Hi, everyone. Welcome to our Fireside Chat with Bicycle. I'm Li Watsek, a biotech analyst at Cantor, and I'm thrilled to have the whole crew here today. Kevin Lee, CEO, Alethia Young, CFO, Santiago Arroyo, Chief Development Officer, and Jennifer Perry, our Chief Strategy Officer and Head of Commercial. So I guess for today, maybe we can start with an overview of Bicycle and what's coming up that's, you know, really exciting for you guys.
Sure. First of all, thank you, Li, for the invitation. It's a pleasure to be here. We're delighted, once again, to be here telling you a bit about the Bicycle story. So for those of you who've not heard about Bicycle before, we're a company that works on a completely different technology that was originally designed by Sir Greg Winter. Many of you will know Greg from his pioneering work on monoclonal antibodies. And basically, what Bicycles are is where small molecules and large molecules converge. The idea of taking small peptides and arranging them around a small molecule scaffold to create two loops through the creation of three covalent bonds to create constrained peptides, which have many of the binding properties of an antibody.
I'm happy to discuss that in more detail. The technology is very differentiated from antibodies. Bicycles are much smaller, are able to penetrate tissue, very short systemic half-lives, and a much greater selectivity profile. And the way we're developing these agents is to deliver payloads into tumor tissue. In terms of what to look out for over the next few months, we've just come from ESMO. We, I think, presented some really great data there. I'm sure we'll discuss that more later.
And what we have to look forward to over the next few months is we're excited to be, in the not-too-distant future, telling you about some of the work we've been doing with radiopharmaceuticals, and we have ongoing work with zelnecirib looking at in combination with pembrolizumab in first-line metastatic urothelial cancer. And we're also looking forward to giving everyone an update of our work, again, looking at zelnecirib in late-line triple-negative breast cancer and non-small cell lung cancer.
Great. So I guess before we dive into sort of the programs, Kevin, just as you look at the conjugate space right now, with ADCs and with radioligands, and I feel like Bicycle is really in a great position to take advantage of both. So maybe just tell us a little bit about, you know, the advantages of using B icycle peptides versus some of the other modalities out there for both modalities, and then maybe touch on your recent set of pipeline prioritization.
Mm-hmm. Yep.
What's the thought process behind that?
As I mentioned, these Bicycle peptides have a number of properties which I think very much differentiate them from other platforms, and there's probably four or five, but three major ones. First is the size. Bicycles are 50x-100x smaller than an antibody, an ADC, able to freely penetrate into tissue, and obviously, the tissue in case in point is tumor. Secondly, these molecules are designed to have a very short systemic half-life. Please don't get confused between systemic half-life and tissue half-life.
Once into the tissue, these molecules are present for a long period of time, but in the systemic circulation, very short period of time, which I would argue is really what you want from a toxin or a toxin delivery system or a radioisotope delivery system. And then the third area is selectivity. Bicycles bind to one protein and one protein only, and that's their target. And that's very different from an antibody, which, as you all know, have evolved over, you know, throughout history to communicate with many very varied cell systems through the Fc family of receptors and other mechanisms.
And then I guess the fourth differentiator is these molecules become ready conjugatable. They're designed to be conjugatable. It's relatively facile for us to conjugate anything onto a Bicycle, and fifthly, these are fully synthetic. So very different set of properties than you would get when you think about ADCs, and I would argue, for a number of reasons, probably a better set of properties for the case in point. What was the second question? Sorry.
Your recent pipeline prioritization.
Yeah. So we've made great progress on our lead molecule, a molecule we call zelnecirib. You may remember them. It is BT8009. This targets a tumor antigen, very valuable and broadly expressed tumor antigen called Nectin-4. As I say, we presented data at ESMO, I think validating this approach, further validation of the approach in bladder cancer. And our ambition there is to continue to move this molecule forward through its registration studies, and into the front-line setting, where we think it has a profile which is very exciting for patients. Our second molecule is a molecule called BT5528. This targets a tumor antigen called ephrin A2, and this is a very interesting target. Again, a target which is very broadly expressed in many tumor types.
