4-negative cells, it's completely inactive. And actually, in these assays, it's a much more potent agonist, even than the super agonist antibody urelumab. I should point out that when we take these molecules into preclinical safety studies, it's extremely well-tolerated. We didn't observe, for example, any of the liver effects or cytokine release that have been observed with other molecules at the target CD137. Now, when we take this into efficacy models, it's important that we observe very, very potent antitumor activity. In this case, with intermittent dosing, people have worried about the short half-life of this molecule, which is in the order of about six hours or so. We see this as a real feature, and I'll show you why in terms of the phenotype in a second. But with intermittent bolus dosing, we get very robust antitumor activity. Importantly, the animals that have responded are now immunized against that tumor. So if we try and re-implant the same tumor line, they are... the animals will reject those tumors. So it induces an immunological memory to the tumor antigens that were present there before, and that's clearly dependent on the presence of CD8-positive cells. If we deplete CD8-positive cells from these animals, then those tumors retake. So it's showing that we've essentially induced immunological memory against that tumor. Now, I mentioned the mechanism of action is very different, and I think this is because this is a tumor-penetrant molecule that mimics the natural physiology of CD137. What we see when we dose BT7480 to tumor-bearing mice is that we see a dramatic pulse of chemokine and cytokine signaling from that tumor, and that's shown in the colored lines in the plot in the center. It comes on very rapidly. We know that that's dependent on certain populations of resident immune cells that I'll talk to in a minute. And that pulse of chemokine and cytokine signaling then attracts in effector cells like CD8-positive cells. You can see on the right-hand side, those tumors become completely crammed with effector cells after a period of about 6 days or so. So we have this really interesting phenotype where we have a tumor-penetrant molecule, gets in there, it activates resident immune cells, and then that signals to the adaptive immune system, which can then enter the tumor and start to kill the tumor. We've done quite a lot of work, as you would expect, to better define this phenotype. Importantly, one of the key cytokines that we observe elevated is CXCL9. CXCL9 has been reported in a study looking at over a thousand patients treated with checkpoint inhibitors to be the number one predictive factor to checkpoint inhibitor response. Our clinical biomarker strategy that Santiago will talk to in a few minutes involves measuring these cytokines in blood, as well as assessing key changes in circulating immune cell populations, such as CD4-positive T cells. Importantly, we know that this pulse of signaling doesn't require CD8-positive T cells to be in the tumor, and so this is very distinct, for example, than a PD-1 inhibitor that typically does. We believe that the key population of cells that provides this signal is resident dendritic cells in the tumor. Again, a very important area of IO research, and again, somewhat different from that reported for typical checkpoint inhibitors. We believe this sets up an ideal microenvironment for combination, and I'll show you those data in just a second. But clearly, we see very nice monotherapy activity. But another important part of the phenotype for BT7480 that we observed is actually upregulation of checkpoint molecules in those tumors, on the immune cells in those tumors. So I'm showing you some raw data on the left. Here you can see upregulation of PD-1 and LAG-3. We don't see those when we dose those animals with an agonist antibody, perhaps because it cannot enter the tumor. We're not sure, but we do not see those signals. It's important, actually, that you do observe this, because this is a signature of an ongoing active immune response. So very different phenotype as compared to that observed for a comparator, a CD137 agonist antibody. I've shown you that we saw very nice monotherapy activity, but this clearly points to the possibility of rational combinations, and we've explored this extensively pre-clinically. So in this study at the top left, you can see in this model, pembrolizumab is essentially an inactive molecule. However, when combined with BT7480, it induces very dramatic anti-tumor activity. Similarly, we see this with CTLA-4 in the bottom left and with some combinations representing those kind of next-generation checkpoint bispecific. So if we combine PD-1 and LAG-3, almost every single animal in the study combines, it fully responds. And the same is true for CTLA-4 and PD-L1 when those are combined. So we really have a unique molecule here, completely different mechanism of action than anything that's out there, fully synthetic molecule, reprograms the tumor microenvironment, we believe offers an excellent combination partner, as well as something that's inducing monotherapy activity pre-clinically. And we believe this could really broaden the opportunity to address Nectin-4 expressing tumors, perhaps beyond those that are sensitive to toxin. We have a really fantastic translational science team at Bicycle. They've done a lot of work trying to figure out what kind of patients might benefit from a molecule like BT7480. They've done this using some pretty sophisticated bioinformatics approaches to look at resident immune cell populations in human tumors, as well as to use high-content imaging studies to actually look at where those Nectin-4 positive tumor cells are juxtaposed with those kinds of immune cell populations that I talked to earlier on. When you run that analysis, the kind of tumors that percolate to the top are non-small cell lung cancer, cervical, head and neck, and others. And I should point out that the other interesting observation with this molecule is it only requires very low and heterogeneous levels of Nectin-4 in the tumor to induce these very potent signaling changes. So in summary, it's a completely new molecule. You can really only produce, in my mind, a molecule like this with the kind of platform that we have. Has a unique mechanism of action, induces this pulse of signaling from the tumor, which doesn't require resident CD8 positive T cells. We see great monotherapy and combination activity in, as I said, in a fully synthetic format. So very exciting molecule, very different data, and I'm now going to hand over to Santiago, who will walk through what we're seeing in the clinic. All right. Thank you. Thank you. Thank you, Nick. So let me go to the clinical side and maybe a few words just to frame what we try to do. As Nick was mentioning, there have been several failures and safety concerns with this type of mechanism. So it was, for us, very important to go slow, to start slow at doses that will be really non-pharmacologically active or minimally pharmacologically active and move forward. In addition, this is a different type of compound. It's not a toxin compound. It's an immuno-oncology compound. So it's going to be very important to have a wealth of data, biomarker data, that will allow us to understand dosing early on. You will see that in addition to going as long, we have expanded some of the initial cohorts to try to get more biomarker data. So we started to think about what dose should we select for starting the dose escalation, and we used several data from the discovery body of data. The most important, obviously, is the Nectin-4 target engagement and CD137 target engagement. But also we have other in vitro pharmacology data, obviously efficacy data in animal. So we put all that together into a model. We started dosing at a dose in cohort 1 that will get about 50% target engagement in CD137 and about 10% in Nectin-4. We predicted that about cohort 5, 6, 7, 8 will be in the right dosage. So this is the current trial. On the left side is the dose escalation, and we are currently enrolling in the cohort 10. We've done all of the other cohorts. Some of them, as you can see, just one patient. Again, they were sentinel patients to try to understand early safety. And in other cohorts, we have expanded a little bit more to get the biomarkers. We will conduct next year a combination with a checkpoint inhibitor and in two doses, and then we will start to put together what will be the Phase 2 program, both in monotherapy and in combination, probably in at least two more types. And right now we are thinking, because of the data that I'm going to present to you today, on cervical cancer and non-small cell lung cancer. The overall baseline characteristics of this cohort, which is 33 patients, were again typical for these Phase 1 studies with a median prior lines of therapy of 4. Patients had up to 9 lines of previous lines of therapy and a ECOG of 1 in 70% of the patients. Over 60% of the patients had both expression of Nectin-4 and CD137.... The adverse event profile is really, really remarkable. The drug, we believe, is very well tolerated. As you can see, the severe Grade 3 or over related adverse event is just 6%, SAE is 6%. Adverse event leading to discontinuations, interruptions or reductions are rare. The adverse event profile is a very general adverse event profile with headache, abdominal pain, decreased appetite, fatigue, all of them in relatively low numbers or low incidence, and related only in appearing in more than 10% of the patients. It was only fatigue in 12% of the patients or four patients. The clinical profile, the clinical PK profile has been very consistent and predictable, and on the right side, you have the concentration time curve and also the AUC and Cmax data. That shows that our PK appears to be proportional, there is very moderate PK variability, and the exposures are increasing consistently with the dose escalation. The PK is, sorry, the half-life is short, as expected, and as is ideal for this type of mechanism, as Nick was talking. We don't expect accumulation in weekly dosing. We obviously look at target engagement, and we could do in several samples target engagement for CD137. We observe progressive dose response up to cohort 5 in target engagement, getting to full target engagement after cohort 5 and basically stays there for the rest of the cohorts. As expected by the preclinical data, it translates really very well. Full target engagement from cohort 5 onwards. Not only that, but we also see the downstream effects for having that CD137 target engagement with the induction of the soluble CD137. We see a dose response, but especially in the later cohorts 8 and 9, we see a significant induction. So the drug gets to the target, binds to the target, and produces a downstream effect. But not only that, we also see an immunological response, so we see real pharmacology from this target engagement. There is an increase in CD4 T activation, CD4 T cells activation that goes from cohorts 1 to 5, 6, 7, 8, 9, and it's clear that there is a progressive activation. And this type of activation is the one that you see in patients that have been responding to checkpoint inhibitors. And similarly, the chemokine that Nick was talking, CXCL9, we see an induction that is progressive and in cohorts 8, 9, appears to be maximal. So all of these indicates that we have target engagement and a pharmacology downstream of that target engagement that has been associated with clinical benefit in the past. We finally did a quantitative modeling to confirm our potential dose range, and as you can see, at the doses that we are working now, 0.6-3.5 milligrams per kilo, we will be reaching max response. This is the initial efficacy data, and in this case, I put the plot by dose, so low doses from left to high doses to right, up to cohort 9, which was 2.5 milligrams per kilo. We observed that there are 2 responses across tumors, but both of those responses are in cervical cancer. We only had 2 patients with cervical cancer, and both patients responded. You can see maybe better here, where we plot by tumor class. You have, you know, GI, non-small cell lung cancer, a few bladder cancers, and cervical cancer, the last one with our two responses. I wanted to talk a little bit about the two responses that we have in cervical cancer to relate the severity of these patients. As you know, this is a relatively rare type of cancer, extremely severe, extremely resistant to treatment. Both of our patients were females that have been treated with several lines of treatment before. They both have quite high scores of Nectin-4, and they both responded. Unfortunately, one of them stopped responding. The other one is still on the trial. Again, both of them have been treated with chemotherapy and CPIs. The other three patients that were also we believe that they are very interesting is because of the long duration of a stable disease. These are two patients with a non-small cell lung cancer and one patient with a squamous cell carcinoma of the anus. The three of them have been previously treated with three lines of treatment, chemotherapy plus CPIs. Again, two of them are still on the study, and we already have seven months of follow-up in these patients. Again, with a, I would, I will say probably a good quality of life related to the adverse event profile that we have with our compound, which is pretty minimalistic on the adverse event side. So in summary, we have a drug that appears to be safe and well-tolerated, in contrast with issues that have been found before when other companies have been developing CD137. We have a very, I consider, a very robust biomarker profile with good target engagement, with good downstream effect, and we have already two responses and some very sustained stable diseases. So we believe that this drug is active. Obviously, we want to do combination therapy. Nick was talking about combination therapy for this compound being ideal and expanding these cohorts, and specifically in cervical cancer, but probably also in non-small cell lung cancer. So we'll be doing that next year, and we'll hopefully reporting on the second half. So let me pass it to JP, who will talk about the commercial opportunity. Perfect. Hi, everyone. Thank you, Santiago. So my name is Jennifer Perry, or J.P., as you just heard Santiago refer to me by. I'm the Head of Commercial at Bicycle Therapeutics, and I'm just gonna provide a very short overview of the market opportunity. And before I start, I have to say that it's an absolute pleasure and privilege to be able to start to set the aspiration for these molecules in the market. First of all, with this wonderful management team, also with my emerging and growing commercial team, as well as the very special talent at Bicycle Therapeutics. Truly a dream come true. And obviously, we're talking about our Nectin portfolio, so BT8009 and BT7480 that you've been hearing about this morning. And you've heard a lot about Nectin-4 as a highly expressed target. It's a high-value approach, and it has the opportunity to unlock opportunity across several solid tumors, and you can obviously see some of our lead tumors here, as well as areas of interest for us. Now, I'm gonna say something, and I know what you're probably gonna think. You know, obviously, we're very excited because these are new Bicycle drug conjugates, first in class, and I know you hear first in class all the time. However, we really mean it. This is actually new technology, a new category, and obviously from a commercial standpoint, bringing something new into the targeted therapy arena is thrilling. Not easy, though. Obviously, any new technology is hard to bring into the market, so we've got a lot of work to do, and we're very excited about it. Starting with BT8009, we believe this Bicycle drug conjugate has market-leading potential, and it starts with the three bullets at the top on the right-hand side. Novel, powerful, selective, small peptide. And those are the words that hooked me, why I came to Bicycle Therapeutics. So like anybody looking at a new career opportunity, I called up all the people I know to ask them about Bicycle. And one of the people I called is a very bright PhD who's in business development. And before I could get Bicycle Therapeutics out of my mouth, she stopped me and said, "Oh, I know all about it. It basically has the power of an ADC without the liabilities." And I was hooked. And the reason why is my mind commercially immediately went to the second bullet. What does that translate into? Well, it translates into great efficacy, potentially better median duration of response and tolerability in the clinic for patients. In addition, this new technology, from a commercial standpoint, has these really unique physicochemical properties. So my brain goes to flexible dosing and administration. What are those life cycle planning opportunities that could take us beyond metastatic disease? And so here I am today, and it's been a great year plus. And we need everything we can get when you're thinking about launching into something like metastatic urothelial cancer, because I don't need to tell you how devastating bladder cancer is, right? Ranked sixth in the U.S., tenth worldwide in terms of tumors. 