Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Bicycle Therapeutics with CEO, Kevin Lee, Chief Development Officer, Santiago Arroyo, Head of Commercial, Jennifer Perry. Welcome. Thanks, Jeff. Thank you. Good to be here. For those who may not be as familiar with Bicycle, can you provide a brief introduction? Sure. Bicycle is a company that works on a very novel therapeutic modality based on the work, the Nobel Prize-winning work of Sir Greg Winter. Essentially, we work on a modality called Bicycles. These are bicyclic peptides. Typically, peptides 9 to 15 amino acids in length, cyclized around a small molecule scaffold through three covalent attachments. And the process of forming these bicyclic peptides conveys upon the molecules significant selectivity and affinity for their target. We think Bicycles have a number of attributes that make them really interesting in terms of pharmacological agents per se, but also where we position them as targeting agents. So, their small size, 100 times smaller than antibody. They're capable of rapid tumor tissue penetration. Their elimination profile, predominantly renal, it gives us a lot of opportunity to control the PK. And their selectivity profile, which is very differentiated from antibodies, which despite everybody thinking antibodies are very selective, we always forget about the pharmacology of the Fc. Bicycles are very, very much more selective. So we think about these, and we're very much focused on developing these agents as targeting agents. First area we've really embarked upon is oncology. We have a number of molecules in the clinic. The most advanced molecule is 8009, and I know we're gonna talk about quite a bit about that today. Great. Yesterday, you announced an expedited development plan for 8009 in metastatic bladder cancer. Can you just walk us through that? Yeah. So we very pleased we reached alignment with the FDA on the plan to develop BT8009 to launch. There's It's a very interesting clinical design, very much aligned with the Project Frontrunner concept. There's a dose selection phase, both in the first line and also in the late line setting, followed by a pathway to accelerated approval using ORR and then confirmatory approval using PFS. I don't know, Santiago, if you wanna spend a bit of time talking about that. Yeah, it's a complex study design, but at the same time, it gets you to basically the whole population of metastatic bladder cancer. So there is no more differentiation between cisplatin-eligible. All of the patients will be able to enter into the study. I think that's something that we are really happy with, is that the FDA agreed on a primary analysis of PFS for the previously untreated patients. These are first-line in bladder cancer. Other bladder cancer drugs have been approved on the basis of OS. And it's a testament of the belief that our survival will be too long to be really measured with OS, and PFS is a more appropriate endpoint for this study. Also, that obviously makes our study much more manageable size-wise. Great. Can you just talk more about your interactions with the FDA and the data for BT8009, that the FDA has seen in kind of in the process of reaching alignment? I would characterize our interaction with the FDA as very collaborative, very supportive. The first interaction was when we received Fast Track designation at the start of the year, and then we've had multiple written and face-to-face interactions or virtual face-to-face interactions. So yeah, very, very collaborative, very supportive, and we reached alignment very quickly, actually. Okay. You indicated that the development plan for BT8009 is in alignment with the philosophy of the FDA's Project Frontrunner. Just for those who may not be as familiar, can you just talk about Project Frontrunner? Yeah. Project Frontrunner is a philosophy that the FDA are moving toward. Where, you know, traditionally, when you think about oncology drug development, you start or any, you know, a lot of drug development, you start with a niche indication and work steadily through the various lines until you get into the first line setting. I think the FDA, I presume the FDA see that as a lost opportunity and are very looking for ways in which, you know, drugs that they deem to be potentially, I guess, safe and efficacious, can be, you know, avoid that stepwise progression through the lines, which takes time, and trying to move into the frontline setting as soon as possible. So that's exactly the sort of context that we've tried to follow, the guidance we've tried to follow in the design that we've now agreed upon. Now, you talked about the endpoints for the Accelerated Approval and confirmation of clinical benefit briefly. Can you just talk a little bit more about the design of the Duravelo-2 trial? Sure. Santiago, that's- Well, it's basically two cohorts, previously treated and previously untreated. Cohort one is previously untreated population. We do a dose selection phase, initially with 30 patients in each sub-cohort. In the previously untreated, we compare with chemotherapy, plus minus avelumab. Those patients that responded to chemotherapy will be allowed to have avelumab if it's clinically indicated. We'll do an interim analysis for ORR, on the basis of a direct comparison with chemotherapy and a final analysis on PFS. On the previously treated population, we'll do again the same dose selection phase with 30 patients in each arm, and then we'll continue the monotherapy arm. Plus, we'll add another arm, which with a combination of BT8009 plus pembrolizumab. Those two cohorts will allow us to present to the FDA data for an accelerated approval in second-line plus, with both the possibility to being approved or potentially approved in monotherapy or in combination therapy. We are working on a future study that will be a confirmatory study for the late line population. So as you know, in the cohort one, we have the confirmatory study built into the trial. For the second line, we will have to build a new study, a confirmatory study. For Cohort 1, how many patients are you expecting for the dose optimization interim analysis and then the ORR interim analysis? We need 30 patients per arm for the dose selection, and then a total of 200. Let me want to make sure that I give the right number. 