But it's interesting because for some reason, approaches using antibody technology have failed, and they failed because they are associated with quite a severe toxicology. We've now dosed more than 100 patients with BT5528, and absolutely not seeing that toxicology. And then our third molecule, BT7480, is another Nectin-4 target, and that speaks, I think, to the high value of Nectin-4 as a target, but also, I think the versatility of our platform. We can take the same binder and append to it different payloads. So that molecule, at ESMO, we gave some data on our dose escalation. Very excited by that molecule profile. Very clean in terms of tolerability.
We're getting the right immune activation that we want, and you know, we're seeing very good responses in terms of very long, stable diseases, so our ambition now is to move these molecules forward, and I guess we'll talk about how we intend to do that during this discussion.
Great. So let's talk about your small updates. So you shared some pretty nice data there.
Thank you.
So I wonder if you can maybe just recap for us on what are some of the key takeaways.
Yeah. I'll start, and then I'm sure Santiago will add some details. We had four posters at ESMO. The first poster was a continuation of data we've already shared at the last update being our R&D Day in December. Here we looked at zelnecirib in late-line as a monotherapy in late-line metastatic urothelial cancer. We'd had some more patients to the study, and we've now studied them for a little bit longer. The response rate was very consistent with what we've shown previously and very consistent with that of Padcev in this setting. The tolerability profile, I think, is starting to become ever more differentiated.
We're not seeing the same extent of things like neuropathy or skin toxicity. And I think that really translates to the third important thing that we showed at ESMO, and that was the long duration of responses, and we're seeing about a 50% longer duration of response at the present time with this molecule in that setting. Then the second poster, I guess, was with 5528. And here we've continued to do dose optimization. At R&D Day in December, we'd shown a fairly extensive dose optimization. And with this particular target, we're being very mindful of the very severe toxicology seen with ADCs. So we're stepping through this in a methodical way.
At R&D Day, at six and a half, we selected a dose of 6.5 mg/m² every other week. But we wanted to just check on a different dose, so we used 5 mg every week, very much aligned with what we've seen with 8009 . And what we'd showed actually was that the biweekly dosing schedule, the every two-week dosing schedule, brought benefits, not just in terms of both in terms of tolerability and in terms of efficacy. So that validates this idea that these molecules are very well-suited to an every other week type dosing schedule.
And we also and using that approach and looking at as expansion, we have about a 45% response rate, which I think is very competitive. The tolerability of the profile of the molecule is very differentiated, appears very well-tolerated, very safe. The third poster, we actually took the data from our zelnecirib, all the zelnecirib work that we've done, which covers about 150 patients, and all the work that we've done with 5528, which again is about 100 patients. And we looked at the propensity of this class of molecule to cause neuropathy. And we find that this class of molecule, it produces a much reduced level of neuropathy and a much less severe type of neuropathy than the class of ADCs.
And then the third, fourth poster was BT7480, our Nectin-4 CD137 or 4-1BB agonist molecule. This was the completion of our escalation. As I've already said, I think we showed very, very nice tolerability, selected our recommended dose, and we're starting to see, I think, a type of the right immune engagement and beginnings of what we believe will be nice responses. I don't know if you have anything to add to that, Santiago?
No. Basically, maybe emphasizing that what we see across the three products, we see overall responses, and with zelnecirib, similar to Padcev, and a very differentiated safety tolerability profile. In the case of zelnecirib, no serious adverse reactions, low incidence of neuropathy, in general, no serious and very low incidence of ocular reactions, low levels of hyperglycemia, et cetera. And you can see that that goes across the three products, the two toxin conjugates and the CD137 conjugate. So, it is a new platform, very differentiated from ADCs, but with at least similar responses as the ADCs, and in the case of BT5528, with a novel target that ADCs were not able to drug because of tolerability issues.
Okay, great. Maybe I just want to follow up on neuropathy rate, which I think is a key sort of factor that sets you guys apart from competition, for instance, Padcev, and where we have a lot of benchmark data. So I wonder if we can just expand on that a little bit in terms of what you see from the neuropathy perspective. And the second is like, how confident are you that you will not see an increase of the neuropathy rate with longer follow-up?