25% of patients will develop metastatic disease, and of those patients with stage four disease, you basically have a five-year survival rate of about 12%. It's really absolutely dismal for patients. That's why we believe at Bicycle Therapeutics that we have this opportunity to really realize the promise of what patients think of as a chemotherapy-free regimen. Something that feels safe, it's more tolerable, and they can stay on their drug. So that really inspires us and pushes us forward. Now, let's talk about the market, though, that we'd be launching into. The first-line metastatic market, it's complex now. As of today, obviously, December 2023, chemotherapy still dominates the market and has for years, but we know it's evolving. And so when you think about the things that happened in 2023, obviously, the accelerated approval of enfortumab pembro, EVP, in the first-line cisplatin-ineligible patient population back in April, and then obviously, the really great data that came out of ESMO 2023 for CheckMate 901, as well as EV-302, this market is changing. Now, a couple of things about that. Like, what does that mean? We get asked that a lot. Like, can Duravelo-2 recruit? Can you launch into a market like this? And we believe we can, and I'd like to tell you why. So first of all, having more regimens in the first line means physicians can now push for better efficacy for patients, right? Get efficacy at all costs, especially in the first line... That's good for patients, that's good for people who have to treat them, and for us, that's really good for Bicycle Therapeutics, right? To have treatment regimens that are chemo-free, Nectin-4 targeted, helps bring recognition to our program, as well as establish a really strong foundation to one day launch from. But what is the opportunity then, still, in first line? So right now, all the current regimens moving into the first line space have what we call treatment-limiting toxicities. Now, I want to be clear. Oncologists know how to manage tox, right? They've dealt with chemo for years. However, when you have treatment-limiting toxicities, means you have to discontinue the drug, it gets much harder for them. And so that is what we're thinking about in terms of opportunity in the first-line setting. EVP, when you look at 103, they have almost 40% of the patients have to discontinue for neurotoxicity. 40%. That means there's opportunity to exploit a toxicity to do better for patients. Finally, is it okay to give irreversible toxicity in the frontline setting? That's a big debate right now in the medical community, because then what do you sequence with? What can they take then in second and third line, which I'll talk about in a minute. And so some doctors think it's okay. You can give them irreversible neurotoxicity 'cause they will live. Some patients think that, too, but not everybody. And so when you're thinking about launching into a space like this, that is still unmet need that we hope we can fill from the profile you saw from Santiago. Now, the second-line and third-line treatment landscape, equally complex, but in a different way. This market is still very fragmented. You can see some of the utilization up here on the screen. Clinicians continue to tell us they're unsatisfied here, and the reason why is, even though there's efficacious agents, like targeted therapies in this space, they actually still would prefer to use something more tolerable in second and third line because the patients are more frail. And this is why you see this fragmented utilization. Really, no one treatment is above 25% in any line. And so even enfortumab, obviously has been on the market for four years, is still in the teens in terms of its utilization. And I know that often surprise people who think it is a market leader in that space, but it's just not what we are seeing. So for us, this is an opportunity to continue to bring tolerable treatments to second and third line. And I think people forget sometimes how big this market is in the solid tumor space. Right now, this is approximately 11,000-12,000 patients who need care. And so our market research, we plug on. We've been doing a lot of connection to respondents and clinicians who are treating patients in the metastatic space, and you can see here on the left, everything they tell you that aligns with the market, what they want more of. Obviously, they want new approaches to current targets that give them efficacy and then better tolerability. Obviously, no-brainer. They also want new targets, which we'll talk more about in the 5528 section. Better toxicity profiles that keep patients on drugs and obviously allows them to have better adherence so that you can potentially further efficacy. This is why we're so excited about the median duration of response that Santiago just showed you in the BT8009 program. Bottom line, if our target product profile actually evolves to where we expect coming out of DURAVELO 2, our respondents also tell us that they would preferentially choose BT8009 alone or in combination because of its tolerability profile over something with similar efficacy. Our key opinion leaders that we continue to engage with tell us something very similar, and they get a little bit more specific. You can see here in the top box, we've put this out before, but I'll go ahead and refresh in case people haven't seen it. Efficacy first. A median duration response of about 9-12 months, combined with improved quality of life, would be very meaningful to them as treaters. And then in the orange box, their views on safety. If you have developed a drug that has improvements in things like skin rash and neuropathy, this is something they would actually use over more challenging treatments. I point that out because that goes to what they perceive to be those treatment-limiting toxicities, things they have to stop other drugs for, and that's why it's so important. And then on the right-hand side, at ESMO, our clinical team, medical team, commercial team, got to meet with approximately 40 key opinion leaders, and you can see some of their quotes here on the screen. That sentiment from the left side carries on through the end of this year, even after the data that came out. Top one, EV data is a proof of concept for BT8009, and DuraVelo 2 is a nice study design, especially where patient preference is thought of. And then the third one, especially from the community setting, you can see here, patients' decisions are not just about benefit, and of course, they're talking about efficacy benefit, but also harms and how bothersome toxicities are to their activities of daily living and their quality of life. And so obviously, from a commercial perspective, we have to be thinking about, can you bring a drug that's differentiated on safety and tolerability into the market? And so we always look to analogs. Now, many of you have heard me talk about the fact that I launched IMBRUVICA at Pharmacyclics at the time. We were often told, "Nobody needs another BTK inhibitor. Nobody needs it. “IMBRUVICA has this locked down.” It was an amazing drug that was launched into the market. Now, of course, AZ bought Acerta, and along came Calquence. Somebody needed Calquence, and so we were definitely surprised. Same thing for Cabometyx in the renal cell carcinoma space. A little closer to home since we're talking about GU oncology and bladder. Nobody needed another TKI. Nobody needed one, and then Cabometyx came along, and people would tell you their profile is not a walk in the park. So a couple of parallels about this story. Calquence and Cabometyx both launched about four to five years after the lead asset. So not a fast follower, obviously some time in between in the market. Both of them had differentiated profiles based on safety and tolerability, and they actually focused in on those treatment-limiting side effects of the first-in-class agents, which were cardiotoxicity, AFib, and bleeding, specifically for IMBRUVICA, reasons oncologists had to stop IMBRUVICA. Calquence focused there. And then you can see here their patient reach. After 9 months for both drugs, both had over 30% of the new patient starts in the market. And last year, in 2022, both were claiming market leader position with over 50% share. And actually, Calquence has hit as high as 64%. And so these types of analogs tell us that a safety profile, again, when you're dealing with those treatments that doctors have to stop because of toxicity, can be quite powerful, bringing new innovation into these spaces. So many of you have seen this before also, but this is our aspiration for BT8009 as a brand. So that novel, powerful, selective small peptide, we hope to see it move into one day be first-line standard of care for metastatic, second-line standard of care for metastatic disease, and then hopefully be able to life cycle plan and move it into earlier lines of bladder cancer, as well as other Nectin-4 expressing tumors, which Santiago showed you some of our very early data. And just to give you a feel for those markets, like why do we think there could be opportunity in non-small cell lung cancer, triple negative breast cancer and ovarian cancer? Well, you can see some of the reasons here. I won't spend a lot of time, but the bottom line is that current five-year survival rates are still very low, single-digit to teens. However, recurrence, progression, toxicity profiles, especially because of the high use of chemotherapy in some of these areas, is still very high. And I always like to point out, in the second line for triple-negative breast cancer, 50% of first-line patients who progress will not receive their second-line treatment. That goes to my statement before, which is: Is it okay to give patients irreversible toxicity in the first line? These women want to live, they want to get treated with something, and their toxicity is so bad they can't. We can do better. So transitioning just very quickly to BT7480. It's actually the last bullet, on this slide, kind of the full last bullet with sub-bullets, that really intrigues me about a Nectin-4 agent combined with something in immuno-oncology. It's because of this ability to push that efficacy that we've been talking about, to really be thinking about you can get great efficacy, but people can stay on their drug. And so, of course, you saw that very early data in cervical cancer, but this is one of those solid tumors which could provide kind of the perfect place to think of launching something like 7480. You see here, over 50% of patients will have disease recurrence in 5 years. Less than 45% who get treated in first line can take their second-line treatment because of toxicity and the high use of chemotherapy. If you haven't spent a lot of time in cervical cancer in terms of the treatments there, standard of care right now is pembro plus chemo. Now, there's a lot of other drugs looking at combinations like Atezo plus Bev plus platinum doublets, but still IO plus chemo with the same chemotox profile. And then really kind of the last innovation in this space was an ADC called Tivdak in 2021 in the second line setting, but unfortunately, it comes with box warnings for a really severe vision loss. So when we think about introducing a new target where there's very little innovation going on, so bringing Nectin-4 to this space to approximately about 6,000 women in the metastatic setting, and then being able to add in the IO component, which is already a foundation in this disease, plus chemo. Of course, commercially, I start thinking about all the combination opportunities, maybe even PD-1 ones, plus BT7480, like mix that as a possibility. I'm just going to end quickly on this slide. This is just a schematic to show you kind of the addressable patient populations in the metastatic setting in each of these tumor types that we've started to explore. Starting with cervical, with 6,000 patients in the U.S., all the way up to 130,000 patients in non-small cell lung cancer. Now, of course, though, we don't just want to be a U.S. option or an option in metastatic. We strive to provide global solutions for patients, as well as try to move this amazing technology into early stages in solid tumors. Thank you very much. I'm going to turn it back over to Kevin for Q&A. Thank you, JP. Don't go anywhere. If I could ask Santiago and Nick to join me. While they're coming up on stage, if I could just summarize what I think you've heard today. I think with 8009, I think we've shown a very differentiated tolerability profile. We believe that improved tolerability is translating to a much longer duration of response than has previously been seen and without any compromise in efficacy. 7480, completely novel approach. I think we've undertaken a really innovative biomarker strategy. The translation from preclinical to clinical is better than anything I've ever seen. I think we're seeing all of the biomarkers predicted of checkpoint inhibitor activity move in the right direction, together with some early responses. So we'll now move to Q&A, and if I could ask people asking the questions to introduce themselves, I think that'd be really helpful. Thank you. Jay? Jay Olson, Oppenheimer. Congrats on all the progress, and thank you for hosting us here today. For 8009, can you comment on the 11-month median DOR? Seems very favorable compared to EV. Is it directly attributed to the improved safety and tolerability? And maybe just to follow up on JP's observations, are there other factors driving that durability and other potential points of differentiation? For example, I think you previously observed some CNS activity with 8009, and then I have a follow-up, if I could. Sure. I mean, the best interpretation of the data, I think, we believe, would be that improved tolerability, the high dose intensity, this ability to give the dose at the right level continually for the right period of time, without, you know, immediate dose reduction and cessation and things like that. I think that has to translate to improved responsiveness. So I would make a strong case that that's the primary driver. But Santiago, anything to add? Nothing to add. We believe that that's the driver. And I completely forgot your second question, and you haven't even asked your third yet, so let's, let's go back to your second question. Other potential points of differentiation, including CNS activity. You know, we don't believe that this molecule is gonna be particularly CNS active. You're gonna hear later in the day about some work we've done where we can get our molecules into the brain. But I don't think the body of evidence we have to date is strongly suggestive of CNS activity. Nick? Yeah, no, I think you, you've covered that well, Kevin. Yeah. And you had a follow-up, I believe. Oh, yes. Thanks. And then, just on 7480, Jennifer, you mentioned potential combination with PD-1 antibodies. Can you just talk about the potential to combine 7480 with 8009? I actually will- I mean, the beauty of the Bicycle portfolio is the very, you know, the great tolerability. So everything is on the table. All of these options are available to us, and I think this is, you know, this is something that we'll continue to consider in time. So it's great observation. Jeff Hung, Morgan Stanley. Hey, Jeff. Thanks for hosting the R&D Day and taking my questions. With the BT8009 plus pembro combo, you saw a low 30s% response rate. Now, understanding this is still