292 patients for the ORR. Okay. And then what kind of historical control data will be used for comparing ORR in potential accelerated approval for monotherapy in combination with pembro? Yeah, we'll use historical data only for Cohort 2, and for monotherapy, we'll use historical data of 25%, which is what historically has been the response from PD-L1s and chemotherapy. For the combination therapy in the second-line setting, we'll use a historical PFS data, which is about 40%. So we have two ways of analyzing the data in the second-line setting. Can you talk about the selection of the two doses in the registrational study? Like, what advantages are there with the 6 mg per square meter, two weeks on, one week off? You know, how will you go about deciding between the two doses since the doses are not too far off from each other? You know, what I would start the answer to that question with is a reminder that in the dose escalation, we did a lot of dose optimization. And so it's not unsurprising to us. And you know, a part of the Frontrunner guidance is that to do a thorough quantitative investigation of doses. Not too surprising to us that given the amount of investigation we did in that escalation phase, we've only been asked to really focus on two doses, and those doses are not so dissimilar, as you say. But you know, Santiago, do you want to talk about how we got to those doses? Yeah. I mean, we've done a fair amount of PK/PD analysis to try to understand what will be the best doses to select. Obviously, 5 mg per square meter is our dose. We needed, you know, the FDA generally, they like to see a lower dose. We were uncomfortable with doing a lower dose that would not have enough efficacy for patients. This is an area of unmet medical need. Patients need something that is efficacious, and trying a lower dose that we know is likely not going to be efficacious was not something that we wanted to do. So we reached a very good agreement with the agency to go to a lower dose, but not too low, even though it is, it looks higher because it's 6 mg, 6 mg, two weeks on, one week off, it gives a slightly less exposure than 5 mg every week. We believe that that dose will have a slightly better tolerability, and we believe that potentially could have the same efficacy as 5. We'll see what the data brings, but it's, it's good to have two doses that potentially could be both efficacious. What aspects remain outstanding on the confirmatory trial design, in second line plus? Are there particular areas that are the focus of discussions with the FDA? Well, we haven't started really that discussion. Initially, our idea was that, you know, the first-line setting confirmatory study will be all that we need as a confirmatory study for bladder in both populations. The FDA did not agree with that. They wanted to have a confirmatory study in each line. So in the second line, we have to build that up. Actually, the good thing, again, as Kevin was saying, it was a two-way collaborative discussion with the FDA. And, we agreed that we would put together a trial design for that confirmatory study. We have to have it up and running and enrolling by the time we gain Accelerated Approval for late-line. So we have a fair amount of time to put it together. It will actually be beneficial to us to get a little more data, especially in the combination therapy, to be able to power adequately the confirmatory study. And then we'll have to decide on what is the best comparator in that arm. There are many comparators, and actually, you know, the market is very divided on what will be the right comparator. And maybe you want to talk about how the market... Because we've talked many times about what is the standard of care in first line, what is the standard of care in second line? In first line, we have decided that chemotherapy, and the FDA agreed with us, is the right comparator. In second line, there are also multiple potential comparators but maybe you can bring some clarity on that. Sure, happy to. So right now, our market research and our early data report shows that, for example, targeted therapies are used 40% or less of the time in second line and third line, with PADCEV having approximately 20% of utilization in second line and about 19% in third line. That tends to surprise people, as many of them think of that them as the market leader. They've been approved there for about 4 years. Actually, IO agents get reused in the second line setting most often at about 40%, with pembrolizumab leading the way. And, PADCEV utilization is similar to chemotherapy retreatment, if you can believe that, in the second and third line setting, which is about 20% also. To Santiago's point, choosing a standard of care in second line and third line is quite challenging because of how fragmented that market is, like you said. Great. Then, so overall, I guess, for yesterday's update, some investors that I've spoken with had been thinking that there would be a chance that you could start the registrational study in 2024, but others were surprised by yesterday's announcement. You know, can you just talk about whether this was a surprise to you or? For me, personally, it wasn't a surprise at all. I think we've been guiding, you know, our opinion for some time now. I think it, you know, when you take into consideration the, as Jennifer's already alluded to, the very fragmented nature of the market, the unmet need that still remains out there. You know, the fact. It was really exciting for me to see in the written feedback from the FDA. You know, they characterize BT8009 