Welcome to the Bicycle Therapeutics call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there'll be an opportunity to ask questions. To ask a question, you may press star then one on your telephone keypad. To withdraw your question, press the pound key. Please note, this event is being recorded. You may listen to a webcast replay of this call by going to the investor section of Bicycle's website. I would now like to turn the conference over to Dave Borah, Vice President, Capital Markets and Investor Relations. Please go ahead. Thank you, operator. Good morning, everyone, and thank you for joining today's call to discuss the BT8009 interim phase I data and preliminary findings from the BT8009 program presented at the AACR meeting. I'm Dave Borah, and joining me on today's call are Dr. Kevin Lee, Chief Executive Officer, Dr. Dominic Smethurst, Chief Medical Officer, Dr. Nick Keen, Chief Scientific Officer, and Lee Kalowski, Chief Financial Officer. Before we get to the presentation, I wanna make you aware of our forward-looking statement. Now I'd like to turn the call over to Kevin Lee, Chief Executive Officer. Thank you, Dave, and thank you to everyone for joining us this morning. Turning to slide three to review today's agenda. Nick will begin with an overview of our technology platform, then Dom will follow by discussing our clinical progress in BT8009. Initially, the efficacy data followed by its adverse event profile. We will then open the call for Q&A, for which we will all be available. Next slide, please. Before we jump into the technology overview and the clinical data presented today, I want to give you a brief update on the company. Our unique bicyclic peptide platform is based on the pioneering Nobel Prize-winning work of Sir Gregory Winter. Our bicyclic peptide platform is truly differentiated. We are focused internally on oncology and look for partners outside of oncology to fully explore the clinical utility of this platform. We currently have about 120 employees working out of our two locations. We also have about $440 million in cash as of December 31st, which should fund all of our development through to the end of 2024. Next slide, please. We have five molecules currently in the clinic. One is an ophthalmology asset partnered with Oxurion, and three others are Bicycle Toxin Conjugates, BT5528, BT8009, and BT1718, all of which are being investigated in oncology indications and are based on our proprietary bicyclic peptide technology. Finally, BT7480, a Nectin-4/CD137 Bicycle TICA, is our first immuno-oncology asset, which entered into the clinic in November, for which we are very pleased with the progress that the molecule is making. Our partner pipeline is also expansive and continues to progress at an impressive pace, and most notably includes collaborations across multiple oncology and non-oncology indications with organizations such as Genentech, Ionis Pharmaceuticals, and AstraZeneca. With that, I'll turn the call over to Nick for a quick review of our technology platform. Next slide, please. Hi. I intend to cover just a couple of slides before handing it over to Dominic for the clinical review. First thing to point out here is the size difference between bicycles and antibodies. A bicycle is about 100 x smaller than an antibody. Bicycles have also been shown to be highly specific for their biological target. On that note, it's important to remember that while antibodies are commonly referred to as specific, they, by nature, bind to receptors present on many normal cells, which can lead to off-target activity. Furthermore, in contrast to antibodies, given their small size, bicycles also have the ability to rapidly penetrate tumors. Finally, they're rapidly excreted renally, not via the liver, which may help avoid some of the toxicities associated with other modalities. Next slide, please. This slide picks up where the last one left off with a very simple illustration of how a Bicycle Toxin Conjugate is constructed. A rigid three-dimensional scaffold is coupled to a peptide at three positions. This generates a bicyclic peptide or bicycle, which is then coupled to a toxin payload in the case of BT8009 via a Val-cit tumor-cleavable linker. It's worth spending a minute on the xenograft images on the right-hand side. In the bicycle-dosed mouse, you can see that the drug is either retained in the tumor or being excreted by the kidneys. In contrast, in the antibody-dosed mouse on the right, you can see the drug is not present in the tumor and is instead circulating through the vasculature, where it will likely reside for up to a week, possibly causing various adverse events. The PK plot below the xenograft shows that in preclinical models, the parent Bicycle Toxin Conjugate is rapidly eliminated while the toxin is retained in the tumor with comparatively minimal plasma exposure. This is important because, as we know, a drug can only be effective if it gets to the tumor, and reducing exposure to normal tissue may lead to a more benign safety profile. As Dom will show, we believe that the preclinical experience of Bicycle Toxin Conjugates is translating well to humans. Now I'd like to hand it over to Dom for a review of the BT8009 clinical data. Next slide, please. Thank you, Nick. On to slide nine, please. I'm super proud to share the next section with you. We'll get into more detail in a minute, but here are what we think are the key takeaways from the data so far. The initial promise that we saw in the 5 mg cohort when we first shared it with many of you at the Triple Meeting in October has been confirmed over the past several months. The efficacy has endured in the form of sustained and deepening responses. The relatively benign safety profile has persisted. We've seen a 50% overall