Good morning, everyone. My name is Kelly Shi, one of the senior biotech analysts here at Jefferies, and welcome to join Jefferies' London Healthcare Conference and in this first chat session we are very pleased to have Dr. Kevin Lee, CEO, Jennifer Perry, Chief Strategy Officer and Head of Commercial, Santiago Arroyo so I hope I pronounced it right for this session. Arroyo, and welcome all of you and the terrific Bicycle team. Maybe the first question to Kevin so what has Bicycle achieved for the past 12 months, and what do you see the company's strategy actually change as of now and compared to 12 months ago?
Thanks for that, Kelly, and good morning, everybody. It's a pleasure to be here, and many thanks to Jefferies for the invitation. I think 2024 has been an incredible year for Bicycle. I think we've continued to build on the promise of the technology. We've shown across multiple programs the differentiation of the Bicycle technology in terms of improved potential tolerability profiles across a range of different tumor types. If I take each asset individually, with 8009, we gave data at ESMO on our monotherapy second-line study. I'm sure Santiago will talk about that later, but we're very pleased with the data there, very strong response rates, and, as I say, very differentiated tolerability profile compared to other targeted technologies.
We guided at the start of this year that we'd give an update outside of urothelial cancer, and we're still on track to do that and look forward to sharing that information with everybody. We've also been executing very well on our open-label combination study with pembrolizumab in cisplatin-ineligible first-line patients, and hopefully we can share an update on that again in the next foreseeable future. Most importantly, we've been executing on our registration trial, Duravelo-2, made good progress there and hoping to provide some guidance around that again in the not too distant future. Outside of 8009 on zelenectide, 5528, we've continued to explore that molecule. I think we've done more dose exploration, seen a very robust signal in metastatic urothelial cancer, EphA2 dependent signal, and we continue to build on the promise of that with a study of the molecule in combination.
For 7480, which is our Nectin-4-targeted CD137, again, we gave an update at ESMO, and we're really pleased with the tolerability profile of that molecule and the early signs of immune engagement. Then the other big thing that we've shared recently is the progress we've made in radiopharmaceuticals. We've gone on record saying that initially we're pursuing two completely novel targets, MT1-MMP and EphA2, and we shared early clinical imaging data on our MT1-MMP molecule, which I think was very well received. So I think that they're the highlights of 2024. I might have missed something, and my colleagues will remind me if I've done so, if I have.
Of course, on the financing front, we did our PIPE in the summer, which we were very pleased about, both from the capital it brought in, but also the caliber of investors who have now joined us as shareholders. I think about 2025, it's building on the execution that we've already seen, really want to accelerate the development of Nectin-4 and really push forward quite hard the work that we're doing in the radiopharmaceutical space, so I'll stop there. I think that was quite a big overview, so apologies.
Very comprehensive and a lot of good things ongoing at Bicycle. Maybe let's stay focused on 8009. And at ESMO, you already touched upon and they will present data, and we have experienced a very positive reaction from the capital market on that. Could you actually dig a little bit deeper into the data, maybe on both efficacy and also the new discoveries from safety profile across both assets, and how does it actually differentiate Bicycle molecules from other classic ADC molecules?
Yeah, this month we presented an update on the cohort of EV naive patients treated with zelenectide. What is probably most relevant of the update is the ORR, which was 45% and long duration of response. The duration of response, we presented it last year, it was 11 months, it's still 11 months, 11.1 months. So that's longer than we've seen with antibodies in this indication. We also presented an update on the safety and tolerability, and this update was especially important because the duration of treatment was much longer. The median duration of treatment was 4.1 months.
Basically, on the three areas that antibodies are notoriously problematic, which is skin, peripheral neuropathy, and specifically sensory peripheral neuropathy, and ocular disorders, we didn't have zelenectide, didn't have any grade 3 adverse events, and most of the adverse events were grade 1, a few of them grade 2, and low incidence overall of them, both in ocular and skin, and moderate incidence in neuropathy. So overall, a very differentiated profile compared to ADCs.
Great. And what kind of expectation do you have that safety profile could translate to efficacy front?