quite early and based on small numbers of patients, any aspects of the efficacy results that surprised you, and had any of the six evaluable patients been previously treated with PADCEV? And then I have a follow-up. CEO's prerogative, you know, if it depends how you look at the data, you know? So the thing about that cohort of patients, extremely sick, very late line. If you do the analysis by line, I would make the argument in second line, we have a 100% response rate. So, you know, it depends how you juggle the numbers, but if you look at the patients all who had stable disease, some patients had 4, 5, 6 lines of therapy. I think it's very, very challenging to, to, to, to see remarkable responses there. And the second- Just wondering if any of the evaluable patients had previously been treated with PADCEV? I believe they were not. Okay. And then for triple negative breast, ovarian, non-small cell lung cancers in 8009, can you just talk a little bit more on what you'll be looking for in expansion cohorts to decide if you'll advance development in those indications? You know, the interactions we've had over the course of the last year with the FDA have been very insightful for us. What we've heard loud and clear from the FDA is that they're looking for clinical benefit, a combination of efficacy, durability, and tolerability. And I think that's, you know, with Project Optimus and some of these other initiatives, this is where the FDA is moving towards. We're living it, and we're seeing it every day now. And so when we look at our next data cut, I think it's gonna be that whole profile, the tolerability, response rate, duration of response. You know, for us, the combinability of these agents is what make them exciting. I don't think we're thinking long-term about moving into non-small cell, et cetera. It's a monotherapy. It will be in combination with IO and things like that, where we know this MMAE mechanism is well validated now, I think, to work well in that setting. So I think it's a little bit early to be drawing conclusions because it's the compendium of the data. Anything to add, Santiago? We are still... I mean, we have to put the criteria here. You're asking what criteria we will use to move forward, and we still are working on that. Obviously, combination, having that and combination is going to be critical to decide that. Peter? Peter Lawson. Peter Lawson from Barclays. Just on the discontinuation rates, really low at 3%-4%, does that get better, do you think, as you move into earlier lines of therapy? Does it need to get better? Kind of, how do you think that actually translates to real-world settings? You know, I mean, my observation of, you know, watching the trials evolve is that we've been... You know, I have to thank the patients who selflessly, you know, given to help us really, you know, understand what we have, and what we're working on. But our observation has been these patients are very sick, and sometimes they come off therapy for reasons that are not drug-related. So I think it stands—the logic for me is that as we move into earlier lines, I think that's gonna potentially improve. So that, that's the way I would think about it. I don't know if you want— Yeah. I mean, it's, it's already very low, right? And, and very differentiated from ADCs. First line, the patients are less sick, so it could even be lower. But again, our-- the, the rate was 4% or less. Maybe just a follow-up for Jen, just around these kind of launches when you're second to market. I really like the stories or other narratives there in the space. Kind of, what other learnings are there from that kind of launching in a marketplace where there's an incumbent? Additional learning. So I mean, to be honest, I think, education in the earlier days, something that Calquence did quite well, was that they began to kind of pre-profile how important their selective profile was and how that could translate into benefits. You know, we're still a small company starting to build those capabilities, and so starting to make sure people understand, number one, that this is a new technology. Number two, that it can't really be lumped in with any other class. And then number three, that our selective profile could offer potential benefits that you've seen today, are gonna be pretty critical, I think, again, to be able to launch very quickly off of a foundation of chemo-free, Nectin-targeted. So that differentiate... That differentiation kind of starting now and getting people in the medical community in the podium, to be participating in that would be pretty important. And Calquence, for example, did that very well. R.K., and I think Lee and Kelly as well. Thank you. This is R.K. from H.C. Wainwright. Thanks for hosting the analyst day, and it's pretty educative. A quick question on tolerability. So especially with BT8009 in metastatic urothelial cancer patients, you folks saw 57% decrease due to dose modification, and there was about 20% due to dose reductions. So what was the reason for these changes? And as you go into the next stage of evaluation, would you be using any prophylactic treatment to handle that? That's a great question. Thank you. I'll let Santiago follow up, but I think it was largely the initial GI that was observed. In the Phase one component, we felt it was appropriate not to use preemptive antiemetics, et cetera. Of course, we'll be introducing them, and hopefully, that will have, you know, a good effect on what we see moving forward. Anything? Yeah, that's it. GI adverse events were the most frequent and especially, you know, again, we have mixed here the data from the escalation and the expansion, and during the escalation, we did not allow patients to have prophylactic treatment for the first cycle. So that, you know, increases the incidence of adverse events. Hi, guys. Faisal Khurshid from Leerink, here for Jonathan Chang. Wanted to ask about... So on OS, so you mentioned that you have OS as a key secondary in DURAVELO 2. Can you just clarify a little bit what the FDA stance was on OS when you engaged with them? And also, did this change at all given that EV now has a proven OS benefit? And then we have a follow-up as well. I mean, the FDA were very clear that the PFS was appropriate endpoint. I don't know. Well, you know, EV has shown an OS of 31 months. So with that type of OS, it has to be even more clear that the FDA would agree that PFS will be a better primary endpoint, more clinically relevant endpoint. So, but there was total clarity that that is the primary endpoint. OS as a secondary endpoint, again, is fully powered. Got it. Okay, thanks. And then, in terms of your ORR and sort of where the ORR is sitting now compared to the EV pivotal monotherapy benchmarks, can you discuss your degree of confidence, both in terms of, like, potential competitive differentiation, as well as degree of confidence in the ORR analysis in DURAVELO 2? Yeah, I mean, I think it's still early. We're dealing with, you know, a broad, heterogeneous group of patients. We think the ORR is very competitive. And again, particularly when we think about that very extended duration of response and that really improved tolerability profile. And we think, as we've been very clear many times now, what we've heard loud and clear from the FDA is the overall clinical benefit they're looking at. It's not a single number. It's the compendium. Kelly? Kelly Shi from Jefferies. I also have a question regarding the durability in the UC cohort in pretreated patients. The overall DOR looks favorable at 11 months compared to Padcev's 7 months in the same settings. But on the slide 25, the spider plot, I noticed something interesting, the early enrolled patients actually achieved a very deep and durable response, but the later comers seems like they have less deeper response. Curious, is this random, or do you notice the baseline characteristics enrolled on the trial actually change over time, for example, like more comorbidities or like uncontrolled diabetes? And also how do you expect the pivotal trial patient baseline compared to the dose escalation and the dose expansion cohorts? Yeah, we believe that is random. We had less response in the second part than in the first part, but we believe this is random. Overall, we put it all together, it's a very reasonable response rate. You know, when you are dealing with relatively small numbers, you know, things can go either way. No, but we look at that, and it's a good observation. Thank you. And also, I have a follow-up question on peripheral neuropathy. We hear, doctors talking about, that's actually one of the key talks. They have a close observation, and that has impact on durability. So on slide 33, it was noted that 11% of the patients with baseline peripheral neuropathy developed the treatment-related worsening cases. I'm curious, what is the overall, patients actually had the pre-existing baseline peripheral neuropathy on your trial? And how does it compare to PADCEV's 301 trial in the same, same patient, population? Yeah, a quarter of the patients had grade one when they entered. They couldn't enter into the study with more than grade one, but a quarter of our patients have grade one. I am not sure about the PADCEV data on that, what was the frequency in their trials, that I don't know. Thank you very much. Lee. Hi, Lee Kalowski from Cantor. Great presentation. Maybe first question, can you just comment a little bit on the duration of treatment of 8009? How does that stack up against EV? And for the combo, can you just talk a little bit about what you see there relative to the monotherapy cohort? The duration of treatment, I believe, is, you know, I believe is approximately similar, but don't quote me on it. It's because I also I don't want to necessarily talk about other companies' data. What was the second question? Is there any difference in the combo relative to monotherapy when it comes to duration of treatment? The combo cohort is a very small cohort. I am trying to remember right now what was the duration of treatment in that cohort. I can come back to you on that one. Okay. Then the second question, maybe for Jennifer, can you just give us a little bit more color around the physicians in the community setting? I believe maybe 70%-80% of patients are being treated there. So would a safer molecule, like BT8009, I mean, how might it, you know, translating to uptake relative to other available agents? Yeah, great question, because obviously the last round of market research we did, we actually focused much more on the community setting. And really, the takeaway for them is that they don't always have the infrastructure or resources to manage some of the tox profiles of, like, ADCs in general, including enfortumab. So they will tell you that, if they can treat with another therapy to minimize the toxicity, fine. However, if they have to start referring out to specialists, so acute hyperglycemia, if they have to find someone to help manage that or get them to a hospital, that is problematic. If they have to be evaluated for ocular toxicity, that's a problem. It can take weeks to get a patient in to see an ophthalmologist in a rural setting. And then finally, the neurotoxicity is problematic for just following patients. Obviously, patients don't want to come off their medicine, and when they're warned that they have to tell a community physician, "If you start to have this, adverse event, you have to come and tell me," many patients don't, and they don't get to follow them as closely as they'd like to catch it before it becomes irreversible. That's why we continue to hear that it's not always grade three that scares physicians, in the community for neurotoxicity. It's often grade two, because grade two in itself can become irreversible. And this is right in the package insert for enfortumab vedotin. They looked at their patient population in monotherapy, and 86% had some type of residual neurotoxicity. And of that, 50% was grade two or more. For the community, those are the types of things that worry them, and we've actually had doctors quote and say, "Those are the scary toxicities," just because they're very challenging to manage in the community setting. So Rajan and then Ami. Hi, Rajan Sharma from Goldman Sachs. Thanks for my question. So, in cohort one of DURAVELO 2, do you have any sense from the agency what level of OR you'd need to show to get the accelerated approval? And then I just have a second as well. We need to The FDA provided very clear feedback. It's the clinical benefit, compendium of OR, duration of response, and tolerability profile. I don't know if you want to- I think we need to find, you know, a significant difference from chemotherapy. So the study's power for that. Okay, perfect. And then just on, ... PADCEV, I guess kind of, do you have any sense of what could be drivers of resistance or relapse on PADCEV, and whether there's kind of any down expression or antigen loss of nectin-4? That's an interesting question. We've been looking at that in some detail. Nick, I don't know, you want to take that one? Yeah. I mean, if you think about it logically, there's probably two mechanisms of resistance, right? So there's reduction in sensitivity to MMAE, probably by upregulation of efflux pumps, and second is likely loss of target. There is a publication from a group in Germany looking at resistance and response to PADCEV. There they did observe loss of Nectin-4 over time as a resistance mechanism. I think, however, what's important to point out actually is the majority, or certainly a frequent reason for discontinuation of PADCEV therapy, is not intrinsic gain of resistance. It's actually loss of tolerability. That, and you'll see later on when we talk through some programs later on, that that actually might represent a pretty significant opportunity. Ami? Hi, this is Ami from Needham. Thanks for taking my question. Got two. Firstly, on BT7480, can you talk about what your conclusion is based on some of the dosing, the dose ranging work across the different indications? Why are we seeing a better response in cervical cancer and not in the others, and perhaps your expectation as you dose up? And what do you need to see to go down an accelerated approval path there? And I've got a second one. 8009, why we're seeing a better response in bladder cancer, right? No, no, 7480. No, 7480 and cervical. BT7480 and cervical. Yeah. I mean, this is an early stage. We are doing the dose escalation, so we have a number of cancers. For example, the ones that you saw there, GI. There are a lot of different cancers there, from pancreas, gastric, colon. So we haven't... Really, this, the idea of this escalation cohort is to try to understand if the drug has activity and if we see any response, to understand that we have a drug. So we have— Sorry? Go ahead. Oh. I was gonna- What we have seen is activity, clear responses in two cancer patients, both of them, the only two that we had with cervical cancer. That doesn't mean that we couldn't see it in others. Actually, we saw some interesting data in non-small cell lung cancer. We need to expand, and we need to choose which cancers we want to expand in what will be a therapeutic dose range. And now we believe that we understand the therapeutic dose range, and we'll start expansion, and we'll start combination. So I wouldn't read a lot. What I will read is that we have an active drug with proof of concept that it works. But I think there is some mechanistic rationale as well. Yeah, just a couple of things. I think you asked about the dose response range as well. Yeah, so what's been incredibly gratifying with this technology is that translation from preclinical systems into humans seems to be much better than I've observed with other types of drugs that I've worked on. And I think what Santiago showed you is that, you know, in those higher cohorts, from cohort probably six onwards, we're very squarely in the predicted biologically active range. A lot of the patients that you saw were not treated in the predicted biologically active range, so I wouldn't necessarily read too much into the population distribution of responses. That said, cervical cancer was a tumor type, actually, as well as non-small cell lung cancer, that we predicted may benefit. And that's because, firstly, cervical cancer and non-small cell lung