response and a 75% disease control rate in this cohort. We've seen durable responses with sustained reductions in tumor burden. We've had no DLTs at the 5 mg dose. We did see some soft DLTs at the 7.5 mg weekly dose. The DLTs were fatigue combined with low-grade GI side effects. We have a very low incidence of skin tox, ocular tox, and neuropathy. I should mention that based on the clinical PK data we collected, an emerging picture of what we believe is a truly differentiated drug is appearing. Just as Nick described in his pre-clinical slide, we are seeing evidence of the drug's linear pharmacokinetics and its short parent half-life. In summary, we are very excited about the 5 mg results to date and are currently exploring alternative dosing regimens. Next slide, please. Now, there's quite a bit of information on this slide, so let me explain what's going on here. We started dosing patients at 2.5 mg, which is roughly the equivalent of, say, 60% of the MMAE payload that Padcev gives at its typical four-week cycling, standard dose. The blue ink numbers that you see in the slide reflect this ratio. We saw clinical activity in the 2.5 mg cohort, our first cohort, and then escalated to 5 mg, where we have seen very strong efficacy and a fairly low incidence of many adverse events. We'll show more details here shortly. We mentioned two 7.5 mg cohorts when we gave our initial peek at the BT8009 data in October. The every other week cohort has been well-tolerated, really well-tolerated, and the weekly, less so. We have one soft DLT, as I mentioned. After that, we regrouped and decided to focus our efforts on the lower successful doses. It's hard to argue after looking at the 5 mg cohort that the sweet spot between efficacy and tolerability isn't somewhere around this level. We are very pleased with the 5 mg weekly cohort, and we are exploring alternative dosing regimens as we progress towards declaring the recommended phase II dose. Next slide, please. Here are the key demographics for all patients in the trial. It's worth pointing out that the median number of prior therapies was three. The patients in this trial had exhausted all other options. Next slide, please. Here's an overview of the 37 patients in the trial to date as of March the 7th this year. This is the total number of patients and not just the response evaluable total. Obviously, urothelial was the majority of patients or nearly the majority of patients. We did enroll several breast, lung, and pancreatic patients in addition to other tumor types as well. We'll now focus on the urothelial efficacy in the next few slides, and we'll give a brief overview of what we're outside of urothelial near the end of the presentation. Next slide, please. This is an updated version of the slide we debuted back in October. On the left-hand side of this slide are updated response rates for the two cohorts that we introduced back then. You can see a continuation and deepening for several responders, and that will be more so apparent in the next slide. The responder in 2.5 mg cohort initially was a shrinkage of 37%. This has since deepened to 59% shrinkage, and that patient still remains on trial. The tolerability profile there is tremendous, really. In the 5 mg cohort, our responders have had some dramatic reductions in their tumor burden as well. We'll spend more time on the 5 mg cohort in the next slide, so I'll wait to dive in deeper then. On the right are brief thumbnails of the 7.5 mg cohorts. In the every other week 7.5 mg cohort, we have two response evaluable urothelial patients who tolerated the drug well but did not respond. In the 7.5 mg weekly cohort, we did have one partial responder and one stable disease. However, the majority of those patients were not urothelial patients. Next slide, please. Now, this is a more detailed look at the 5 mg cohort. We had four out of eight responders or, if you will, an overall response rate of 50%. One of them was a complete responder. The other three included a 71% recorded shrinkage, a 65%, and a 54% shrinkage. The 71% responder was actually formally a complete response in the target lesions. However, because the residual lymph nodes that were being measured were still left at a measure the 71% reduction there appears as a kind of artifact from the electronic data system. That patient still had non-target lesions that were ongoing. Hence, it is not an overall complete response, but still very pleasing all the same. The longest responses are greater than 5 months and rising. Three of the four responses are still ongoing to this day. Median progression-free survival and median duration response have still yet to be reached. At this point, we know they're going to be significantly above the five-month date from which we'd had the cutoff point. As I've said previously, having been involved in running solid tumor clinical trials for as long as I have, I just haven't seen results like this in the monotherapy setting for an entirely new therapeutic class. It's deeply gratifying that I can continue to keep on saying this. Next slide, please. Here's a look at the complete responder. When he started treatment, he had two relatively large lung lesions. You can see, as we previously shared, that he had responded fairly dramatically to the treatment. After one scan, the tumor shrunk by over 87%. Subsequent scans have shown a repeat complete response, and this has persisted to the most recent scan and to this day. As many people on the call, next slide, please. As many people on the call will perhaps realize, BT8009 is similar to an FDA-approved drug. It shares the same linker, targets, and payload. This article was written by Rosenberg et al in 2016 and covered their interim phase I trial. Since we are giving an interim phase I analysis, we feel this is a reasonable benchmark for our drug, but of course, these are very different trials set in different settings and trial centers and at different times. There are several items in this article which we have highlighted and continue to concentrate on. 100% of the patients in their trial at the time of reporting were pre-screened for Nectin-4 positivity. 