If you can keep the patients on treatment, you will expect that the duration of response, which will be longer, and that's what we are seeing. We are seeing, I mean, if you recall, the duration of response of Padcev in a similar population was 7.4 months. The duration of response that we are seeing is 11.1 months, so significantly higher. And the other particularity is that we don't see many patients having to be withdrawn from the medication. Our withdrawal rate due to adverse events is 4%, and that compares very favorably with the withdrawal rate that has been presented in the past with ADCs.
Okay, fantastic. Maybe follow the same line you have guided to give the initial PD-1 combo data with 8009 by the end of the year. Can you help us to set expectation? What kind of data we should look for and what should we focus on in terms of both efficacy and safety signals?
Yeah, this is a cohort that we did separate from other cohorts. It was in 22 patients that were EV naive and cis ineligible population, and we went to this sicker population just to be able to get to first line relatively quickly, so we will present an update on that. We haven't presented the data by the end of the year, and we'll probably get it also presented in a meeting next year.
I say, do you think the year-end update is the data mature enough for us to tell how much of benefit we get on the durability front?
The data is not mature, but I think it's mature enough to have an assessment.
Okay, so we're going to focus on ORR?
Yeah.
Okay, fantastic. Maybe let's talk about the registration trial, as Kevin just mentioned. There's some nuance there regarding FDA's Project FrontRunner program. And can you actually walk us through why this accelerated regulatory path gave you a competitive edge in the context that besides Padcev, we also have an array of new Nectin agents actually in clinical development?
Yeah, so the trial design is a novel trial design. What we tried to do in this study is to first, a pivotal study is a registration study by itself, and it has two main cohorts. First line, in which we test two different doses in combination with pembrolizumab, and then a cohort two, which is second line treatment. The second line treatment also serves as a contribution of components to understand monotherapy and combo therapy in order to be able to evaluate the first line. And that's something that the FDA insisted that we should demonstrate. The study is fully powered to get an accelerated approval, a potential accelerated approval in first line, and we'll do that on the basis of ORR comparing our treated arm, one of the doses, versus an active control, which is chemotherapy plus avelumab.
The study will continue because the confirmatory part of the study is built into the same study. The confirmatory part will be the primary efficacy analysis with PFS, and OS will be the secondary critical or key analysis.
Okay, and on the clinical operation front, do you expect different enrollment pace for front line versus second line? And also for second line, can you give us more specifics? How do you anticipate a patient baseline, like the prior treatment?
Yeah, I mean, the study is recruiting. As you recall, we announced that we started the study in the first quarter of this year, and we are opening sites and recruiting according to our plan, and we will present an update on that probably sometime early next year. And the study basically is doing, I mean, is doing well. There is a window of time to recruit this study, right? Padcev is in the market now here in the States. It is approved in Europe, but it's not in the market in most countries in Europe, and worldwide is still not in the market in most countries. So there is a window of time that we are using in order to be able to bring this drug to the market.
I think that we'll be able to stay on those timelines, so I will be able to complete the study before any of these things happen.
I see. Maybe also given the Padcev progress in front line, do you expect in terms of patient baseline characteristics, in your pivotal trial, the patient baseline could be like a little bit different from like a dose escalation and a dose expansion?
I don't think so. In the United States, patients that are being included in, for example, in the first line cohort is because physician patient preference for a drug that is potentially better tolerated. In Europe, they don't have availability, so they basically continue to, I mean, they get patients into a trial that will be otherwise potentially candidates for Padcev. So I don't think that we are going to see major differences.
Okay.
Again, because of this window of time.
Okay, fantastic. Maybe pivot one question to Jennifer. And although it's still like early days, but I'm curious your thoughts upon the pivotal trial success in the future, what kind of market opportunity you eye on in second line?
Thank you for the question. So I mean, maybe we first talk a little bit about how we see the bladder market and then a little bit what that means for zelenectide. So when we evaluate the market, it's still very complex and nuanced. So the second line setting on our latest market information, IQVIA claims data is fragmented. No one agent is really pushing above 20% share. That's EVP, that's pembrolizumab therapy, that's chemotherapy. So with that, still lots of opportunity to affect change and bring new agents into the unmet space. However, we really have our eye on the first line market. And in that space, everyone knows with the introduction of EVP's approval in the U.S., and they have their full label for almost a year now, that they've rapidly changed that landscape.