quite correctly as a novel modality that targets Nectin-4. When you look at the safety data that we've shared, you can compare that with, you know, the concern that people have had around PADCEV, which carries a black box warning. I do think black box warnings are not really given the importance that they obviously are meant to have, and that's concerning to me, as a pharmacist. And so when you put all of that together, I thought the FDA would do the logical, sensible thing, and I think they've done the logical, sensible thing, so it wasn't a surprise at all. And how long do you expect it to take to enroll patients, and when should we expect to see data from the study? The first thing we are focused on is getting the trial operational. Once we have it operational, we'll be able to more accurately provide information related to that. So, give us a little bit of time, and we'll come back on that one. Okay. Maybe worth to mention that, this study is very efficient. You know, for investigators, basically it represents a one-stop shop. Patient with metastatic bowel cancer can enter into the study, either in one cohort or in the other. So we think that that will be advantageous for our recruitment. And how are you thinking about the benefit with 8009 plus the pembro combo in cohort two, relative to, I guess, the combo in cohort one and monotherapy in cohort two? Like, can you just frame for us how you're thinking about the different pieces? Well, in Cohort 1, BT8009 plus pembrolizumab, you know, we anticipate that we're gonna see, you know, additive synergistic effects and so, you know, improved benefit for patients. It's gonna be very interesting in that cohort, too, to compare the monotherapy with the combination. I think some of the reservations that people have had about putting, you know, the pembrolizumab with an ADC, is you do get these inflammatory responses with the ADCs, and the checkpoints then enhance those inflammatory events. We don't see that same level of inflammation in the monotherapy setting, so we don't think we'll see that in the combination setting. I think it's going to be really excited to see how that combination performs in the cohort two setting. Actually, our initial data, we have one cohort in combination in patients in the later stage, not early. And the safety profile that we are seeing is actually very similar to the one that we see in monotherapy. So we don't believe that there is going to be a major issue when we combine both drugs together. And we share that data with the FDA, actually. Can you highlight the clinical infrastructure you've established that allows you to begin the registrational study in the first quarter of 2024? You'll be aware that we did a, you know, a financing in July. Santiago, do you want to talk about? Yeah, we're actually very well resourced. We are doing a little bit more hiring, but we already have a good operational footprint. We have identified our CRO for the main study. And we have all the processes in-house to be able to carry this study. Jennifer, maybe talk a little bit about the physicians and how they're viewing this study. Yeah. So right now, obviously in first line, like you've heard laid out, chemotherapy continues to dominate the, the marketplace. You know, depending on cisplatin eligibility, it's used anywhere from 60%-80%+. So the Duravelo-2 study, going against standard of care, has been quite positive and also extremely positive that we can combine BT8009 with their IO agent of choice, which is pembrolizumab. What they have said is that when you have patients coming into a study that's really, kind of self-contained, they can go into any line. If they progress in first line, they can still go into second line within the same study. Really provides an ease of enrolling and opening and enrolling the trial at their site. I think the other thing that's important from a KOL feedback is that, when they're looking at patients coming into this setting, obviously, what they received in their prior line of treatment, systemic could be an MIBC, for example, really dictates what goes into this line. Often, sometimes that is platinum-based chemotherapy, so baseline characteristics matter. If you can actually have a combination that they look to be efficacious, but potentially with better clinical benefit, duration of response, safety profile, you can sequence after this therapy, they look at that as a win and a study they'd like to actually have at their site. How do you see 8009 fitting into the treatment landscape, given other drugs targeting Nectin-4, like PADCEV, are available? Yeah, I think it's along the same vein, why we think we can actually recruit the trial. So, what we often hear is that, again, you have to be efficacious, but you're gonna have to beat chemotherapy on the tolerability profile, duration of response, and managing overall toxicity. EV plus pembro, it's a good combination. It's approved and accelerated approval right now. We expect it will get approved. However, right now, the general sentiment in our market research is that the toxicity profile in combination with pembro is still very hard to manage. And right out of their package insert, 70% of patients have to dose interrupt, about half have to dose reduce, and about a third, about 36%, have to come off. The number one and number two reason for discontinuation is neuropathy first, and then skin rash in the combination, and much higher overall rates of both in their combo. So, right now, we know there'll be a treatment choice in first line. However, we believe that BT8009 in the Duravelo-2 study has the opportunity to be like the treatment of choice and become standard of care because of the overall clinical benefit of the combination. From your conversations with KOLs, what kind of duration of response on the efficacy side, you know, would be viewed as clinically meaningful? You want me to start? No. So in the second line