60% of them had at least two prior therapies, which means 40% had had only one prior therapy. Median progression-free survival and duration response was recorded at 16 weeks each. The overall response across all cohorts was 30%. I think it's worth pointing out as well that 1.25 mg/kg is their FDA-approved dose. Next slide, please. Now let's look at our updated results for the 2.5 mg and 5 mg cohorts. I showed you a slide like this back in October. Since then, the 5 mg cohort has grown by one full patient, who incidentally responded. Most of the responding patients have been on therapy for about seven or more months. Our patients were not pre-screened for Nectin-4 status at all, and one of our responders was indeed a low-scoring patient on that front. All of them had at least two prior therapies, with median being three. Median PFS and DOR, thankfully, have yet to be finally calculated. That is because we still have many patients ongoing. They are both responding and tolerating the drug well, with none coming off due to neuropathy. Other stats that I think are helpful for the 5 mg cohort was that there was a median age of 67, ECOG performance status 0 at 62% and 1 at 38%. The overall response rate from these two cohorts combined was 42%, and the disease control was 75% again. The 5 mg cohort with an overall response of 50%, disease control rate of 75%, gives us a view of a product with a very impressive tolerability profile in the context of an oncology phase I trial. Next slide, please. We're going to shift to discuss the safety data now. Apologies, this is a bit of a data dump, but it's a phase I trial, and you get lots of adverse events. It's a table of the most common adverse events scoring off at the 15% or more prevalence ratio. We saw fatigue, nausea, and diarrhea being the most common side effects. Next slide, please. This is data directly from Padcev's label, and we present it here because we receive many questions asking us how our safety profile differs from theirs. Truthfully, we do not know, but the adjacency is quite striking. You can see certain of their common adverse events have very different median times to onset, with skin tox and hyperglycemia having median times to onset of the order of less than a month. Something like neuropathy, however, has a distributed onset, which is of the order of four months at grade two or higher, scoring slightly earlier on for a grade one event. These are arranged roughly in descending order of incidence. I will not go through all of the data on this slide. I'll leave you to peruse that yourself, but I would draw your attention to the incidence and severity columns in the middle. Next slide, please. Here's our incidence and severity data to date. Before I briefly describe these numbers, I would just remind you, these are heavily pre-treated patients with a median of three prior lines of therapy. What's really striking at first are the relatively low levels of incidence across all of these adverse events. The skin tox at 19% is generally resolved with some type of typical ointment, and that being mainly moisturizers. Our investigators on many occasions turned down the advice around topical steroids, stating that the severity did not merit it. What's really comforting and striking is the absence of grade 3/4 events across all but one of these side effects. We believe this indicates a fairly clear distinction between our approach and that of antibody drug conjugates generally. You just don't see this type of safety data with ADCs. Next slide, please. This is another slide of adverse events of potential interest. The neutropenia is treatable and transient. I think it's worth mentioning that none of the neutropenias were associated with pyrexia. Nausea and diarrhea incidence is 38% and 32% respectively. We're still in the dose escalation phase, and a lot of the preventative measures that our physicians are now subsequently employing were not employed during that period. Therefore, I would suggest that we have hoped that this kind of rate will be able to come down. Next slide, please. To be clear, this is a phase I trial whose primary mission was to explore safety and tolerability, and secondly, to explore efficacy, particularly with an interest in urothelial cancers. The investigators naturally geared enrollment towards urothelial cancer because you would, and because of the high prevalence of Nectin-4 and, of course, because of the precedent set by Padcev in terms of efficacy, which remains to this date, very impressive. The investigators were happy to oblige us, and as a result, the majority, almost 50% of patients, were ones suffering from urothelial cancer. Nonetheless, we received many questions about efficacy outside of urothelial, and this is an area of interest for all Nectin molecules. Here's a look at some of the outcomes we have had thus far. Now, I make no apologies for asking you to remember that these patients have had several prior lines of therapy, so any type of response is really something worth following up on in an investigative setting. Of course, many of these patients were dosed at what is perhaps considered to be a lower dose of 2.5 mg. We, however, are encouraged by what we've seen so far and looking forward to taking this forward in our phase II expansion. Next slide, please. This is the final slide, and then we'll be happy to take questions. The efficacy