Welcome to Barclays Healthcare Conference in Miami. Really pleased to have up on stage with me, management from Bicycle. So we've got Alethia Young, Chief Financial Officer. My name's Peter Lawson. I cover biotech at Barclays. I guess the first set of questions I'd love to talk through the Nectin-4 story and kind of thinking about the safety advantages of PADCEV's, kind of what do most physicians kind of hone in on when they think about Nectin-4 versus PADCEV?
Well, I mean, first of all, Peter, thanks for having us. Thanks to Barclays for having us as well at your conference and here in sunny Miami for the whole week. Okay, so talking about what physicians look for, basically, and kind of the comparabilities of sorts?
Yeah.
Well, I mean, if you think about kind of the core toxicities that come up of Enfortumab, there's peripheral neuropathy, there's ocular, there's hypoglycemia, and there's skin. We know that, you know, when you think about BT8009, we showed, at R&D Day in December in around 113 people, what we believe to be pretty differentiated safety on some of these inherently. So I'm gonna focus on BT8009 in particular. You know, we have no ocular toxicity, right, and skin of grade three. The incidences are lower across all grades as well. Essentially, one that's of a major focus is peripheral neuropathy, which also we had, you know, very low incidence of grade three, and lower incidence of all-grade peripheral neuropathy.
I think, for physicians, you know, that is one that's a significant focus because if the neuropathy inherently becomes irreversible, it becomes hard to, you know, think about what treatments could come after that. So, you know, that those are kind of the core ones of interest. I mean, there are obviously other toxicities that are related to almost any cancer therapeutic, you know, when you think about, you know, kind of GI-related things. But that happens with everything. So I think these are the core ones that people think about, you know, as it relates to Nectin-4.
Gotcha. Thank you. And then the update in the second half, what should we be focused around?
Okay. Well, let me level set on what the update perhaps is and what, Peter, you're talking about. So BT8009 is a Nectin-4 program that we have that's in phase II, phase III. At R&D Day in December, we presented a study called Duravelo-1, which has many different cohorts, right? So we had bladder second line. We had ovarian, lung, breast. We also presented as well. Also at this update, we will be presenting first line for 20 to 25 people, which is about, you know, as well, which that'll be kind of new information that's presented at this whenever we choose to present. But let's be clear, all of it's the second half of the year. We haven't seen more than that. So talk about some of the expectations.
I mean, well, I mean, we presented a certain set of people at B at the R&D Day in December. You would expect that there will be likely more people. And there will the people who we saw at R&D Day will get to see, you know, how the time has progressed for them as well. So that, that'll be important and interesting in my perspective. And then in first line, you know, which gets a lot of focus for people, I suppose, is that that's the first time we've all shown it. And I think even though it's a relatively small cohort of people, people will be looking at how that maybe response rate looks relative to other competitors as well, you know. Obviously, it hasn't been rate limiting for us starting Duravelo-2. But, you know, that's a cohort that you'll see as well.
You know, which and the other three cohorts, which are a bit more white space, are BT8009, as I talked about, in non-bladder indications. These are monotherapy studies. We'll be presenting, you know, additional data. We present some data in December. We'll be presenting additional data as well there.
Gotcha. How many patients should we expect for, like, that non-bladder set?
Well, I mean, again, it's like, you know, these cohorts probably tend to be in the 20s, maybe low 30s. I mean, it's not, they're for proof of concept cohorts. You saw before at the R&D Day that the cohorts in the non-bladder were probably like, yeah, maybe 15 or so, 15, 20, you know. So you'll probably see, you know, incremental amount of patients. We're not making this a massive update, but this is, you know, obviously, like, you know, proof of concept type of information and will help us inform, you know, how to move forward.
Perfect. Thank you so much. The first line data set, so that's like 20, 30, 20, 25 patients. And is that combination?
Yeah. It's combination with BT8009 Pembro. So, you know, we before, when we were in, December, we showed kind of BT8009 Pembro in, like, late, late line exposed. It was about seven people, right? And that was kind of a safety cohort that we also showed to the agency. Now you'll be seeing a first line that we're studying, as well. You know, obviously, it's a relatively small group of people because we're starting Duravelo-2, which is the phase II to III study, which is BT8009 and Pembro.