setting, monotherapy, actually, for us, we thought, oh, that's actually meaningful to them, that a duration of response of just nine to 12 months, and that would be impactful to their patients in that setting at this point. Obviously, they'll be looking for duration of response, probably similar to the 103 data, which has obviously still not been hit in our, in our front line setting. In terms of what they want that combined with, I think is an important next step is, yes, staying on therapy is great, duration of response is great. However, they'd like to see an improvement of approximately 20%-30% in neuropathy and rash, and, and neuropathy and rash being the most meaningful adverse events to them. Yeah, nothing to add, I think, so yeah. Great. Well, you reiterated yesterday that you'll provide updates on 8009, 5528, and 7480 later this year. What should we expect to see for each of these programs, and what do you think would be considered positive results? So, BT8009, in I think it was November we indicated that we were doing expansion cohorts in bladder, non-small cell, triple-negative, and ovarian. So we'll give an update on the progress we've made there. We'll, Santiago has already mentioned we've done a safety run-in cohort looking at BT8009 and pembrolizumab in combination in late-line bladder, and we'll give an update on that. So I think that, you know, there'll be a lot of safety data. The nature of these studies, the safety comes first, and which, you know, and we're very focused on that. So I think there'll be a lot of safety information for people to look at and think about. And then we'll obviously have the efficacy data that we've seen, both in the bladder setting, the duration of response that we're seeing, and any activity we might have seen outside of bladder. And even in March of this year, we were beginning to see the first signs of activity in other tumor types. So that's BT8009. BT5528, we've done a fairly large expansion study looking at six different tumor types, and we'll provide an update there. And I obviously, I'd be this is the first and only, as far as I'm aware, Ephrin A2 targeted agent. The antibody technology doesn't appear to be able to drug that target, due to toxicity. So again, the safety is gonna be important. And you know, activity, given it's a very novel investigational product and a novel antigen, I think is gonna be really interesting for people to see. BT7480 is our Nectin-4 CD137 bispecific product, if you like. I think we've done a dose escalation there. As always, particularly with the IO products, the safety profile is gonna be really interesting to look at. You know, what we've seen in terms of activity in various tumors The numbers won't be large because it's an escalation and a basket-type study, so small numbers in each tumor type. So I'd probably be more looking at the safety there, and you know, what we're seeing in terms of early signs of activity. Lot to get, a lot, lot to share, very excited to, to be in a position where we are able to share, the information and really looking forward to, seeing what people think to it. Great. Can you just remind us of how much cash you have and the runway that gets you? Yeah, with the raise that we did in July, plus the two collaborations that we did earlier in the year with Bayer and Novartis, we're, I think, currently at $600 million. That finances our BT8009 Duravelo-2 trial, and finances the company through the next foreseeable, you know, through the next milestones. Obviously, the runway is dependent on what we do and what other catalysts we have and what, you know, what we decide to do with those other products and the other products that are coming behind. So, the important thing is that we have the finance to do Duravelo-2, and then everything else will be kind of catalyst-driven. Okay. Maybe one last question. What, if anything, do you think that the street most misunderstands about Bicycle Therapeutics? I think we should each have a go at that. I think there's a disconnect in their understanding of PADCEV and its position in the bladder market. Yeah, and I think it's the modality. I mean, it's a novel modality of treatment, and it's clearly differentiated in the safety. And that safety is a very, very important. I mean, efficacy is always important in cancer therapy, but safety is what brings, you know, the patients to get the treatment. I mean, something that we were very surprised to see is that many, a large proportion of patients taking PADCEV had to reduce the dose and are in lower doses. So that reflects, you know, they are not obtaining the full benefit of the drug, which we believe is a very potent drug, PADCEV. So we are hoping that our drug, by being safer, better tolerated, will have the full duration of effect that we expect. You know, I don't think it's anything that they actually misunderstand. I think it's just a reminder that there are good examples out there where you've had a follow-on agent getting approved years after the original, and I'm gonna put in quotes, "standard of care," or what was perceived to be standard of care, and being able to outcompete them within the first year of launch. I always reference the ibrutinib, acalabrutinib example, because I launched ibrutinib, and we were very reassured no one needed a new BTK inhibitor in the market. They got approved five years later and started to take 35% of all new patient share in the first 9 months, and obviously last year, we're taking 64% of that share in new patient starts. Their message was targeted, less off-target effects and a better tolerability profile, really around those issues that ibrutinib was struggling with in the clinic, you know, AFib and bleeding. And here, rash and neuropathy continue to come up. So if we can perform there, I think that's something and one to watch for our profile. Great. Looks like we'll leave it there. Thanks so much for your time. Thank you. Thank you. Thank you.