and tolerability of the drug is kind of beginning to speak for itself. Some of the responders have been on therapy for over nine months now and are still going either strong or even stronger than when they came on. We see the potential for a differentiated product profile, especially with regards to the drug's promising efficacy and increasingly difficult to deny safety profile, which in certain categories, such as the eye and skin, is notable for its absence of irritation or worse among our patients. It has to be a mechanism of action by discussion, I think here. Indeed, it is a mechanism of action that does not appear to impinge on the impressive levels of efficacy we are seeing in our patients, which quite frankly, has been beyond my happiest predictions. We are confident we are nearing a realistic phase II dose and are of course also exploring alternative dosing regimens. With that, operator, if I may, I would now like to hand it over to you to begin the Q&A portion of the call. Thank you very much. As a reminder, to ask a question, you'll need to press star one on your telephone. To withdraw your question, press the pound key. Our first question comes from Jay Olson with Oppenheimer. Your line is open. Oh, hey, congrats on these results, and thanks for taking the questions. Could you comment on what you see as the most differentiating features of BT8009? Is it mostly on the safety tolerability front, or do you think there's a potential to show superior efficacy? Could you comment on whether or not you intend to study BT8009 in patients who've experienced Padcev? Which of the additional tumor types are you most excited about studying? Thank you. Thanks, Jay. I'll pass that on to Dom. Do you want to take that, Dom? Thank you. Jay. Yeah, obviously the skin rash has been a bit of an issue du jour, and it's very reassuring, both the qualitative and the quantitative elements having talked to investigators who have experience of both Padcev and our product. I think as well, there probably is a trended preferable profile on the neuropathy. The eye stuff is just clear-cut. I think it's not there. With respect to the efficacy, it's been a pleasure watching the 5 mg cohort unfold, and I'm sure you'll understand that I'm gonna reserve any predictions around where that might end up until it's kind of ended up. I think with respect to which non-urothelial types there are. I think the lesions that disappeared were plural and they are notoriously tenacious. The investigators were very pleased with that result despite the fact that they were non-target lesions. It was in the context of a stable disease. I think it's still worthwhile maintaining a broad view of what we will and recruit in that aspect. Of course, the patient with the squamous non-small cell carcinoma was one of our very first patients who kind of stuck around at 0% from multiple repeat scans. That was also very interesting because that end-stage patient might reasonably have only been expected to stay on study for eight to 12 weeks, is the median I've got from looking at other end-stage such studies. I think all those things mean there is something to play for. We need to be cautious. We're not gonna clear any major hurdles on this front yet, but I also think it would be negligent to not explore those areas further. Great. Thanks for taking the questions. Thank you. Our next question comes from Reni Benjamin with JMP Securities. Your line is open. Hey, good morning, guys. Thanks for taking the questions and congratulations on the data as well. Just a couple of questions. One, can you talk maybe a little bit about the alternative dosing regimens that you're gonna be exploring at 5 mg? You know, is it just maybe going to once every two weeks or are there other things that you are looking at? In terms of next steps, when do you think, you know, I guess I'd love to get an idea as to what the expansion phase of the study might look like, when that might start and whether you might start evaluating combinations, such as with Keytruda? Thanks, Ren. They're great questions. I'll let Dominic, do you want to take that and then maybe I'll follow up if necessary. Thank you for the question. We're looking at variety of regimens, all of which essentially involve the same kind of dose intensity as the 5 mg, but with potential for more breaks in between. Indeed, we are still escalating on that front, which is very exciting. I'm sorry, I forgot the second component to your question. Oh, just in terms of next steps with the expansion studies, when that might start or either you might look at combinations? Well, I'll deal with that one, Dom. We're pushing as hard as we can. We wanna do the most comprehensive study we can at this stage. You know, we feel really excited by this data. We think we have, for all the reasons Dom just said, something very interesting to explore, and we really wanna make sure we get it right first time. We'll spend a little bit more time exploring the various dose options to us, and then as quick as we can, move into expansion. You know, the obvious candidate for combination is obviously a checkpoint, and that's something we'll consider. We'll let you know, keep everyone informed as we progress and as our decisions are made. Got it. If I can just throw, you know, one more in there. You had one patient who had stopped responding. I'm kind of just curious. You know, do you have any more information about that patient as to why that might have happened? Was there a decrease in Nectin-4 expression or anything you might have learned? Dom? Yeah. I don't recall a particular Nectin expression for that patient. It was a particularly precarious patient who had a lymph node very close to the urethral outlet. They got urethral dilatation very early on, and