Gotcha. Thank you. And as we think about kind of the physician feedback in that kind of first line set of patients, what do they wanna see? I know, you know, you've got PADCEV plus PD-1. Kind of what would drive them to switch or, or think about enrolling patients in that first line set of patients?
Well, I mean, I think not every—unfortunately, every first line patient was created equal. So there are decision points that people make around, you know, kind of prior treatment, what they did before, heading into this, into the first true first line. And, you know, there's eligibility versus not. But to some degree, it's gonna be, you know, a judgment call. And I would just focus on, like, when we've had a lot of conversations with physicians, or at least our head of commercial and chief development officer have. And it's not as straightforward as, you know, everyone's gonna go start on this regimen. There's some decisions. And, you know, we're kind of still doing that work to understand how the decision-making's formulating because it, you know, it's been approved on non-full approval basis.
But, you know, the share was still relatively modest. But of course, with a potential survival advantage for a competitor, that will help drive share. But, you know, I think essentially, it's gonna be kind of doctors trying to understand the inherent toxicities and the risk of, like, putting patients on some of these toxicities that pop up. So they'll, you know, there'll be decisions that'll be made between the physicians.
Gotcha. Did the bar for success in, like, first line for ORR, PFS, where do you wanna get to?
I mean, well, I think we have to be comparable to our competitor, you know? Like, so you guys can look up what they've shown, which was last year at ESMO. Again, it was a late-stage pivotal study, which had way more patients, right? So we're talking, like, as a relatively small proof of concept study where you can look at what their response rate was. I think when you get to this data in first line for us, it we probably started this study late last year. So, I mean, you're not gonna have PFS or anything like survival, right? That's gonna take a little while to emerge. So I think the focus will be on overall response rate and hopefully some early trends with duration of response.
But, you know, we'll have to see where we're at when we get to, you know, when we fully enroll. But, like, some of this stuff takes time to mature.
Gotcha. Do you think you can potentially beat them on duration of response with a better safety profile?
Yeah. I mean, look, I think we have to let the data show what it's gonna show. But if you go back to the second line plus population, we showed in Duravelo One, even though it was a relatively, you know, still early curve that we showed, we showed 11 months in second line plus, which is probably more of, like, a 35% to 40% improvement over what's been shown by our competitors. So I, you know, I don't know. We have to see what the data shows. But, like, I think the premise, if you go back and think about Bicycle Therapeutics, is that the platform is creates greater specificity targeting, and ultimately, it's eliminated faster. So it right now, as it stands in the second line plus, we're starting to think we're, have an emerging differentiated safety profile.
And we all know that for us, our discontinuation rate in second line plus in that study was around 3%. So you hope that patients 'cause we know that Nectin-4 clearly has benefits, and drives efficacy. So if a patient's gonna stay on the drug longer, one would hope that, you know, duration of response would perhaps be longer. But again, you know, we have to let that data mature and see what we have in first line. But I guess I'm kinda talking about second line so that you're clear on what happened at the R&D there.
Gotcha. Thank you. What, what do you need to achieve, do you think? Is it clear to get, accelerated approval, or is there a particular set of metrics you have to hit?
Well, I mean, again, I think when you think about, you know, therapeutics, it's the totality of the evidence, right? So yes, we have a design in Duravelo-2 that, you know, in the first line, there's a comparator of chemo and pembro maintenance, and in the second line plus cohort, you know, obviously it's basically an open-label comparison. So I think we have to obviously hit the things that we need to say relative to, you know, historical controls in second line. First line, we have to beat the comparator, right?
Yeah.
I mean, it's a typical, you know, kind of late-stage study. You know, also, I mean, you know, we'll hopefully have a safety profile that continues to look, you know, hopefully, differentiated. So ultimately, I think all of these things will come together to drive the totality toward approval. But I mean, if a trial, you know, hits the endpoints, that's usually a pretty good sign. And like we've seen so far, the emerging safety profile looks differentiated. So I think that'll put us in a very good position on clinical benefit, you know, to obviously, you know, kinda have the conversations around accelerated. You know, we obviously had alignment on what the regulatory endpoints would be, you know, that we talked about. I think we issued a press release on September 11th.
You know, this is the study we're gonna run. You know, I think if we hit our endpoints, we'll be in a good position.
Gotcha. Do you think, beating on safety is good enough for physicians to kind of think about using a, a combination, you know, PADCEV, Pembro plus or?