cancer, the majority of patients are really quite high for Nectin-4 expression. But probably more importantly, we know that those tumors harbor CD137-positive immune cells as well. So again, it is very gratifying to see that prediction perhaps translating into humans. Now, I wouldn't rule out, absolutely wouldn't rule out activity in other tumors, especially perhaps in combination. You saw how different the phenotype of the molecule is. But yeah, it's in line with what we predicted, so it's quite gratifying. Okay. I think Tony. Thanks, Kevin. Tony Butler, I wanted to ask about the binding of Nectin-4 and BT7480 relative to the binding in BT8009, if they're equal to, less than, or greater than. And the reason really goes back to the BT7480 slide with cervical cancer, where one of the patients did develop some level of resistance. So I didn't know if that was antigen loss maybe in her case, but it goes back to this notion of binding relative to tolerability, and I wanted to just understand that from a biological perspective. I mean, Nick can provide the details, but it's the same binder. One of the beautiful things about the Bicycle platform is once we have these binders, it's... My chemists will hate me, but it's trivial exercise putting them together. It's really like Lego, a very, very, very efficient, very predictive, very... You know, it's, it's, it's a real toolbox that we can deploy. I don't know if you have any other comments, Nick. No. I mean, it— That molecule is interesting. Of course, we didn't have a lot of time to go through it. It's bivalent on the CD137 side, so you get higher avidity to CD137, 'cause you've got two binding arms with lower avidity to Nectin-4. And if you looked at the projected curves, you occupy Nectin-4 after you occupy CD137. But it has approximately the same binding characteristics to BT8009. ... Yeah, Kalpit Patel, B. Riley. One on the safety profile, were there any obvious differences between treatment-related and treatment-emergent adverse events, particularly for the ones of interest like neuropathy and rash? And then, you know, how do those TEAEs compare historically to PADCEV, if you compared those, those specific ones? Yeah, there are no major differences, and it compares favorably. Actually, it's pretty proportional what we see. We just presented the related as, you know, previous ADCs have presented related, but it's basically well, there is more obviously because they are non-related, so it's everything. But it's on the same similar proportion. I think we have one more question. Hi, Bill Maughan, Canaccord Genuity. So 2 questions. On the peripheral neuropathy on BT8009, you gave some stats about time to onset, and I think 44% of patients it resolved. Just wanted to know, were those all due to either dose reduction or interruption, or was there any, you know, spontaneous resolution? Just any kind of commentary around the kinetics of the neuropathy. Yeah, in most cases, it needed dose reduction. Most, or...? In most cases. I cannot give you the number for that, but in most cases. Okay. And then on BT7480, you said that more than 60% of patients had both Nectin-4 and CD137. In those patients that didn't have both, was it more commonly Nectin-4 or CD137 missing, and is there potential to refine the patient population going forward? I can't answer that because I don't remember. Certainly from what I recall from the plots, there was no bias in either direction. Yeah. There's always gonna be an opportunity to better re-refine predictions to response. What I should say is, in general, using archived histology, where samples are taken at the point of diagnosis versus therapy can be a bit noisy. But we did, as I said, a lot of integrated analysis you saw in the slide set to look at very broad patient populations and to try and narrow those down into those where we believe that the necessary conditions are available for response. Thanks, Bill. Okay, if there are no more questions, I think we're gonna move now to a break, and then, if everyone could come back in 10 minutes, we're gonna tell you about a really exciting program against the drug... a target that so far has been undruggable, and that's Ephrin A2. So thank you for your attention. Talk to you soon.... Okay, thanks for coming back on time. So in the first session, we talked about our Nectin-4 portfolio. What we're gonna do now is move on and tell you about the work we've been doing on our Ephrin A2 portfolio. And as a reminder, once again, Ephrin A2, high-value target, very broadly expressed, but a target that has hitherto been extremely difficult to drug. We think we've applied our Bicycle technology, and I think we've done something that no one else has done to date. So I'm gonna hand over to Nick to give you the background, and then Santiago and JP will follow. Thank you, Kevin. Thanks. It's my great pleasure to talk about EphA2. I suspect many of you haven't heard very much about this target before, and if you have, it's because you worked in the industry for a long time, and I'll explain what I mean by that. EphA2 is a tumor antigen with really, pretty much, I would regard, ideal properties. Broadly expressed in multiple solid tumors, very restricted expression in normal tissue, and very interestingly, it's also a tumor antigen whose expression seems to increase with stage and progression of the disease. Because of those properties, it's something that people have been interested in in industry for a long time. Unfortunately, pretty much every approach that's been taken to target EphA2 expressing tumors has been unsuccessful. Firstly, to turn to antibody drug conjugates, because it's an obvious antibody drug conjugate target. Two approaches there, one from MedImmune, AstraZeneca, MEDI547. That antibody drug conjugate produced really interesting, and interesting is always a bad word with toxicities, toxicities, but really interesting toxicities preclinically. They observed bleeding, uncontrolled bleeding events in preclinical studies. They progressed that molecule into the clinic at very low doses, and even at low doses in their first cohort, about half of the patients who were exposed to MEDI547 had uncontrolled bleeding events, and also very significant liver enzyme elevation. So that was pretty much the end of that target as far as AZ was concerned. More recently, a company, Atrecaa, had an antibody drug conjugate that targeted a different epitope of EphA2. Again, however, they saw uncontrolled bleeding in preclinical studies, and that was the end of EphA2 as far as they were concerned. So for targeting toxins, EphA2 is essentially a non-druggable or undruggable target with antibody drug conjugates. Given the value of the target, Daiichi pursued it with a non-toxin-bearing antibody, an ADCC-enhanced antibody. That really didn't move the needle from an efficacy perspective. It was also reasonably toxic, and interestingly, they did some imaging studies with an imaging version of that antibody and observed that they were unable to effectively penetrate solid tumors. So I think what I'm trying to tell you here is that you can regard EphA2 as being an undruggable target using traditional biologics approaches. Now, when we looked at the expression, just as we did for Nectin-4, we observe a significant overlap of the expression of EphA2 with tumors that we believe will be sensitive to MMAE. And when we prioritize those or when we look across those, we see bladder, non-small cell lung cancer, ovarian, and breast, among others, as being key indications where there are high levels of expressions of EphA2, paralleled with MMAE sensitivity. We've also done work internally, looking at expression of immune cell populations with EphA2 positivity, just as we did again for Nectin-4, to try and start to build an EphA2 portfolio. And there we see head and neck, stomach, and colon, as priority indications. So again, we are thinking about taking two orthogonal approaches here, both direct delivery of toxin and reinvigoration or activation of the immune system. So in a mirror to what we're doing in nectin-4, we have BT5528, which is an EphA2-targeted Bicycle toxin conjugate. This molecule was engineered and designed to overcome those dose-limiting toxicities that were observed with prior generations of antibody drug conjugates. In addition, we have BT7455, which is an EphA2-targeted nectin-4... Sorry, EphA2-targeted CD137 agonist that will only agonize and activate CD137 in the presence, this time, of EphA2-expressing tumor cells. We're not going to talk much about that molecule today, but we are actively working on it. So the structure of these molecules should be familiar to you by now. Again, I think extremely elegant, actually. So this molecule, 5528, carries a selective binding Bicycle out to EphA2. Again, what do I mean by selective? Well, we did the same kind of study where we looked across about 5,500 membrane proteins, and in that study, the only thing that binding Bicycle and BT5528 would bind to is EphA2. Carries a similar protease-cleavable linker system and toxin to BT8009. And again, that plays to the example Kevin was using earlier on, of the sort of plug-and-play nature of the platform, where we're able to swap out binding Bicycles in a relatively facile way. Now, when we took this molecule into preclinical safety studies, because of course, we were obviously concerned about clotting defects, even at very high doses in primates, we observed absolutely no effects as compared to controls. This molecule was completely clean from a preclinical safety perspective in terms of those toxicities that were identified for MedImmune 547 and for the Attraka molecule. So we got very good antitumor activity. We got a very distinct preclinical safety profile. In effect, preclinically drugging a target that could not be drugged before. Now, we've mentioned several times that Bicycle data seems to translate very well from preclinical species into humans, and I think this is a really beautiful example. What we're looking at here on the left-hand plot is a mouse model. The sort of fuchsia line that you can see going across the center there is a level of payload in tumor, and you can see in orange the parent molecule... Sorry, in black, the parent molecule in plasma. So we get rapid elimination of the parent from plasma, but very efficient delivery of payload into the tumor. On the right-hand side is data that, of a type that I don't think that I've seen before, which is in humans. So what we did here is to take biopsies from patients that were dosed with BT5528 and to measure the concentrations of MMAE in real patient tumors as compared to plasma. And you can see at 24 hours, we're getting very efficient delivery of MMAE to tumors in humans, with concentrations about 10-fold higher than those observed in plasma, and very nicely reproducing those preclinical studies. So in summary, I think we developed a molecule from a preclinical perspective. It's very safe. It's very efficient in its delivery properties of MMAE to EphA2 expressing tumors, and we're starting to observe, again, this very nice preclinical to clinical translation. So at that point, I'm gonna hand over to Santiago now, who will walk you through our clinical data. All right. Thank you, Nick. So I, again, as I was doing before, I want to frame a little bit how did we go about developing this, this compound. There have been, as Nick was saying, there have been a lot of failures previously... and there were failures related to safety, specifically coagulation disorders and hemorrhages. So we were concerned when we started the development about our ability to do that safely in patients. So we went, again, very cautiously at very small doses, and progressively, we went up in dosing and expanding when necessary. So what I'm going to show you here today is our initial dose escalation data in monotherapy. I will go over also the expansion data at 6.5 milligrams per square meter every two weeks. We are currently enrolling at a higher dose that we believe will provide further responses at 5 milligrams per square meter every week. Overall, the efficacy population that I'm going to present is the monotherapy in metastatic urothelial cancer, but also some data in other types of tumors. The safety data will be in all patients, which is 109 patients, and in patients treated at 6.5 milligrams per square meter every two weeks, which are 74 patients. The overall population, and you will see in the next few slides, two columns. One is the monotherapy, all patients column, and the other one is the 6.5 milligrams per square meter every two weeks. Overall, the characteristics of the patients are typical of a Phase I type of a study with an ECOG of 1 in 60% of the cases, the median lines or prior lines of therapy of 4, so heavily pretreated population, and the median duration of treatment of 6-7 weeks. The type of cancers that we studied was very, very typical solid cancers, but with a special emphasis in ovarian and urothelial, because we saw a clear signs of response in those two cancers. The overall safety profile was adequate. If you, again, if you focus, and this is a very busy slide, but if you focus in the severe grade 3 and over treatment-related adverse events, 27% in all cohorts, 19% in the 6.5 milligrams per square meter every two weeks cohort. If you look at the related SAEs, 11%, 8%, so relatively low numbers. And the AEs leading to discontinuation occur in 3%-5% of the patients, again, emphasizing the good or relatively good tolerability of these compounds compared to ADCs. The typical adverse events that we saw, the most frequent adverse events that we saw were GI-related and general adverse events, nausea, diarrhea, vomiting, fatigue. We saw some cases of anemia, headache, neutropenia, and myalgia. The incidence was relatively moderate. The severity was, in general, low, with single digits across all the categories. It's maybe to mention that this adverse event profile is not very different from the adverse event profile that we have shown you with AT09. This compound behaves very similar to AT09. We did an analysis for those adverse events of interest that had been seen with ADCs, plus hemorrhage, because hemorrhage, obviously, previous compounds with this target have been discontinued due to events of bleeding disorders. So peripheral neuropathy, 17% overall, 19% at 6.5 per square meter. Skin reactions, 10%, and ocular disorders, 2%. No grade three or severe adverse events were seen across these type of adverse events. On the peripheral neuropathy, we analyze the incidence of peripheral sensory neuropathy. That was 6 out of 19 patients or 4 out of 14 patients, divided between grade 1 and grade 2. Again, we didn't have any grade 3 neuropathy. This is the data on the responses. That includes most patients are at 6.5 milligrams per square meter. And this is in metastatic bladder cancer. We have two patients that responded at different doses, 8.5 per square meter every two weeks and 10 milligrams per square meter every two weeks. The overall, including all the cohorts, which is 18 patients, we had an overall ORR of 39% with a CVR of 39%. If we go to the patients treated with 6.5 milligrams per square meter, we have an overall ORR of 31%. The median duration of treatment was 14 weeks. We didn't see. I mean, we saw responders in EphA2 positive, many of them, but some of them also in EphA2 negative... Our data right now is still inconclusive about the importance or relevance of EphA2 measurement for inclusion of patients. In the spider plot, you can see that we still have one patient ongoing, and you can see the responses that we have on the whole population. For the seven patients with partial response, we have a median duration of response of four months. We wanted to share with you a case report of a patient with metastatic urothelial cancer to emphasize the severity of this patient population. This patient, a female, 76-year-old female, had already had four lines of therapy when she entered into the study, and she successfully undergo about six months of therapy with our compound, with a response. And maybe more importantly, this patient had been treated in the past successfully, initially with EV. Eventually, the patient had to stop because of pancreatitis related to EV. But overall, it shows that this is a different target. It has the same