there wasn't really sufficient signs of response for them to justify, given what was going on with the obstructive processes. They came off study. Terrific. Well, thanks very much for taking the questions and congrats again. Thanks. Thank you. Thank you. Our next question comes from Jonathan Chang with SVB Leerink. Your line is open. Hi, guys. Thanks for taking the questions. Three for me, if I may. First question, can you discuss how you're thinking about the kinetics and potential cumulative nature of the safety profile? How could these toxicities that are also seen with Padcev evolve over time? Okay. Dom, do you wanna take that one? Yeah. The kinetics. Let's do the simple ones first. Neutropenia, bone marrow, they're very pleasantly reversible. We've stuck in some growth factor and one of the patients with neutropenia, the neutrophils rebounded massively to eight within a few days. Those are all relatively straightforward. Likewise, the kinetics of the skin don't really seem to be that troubling at the moment, and therefore, we haven't really had to you know anxiously await any kind of reversals. I think with respect to the neuropathy, there's a cumulative effect generally there with MMAE-based therapies. However, we've had a patient with a grade two who we gave them a holiday, a dose reduction, and they really have prospered and the neuropathy relaxed and the physician commented how they kept expecting with every week for this kind of narrowing tunnel phenomenon to occur, and it just did not. Then they're super pleased and that patient's ongoing and continues to respond. Also, you know, I think reflecting on the experiences with the year-long patient on BT5528, because of course it's the same comparable dose loads and dynamics, albeit with a different target. That patient's neuropathy got better. I think that there's a level, a sort of a threshold that we can drop down to here where we may well see a very pleasing rebound in patients' well-being. Not that it's been that particularly troubling for them generally. Got it. Thank you. Second question, how many patients in the 7.5 mg cohorts had neuropathy? I'm asking 'cause it looked like there was an increase in the AACR presentation versus the abstract. How many of the patients across doses had a history of neuropathy coming into the study? Yeah, it's a great question. Indeed, some of the uplift going from the abstract to the presentation was very much related to the non-tolerated doses and doses that we were not projecting to be worthy of pursuing. That was part of the increment. We also did quite an exhaustive kind of MedDRA-based search term. This is a bit technical, it's a bit, but we really wanted to get everything out there with this presentation and be as conservative as we could. We looked at everything from neuropathy, neurotoxicity, paresthesias, hand-foot syndrome, tingling, mononeuritis multiplex, myalgias, to be as all-inclusive as possible. That's partly also why it happened. I think the most relevant, the most reassuring cohort here, again, is the 5 mg cohort, where patients have been on for kind of seven to nine months. What we have there is an incidence of neuropathy of 25% and no patients, as I said in my presentation, have come off on that cohort due to neuropathy. Got it. I'm sorry. How many of the patients generally came onto the study with a history of neuropathy? Oh. Any color there? Yeah. Yeah, there were. I don't actually know the numbers, but we have had repeated comments in site calls that the neuropathies that are being reported were legacy neuropathies from prior chemotherapies. We welcome those because they represent a more sensitive index to the likelihood of developing neuropathy. They are also a representative sample of any likely populations we may wish to treat going forward. I don't know the actual number, but I suspect it's probably around a third. Got it. All right. Yeah. I think it also partly explains the difference between the prevalence and the relatedness. Some of those neuropathies were very firmly told to us that they were not related. They were just same old, same old from a patient that had them for a long time. Got it. Thank you. Just last question from me. How are you guys counting neutropenia and neutrophils decreased? It looks like it's being combined in the AACR presentation, and I'm curious how this compares to Padcev? Thank you. Yeah. I've got some insight into that. We, my team very assiduously attempted to replicate a very formal, as formal as can be in the middle of a dose escalation, a formal analysis of these events. It again tried to be as inclusive as the white cell counts, the lymphocyte counts, the white cell counts. We particularly concentrated on the neutropenia because we noticed that was predominantly the adverse event of choice for communicating to the FDA and various other antibody-drug conjugates. We put in as many terms as we could, including nuances around different different European countries and how they might spell them. I think that represents the most inclusive level. It was during the dose escalation, so we kind of had our hands tied behind our back, properly so. If you're trying to find out what the adverse event profile of a drug is, you do not intervene prophylactically because otherwise you're kind of bending the thing out. I think as has been seen with other agents that cause neuropathy during the dose escalation period, there is an opportunity to you know substantively diminish the overall incidence by taking future actions in a more prophylactic or immediately reactive way, if you will. We have some hope that those will come down. Also the 7.5 mg cohort made its presence felt in that adverse event as well. Got it. Thank you. Thank you. Our next question comes from