Well, I mean.
Your Nectin-4 plus Pembro?
Well, I mean, to be clear, like I said, I mean, if you're talking about the clinical, the regulatory endpoint, we have to hit we have to beat the metric of chemo and avelumab maintenance. And what we've seen so far is that the efficacy looks comparable, as it relates on response rate, at least. And, you know, I think we'll see in the second half of the year whether, you know, duration of response continues to look, you know, promising. So, I mean, it's not you know, I think response rate in, in our minds, to some degree, is always a biomarker of activity. But it really, you know, is, you know, kind of duration and different things that help to frame the entire story.
And so, yeah, I mean, I think when you have a drug that's comparable with better safety, you know, benefits, especially ones of interest, like, that's pretty well positioned. I mean, you're still in the market of treating patients, caring for them, and trying to help them, and especially in first line, have the best shot of success, you know, in other lines if they were to unfortunately progress. So, I mean, we're gonna have to, you know, show efficacy looks similar, right? But that's more of a commercial consideration. The regulatory consideration is what I talked about, which is the trial designed against chemo and avelumab maintenance.
Gotcha. Thank you. Then, with your registrational trial running, do you think is there any worry that the confirmatory trial from Seattle is gonna kind of impinge upon the ability to recruit patients?
Well, I mean, you know, if you look at EV-302 itself, I mean, the majority of the patients were ex-US in the trial. So certainly, we know that if you think about ex-US, it's likely that, EV and, Pembro will likely be available a little later because you have to go through the approval process and the reimbursement. So that takes some time. And I think a lot of people, you know, don't appreciate that ESMO was certainly a tailwind for us. I mean, you know, it, like, helped push the story because Nectin-4 became prominent and a mainstay in bladder cancer treatment. So, you know, if it's like that, that kinda helps us, right? There's a lot of excitement. We were emboldened by coming out of the meeting and having a lot of feedback excitement about getting, you know, participating in that study.
So to be also very specific in the U.S., yeah, it probably will be a little bit more difficult for sure, you know, because it's, it's available, and it's probably being reimbursed. And, you know, physicians, some physicians certainly will use it. But I think it went back to what I can't remember if it was your first or second question. You know, when you're talking about, like, people have to make decisions, you know, about kinda treating their patients, you know, kinda end to end. So I think we have the opportunity; there's definitely different opinions, about, you know, kind of what, you know, thinking about either the safety, even though the efficacy is very, very good. So that's an opportunity. We're gonna have to, you know, certainly work to do that. But, like, I think that's, you know, very achievable. We remain very confident.
No, you made a really good point about treating the patient so that the side effect profile doesn't impact the next course of therapy. So in the data we see in the second half, where you have, like, patient vignettes where you kind of see what happens to those patients post, that would perhaps encourage physicians to put patients on trial?
Well, I mean, are you talking specifically about BT8009?
Yes.
Well, I don't know. We've decided what we're gonna, you know, exactly show. But I mean, I think if you go back to the R&D data, you know, there was different times when we would discuss, you know, patient cases. So we could potentially do that. I think we have to see what emerges. But I mean, a safety profile is quite definitive, right? Like, if your rate of neuropathy in grade three and all grade is lower. I mean, I don't know if you need a success story per se. But and or if you think about there's no ocular toxicity where there is, or you think about lower rates of skin where there you know, grade three where there are, it's pretty definitive. But yeah, we, you know, we could always think about something like that.
We just, you know, we have to kinda see once we get to that readout what, what kinda how the data's looking and if there's some, you know, you know, helpful stories to share. But I mean, certainly, you know, the safety, a differentiated safety, a safety that helps not only patients but caregivers manage everyone's lives better is, you know, it's notable. So we'll have to see.
Gotcha. Thank you. Are there particular groups of patients that physicians you think will target to go into your trial in first line versus second line?
Well, I think—I mean, look—it's happened in the past couple months with the full approval. So I think we have to see how that landscape evolves. But I mean, it's not a one-size-fits-all. I mean, there's definitely, you know, and if I had a commercial over here, she could give you the very in-depth answer. But, you know, my general perspective is that it's not one-size-fits-all. And there's gonna be decisions that have to be made. Like I said, for example, you know, treating in first line, you know, then you're usually thinking about what's gonna be, you know, if somebody progresses after. Because we know, unfortunately, these patients do, even though the survival's significantly elongated. But ultimately, people with this cancer usually progress.