payload as EV, but different target, and you can get responses with a different target in patients that have already been treated with EV. I will not go in detail over the efficacy in other cancers. We are still going through the data. In ovarian, we are currently expanding to 5 milligrams per square meter. We've seen some responses, but we want to understand at a higher dose, what that will represent. We saw also a couple of responses in head and neck. And in other type of tumors, we haven't seen responses. We have seen a fair amount of patients with a stable disease. And again, what is important to remark is that most patients have been treated on 6.5 milligrams per square meter, which we consider a relatively low dose. And we've done a fair amount of PK/PD modeling to understand dosing. Obviously, with 6.5 milligrams per square meter, you are giving per cycle, 30 milligrams. If we go to 5 milligrams per square meter, you'll give per cycle, 20 milligrams. And obviously, giving it 2 weeks versus giving it every week, it makes a big difference, where you will get about 54% higher exposure, MMA exposure at 5 milligrams per square meter. We have also done some modeling between BT8009 that behaves very similarly than BT5528, so across both compounds. And we believe that the dose of 5 milligrams per square meter every week, every week, which is the one that we selected for BT8009, will have similar tolerability than the BT8009 dose and higher efficacy than the one that we have shown today, which in our mind is not necessarily bad. We have actually shown, you know, an ORR in the whole population of 39%, with a moderate duration of response, but very good tolerability, again, at what we believe are still low doses. So we are expanding currently at 5 milligrams, both in urothelial cancer and ovarian. We will bring data on the second half of the year on those two cancers, and we are still in the process of thinking what type of combinations we will do with this compound and what other tumors we will be directing our efforts to. So it's still early times, but we have, again, an active compound with a novel target that has been considered undruggable, and I believe that we have convincing data that has promising safety and tolerability. JP? Thank you, Santiago. So I just have a couple of slides to round out the discussion on BT5528, similar to our Nectin franchise market overview. And so obviously, I ended my section before talking about kind of the impact that a Nectin portfolio could have, and now we add in BT5528. And when it comes to our portfolio, we always joke we love all of our children, but this one is really near and dear to my heart because I talked in my opening about first-in-class and how important that was to us, related to new technology in this space. But to potentially be first and only, from a commercial standpoint, that is extremely exciting. And so I say that because obviously you can see here on the slide that we have an EphA2 agent potentially going where ADCs have been unable to go. You heard from the earlier sections that the earlier development was plagued by catastrophic bleeding, which in our clinical program right now, we've seen no signs of. So how do we think about BT5528 at this early stage, potentially fitting into the market? Well, there's two kind of strategic imperatives for us to explore. One, you've seen the data in urothelial cancer, which I'll talk more in the next slide about, but also that we could potentially move into places that need greater efficacy and additional gains, areas of high unmet need, gastric and head and neck in particular, as well as ovarian. So let's talk about urothelial, because we get a lot of questions. Well, how does this fit with BT8009? So we think of BT5528 as an opportunity to bring a new target into the metastatic urothelial cancer space in places where we've had patients who have intolerance or progressed on their first-line or second-line treatment. We could actually demonstrate efficacy in sequence or in combination, as well as in primary versus secondary resistance. And why that's important for us as a small biotech is that we can leverage our current infrastructure, our talent, our resources, to efficiently and effectively move into bladder cancer, because we already are exploring this with BT8009. But most important, we can develop a portfolio of solutions for patients in this disease area. And the early KOL feedback is really encouraging. So you can see here in the left, green box, the first quote: "There's a potential for two targets in urothelial cancer, since 80% plus express Nectin-4, but in monotherapy, you're only getting approximately a 40% response rate with current agents. EphA2 could help close the gap in objective response rate." And then feedback on the approach, you can see in the purple box on the bottom. "If you see a durable response post EV, good tolerability, and objective response rate of 25%-30%, it could drive potential accelerated approval in this space." And so they encourage us to continue to evaluate, and you can see they would like to see a new target. And like I said, in our unmet need research that I showed you before, this is really interesting to clinicians. But look at EV naive, look at EV exposed, look at sequence and combinations, and like I mentioned, primary and secondary resistance. And I would argue, as you can hear from kind of our ability to plug and play our molecules, we could even be doing this with BT8009, not just EV, obviously. And then just to think beyond bladder cancer. Again, I won't go into a lot of detail about these areas, but similar to some of the other solid tumors we talked about before in the nectin section, these are still areas of very high unmet need. Again, current five-year survival rates are very low, teens or single digits. Now, in ovarian, obviously, new efficacy benchmarks have been set by drugs like Elahere from ImmunoGen. However, KOLs tell us that sometimes upwards of 15%-20% of women, because there's still high use of chemotherapy in first line, cannot be treated. So we need more efficacious treatments in this space. Now, in gastric and head and neck, it's a bit of a different marketplace. Obviously, there's a lot of use of IO. Pembro plus chemo is approved here. Atezo plus Bev plus platinum doublets are trying to move into this space, data recently at ESMO. And they're right now still only offering about a 1-2-month benefit in efficacy endpoints compared to chemotherapy. So an idea of a new target with meaningful efficacy and a good tolerability profile could mean a lot of opportunity. So I'm just gonna end on this slide, which is kind of an expanded version of what you saw earlier, adding in BT5528 and looking across our clinical program. Right now, if you're thinking of the U.S. addressable patient population, our programs have the opportunity to potentially help up to 250,000 patients in the U.S. But like I said, we don't want to stop at the U.S. solution or just a metastatic solution. We're looking for global solutions into earlier stages of cancer. And like Kevin said earlier, we want patients to live long, but also make sure they're living well. Turn it back over to Kevin for Q&A. Thanks, JP. Santiago, Nick, if you could join us. So again, I think we've really interesting example how we've used the power of the Bicycle technology to take a EphA2 undruggable target. We've shown that we can safely develop agents to the target and those agents have a clinical activity. Okay, so, I'll take questions. Lee? Li Watsek from Cantor. So, just on this molecule, can you just comment on the correlation between the response and the EphA2 expression levels, and how are you thinking about the right cutoff for the expression levels? Yeah, I mean, you know, we are. We continue to explore this. The challenge that, and I think there's some confusion as well around this. These tumor antigens that we're exploring are not driver mutations. They're markers of tumor activity, and they change with time. In the case of Ephrin A2, the expression goes up. So you've two ways really to look at expression. One is to use your archive samples, knowing that they may have been taken several years ago, and the expression panel in the tumor may bear no resemblance to present day. Or you can take fresh tissue biopsies, and that has a lot of challenges. So what we're planning to do is continue to understand, retrospectively, the relationship between expression and activity. Clearly, if we start to... At this higher dose, if we and I think it's a general consideration, if we're at the sort of 40+ response rate, the requirement for a diagnostic is less appropriate. So I think we'll continue to monitor it. And we'll make a decision whether we need to use Ephrin as a marker in due course. Anything to add? Yeah, I mean, I think, I think in general, I think I mentioned this earlier on, the predictive power of histology in the antibody-drug conjugate field is very poor. So I mean, it's highly, firstly, the scoring tends to be quite subjective. Secondly, the samples are often taken at presentation, not at treatment, and they can be years apart. Thirdly, the tumors are very heterogeneous, so even a few millimeters difference in sample site can give you positive and negative. And we've actually seen that in tumor samples from you know, taken from a single tumor. You can. In one region, the tumor looks negative, and another, it looks positive. So I think it's probably only realistic to see any correlation when the data sets are very large and meaningfully statistically powered. I think in the larger drug conjugate field, the predictive power is really quite poor. And then maybe just a second question, as you're moving into a higher dose, can you just comment on your level of confidence for potential side effects based on your internal modeling and your clinical experience? Santiago. We are actually pretty confident because, again, because we have also the data from BT8009, and we model it. We know that with 5, we will have higher dose, more than 50% higher exposure of MMAE. So, it's expected that we will have that kind of efficacy. If you look at that, with BT8009, from 2.5-5 milligrams every week, we saw a substantial more efficacy, so we expect that to happen here. Okay. This is RK from H.C. Wainwright. It's good to have two molecules for urothelial cancer, both 8009 and 5528. How are you folks thinking about scheduling them in the continuum of therapy? And do you see, or is it toxicity, could that be an issue when you get to the later stage of the disease? Thank you. You know, I think right now there are a lot of options for it on the table, and that's the beauty of what we have in hand. You know, we're moving 8009 rapidly now into that first line and also with the potential of a second-line opportunity. We know from the biology of ephrin that it's a tumor antigen whose expression appears to increase as the disease progresses, and I think that gives us a lot of opportunity to think about coming behind 8009. We have potential for combinability as well, which I think is also exciting. I don't know if you wanna add anything. Yeah. I'd love just to kind of go back. It's a great question because, as a first and only, from a commercial perspective, you would potentially want to see it eventually move way up in line. However, for where we are in development and the fact that we have eight zero nine, and then some of the reasons you just heard them talk about around like expression changes, we would see this first opportunity in second line, second line plus. For a couple of reasons. One, with the use of nectin agents moving into first line, it's a great opportunity to be able to sequence both behind eight zero nine or EV in the first line setting. Also, the second-line market, like I was showing you earlier, is so fragmented, like there's no dominant player right now in the TME, so that's from a market opportunity standpoint, again, 12,000 potential patients, that gives us a potential foothold to be a leader in that space. And so for us, it's an easy fit to kind of have it right now in a sequencing position after 8009 in second line, second line plus. Plus, the benchmarks in that space, like sacituzumab in third line, when you're looking at its overall response rate, being in like the low 30s, depending on the study data set you're looking at. The fact that we currently have, you know, a response rate pushing into the 30s+, and we still are pushing the dose, gives us a lot of opportunity that we could dominate that space. Yeah, and don't rule out combinability as well, right? Not with other agents and also within our own, our own pipeline. Jay Olson, Oppenheimer. So thanks for that update on 5528. It seems like for 5528, you have more PADCEV-exposed patients and maybe more heavily treated patients. Can you just help put that into perspective for us, given the data you've just shown us? And then can you compare the profile of 5528 versus Trodelvy in late-line bladder cancer setting? Thank you. Yeah. You know, I mean, Santiago can jump in a second, but I think when we look at Trodelvy, obviously Trodelvy, as I understand, has two black box warnings. I don't think the profile here is very clean. Again, I would argue it's a fundamental step change in tolerability for drug conjugates, and, you know, I think it's very meaningful. The patient populations, it's a random process, right? So we bring the patients on from the sites. If they meet the criteria, we bring them on study, regardless of prior therapies, et cetera. We want to really understand the potential, the technology. Anything to add? Yeah, I mean, we didn't have a lot of patients, EV-exposed patients. We have two. I just wanted to bring that to attention because, again, this is a novel target, and one could say, "Well, if it's the same payload, it will not work." It actually works. So I, you know, makes it ideal for second line after after EV. But I wanted to make sure that we don't narrow necessarily this compound. This is a novel target in cancer therapy, so we still need to understand it fully. Again, we need to increase the dose. It's well-tolerated. We believe that the tolerability is not going to suffer too much by increasing the dose, and then we need to expand and understand in other tumor types. We have some emerging interesting information on head and neck, on ovarian, and obviously metastatic urothelial cancer. So we are still not narrowing it. Obviously, urothelial cancer is our first stop, but I feel that it can offer a lot, especially when we start with combinations. Kelly? Kelly Shu from Jefferies. So for the development path of 5528 in ovarian cancer, I wonder if you look at expression pattern of EphA2 and FR alpha, their overlap, or maybe also with CDH6. Nick. No, I don't think we've done those analyses. Also, have you observed association of overexpression of EphA2 with the later stage of ovarian cancer as shown in non-small cell lung cancer? So again, we will, we'll talk more about that in a later update. So we have data, but it'll be interesting. Thank you. You guys, Faisal from Leerink. I just wanted to ask, so for the ovarian data next year, can you give us a sense, even just roughly, of the numbers of patients you expect, in that update for BT5528? And also, if you have any sense for what kind of efficacy you would be looking for to support a potential path forward. Yeah, we are currently recruiting another cohort of 12 patients in ovarian cancer. As I mentioned, there is a slide in which I put the number of patients at the beginning. What was your second question? I couldn't hear it. What is support path forward? We are still working through the criteria again. You know, ovarian is tough on the combination pathway, so we need to think what would be the best therapy to combine. So it's work in progress. Again, we'll, we'll let you know sometime on the second half of the year. Yeah, for 5528 of those seven partial responses, how many patients got PFS off before? One. Only one. Okay. Thank you. And, and- How are you thinking about combinations of 5528 with IO or any other combinations? And perhaps, what could the safety profile look like? Yeah. -relative to what you've seen with 809? Yeah, I... It's a really interesting question. I mean, I think we need to work this through stepwise, you know, and just