Arlinda Lee with Canaccord. Your line is open. Hi, guys. Thanks for taking my questions. I have a question about if you guys looked at Nectin-4 status in prior treatments. Was there any relation of that to efficacy and safety? Thank you. Yeah. We did. We have had no patients who have previously been treated with a Nectin-targeted agent or an MMAE-based agent. We have changed the protocol. We're looking forward to seeing those patients and seeing how they get along, but so far there's been none. The only sort of tangential comment I would again make there is that we had patients on the BT5528 program targeting EphA2 who had previously been exposed to enfortumab, and they prospered very well on that agent with ours, and that was a patient who had been complicated by pancreatitis on enfortumab, and their pancreas was fairly fine on the EphA2. But I won't dwell too long on that because it's perhaps too tangential. Yeah, we're very much looking forward to exploring that in the future. Thank you. Thank you. Our next question comes from Tony Butler with ROTH Capital. Your line is open. Yes, good morning, and thank you very much. Three brief questions. Number one is, you mentioned prior lines that the patients had a number of prior lines of therapy. Did they all or the majority include an anti-PD-1 inhibitor? That's one. Number two is, with respect to Nectin-4 expression, is it the goal to actually end the phase II to determine an H-score which is most optimal? Number three is, do you have any information. This is just a biological question. Do you have information that over time, with additional lines of therapy, Nectin-4 expression diminishes such that, you know, a frontline expressor may have an H-score extraordinarily high, but yet a third or fourth line expressor, it may be very low? Thanks very much. Okay, thanks for the question. There was a predominance of prior PD-1 therapies. I'm not sure if all patients had had them, but there was a predominance, as one might expect, especially with you know median of three prior lines, one of them is gonna be a PD-1. With respect to the nectin status, and this is a two-part question. I'd love for us not to have to establish an optimum nectin level. I don't think there necessarily is one. Anecdotally, we have had one patient with a low nectin score who had great tumor shrinkage. So we're very optimistic going forward. Indeed, we were talking to some colleagues at the conference yesterday who very much said that stable disease was also an important component to look at there with respect to whether those patients are getting benefit. Not stable disease for two months, but meaningful stable disease along in the context of also responding. I would hope to prosecute a campaign around Nectin-4 that means that we can, at some point, not now, we probably need, you know, maybe many 10s more patients, but it's not my intention to get in the way of patients getting access to our drug by imposing any kind of Nectin requirements on them. Thank you. Does Nectin expression decrease over time? Do you have a view? Oh, yes. No, thank you. Sorry. I'm actually writing these questions down, and I missed that one, Lee. There is one paper that's been published, which was a case series. We've not particularly been able to look at that in our program because, of course, we get them at the end and we're finding, you know, very prevalent levels of Nectin expression generally, on par with what has been reported in the literature and what we found from our preclinical point of view. There is one case series in the literature that one of our investigators brought to our attention, where it is quite fascinating that those patients, after being treated with enfortumab, appeared to show an increased expression of Nectin levels, which, I mean, I guess you could make up an explanation to why that is, but it is counterintuitive as in the nature of your question, one might expect a degree of depletion. However, there is no evidence of that thus far. Appreciate the time. Thank you. Thank you. Our next question comes from Ami Fadia with Needham. Your line is open. Hi, good morning. Thanks for taking my question. Just with regards to the dose that you're evaluating, would you say that the recommended dose going forward is in the 5 mg range, or are you still exploring 7.5 mg? And then, would you consider evaluating or studying patients that are previously treated? I'm sorry, I didn't catch the last part of that question. Oh, the second part is just separately, as you think about, you know, further trials or adding more patients, would you consider adding patients that are previously experienced in your studies? Oh, right. Yeah. No, I got that. Thank you. Yeah. So yeah, we are looking at doses that are higher. I think that the main rule around what we're looking at is 5 mg every week is a good dose. But if you can give kind of twice as much, half as often kind of thing, that will be, you know, also incredibly valuable. The prospect of having, you know, and our investigators feed this back on regular occasions, both with enfortumab and our trial that is essentially weekly or almost every week dose load is, it's not something that cannot be improved upon. Yeah. With respect to the other question, w e are very much looking forward to exploring whether patients will respond to Padcev. I think we have a very good proposition around why patients may not need to have been exposed to Padcev. I think there are potentially some individuals out there that might not want to be exposed to Padcev, but it is currently the only approved agent. If I was out there, I'd want it. I might also not want to be denied the opportunity in the future of having alternative options available, for sure. Thank you. Thank you. Our next