When you start at a baseline, you know, bladder patients are relapsed bladder cancer patients are unfortunately relatively frail, and sometimes can be older. So I think they're, you know, important decisions to make. I mean, you know, coming out of some of the medical meetings in the past, you know, you've seen things on Twitter or what's it called now, X, you know, kinda talk about with physicians talking about, you know, having to think about managing new toxicities to them and having the infrastructure to do that, right? You know, chemo has a certain set of toxicities that are known. Obviously, new therapeutics have toxicities that are different. And so you have to have the infrastructure to kinda do that as well within your practice.
You know, a lot of the trials are obviously run in academic facilities where there's a lot of resources. But then when you think about a broader population, there's community doctors, you know, obviously, around the US, around the world. And so, you know, that can be sometimes, you know, taxing on resources to kind of have to think about, "Okay. Well, now we have to bring in this expert or this specialist to kinda help patients through, you know, even if it's a release of skin or ocular or hypoglycemia," which are all kind of, serious toxicities.
Gotcha. How many years behind do you think you are for getting to market versus Pembro plus?
Well, I mean, we don't know because that indirectly asked me whether we're providing guidance on whether we're gonna talk about enrollment when the trial's gonna read out. And right now, we won't; we're not doing that because we just started the trial. But, you know, we do expect at some point, we will probably try to help investors and sell-side and everyone, the public, understand. But, you know, we wanna when you give guidance, as you know, Peter, you want it to, like, be guidance that you have confidence in. And then when you're in the early stages of things, you kinda have to get the ball rolling and understand the trends. So I think, you know, I'm sure you'll ask us that question throughout the year again. Hopefully, you know, at some point, we'll be able to give you some perspective on that.
We're keep on asking the question.
That's cool. It was a good way to ask it, though.
Yeah. EphA2, would love to move onto that. Just how many patients we should expect to see in the update, that's also in the second half.
Yeah. I mean, the cohorts are like, wait. If you remember, just to kinda go back, BT5528, the EphA2 program, is, it's a first-in-class. It's been hard to target by ADCs due to bleeding risk preclinically and clinically. So when we were R&D day in December, effectively, we had, like, over 100+ patients across different tumor types and doses. So and we also showed a 31% response rate at the dose that we studied, which was the six mg per meter squared, once every other week. So as I'd said, we've been pretty careful with safety on that. Now we're studying a dose of five mg per meter squared in bladder and ovarian. The cohorts are relatively small. And that's why I gave you kinda the context. They're relatively small, probably, you know, 10 to 15 or so, somewhere in that range.
And why is because, well, that dose is now 54% higher than the prior dose where we showed a 31% response rate. And, and so the body of evidence which exists for BT5528 is already robust. So we just need a small cohort to test, you know, in bladder and ovarian to see what we have, with that and see if that how that response rate moves in, in, in duration and different things relative to having a dose that we believe is at the right PK. So it's relatively small groups of people. But I think it's a really important, impactful data set when you think about the body of evidence that goes. It can give us a lot of important clues about how to potentially move forward, with BT5528.
Yeah. And so just on that point, how do you move forward? Do you think about this as a combination? Do you think, you know, as a monotherapy? Just, just.
Well, I mean, some of it's driven by what we see in this next dose at monotherapy. But the great thing, you know, and generally about our platform is that it's been quite safe. And so we have optionality to do combinations if we should need to. And we know, you know, at least, you know, we'll have to see with the EphA2 program. But with the Nectin-4 program, adding a checkpoint has been additive. So that could be an option. I mean, there could be other combo types of combinations that we could think about as well. So I think we have to see. It starts with seeing what the response rate looks like and, you know, at the dose, which we believe that will be the most efficacious dose, hoping that that safety remains in line with what we've seen as well.
Then I think we can think about what the next plans are. But, you know, we have two cohorts. We have bladder. We have ovarian. In there, you know, right now, they're in second line plus of sorts. So I think that could be a potentially interesting place for us as well because I think we'll focus on first-line bladder. But, you know, obviously, as I've just said now multiple times, patients progress from first line to, you know, unfortunately, second and later lines. And so that market potential, you know, if you think about in the next, you know, six, seven years, probably $2 billion in its own right. So I think it's a large, like, total addressable market opportunity to some degree. It's a large addressable patient opportunity where it remains very fragmented, right?