to, you know— It's very tricky developing a drug with a history like ephrin A2, against a target like ephrin A2. So, you know, we've tried to be appropriately cautious. We've been very mindful of the, you know, the Project Optimus initiative. As we've taken the molecule into more patients, we've grown ever more confident. And also, you know, we look across all our studies and cross-correlate, and we feel 5 milligrams is a very good dose for us to try. Once we've understand what that provides, then we'll think about how to combine it. I think it's reasonable to think, you know, if the tolerability profile continues to be as good as it currently looks, the notion of bringing in checkpoint inhibitors would be a very sensible thing to do, certainly in bladder cancer. And as Santiago said, we need to think a little bit more about what we do in ovarian. Hi, I have two— This is Yi Chen from H.C. Wainwright. Two questions for Nick. So in the slide where you show there's 10 times tumor penetration, is that tumor penetration? Mm-hmm. of 5528 in the preclinical model, I wonder what tumor type that is, and, a related question is: How variable is that across tumors with different volumes of tumor stroma? And I have a follow-up. Yeah, no. So the first question is-- The answer to the first question is I honestly can't remember which tumor model that is. The model-- We've looked at 5528 across a lot of difficult, different preclinical models. It will be in the publication that's cited at the bottom of the slide. The question around tumor volume is a really good one, actually. So something that we found with Bicycle toxin conjugates in general, not just with 5528, is really fascinating, which is in preclinical models, the rate of regression that we see is independent of the volume of a tumor, which is exactly what you'd expect from a fully tumor-penetrant molecule. And of course, we observe, and I'll talk this later in the radiopharm section, we observe really complete tumor penetration as compared to antibodies. When we do those comparator studies with ADCs, we find an inverse relationship, i.e., the larger the tumor, the less likely it is to respond to an antibody-drug conjugate. So the properties are quite distinct there. Was there another part of your question? You asked about the clinical data? No, no, that's it. And then the second question is: What's the trigger for increase of Ephrin A2 in late-line diseases? Yeah, again, I don't think that's really well understood. I think it's a target that's kind of. It was very fashionable and then became unfashionable. When targets become unfashionable, people don't really study them very much. ... It clearly is either associated with, so it's either a passenger or it's conferring some growth advantage to those tumors. I would guess the latter. What you tend to see under therapy is, of course, selective pressure and evolution, and I'm guessing it confers some growth advantage to those tumors. It is, after all, a receptor that signals. The biology of that family is quite complex, and I don't think it's really been fully established yet. Okay. Rajen? It's Rajan Sharma from Goldman Sachs. Thanks for the questions. Just looking at the spider plot in urothelial cancer, it looks like there was some kind of rapid responses early on in some patients, and then there was some more modest, including in the, the continuing response, which is kind of more modest. Is there anything in that baseline characteristics that you could kind of point to that may explain that? No, we haven't been able to pinpoint to some characteristics that would drive you to that. Okay. And then secondly, just thinking about kind of potential synergistic efficacy with 8009, do you have any sense of what Nectin-4 kind of what proportion of patients have Nectin-4 expression and EphA2? I think that's a really interesting thing to think about. I think it's something that we are working through at the moment, and we'll, you know, provide more information in due course. Don't want to say too much about that at the moment. Thank you. Any more? Okay, any more? All right, so we'll now move to our third session. I think Nick will stay on stage. He's gonna tell us about how we've applied the learnings from our clinical programs into our next generation of molecules. So over to you, Nick. Yeah. Thank you. So I'm gonna run through the next generation approaches in oncology, and then my colleague, Mike Skinner, is gonna run through applications of the technology outside of oncology, which I think really, really exciting and really interesting. So I'm gonna first off, talk about next generation Bicycle toxin conjugates. So I'm really excited about what we've seen with 8009 and 5528, in particular, being able to drug a target that we couldn't drug before. But there is always room for improvement, and so we're developing next generation Bicycle toxin conjugates. And I think, I hope what we've convinced you with is that the current generation of molecules really avoid off-target delivery, either by non-selective delivery to Fc receptor expressing cells or through intrinsically poor selectivity of antibodies and by reducing systemic exposure. But we are seeing a sort of a common spectrum of relatively low-level toxicities across the Bicycle toxin conjugates, typically GI that you've seen, along with some neutropenia, and that's likely driven by free payload release. And so a very obvious thing for us to do is to try and mitigate for that. The linker payload systems that we're using are about the only thing that we've really truly borrowed from antibody-drug conjugates. So BT5528 and BT8009 both carry a Val-Cit linker system that's cleaved by the cathepsin family of proteases and was, of course, developed for antibody-drug conjugates. We believe that we can improve on the properties of linker systems by designing linkers that are tailored both to the biology of the receptor which we target and also to the Bicycle itself. The very nice thing about being a peptide company is we're very experienced, really experienced in being able to screen across hundreds of different kinds of peptides and different sequences of peptides. So we've been doing a lot of work now to try and tailor bespoke linkers to bespoke Bicycle drug conjugates. I think an important message here is it's very unlikely that one size will fit all. Each molecule that we produce in the future may well have a very different linker system, as I said, dependent on the biology of the target and the tumor type that we're going after. But I'm just gonna show you some early data. We have identified linkers with improved stability, cleavage trade-off in model systems. So the data here is for one target in particular. I'm not gonna name the target yet. But what we're doing is looking at a Bicycle Toxin Conjugate carrying the current generation linker on the left-hand bottom panel. So that's a Val-Cit linker system. At this dose, at 0.67 mg/kg, the active molecule and the control molecule, non-binding molecule, overlap with the vehicle control, so the molecule is inactive at this dose. However, with the new linker system on the right-hand panel, you can see that we see this really beautiful behavior at the same dose. So this molecule has been given exactly the same dose, it has the same payload, but here we're seeing almost every animal in the study, the tumors are completely regressed and are being kept disease-free out to 63 days plus in this study. In addition, we see really beautiful separation between a binder and non-binder control. When we look at what that means for systemic MMAE exposure, and these are dose normalized for activity, you can see that we've hugely reduced the Cmax exposure to free MMAE in these animals, and we dramatically reduced the AUC. In essence, what we've done here is to design linkers are much more efficient at depositing their payload in tumors, thus minimizing systemic exposure. So we're excited about this. I think our first-generation molecules have already shown a very significant step forward, but I think we're going to improve on that, or we aim to improve on that in our subsequent generations of molecules. We will be incorporating these next-generation linkers into those future molecules, and we're aiming to select a clinical candidate using this new generation technology in the second half of next year. So now to move on to a related field, and it really takes us right back to the slide that Kevin showed you at the start of the meeting, with that beautiful imaging study in a mouse. That imaging study was possible because that Bicycle was carrying an imaging radioisotope. And it turns out that Bicycles, I think, really will find a place now in the new and evolving field of targeted radiotherapy. Indeed, the applications here for Bicycles might be even simpler than they are in the other, other approaches that we've discussed today. There's no need here, for example, for a cleavable linker system. What we're aiming to do is to is to identify molecules that are highly selective and tumor, tumor-penetrant, those being two key properties in this field. Something that really is a big issue in this field, and I'll talk to it more in a second, is that we want a broad opportunity here. We don't just want to target the same receptors that everybody else is going for, and we want molecules that really minimize systemic exposure. Having prolonged systemic exposure to, for example, a high-energy alpha emitter, is probably not a very nice thing to do. So we know now that this is a field that can work. It's been pioneered, I think, really by, particularly by Novartis. There are many companies now, because of that pioneering work, that are chasing after the same receptors. Many, many people are targeting PSMA and the somatostatin receptor, and there's a really good reason for that, which is there are existing small molecule ligands to those receptors, which are actually peptide-like. That represents a huge opportunity for us because there are now, I would argue, multiple opportunities for novel radioligands. The real issue has been that people just don't have the ability to identify and design well-behaved small molecule against the target of choice, and that's really the Bicycle advantage here. We are a precision delivery company, and we can pretty much design Bicycles to target any extracellular tumor antigen of interest. That's not escaped the attention of external companies. I'm sure you've heard about our collaborations with the two leading companies in this space with Bayer and Novartis. They came to us, and we're very proud to be able to work with them, and of course, that brings additional non-dilutive financing into the company. We're actually developing our own internal pipeline, and here, we're collaborating with the DKFZ in Germany. DKFZ in Germany, being probably the world's leading imaging and therapeutic radioisotope institute. So we are building a very deep pipeline of Bicycle binders. Given the success of the platform, we're building a very deep selection or palette of Bicycle binders to high-value tumor antigens. We're clearly not going to name them all here, but this is just to illustrate just the kind of binding potencies that we're able to get with these molecules. Again, in this small, fully chemically synthetic format, with, we would argue, pro-properties which are ideal for radioisotope delivery. This is just to show you a few imaging examples. These are actually molecules that are not optimized for radioisotope delivery. This is just to show you that this is something that we do actually quite routinely at Bicycle to evaluate the biological distribution of our molecules. In the left hand here, we're looking at a target called MT1-MMP, and I'll talk more to this in a minute. This is a very interesting tumor antigen, has really beautiful differential biodistribution. We really see with this target that we only see imaging in the tumor or in the kidney and the bladder as the molecule as it's on its way out. In the center is a Bicycle that binds to EphA2, the target of BT5528. We're looking here in two really quite challenging models. The image on the left-hand side is a disseminated breast cancer model, so these are actually metastases throughout the mouse. You can see that they're being rather beautifully imaged by that binding Bicycle. The little inset in the right-hand side is an independent academic study. Here, they're looking at an orthotopic pancreatic cancer model, which is about as tough as you can get. So trying to get into an intact pancreas and to image pancreatic tumors is very difficult. But again, in this study, they saw really beautiful imaging and access into that orthotopic model. On the right-hand side is a Bicycle targeting CD38 in a multiple myeloma model. Again, showing really stark contrast between the tumor and the normal tissue, and actually, in the inset figure there, imaging bone metastases. Again, bone being a very difficult site for larger biologics to access. Now, these studies were preclinical. We're very pleased that these are now translating into clinical imaging studies. This, again, is third-party validation. This is from a group in China, collaborating with Johns Hopkins, where they took a binding Bicycle to Nectin-4, similar but not identical to the binding Bicycle in BT8009, radiolabeled that in an imaging study and dosed it to patients with metastatic bladder cancer. They saw really beautiful contrast, actually, and uptake into Nectin-4 positive tumors in humans. This illustrates that Bicycles can both access, bind to, and distribute effectively in humans, as well as in those preclinical studies. In fact, they saw very significant accumulation within 15 minutes of dosing, again, mirroring the kind of preclinical time lapse that Kevin showed you earlier this morning. Now, to turn to our internal programs, this is a chemical platform, not a biologics platform, so we can engineer the behavior of these molecules.... Looking at the top left-hand panel, we can dial in potency against this target, which is the target of a molecule that we're taking forward. We've dialed down the potency to a binding affinity of 20 picomolar, which is an incredibly potent binding for such a small molecule. We can also engineer internalization of these molecules. I believe internalization is important for certain radioisotopes. And finally, on the right-hand side, we can dial out binding in non-target tissues. Kidney accumulation is a significant issue for peptide-like molecules, and again, you will have seen this for other radioligands. We're very excited, actually, that we can now engineer our molecules to avoid or significantly reduce kidney retention. The image on the left-hand side here is a non-optimized Bicycle against a specific tumor antigen. On the right-hand side, this Bicycle has now been optimized to reduce kidney retention but retain tumor retention, and we're seeing this beautifully clean imaging profile. So just to turn to MT1-MMP, this will be the first target that we'll take into human imaging studies as a wholly owned program, and we are developing therapeutic molecules against this target. Unique target to Bicycle. It's a very interesting target biologically. It's involved in embryonic tissue remodeling. It has very restricted expression in normal tissue in adults. It's expressed across multiple solid tumors. You can see in this insert table frequencies of expression in multiple tumor types. On the right-hand side is an early study with an MT1 targeting Bicycle. Again, you can see that we get this very clean distribution profile biologically. This is an early study now and an efficacy study. What we did here is to take a binding Bicycle that targets MT1, and in this case, it's carrying lead-212, which is an alpha particle emitter. This work was done in collaboration with Orano Med, who are a lead-212 supplier. Interestingly, in this molecule, we engineered the half-life. We engineered the half-life here to be in the order of about, I think, about 6-10 hours for this molecule. Typically, the half-life of a unmodified Bicycle will be around 1 hour or so. We wanted to make this compatible with the decay half-life of this particular payload. We see extremely nice payload distribution in tumors. These molecules effectively completely penetrate tumors. We did comparator studies