I think we have now good follow-up on the patients. We have an overall duration of treatment of four months, 4.2 months. So, it's sufficient to see if we had emerging neuropathy. The time to onset of neuropathy is relatively quickly, but in the case of Padcev, it's longer, but still within the four months of treatment that we have is sufficient to see what is the real incidence. So we believe that the incidence that we have currently, which is half of Padcev, will be maintained. But not only the incidence is lower, it's also the severity.
We have in the whole database of 146 patients, we have one Grade 3 neuropathy that was actually reversible and actually occurred in a patient that had been treated previously with Padcev and entered into the study with a Grade 1 neuropathy. So totally differentiated. In addition, about half of the patients were Grade 1, half of the patients have Grade 2, and 40% of the patients with neuropathy, they reversed to Grade 0, Grade 1. So again, it's a much more treatable or neuropathy. And it also goes along with the feedback that we've had from investigators and key opinion leaders that have been able to use the compound. The neuropathy, they call it like non-sticky compared to the ADC neuropathy that sticks around for a long time.
You know, one of the most interesting things for me from ESMO was actually a paper by someone else. And one of the things we've always wondered was, you know, have we given our patients long enough, enough patients long enough to know that the neuropathy we're seeing is not gonna worsen with time? And we've always thought that the ADCs and Padcev takes five to six months.
Yeah.
But there was a really interesting paper from the Rosenberg group, which was a follow-up to the EV103 study, where they followed the patients for five years now. And what they report in their analysis is that the onset of the neuropathy with Padcev is actually two and a half months. So with our median duration of treatment being four plus months, I think we're ever more confident now that what we're seeing is the full extent of the neuropathy profile.
Right. Great. So that's on the monotherapy side, and obviously, you guys are gonna share some combo data in front line later this year. I think this is a key focus for a lot of folks. We're trying to compare you with the benchmark here, which has pretty high bars. So maybe just set the stage for us. What should we expect? What is the good data?
I mean, you know, I mean, we. I think this is an opportunity to kind of start to compare apples with apples. I mean, the only caveat I would say is that we're in the cis-ineligible population, so a slightly sicker population. I think we should be looking at, you know, the response rates that we're seeing. I think Padcev's in the range of around 60%, so if we're in that ballpark, I'd be... I think that's interesting. I don't think we're gonna have be at a point where we can give duration of response. This is a relatively early study, so I don't think there's a lot we can anchor there. And then again, the tolerability profile. Padcev pembrolizumab combination is showing about 70% neuropathy, about 70% skin toxicity, and so I'd be looking at those types of levels. Anything to add, Alethia?
Yeah, I think the safety, I mean, truly the all grade matters here, too, like Grade 3 different things. So, I mean, you'll get a, I mean, because we've tested this drug mostly in people that are sick, not first line. Right? And so we'll see how the safety profile continues to evolve, number one, as we move up the line of therapy, but also in combination, right? And so I think that'll be quite interesting to look at.
And then in terms of your phase II, III study or to, which you guys are running, how are you seeing in terms of, you know, patient enrollment?
Santiago?
I mean, the study is actually enrolling well. It's a global study, so we're going to United States, Europe, you know, South America, China, Japan, everywhere. We are opening up to 300 sites. We will be able to give guidance on the recruitment, et cetera, and timelines in the future over the next few months. And we've seen a lot of interest, actually, for the study. Padcev is approved in United States, has just been approved in Europe.
Unfortunately, in Europe, there is not good market access, and we think that it's not going to be good market access for a while. So there is a time window for good recruitment in Europe. But even in the States, for first line, we have seen a lot of interest of getting patients into the study. Again, I think that p hysicians are starting to understand the safety profile of Padcev and how, you know, the tolerability is impacting these first-line patients that otherwise were pretty untouched before it.