However, we do see some slowing and stabilizing of their market share in our claims data, and so that's going to be an area to watch right now because to me, that still means not every patient is going to be an EVP patient, mostly because of the profile. There's just limitations in terms of those treatment-limiting adverse events like peripheral neuropathy and skin rash and other things, and then the last thing, you mentioned the new nectin agents. Yes, we've got Mabwell, Corbus, Lilly developing them, and we expect that that's going to make things more complex, both in bladder and outside of bladder in terms of more ADCs coming to the space.
So what all of that means for zelenectide, though, is the first thing is it proves to us that nectin, where we are aggressively developing in bladder, is still a very high-value target and a place that we want to continue to move very aggressively, especially with our phase II, phase III study. The other thing is we're still exploring outside of bladder. Obviously, we're going to have data at San Antonio Breast, as well as we continue to explore things like lung because we feel that's very much an untapped space for nectin. The ADCs that come to market right now in the commercial view will be trading toxicity for treatment. So some will have more skin rash, some will have more neuropathy, some will have hyperglycemia, some will have ocular, some have all of the above.
For zelenectide, this is a very elegant molecule, which to us is starting to become a really beautifully emerging medicine that's very differentiated. It's not an ADC. So we spend a lot of time trying to educate around that so people understand the profile is just different. And where we see that playing out is in our market research, some simple changes in terms of the profile. So for example, an absolute reduction of about 20% in serious adverse events compared to, let's say, EVP in the first line bladder actually drives in our quantitative market research a doubling of preference share. Basically just means they would check and take zelenectide plus Pembro over Padcev plus Pembro most of the time. And so for us, that's just untapped opportunity still in bladder. Plus, again, we have things going on outside of bladder.
Fantastic. And from your market research, what is the current consensus of peak sales for Nectin-4 agents in frontline bladder cancer?
We are doing a lot of modeling right now, watching peak sales. We won't yet reveal what we believe our peak sales will be, but obviously they do think that Padcev in the first line will be pushing to a $2 billion+ drug. And again, not having the whole market to us, again, that just means untapped opportunity. Chemo will still be used. Right now, we're seeing in our claims data, it's probably still around 40% utilization. So you feel you can take share from chemotherapy with a better profile for sure. But we also believe that we can replace Padcev in their combination just because of that better profile.
Okay, fantastic. Maybe beyond the bladder cancer, what other tumor indications you think Nectin-4 could tackle? And where are you in terms of clinical trials ongoing in those additional indications and what kind of data expectation you can set up for your molecules?
Nectin-4 is widely expressed across many different cancer types. We find this a really high-value target worthy of a lot of exploration. As we guided to last year and as we've said in this format, that we will be given an update on the work we've been doing in breast cancer and in lung cancer. But I do think the opportunity is much bigger than even that. If you just look at the expression profile of this molecule, it's very broadly expressed. With that in our mind's eye, that was one of the reasons that we actually started a second Nectin-4 program, the 7480, which is a Nectin-4 CD137 molecule. Huge potential for Nectin-4 both within and beyond bladder, and we're looking forward to sharing our data.
Okay, fantastic. Maybe moving to BT5528, you showed promising results in bladder cancer as well and also efficacy signal in ovarian cancer. Maybe first focus on bladder cancer. How do you position BT5528 development plan next to BT8009?
Yeah, we continue to explore 5528 in bladder cancer. EphA2 is a target that is, for us, I think completely blue sky to us. There is no one else with an EphA2 agent. ADCs to this target have a catastrophic toxicity, so precluded from moving into the space. So one of the things that's guided our strategy with EphA2 is given the baggage that we've had to sort of manage around the ADC toxicities. We've been quite careful and thoughtful about how we've worked through the different doses. In the second line setting, when you look for EphA2 selected patients, I think you get a response rate, again, around 45%, so a really robust response rate. The thing that we're looking at now is what does that translate to in combination with avelumab? So we'll share data on that.