with an antibody, which would be very boring to show you because they'd be completely black. We really did not see tumor penetration with a comparator antibody. When we took this molecule into efficacy studies, and we gave three 10 microcurie doses to animals, all of the animals in the study were tumor-free at the end of that study, and actually, the molecule was really very well-tolerated. I think that, along with the clean imaging profile, I think represents a unique opportunity for Bicycle and a discrete target as far as we're aware, there aren't any other radioisotope companies that can tackle a target like this. So in summary, I think we're really solving for a significant issue in the field here, which is the generalization of the identification of binders to any target of choice. We are being validated now by external collaborations with the two leading companies in this space, Novartis and Bayer. We're building an internal pipeline. We aim to go into humans next year to look at biological distribution and imaging, and we are also developing therapeutic versions of those molecules. So we're nearly at the close here of the oncology section. I did want to talk about our next-generation approaches in immuno-oncology. I think the data that we've seen for BT7480 are very exciting. They show you that a completely new modality can both bind to and activate the immune system in humans. We consider that a big deal. It's rare that you get a new technology that can both deliver against tumors and influence the human immune system. So we're building options here. We've already identified binding Bicycles that can bind to and activate key receptors on NK cells. Indeed, they do that in an extraordinarily potent way. We've identified molecules now that get down into the picomolar range for cell killing. It's very simple bispecific-like constructs with a tumor antigen-targeting Bicycle, and in this case, an NK cell-activating Bicycle. We can also build in polypharmacology to our molecules. In the green-headed box here is a molecule that blocks the PD-1, PD-L1 interaction with a Bicycle and, at the same time, activates CD137, so we can build in multiple pharmacologies within a single Bicycle molecule. And finally, in the purple box at the bottom left, or in the center, rather, we've recently discovered that we can very effectively drug in pre-clinical systems, key cytokine receptors. That's a big deal 'cause those have been very hard to tackle, other than with really quite ungainly artificial biologics. We can do this in a very small, very precise molecular format. So we're building... actually, quietly building quite a deep portfolio, not just of tumor antigen binders, but also of Bicycle effectors against the immune system. And so to kind of summarize and round out the pre-clinical oncology section, we're building a deep pipeline now of tumor antigen binders, and we're parsing those out with different effector arms, either to deliver small molecule payloads like MMAE, to deliver radioisotopes or to activate the immune system. And we're hoping to build on the foundation that we have with our Nectin-4 portfolio and our EphA2 portfolio, and to start to extend out into other tumor antigens. That's the last slide I have, and it's my great pleasure to hand over to Mike, who will walk you through our applications beyond oncology. Thanks very much, Nick. Good morning, everyone. My name is Michael Skinner. I'm the Chief Technology Officer for Bicycle. And unsurprisingly, I joined the company because of the technology. But I have to say, on a personal note, it's been a career privilege to be the custodian of that for the last eight years and to turn Sir Greg's invention into the industrialized platform that we have today. So Bicycle has been active beyond oncology for many years, and the same factors drive success beyond oncology as in oncology, namely, the ability to drug targets inaccessible to many other modalities with a high confidence of success. The properties of the molecules, high affinity, high selectivity, tunable properties, mean you can make Bicycles with that can address multiple additional applications and therapeutic uses. But the way we decided to go about this is somewhat different. We've done this through partnerships. Partnerships bring expertise from the partner, meaning you don't need to build that in-house, saving money and allowing you to prosecute multiple areas. Collaboration also brings non-dilutive funding, and I'm really proud of the fact that we've covered all of this work through non-dilutive sources. But ultimately, it helps us deliver on our mission, which is to get as many Bicycles into as many patients that need them as possible. So where have we been active? We've been active in a number of therapeutic areas, including but not limited to neuroscience and neuromuscular disease, I'll say more about that later, anti-infectives and antivirals. We've done this in collaboration with large pharma companies, biotech companies, and we've been the recipient of significant grant funding from both governmental and non-governmental sources. A priori, we've decided to work in collaboration with academic centers of excellence, and KOLs. They bring insights and expertise into these areas, but also give us access to specialist biology models. Collectively, over the time that we've been active here, we've brought in $88 million of non-dilutive funding. That's clearly covered all our work beyond oncology, and importantly, allowed us to cross-fund oncology with much of this funding. Now, when we talk to potential partners, two aspects of the platform come to the fore. Firstly, our ability to drug very high-value targets to the partner, with a high degree of precision, because these targets are inaccessible often to their internal pipeline and platforms. And the ability to couple these to a range of payloads, payloads which would be inaccessible to Bicycle if it weren't for partnership, all of which are enabled by improved cell targeting and better cell delivery. And that's what gives us our plug-and-play approach to precision targeting, coupling the ability to drug cell-specific antigens with the pharmacology of the Bicycles to generate novel therapeutics with new and novel, mechanisms of, mechanisms of action. So to exemplify that, I'd like to talk now about our work in neuroscience. So in neuroscience, the problem here is that most drugs don't get across the blood-brain barrier. The blood-brain barrier being a series of tight junctions between endothelial cells in the blood vessels that line the brain. One way to get around this is to use transporters as Trojan horses to deliver into the CNS. The most well-characterized of this is the transferrin receptor or TFR1. So as transferrin carries iron into the brain through transcytosis, other molecules can hitch a ride and piggyback into the brain. The first task we faced was to screen this target and find binders to a particular site on the TFR1 receptor, namely outside of the ligand binding domain. So we deployed the platform in one of its many screening configurations to enrich for binders to the desired site. We found a Bicycle and worked out where it bound to the receptor using X-ray crystallography, and you can see it there bound into the target in orange. Our strategy was quite simple: to use this TFR1 shuttle to conjugate to a range of otherwise peripherally restricted molecules, and then deliver those into the CNS for pharmacological and therapeutic effect. So having found a Bicycle, we then had to show that it worked. The first stage in doing this was to perform a definitive pharmacokinetic experiment in non-human primates. So we took NHPs and inserted a microdialysis probe into the brain. Importantly, we then allowed the blood-brain barrier to reseal, and then we took a Bicycle and infused that in the periphery, and then measured the transit of the Bicycle into the CNS by analysis of the dialysate in the probe. As you can see from the left-hand panel, the Bicycle over a five-year hour period accumulated in significant quantities in the CNS. The second question, could we use this technology to deliver something that had a pharmacological effect? Here, we did a pharmacodynamic experiment, where we took an otherwise peripherally restricted small molecule and conjugated that to a TFR1 Bicycle. Now, if this molecule gets into the brain, we would have forecast it to have an increased, it would increase the activity of the animals. And that's exactly what we saw, as you can see from the middle panel. We, of course, did the control experiment and also injected a null Bicycle that didn't bind TFR1, conjugated to the same small molecule, and saw no such effect. So we're continuing to develop this technology. We're very active in looking at additional payloads that we can deliver with TFR1, but we're not restricting ourselves to TFR1. We're also developing a portfolio of cell-targeting Bicycles to both deliver the next generation CNS shuttles, but also Bicycles that can deliver to other cell and organ systems. Now, we also managed to monetize this TFR1 by forming a partnership with Ionis to deliver antisense oligonucleotides. I think it's particularly powerful when you put your technology into the hands of third parties, and they report out on their activity, and this is a slide taken from Ionis's Investor Day in October. Ionis had the intent to deliver ASOs into the brain. So we supplied them a series of Bicycles to TFR1, and they conjugated them to their ASOs and showed no loss of activity of the Bicycle, despite being coupled to this large moiety. They then injected these molecules into the periphery of mice and showed that not only did these molecules get into the brain, but they also got into cells where the ASO had to exert its action, in this case, on inhibiting a housekeeper gene, MALAT1, in a range of brain regions, as you can see from the right-hand side. What you can also see is that they also saw knockdown in the musculature, both in skeletal and cardiac tissue. This is to be expected, as TFR1 is also expressed in these tissues. And actually, this is something that we could exploit because Ionis also had an interest in neuromuscular disease. So we posed the question: Could we make simple design changes to the Bicycle and optimize these molecules for neuromuscular delivery? We did that, and as you can see from the left-hand side, we achieved the profile that was desired, namely, to reduce CNS delivery to maximize delivery to the muscles. And this talks to the tunability of the Bicycles, the ability to make very small changes to them and actually profoundly change the way that they behave, uniquely enabled because Bicycles are small molecules. So what's coming next? Well, we're not resting on our laurels. Over our history, we've got a very deep proprietary dataset on Bicycles binding to particular therapeutic targets. Remember that Bicycle is the only company that has this technology, so this database is proprietary to us and us alone. We've also been very active in taking these molecules and trying to understand the secondary and tertiary structures of Bicycles and how they bind and interact to their therapeutic targets. Again, a second proprietary database. By combining the two databases together and now working with experts in the field of artificial intelligence, as we are, such as Google, we can apply machine learning to our databases to then predict the next generation of Bicycle molecules more effectively. So in summary, we've been active in areas outside oncology for a number of years. We've done it through third-party interactions and shown success there. It's also allowed us to evolve our technology. In the future, we intend to continue to do this. It'll bring in important funding for oncology and for our work outside oncology. More importantly, it will allow us to put more Bicycles into patients that need them, and we can hopefully accelerate what we do in this area by use of artificial intelligence and in silico work. Thank you. I'll hand back to Kevin now for Q&A. Thanks, Mike. So I'll ask Nick to join us on stage. Hopefully, what you've heard in this session is how we're taking the learnings from our clinical programs. We're applying them to bring forward a new generation of molecules. We're generating proprietary linkers, looking at new payloads. We're innovating them in the IO space. We continue to innovate beyond oncology, very exciting work, I think, in neuroscience. And again, even with our platform, we're not resting on our laurels. We're bringing forward an ever, ever more new and adaptive ways to improve the efficiency of the platform. So I'm very happy to take any Q&A. Jeff? Thanks. Jeff Hung, Morgan Stanley. Can you just talk a little bit more about how your TFR1 approach differs from Denali's approach, and what are your expectations for differentiation on efficacy and safety that you might see with Bicycle designs? Thanks. Sure, yeah. I mean, the Denali design is clearly based on biologics. We, we think our differentiation is quite simple, with, to our knowledge, the only small molecule delivery system. So part of that is actually the power-to-weight ratio that you have in the delivery system versus the payload. So for example, for ASOs, they're about 5,000 molecular weight. A Bicycle is half that size, so it's a smaller element to deliver a larger element. It's the reverse with biologics. They're, they're 40 times the size of ASOs. So we believe just the nature of being small molecules will actually differentiate us. Jay? Jay Olson, Oppenheimer. Now that you've done pretty extensive dose escalation of three clinical programs, including two BTCs and one bispecific T-cell engager, can you just talk about some of the lessons that you've learned and how you may be able to narrow the dose range and accelerate future programs based on the findings from the work that you've done? Then I have a follow-up question. Yeah, you know, I mean, the- ... Obviously, we had to be appropriately cautious when we moved the first molecules into the clinic. Completely new technology, very challenging targets. But we've also been very thoughtful and very respectful of the emerging FDA initiatives, Project Optimus, et cetera. I don't think Project Optimus is going anywhere. I think it's gonna be something that is a really important initiative, and it's here to stay. I think we've learned, you know, how to navigate through Project Optimus in an efficient way that addresses, you know, the FDA requirements. And I think that's something that we'll continue to learn from. When we think about our IO molecules, you know, I think we... You know, given the history of IO and some of the challenges, particularly around CD137, I think we've certainly addressed those concerns, and if we bring forward more CD137 molecules, I think we've probably alleviated some of the regulatory concerns about slow starting doses and how we might be able to accelerate there. So, yeah, exactly, we're applying those learnings. Great. Thank you. Super helpful. And then just to follow up on your TFR1 Bicycle, is there any read across from recent data on Roche's Brain Shuttle program for trastuzumab and potentially Ocrevus in terms of using your TFR1 Bicycle for antibodies or any other delivery into the CNS beyond the work that you're already doing with antisense oligos? You know, where we're very focused on in our TFR1 programs is, you know, working with Ionis to deliver antisense to the brain and to skeletal muscle, and in our own programs, small molecule payloads into the brain, and I think we're making really good progress there. I don't know if you have anything you want to add, Mike? I think that we do believe that the TFR1 technology is amenable to delivering multiple different payloads. That's an area of particular interest to us. Beyond that, we haven't made many other disclosures. But yes, we believe it has a broad applicability. Any chance it could be used for capsids? Potentially. Thank you. Hi, Ami Fadia, Fadia from Needham. Just to follow up on the TFR1 questions. You know, this is a small molecule relative to the Denali approach, which is different. What does that change in terms of the bookends of what you can add on as a payload to a small molecule? And is there some sort of a way to think about the relative size of- I don't think