Great. Maybe Jennifer can comment on that as well. Just obviously, you're doing a lot of market research, right? So just from what you have seen, your interactions with physicians, I mean, what do you see in terms of, you know, the interest relative to, you know, Padcev?
Very high interest. We've talked a little bit before about our qualitative and KOL insights, basically, reflecting that if you can maintain that efficacy and improve duration of response to approximately nine to 11 months in monotherapy, that would be really impactful to their patients. However, when you couple that with also an improvement in skin rash and neuropathy of 20%-30%, which is where our profile is trending, that would drive prescribing over Padcev. Obviously, we wanted to confirm that and look at EphA2 and zelnecirib pevedotin in the first-line setting, too, which was a big question that we were just discussing. We did go out and do research with 150 oncologists, a mix of community and academic that represent the U.S. kind of split.
And what we found in that is that, that things like serious adverse events, especially in the first line, are really meaningful to how they would like to treat, and just an absolute reduction of 20% in your profile on those SAEs, like skin rash, neuropathy, hyperglycemia, ocular events, which can really plague keeping patients on Padcev, that would drive prescribing, would almost double their preference share for zelnecirib.
So that just really, for us, reinforced that we have looked at analogues where you can have an established drug in the market, it's a market leader, considered standard of care like Imbruvica, and you can have someone like Calquence come, and if you can solve for those treatment-limiting side effects, in the case of Imbruvica, it was AFib and bleeding, you can take the market very quickly, just like Calquence did. You know, they had 60% new patient share in nine months. So for us, this research starts to confirm what doctors really are looking for. Padcev is a very good drug. It works extremely well, but we just believe zelnecirib and pembro can do better.
Okay, great. So maybe just last question on Nectin-4 is obviously you're looking at other tumor types as well. So I wonder maybe, Kevin, you know, touch on what other, you know, data that we may see later this year, in other tumor types. And then I know maybe you're looking at some novel payloads, there as well. Maybe touch on the work you're doing there.
We see Nectin-4 as a very high-value tumor antigen expressed across a very broad range of tumors. We recognized that four or five years ago when we took two orthogonal approaches: zelnecirib using a toxin conjugate and BT7480 using an IO activator. And I think you know, that's playing out now. We're seeing, you know, quite a lot of opportunity in the Nectin-4 space. In terms of what we can expect in the near future, we have zelnecirib being tested in late-line triple-negative breast cancer and late-line non-small cell lung cancer, and we're looking forward to sharing that data towards the end of the year.
Now, I want to switch gears to 5528, which is your ephrin A2 program. Obviously, you shared some nice data in bladder cancer. So I'm curious, like, how are you thinking about, you know, positioning this molecule relative to your Nectin-4?
It's really interesting because ephrin A2 is, again, broadly expressed across multiple tumor types, including, you know, there's a collision in bladder cancer, and we're excited about the opportunity of taking two molecules into that space. Nectin-4 is a tumor antigen that I think is relatively early expressed. The literature suggests that ephrin is expressed in more advanced types of tumors, but ephrin is also expressed broadly in other tumor types, so we will continue to explore there as well. At R&D Day, I think I showed the beginnings of good activity in things like head and neck cancer, and I think that's a big opportunity for us.
The next step for us with that molecule is to test this in combination with checkpoint inhibitors to demonstrate safety, because I think the future is combination, and I think that's where the Bicycle platform and this really good tolerability profile really puts us in good stead. Our ability to combine with other agents and with a much better tolerability profile can only bring good things to patients. So, yeah, watch this space. We've got high hopes for BT5528.
I think another very interesting story that is emerging from your pipeline is obviously on the radioligand side, and it sounds like you guys are going to share some initial imaging data really soon. So I wonder if you can talk about, you know, the target. What should we expect to see? Like, what do you hope to, I guess, in terms of the information, what do you hope to get from that imaging data?