Like, no, no therapy in basically second line has, you know, a significant share. And that's mostly due to the toxicities related. So I think we have a very nice, you know, opportunity set. But we have to see, you know, how this data set emerges. And then we can think about, but I do always love with our platform that we have usually a lot of different options to think about. We can think about monotherapy potentially. We can think about a combo if we think that's additive and helpful to patients.
Have you seen postpartum patients with EphA2? Do you expect response still post?
Well, I mean, there was one, at the R&D day which you guys can review. But I think we'll have to see, you know. I mean, we know that, or we hypothesize that basically, EphA2 expression goes up as bladder patients progress. So that, that could be interesting. So I mean, you know, you're most likely gonna see people that have had, like, prior Nectin-4. But, you know, we again, we have to see what we get in this study, right? It's still a relatively small cohort of people. But, you know, as, you know, as new regimens move into the first line, you know, then that'll affect it probably. That's what we use. But, you know, you also could see a lot of people have chemo as well.
I mean, should we really be thinking about EphA2 as kind of a later-line therapy in bladder at least?
Well, I think we have to see what we have, right? I mean, to some degree. But I do think, like I said, if you think about the fact that the EphA2 expression could go up as patients progress and we have a you know, already, I think when you see have a monotherapy that has a 30% response rate or so, that's, that's very encouraging. So, you know, it might be a great place for that to fit there. And like I said, the unmet need for patients still remains very, very high, you know, in the population.
Perfect. Thank you. In the last few minutes, I'd love to pivot over to the radiopharmaceutical side of the business. So just what we should expect to see. I know there's gonna be a program update in mid-year. So, you know, what should we be focused on? What do you think about that?
Yeah. We're obviously very excited about the BRC or the Bicycle Radio Conjugate platform itself. So we have, you know, an unpartnered program where we're doing a collaboration with a German academic institution. And if you go back to R&D Day again and talk about the lab because a lot of the stuff that we had a robust update, you look at the preclinical evidence that was seen there in that meeting, you know, looking at the mouse and, like, making sure that you know, validating target and also making sure that it's going to the specific organs where it needs to go. And you kinda can see that with imaging. This is a human imaging study. So it's not necessarily that we're developing yet a therapeutic. But we do believe this is an important kinda proof of, like, validating target.
We're going after MT1-MMP, which is a target that most, you know, radiopharma companies have not sourced because we can with our Bicycle binders, we are able to be a bit more tumor agnostic. So I think if you look back and you think about what we saw at the R&D day and then you look at, like, being able to hopefully replicate that in a human imaging study, that'd be very encouraging to think about, you know, the next steps of developing a therapeutic. But, you know, it's probably in a handful of patients. And, you know, we think that the Bicycle platform is really well-positioned in radiopharm. But, you know, we have to see what we get. So it's an early update.
But, you know, it can give us important clues about how to think about, you know, kinda proof of at least that it's validating the target and that, you know, the technology is going where it needs to go in the body. And then we can think about developing a potential therapeutic if it proves to be that case after that.
Gotcha. Just in the last minute, do you think you can break out of, like, prostate cancer and NET, which is kind of the classic?
Yeah.
Radio-pharmaceutical spec?
I don't know. I think we'll have to see. You know, like, the reality is, let's get this early imaging data. And then we'll think about, you know, therapeutic development and where it might be a fit. But, you know, I still would, you know, kinda close with I think this is an important moment just to show for the platform that we're, you know, able to do what the platform says, especially with a target that's not been used before. And so that could create a lot of different opportunities beyond, you know, what other people have done potentially in different, you know, particular indications. But it really does come down to seeing the data. And then and then we can think about it.
And I mean, that's kind of a summary on, you know, some of the earlier programs that you talked about, whether it be 5528, 7480, or the radio platform. You know, I think this year's gonna be an important year to kind of, you know, establish what the proof of the proof of concept and the go-forward. And then that's gonna, and I think we're gonna have, you know, interesting opportunities to think about further development for all of them, including radiopharm as well.
Perfect. Thank you.
Thank you, Peter.
Thanks for the time. Appreciate it.