question comes from Swayampakula Ramakanth with H.C. Wainwright. Your line is open. Thank you. This is RK from H.C. Wainwright. Most of my questions have been asked, but I'm just trying to see how you folks are triangulating kinetics with some of the, you know, the safety that you're trying to understand. It looks like you want to explore more on the 5 mg/m² every week. Is there a reason to go for that versus because 7.5 mg every two weeks is not. I don't know if it's completely been explored. Do you need to do that before you decide on it, or you pretty much decided on the 5 mg? Thanks, RK. Let me take that one. The 7.5 mg every other week was extremely well tolerated. From our perspective, we can, you know, we can escalate beyond that. We absolutely believe 5 mg once a week is an extremely competitive dose for us to take forward. You know, it's the FDA require full exploration of dosages now as part of Project Optimus, and that's what we are committed and focused on doing. It's a relatively short period of investigation, which will yield huge dividends both for us and the patient in the long run. The question you asked about the kinetics, we have an extremely differentiated kinetic profile. The lifetime of the parent in the circulation is a tiny fraction of that of an ADC. One interpretation of the difference between the tolerability profiles between our molecules, and I talk about molecules as a class, and the ADC class of molecules, and the clear lack of toxicities around skin and eye. You know, even in the case of neuropathy, and it's early days and to draw any conclusions from that, but I would make a couple of points. Very late line treatment compared to some of the other comparatives. Even in this ongoing escalation where we're late-line, we're late compared to Padcev, we're seeing, you know, at very worst, we're half of the neuropathy, and that's being incredibly conservative. One might think or propose or hypothesize that one reason for the difference in the tolerability profiles of the two classes of molecule ADC and BTC is actually the parent molecules. We are very drawn to the very, you know, the broad pharmacology of antibodies and particularly their Fc pharmacology. Maybe that has something to do with the class effect that people see with the ADC. A lot of work to be done. Not ready to make any conclusions yet, but we're now in this position where we have something we can actually compare with, which I think is a really different place than we've ever been before. We can start to see the good things about the ADC class and also some of the negative things. Really excited actually, both for our molecules and for the learnings we're gonna make over the next few years. Anything to add, Dominic? Great. I don't think so. Sorry, Jim. Just to say that the FDA has completed its own pharmacological review of certain antibody-drug conjugates. As you said, there's this sort of SC component to that, but there's also sort of nonspecific entry into cells as well. They've correlated- Mm-hmm. Circulating exposure levels of the parent antibody drug conjugates, so the whole thing, and the metabolite, MMAE, with various adverse event profiles like rash. What they've commented on is the correlation between exposures there is greater for the parent than it is the MMAE. It appears not to be the sole effect of the MMAE alone. There's some kind of toxic Trojan horse effect that the antibody has in introducing itself into those normal tissues. Perfect. No, thank you very much. Thanks for- Thanks, RK. Thank you. Our next question comes from Li Watsek with Cantor Fitzgerald. Your line is open. Hey, guys. Thanks for the update. I guess I have a question on 7.5 mg every other week dosing. Can you just share expectations around maybe safety and efficacy versus the 5 mg weekly dosing? How, I guess, what additional data that you need to generate before you decide a phase II going forward dose? Then on the Nectin-4 expression levels, I know you guys are collecting the data here. Just wondering when you can share that and, I guess how relevant do you think the Nectin-4 expression level is for your drug given its bystander effect here? Thanks. I didn't catch all the questions, Lee, and I'm sure Dom will comment on some of the latter ones. Just the 7.5 mg biweekly. So when we saw the great activity with 5 mg once a week in October, we made the decision to escalate to explore as per Project Optimus and the FDA, but also that was a trigger for us to explore the biweekly dosing. We've now successfully completed the first cohort, 7.5 mg every other week. We will escalate higher and see what happens there. With a mind that, you know, we feel very good about 5 mg, and I think the data speaks for itself. now it's a question of really making sure we've fully explored and get the right dose, both for our own benefits and primarily for when the FDA interacts with us and we demonstrate we've done a full range of doses and investigated completely. Dom, I think that's the second question. I don't know if you can answer it, please. Yeah. No, I did. I think it was around bystander effect, its contribution to well, potentially disrupting the correlation between Nectin expression and response. I think that is very much one of the hypothesis to embrace. The other one, of course, is that always comes up is the prospect that the particular part of the tumor that you biopsied may have been heterogeneously expressing a misrepresentatively low amount of Nectin versus the rest of the tumor. Ergo, the patient's status is low Nectin, but the patient's tumor status more pervasively may have sufficient Nectin to justify the response. I think either of those two are worthy of further consideration. Finally, with respect to publishing our nectin correlates