I mean, maybe just the level set for everyone. This is a technology that we've been looking at for years, right? So it's not something that we jumped into. And we have collaborations with Bayer and Novartis, but we also have a separate program with DKFZ, which is a German academic institute that specializes in imaging and radiopharm. So, you know, basically, this data set will be coming from the work that DKFZ has done, and what we've said is that middle of the year, wide error bars, and we've remained on track. So basically, next month, we'll be looking to have data at a medical meeting in Europe to show the initial data in early human imaging, clinical imaging, right? So it's still a microdose of the isotope, but again, you know, like I like to say, a picture speaks a thousand words.
And so that target is MT1-MMP, which is also part of. We have a lot of biological expertise there from the toxin conjugate work. But when you take a step back about how we think about radio and our platform, the reality is that there are a lot of people clustered around two particular tumor antigens and maybe three, at best, indications. And what we're really trying to do over time is broaden that and play as a next-generation radioligand player here. So that's why we actually thought about MT1. And we have another target behind it that we've not disclosed, but we wanna show that we can possibly go after things beyond PSMA and somatostatin. And also, when we think about isotope, because we get the question a lot, our ultimate goal is to be isotope-agnostic, right?
Because we think that the platform enables any use of the isotope, but we have to validate that and play that out over time. So the first step is getting this early human imaging data. So, you know, how to think about what we would find particularly exciting here, I mean, of course, we wanna see, like, a good percentage of patients expressing MT1, expressing lesions, right? That's a big piece of the storyline here. Another piece of it is we wanna see that, the linker technology ourselves with Bicycle is enabling, you know, very direct hit to the tumor and not a lot of systemic exposure, which is in line with the toxin conjugate platform itself. Then, on the distribution case, you wanna see rapid uptake, and you wanna see it get out quick via the kidney.
Y ou know, I think when you take it that, like, when you think about the fact that, you know, imaging information is different than, like, what you have to think about in small molecule, in different lands where you don't have it. But, you know, if we see, like, any, you know, constellation of these events, we would be very encouraged, right? And what we would be looking to figure out what to do next, because we think that what we have here could be really differentiated from where the current landscape is, but also technically where the current landscape truly wants to go.
Okay, great. So I wonder if you can touch on sort of the clinical development plan for this molecule, or maybe, I don't know, maybe you might wanna try a different isotope.
I think realistically, it's too early to say. But, like, I think that's why I said the first step is you get the imaging data. The next step is we think about where to develop a therapeutic, right? Obviously, in MT1, you know, if you look at the literature, and it was in our R&D data deck, it's expressed in the lung, it's expressed in breast, and it's expressed in various tumor types. So we have to think about that.
And I think we have to be thoughtful about what isotope might best fit. But again, remember, we're trying to think about how to develop the use case that you don't need. It's not one isotope. It could be any of them, right? And with our technology, we believe. So I think more to come. You know, hopefully, when we talk about this and, you know, present the information in October, we'll be able to help give a little bit of insight, right? If the data look compelling, right? So we'll think about that.
Were we getting any information in terms of the tumor types that you guys may go after? Obviously, expression data is one, but also, what other sort of, you know, tumor types that you guys think you may have, I guess, a path?
I think it depends on, you see, right? I mean, our intent is to share with you the data that we have in hand and delineate the next steps. It's not so far away, so we look forward to doing that.
Yeah, I mean, it's gonna be a stepwise function, right? Like, we need to get this data. We'll talk a little bit more about it, and if it looks interesting, we'll continue to talk about how we think about developing, right? Now, obviously, we have the capital to do this, right? So that's also very enabling for us if we see good data.
Maybe last question from me is, obviously, you have collaborations with Novartis and Bayer. Obviously, they have a lot of expertise in this area. So I wonder if you guys are leveraging sort of that kind of, in a partnership, to help you develop these molecules?
Yeah, I mean, we decided to do a two-target collaboration with Bayer and a two-target collaboration with Novartis simply because they are the most, they're the only two companies on the planet who have actually commercialized radiopharmaceutical products. Inevitably, there is an exchange of information that is gonna stand us in good stead for the future, and that was part of the strategic reason for doing those collaborations, and we're very happy with those collaborations. They're going very well.
Okay, great. Thank you so much, guys, for a great discussion.
Thank you.
Thank you.
Appreciate it. Thank you.