there's any limitation. If you remember, the technology emerges from attaching bacteriophage, very large. The way we do our screens, we screen with the Bicycles attached to phage. So we know the Bicycles work with very large payloads attached. They perform well. So I don't think there's any limitation. I think the advantage is these are fully synthetic, and we're not having to, you know, do complex biological engineering to attach, as is often the case with antibody approaches. So I think that's where there's an advantage. But Mike, anything else to add? Yeah, I think you covered it, Kevin, actually. Okay. Ali. Ali Wassef from Cantori. So, just for your radiopharma pipeline, can you just comment on the isotope that you might pair with your binders? Is it going to be, you know, target specific, or do you have a favorite type, for instance, like- Yeah, we think we have an advantage in that we're agnostic. We explore all radioisotopes. I don't know if you want to be more- Yeah. I mean, I again, I think there, there's unlikely to be one size fits all, so I think it's rather target dependent. As Kevin said, you know, we're really a targeted precision delivery company. And we want to generate the best next generation of molecules to have the best benefit for patients. And we're obviously not a radioisotope company, and we'll work with companies in that space to deliver the best molecules that we can. And then just for your MT1 radioligand, I mean, do you anticipate any off-target or maybe on-target, but off-tissue toxicities that we've seen with Pluvicto? One of the great things about MT1, and the thing that excites us, and it's also known as MMP14, it's a target we've been, you know, working on for quite some time now, is that it's one of those molecules that is expressed naturally very high during embryonic development, and then the expression falls away quite rapidly in the adult. So hopefully, that should translate very well into what we see in the clinic. I think Rajan and- Yeah, Faisal from Leerink. I just want to ask on the radioconjugate platform, maybe for Nick. How do you compare a Bicycle radioconjugate to other peptide-based approaches in the landscape, like DARPin or mono macrocyclic peptides or just regular peptides? Yeah, really good question. So I mean, I think it's quite telling that both Bayer and Novartis are working with us, given they have the ability to survey across both internal and external platforms. I don't think biologics are a good fit for this space, to be perfectly blunt. We had a really excellent Oppenheimer Radiopharm conference this year, which was a really wonderful opportunity to look across many different platforms. It kind of amused me to see images of antibodies in humans where the claim was being made that they were kidney protective by delivering to the liver and the GI tract with fairly minimal tumor penetration. I mean, it's a cliché, but this platform just plays really, really well in this space. It enables us to engineer in properties, and that's really important. I, I've worked on other peptide platforms in the past. I used to lead the preclinical oncology research group at Novartis, and we had a collaboration with another peptide company there that worked on monocyclic peptides. The issue with monocyclic peptides is that they're typically stabilized by intramolecular interactions, and they're very hard to optimize away from things like lipophilicity. The beautiful thing about the scaffold in a Bicycle is it enables us to make point changes in amino acids and to, for example, to substitute them for non-natural amino acids and engineer those properties. I showed you the example of engineering away from kidney retention. That'd be very hard to do in a, in another platform. So we think we're really uniquely positioned in this space, and as I said, we're kind of getting the external validation on that. Bill? Hi, Bill Maughan, Canaccord Genuity. So hopefully these aren't too broad as to not be useful. But- Mm-hmm. When you're thinking about developing a radiotherapy program and thinking about the ultimate commercial presentation and the complexities of administration and potential supply chain issues, how do those factors factor into go/no-go decisions and decisions on which tumor to go to? Is the bar for unmet need higher to bring forward a radiotherapy program? Let me start. You know, I mean, I worry a lot about supply chain. You know, I worry, I worry the way, you know, we're all kind of driving towards radiopharm now as the new panacea. I think there are some parallels with historical approaches in cell therapy, et cetera, and we'd fall over due to supply chain. And supply chain, if you don't get your supply chains right, there is no drug. And it, it's no coincidence that we've chosen to partner with the two companies on the planet who have done this and do have supply chains. You know, we feel that we've got a really big opportunity in toxin conjugates. That's our core. Radiopharm is a big opportunity as well, but we have to do that stepwise, working with people who have experience, you know? So this is something that we think a lot about, we worry a lot about. And I think in the short term, we think very much about how we can, you know, maximize collaboration to bring forward products. As we learn more and as the industry learns more, that's when we'll start to think about how we can take our own products forward. Nick, anything to add? Yeah, I mean, I think your question was about targets, about selection of targets. I did have a slide in on selection of targets, but took it out for the purposes of time. So the features that you want for a target in the radiopharmaceutical space are discrete from what you might want in IO or in toxin delivery. In toxin delivery, you want a very high level of expression in tumor, and you can bear some normal tissue expression, because you want to deliver as much drug as you possibly can. I should have pointed out in the MT1 section that lead-212 carrying Bicycle is about somewhere between 10-100,000 times more potent than a toxin-bearing Bicycle. So what you really want with a molecule like that is you want a target that has really exquisite normal tissue to tumor selectivity, but you can bear a lower level in tumor. And that pool of targets is significant, but relatively small, and we're gonna go after as many of them as we can because they will be commercially extremely attractive. Again, I said, you know, one of the things that struck me in the conference I attended earlier this year is just how many people are chasing after PSMA and somatostatin receptor. There has to be much more opportunity than that, and I think we're the company to solve for that issue and broadening the pipelines. Any more questions? Ah, Rajan. Hi, it's Rajan Sharma from Goldman Sachs. So, just kind of thinking a little bit more about how you select antigens and maybe on the BTC side of things, could you maybe just kind of talk us through that? And I guess, are you now confident in the technology and the platform, that you feel like you can kind of use ADC data as almost proof of concept and target those antigens? Yeah, I mean, I'll jump straight into that. I think there are three pools of potential targets. So one is ADC targets with an associated significant toxicity risk. Okay. And those are known and out there. What people tend to forget is that there were a huge number of... And I worked in this, unfortunately, I worked in this era of ADCs. There were many, many ADC targets that fell over, that had appropriate expression profiles, but failed for tox in preclinical systems, in preclinical and early clinical testing. So there's a rich scene to mine there with a platform that can give an improved safety advantage. I think the second sort of scene to mine is targets that don't require internalization. So ADCs obligatory require internalization for activity. That's how they're cleaved. ... and how they're processed. There are many tumor antigen targets which are not well internalizing, but are broadly expressed in cancer. And then, you know, I think the third is that a lot of companies have focused on pure bioinformatics approaches to try and identify tumor antigens. And actually that... In my mind, it's equivocal as to whether pure bioinformatics approaches actually translate into true biological distribution. And as you saw earlier on, something we do very commonly is to image our Bicycles. And some of the results from that are quite surprising, in that there are targets that you would not predict are tumor-restricted, really are tumor-restricted. So for example, cell surface expression can be different than intracellular expression. You'll never pick that up through an mRNA-based profile. So we're looking at it. We have a rich source. Let's put it this way: there's a lot we can go after with this platform. A broader palette, I think, than is available to pure ADCs place. Thanks. Just one follow-up. Obviously, there's kind of been a huge amount of industry and interest in ADCs. Just thinking about kind of as you progress the pipeline, is there a point in time where you think it could be logical or helpful to have a larger pharma partner that may be able to kind of help progress the pipeline, be that from a commercial perspective or from a development perspective? You know, I think what we've shown today is that we're, we're accelerating. We're accelerating the rate at which we can bring these molecules forward, we can apply the learnings. There's gonna be more than we can do ourselves, so we have to think about... And I think we're a very collaborative company. You know, our goal is to do the very best we can for patients, and we have to accept that there comes a point where our ability is saturated, and we have to partner. And we've always said, I've always been very clear, we're always interested in collaboration and partnership. We have two criteria. One, we have alignment on value, and two, the partner can bring forward something that we can't do on our own. As we've got more molecules than we can handle, that seems like a very sensible and logical thing to think about. Thank you. Hi, Doug McPherson from H.C. Wainwright. So Nick, we spoke super briefly during the break about the half-life extender. So I have a two-part question. The first is: What is the mechanism of action for the half-life extender? Is that based on charge? Is it based on sterics and size? And then the second is, second part of the question, you know, use the example of extending from 1-hour half-life to 10. What is your upper limit? Like, for some applications, you might want with a longer-lived isotope, you might want 48, 72 hours. Does that exceed the current capabilities, or is that no problem with your half-life, half-life extenders? Thank you. Yeah. So for, so for the first question, there are many routes available to modulate half-life, half-life, both by modulating the intrinsic properties of the Bicycle, but also by appending them to small molecules that can bind to other proteins, so for example, human serum albumin. And that, and that's well established for the peptide field in general, as well as for other small molecule approaches, and we can pursue any of those. In terms of how long can you make a Bicycle in terms of half-life, I think we've... Mike, we've done this out for, we've got some really long half-life extension when we've- We've managed to extend half-life out for multiple hours. But I think there is a point where you become an antibody, if you extend the half-life, and that's a place that we've always been very clear we didn't want to go. We wanted to stick within the Bicycle advantage, which is, as Sir Greg said in his video, it's around, "Get the job done and get out. Okay. I appreciate that. Thanks. Any more questions? Okay. So, it's now my pleasure to bring this meeting to a close and make a few final remarks. I hope you found the morning enjoyable. I'd like to thank our presenters. As Sir Greg said, it's never an easy task introducing a completely new modality, but that task has been made all the more easy by working with such great people and all the great people behind our speakers who make up the Bicycle team. I hope you found the morning enjoyable. I hope you see how excited we are about our technology. We think we have a very significant opportunity. Hopefully, you've seen that as we've moved into the clinic, we've been, I think, appropriately thoughtful and cautious, particularly in light of some of the targets that we've been targeting. But we're now accelerating towards pivotal trials, and with those pivotal trials, towards commercialization. You know, we're building an end-to-end pharma company. We're already building our commercial organization. We have our manufacturing supply chains being put in place, and we're absolutely delighted that the FDA selected us for their pilot CMC program. I think that gives us increased confidence that when the time comes for launch, we're gonna be ready. If we think about 2024, it's gonna be a very catalyst-rich year for the company. Now, of 8009, I think we showed, we have a very, differentiated safety profile, I think a fundamental step change. We've shown that that translates to a, a much longer duration of response, and we've done that without any real compromise in efficacy. Next year is about initiating our pivotal trial, DURAVELO 2, and we'll report out on the completion of our DURAVELO 1 open label studies across a range of different tumor types. ... For BT5528, we've taken an undruggable target, we've made it druggable, we've shown it's safe. I think the tolerability profile is, again, a fundamental step change for the industry, despite the challenges of that target. And we've shown that drugging that target does deliver tumor shrinkage and benefits the patient. Next year will be about reading out on our 5 mg/m² cohorts in urothelial and ovarian. For BT7480, I think we've shown the benefits of precision targeting, the benefits of a really well put together translational package. We've shown that you can get good translation between preclinical and clinical, and we can activate the immune system in a way that's consistent with sensitivity checkpoint inhibition. We've begun to show signs of early activity. Next year, and for BT7480, next year, it will be about completing our dose escalation and starting combination cohorts with checkpoint inhibitors in cervical and non-small cell lung cancer. Next year will also be the year that we bring forward our next generation of molecules, our first radiopharm programs, and we're looking forward to sharing with you patient imaging data from them, and also we'll be nominating the first of our next generation BTCs. On my last slide, I'd like to go back to the challenge that was set to us by Sir Greg. How are we gonna turn the Bicycle advantage into a reality? I think we've taken this Nobel Prize-winning science, we've industrialized it, we've taken 3 molecules into the clinic. We've shown, I think, really promising emergent signals. What we're gonna need to do now is really focus and deliver on the promise of those early clinical programs, building big portfolios in Nectin-4, EphA2-expressing tumors. Not just one tumor type, a range of different tumor types. And then we need to bring our next generation of molecules to continue to consolidate our leadership position. As I bring the meeting now to a close, I really wanna thank you all for being here. Hopefully, you can see how excited we are about the promise of this technology. We feel we have something, a very significant opportunity for patients. We feel we have the tools to enable patients not just to live longer, but to live well. We're very committed to these patients, to bringing the maximum benefit to patients. We feel it's actually our mission to do that. And so as I draw the meeting to a close, I'd like to thank you all for your attention. I hope you found the day informative. I hope you share our excitement. I hope you continue to support us in this journey. My last big thank you is the most important thank you. It's to the patients who've selflessly given themselves to enable us to realize the potential of this technology. We're very, very grateful to our patients. On that note, I'd like to end the meeting. Thank you for your attention, and safe journey home. Thank you.