in the future, I think that's something we very much like to do, but I think I'd like to generate a more fulsome data set. As I said, there was the one patient with the low score that responded, so I think that'll be a very worthwhile enterprise. Great. Thanks, guys. Thank you. Our next question comes from Kelly Shi with Jefferies. Your line is open. Thank you for taking my question. For 18 UC patients treated at 5 mg, have you observed any patients actually discontinue the treatment due to intolerability? Also, were you able to share the information regarding the neutropenia rate at all grades and at a grade 3 and greater at a 5 mg dose cohort? Thank you. Dom, I think that's one for you. Thank you very much for the question. There were no patients in the 5 mg cohort who came off due to intolerability. I think we need to get more numbers. Just anecdotally, it's recovering quickly. Yeah, I think we just need to get more numbers in the context of the use of growth factor as well. Although I don't see it being, you know, so overtly different to that which was reported for the ADCs, but I think with more data, we'll have a clearer picture on that 'cause it's clearly something that we remain very interested in. In the past, it has been noted to be correlated with efficacy as well. Thank you very much. I want to add one more question, if I may. As you're exploring the alternative dosing frequencies, will you also consider enroll more patients at a 5 mg weekly dose to gain better insight on both efficacy and safety before your RP2D decision? Possibly, Kelly, but we have to also, you know, reconcile that we wanna get into the expansion as quickly as possible as well. We have to balance the two. We're collecting huge amounts of data from the ongoing cohorts at the moment. But it's a good thought. Thank you. Okay. Thank you. Thank you. Our next question comes from Jeff Hung with Morgan Stanley. Your line is open. Thanks for taking the questions. My questions were asked. I just want to clarify a couple things. Of the 18 urothelial patients, you indicated that four were on 2.5 mg, eight were on 5 mg, and four were on 7.5 mg. Just were the two remaining patients not yet response evaluable? On safety, were any of the cases of neutropenia febrile? Thanks. I think Dom's already mentioned we've had no cases of febrile neutropenia. Dom, do you wanna answer the question around the number of patients? Yeah. I haven't actually got. I mean, it's quite a nuanced question. There were some non-evaluable. If I may, I'd like to get back to you on that one, not within the context of this call, but at some later date. Sure. All right. Thank you. Thank you. We have a question from Kalpit Patel with B. Riley. Your line is open. Yes. Hi, good morning. Sort of related to one of the previous questions. In the presentation yesterday, you showed that MMAE concentrations are detectable in the plasma for up to seven days or so after dosing, at least for that one patient in the 5 mg/m² dosing cohort. I guess what gives you the confidence that the dosing in the 7.5 mg/m² every two weeks cohort could be sufficient to maintain exposure levels for antitumor activity? Have you conducted any sort of PK analysis for any patients enrolled in this cohort yet? Yeah. That's you know, I think we need to take a step back from what the MMAE level. There's a number of things to consider when we're looking at the circulating MMAE. One is we're not seeing any apparent metabolism of the MMAE in the same way that the ADCs are metabolized. So we're clearly not exposing the liver in the same way to MMAE. The other thing is we're not entirely sure of the source of the MMAE. It could well be coming from the tumor itself. What we do know is that the levels of MMAE we are achieving are clearly not driving the same sorts of toxicities that the ADCs are driving. Therefore, that gives us, I think, some license to explore different dosage regimens to try and correlate the levels of MMAE and toxicity or parent and toxicity. Right now, we think we have pretty good tolerability in the every other week schedule. We'll explore that as we say. We'll still also continue to keep a mind on that five-week weekly cohort. Okay. You mentioned that you changed the protocol to include patients who were previously treated with an MMAE-based ADC. Apologies if I missed this, but have you enrolled such patients to date after that March data cutoff? Mechanistically- Uh, we- I understand. Sorry, go ahead. We certainly have disclosed that as yet. Not disclosed yet. Mechanistically, I understand you have a different, you know, therapeutic modality here. Are you optimistic that repeated use of the same toxin, the MMAE, would generate activity in previously treated patients with an ADC? Previously treated patients with an ADC. We already have data on that, Kalpit. Again, different program, but we've taken a patient who was a bladder cancer patient who was hospitalized with Padcev, had an acute pancreatitis, was no longer eligible for therapy. We dosed them with 55-28, and that was our first 55-28 responder in urothelial cancer. Yeah, we are confident. Okay. Thanks very much for the question. Thank you, and I'm showing no further questions at this time. I'd like to turn the call back to Mr. Kevin Lee for closing remarks. Thank you very much, operator. Thanks, everyone, for attending the call. Really appreciate the ongoing support and interest. We're very excited by these data. We think we have achieved another milestone in the progress of our programs and the company, and we look forward to sharing more data with you as it arises. Thank you very much for today, and I'm sure we'll talk soon. Bye-bye. This concludes today's conference call. Thank you for participating. You may now disconnect.