EphA2, all of our targets we've chosen to be very broadly expressed, very high-value targets. And EphA2 is similar to that. It's highly expressed across a number of cancers, not just bladder and ovarian, the GI cancers, head and neck cancer, pancreatic cancer, non-small cell lung cancer. So we've used the bladder as somewhat of a testing ground. We continue to evolve that work, but understanding the optimized dose, understanding what we can do in combination with the molecule, we'll also explore beyond bladder as well.
When could we expect data from Nivo-Combo?
We haven't guided to that yet, so wait till we give our 2025 guidance.
Okay, see you at the JP Morgan's conference, and we would like to hear more data flow for 2025. But now, actually, jump to Radiop harma efforts Bicycle has made. Maybe for investors actually not familiar with the data you have presented from first-in-human imaging data, can you walk us through the data details and also maybe talking about why MT1-MMP was chosen as the first target for Radiop harma?
Yeah, I mean, again, so Nectin-4 aside, and there are various reasons we chose Nectin-4. The other targets we have in our portfolio are targets which are completely novel that no one else is working on, sometimes because they're intractable, largely because they're intractable to other modalities. MT1 is one of those targets. We've had an interest in this molecule for a long time, this target for a long time. It's got a very important role in tumor invasiveness, metastasis formation, and we think there's a huge opportunity for this molecule. We presented some data recently that we did with collaboration with DKFZ, who are the most prestigious nuclear medicine groups on the planet. I think the data was very compelling.
We showed that our molecule, which was an imaging agent, not the optimized radiotherapeutic, was able to image MT1 expressed in tumors, very clean background, very little sign of any interaction with other tissues, MT1 dependent or not, which I think speaks again, validates the target as being very specific to tumors. So we think this is a very high-value target, very broadly expressed in many different tumor types with very low expression elsewhere in the body. We're going to aggressively pursue this. We're going to take orthogonal approaches, and we really want to dominate the MT1 space as we want to dominate the Eph A2 space and as we want to dominate the Nectin-4 space. Nectin-4, we've had a little bit of catching up to do, but I think the molecule, the data will speak for itself.
Fantastic. And you also have chosen EphA2 as another radioligand. And take one step back, could you actually share with us your general principles when you expand the BRC pipeline?
Yeah, so with EphA2, this is a target when ADC approaches just haven't worked. There's gross toxicity there. We've now been in more than 100 patients. We don't have that toxicity with 5528. We think it's an area we can really, as I say, dominate. We think it's a target which is very broadly expressed and orthogonal approaches make sense. We have 5528 in clinical development. A radiotherapeutic makes sense for us. When I think about 45% response rates, I think about 55% of patients who are not benefiting and how do we get benefit to them. And taking different payload approaches makes a lot of sense to me. So we try and choose targets where we think the Bicycle platform will play well, that are where we have a significant advantage and where there's a lot of blue sky for us to move into.
Do we expect more targets actually join this BRC pipeline in the next?
We're working on a lot of targets. The beautiful thing about our pipeline is a binder for a toxin conjugate is a binder for a radio conjugate. It's just a different, for us, it's just a different payload. So it's very facile. So everything, all the multiple targets we've been generating for a long time now have always been in our mind's eye for radio conjugates and for toxin conjugates.
That will be internal development for the future?
We have. There's a lot going on. We'll share when we're ready.
Okay, fantastic, and maybe lastly, could you remind us again for the catalysts and the milestones for next 12-18 months and a general where are your minds on the future front?
Yeah, I mean, just general, we've run out of time. Can I keep going? We've run out of time. Can I keep going?
Yes.
You know, I think with BT8009, we've got some updates before the end of the year, and then I'll be focused on Duravelo-2 and the readouts from that. As I've already said, with 5528 and 7480, we've got some combinations with nivolumab. So they'll be the big, big, big things to watch in the next 12 - 18 months.
Fantastic. Thank you so much for the discussion. Thank you everyone for attending.