Thank you so much. Good morning. Welcome to Barclays Global Healthcare Conference. We're in Miami, and do email us or I'm on Bloomberg as well, so just ping us with questions if you need anything addressed. My name is Peter Lawson. I'm one of the mid-cap biotech analysts at Barclays, focusing on oncology. I'm really delighted to have management team from Bicycle Therapeutics. We've got Alethia Young, CFO, and David Borah for the VP of Capital Markets and Investor Relations. Thank you so much for the time today. I guess first place to start really for me is like Nectin-4 and kind of how enrollment is going for the expansion cohorts and kind of where you stand for kind of post PADCEV bladder cancer patients.
Sure. Thanks, Peter. I appreciate the invite and the opportunity to be here. The expansion cohorts are going well. I think we've shared the different cohorts that are open and enrolling. Enrollment's going well. As you point out, there's the dedicated cohort for late line post PADCEV that's going well as everything else are. Excited to be advancing them all and moving it forward.
You're able to recruit those patients. I know there was kind of questions at one point whether you could get post PADCEV patients.
Sure.
change criteria.
Well, that was in the dose escalation. In the dose escalation, for most of it was an exclusion criteria for prior Nectin-4 exposure. For most of that trial, those patients were excluded, and we weren't able to recruit them. We did remove that criteria, but it was late in the trial. At that point, most of the slots had been filled, so there were limited opportunities. Now that we have a dedicated cohort, there's no exclusion. In fact, that's in that cohort, they have to have prior Nectin exposure, so we're able to recruit that. The dynamics are very different at this point.
Yeah. Has there been any pushback from experts or KOLs in the space of just like doing one Nectin-4 followed by another Nectin-4? Just the thoughts there or do they have to have another treatment before in between the two Nectin-4 therapies?
Nope. I don't think there's any pushback. There's a variety of reasons why a patient might come off of a Nectin-4 ADC. Some of them can't tolerate it, as one of the reasons. No. Obviously, we have to continue to enroll and generate the data, and that's what we're doing.
Gotcha. Is it the case. In some instances, it will be they can't tolerate PADCEV. I guess in other instances, it could be that they progress on PADCEV. I mean, what... how should we be thinking about the mix of those patients?
I think there could be some heterogeneity there. Some patients might not be able to tolerate it. Some patients may have not received, you know, complete dose, whether they've been dose-reduced or received it on less frequency. The amount of MMAE they've been receiving may be less when you think about, you know, vis-à-vis BT8009. If you compare our go-forward dose, 5 mgs per meter squared weekly versus the approved dose of PADCEV at 1.25 mgs per kg over a 28-day cycle, we're delivering 35% more MMAE. We have to compare that on what we're our dose versus their their label, but not every patient, a lot of patients aren't receiving that. That delta could be even greater.
You know, we're enrolling the patients and we're generating the data, stay tuned.
Gotcha. Would you expect to see, less efficacy in these kind of post PADCEV patients?
Less than what?
Less than, if they were pre-PADCEV. Naïve.
Yeah. Naïve.
Yeah.
Yeah. I think that's a reasonable assumption, right? for sure. Patients, you know, by nature are going to be, you know, later line, more heavily pretreated. That's a reasonable assumption.
Gotcha. kind of if you could help us kind of frame what clinical success looks like for the expansion cohorts, kind of pre, post, ovarian triple negative, et cetera.
You know, it's gonna depend greatly on the different indications and the different settings, and even within an indication, the line that you're treating them is going to vary of what you would look to see. As we were just talking about, in the bladder naïve, Nectin-4 naïve, you know, we've demonstrated a 50% ORR now amongst several cohorts. That's what we've generated to date. If you think about bladder in the late-line setting, you know, post PADCEV, you're talking about last-line salvage chemo, where it's very efficacy is quite modest. My recollection is probably high single, low double digits, short responses. It's obviously gonna be a lower bar there. It's gonna depend on the other tumor types.
For example, we demonstrated a response with nice durability in lung cancer. This was a late line, Post PD-1 patient where, you know, the efficacy is going to drop off considerably as you move into later lines in lung cancer. We saw a nice response, durable response. Again, it's really going to vary based on not only the indication but also what line within any indication is. It's probably a little early to say with the deal specificity, but we're looking forward to being able to provide data from all these cohorts.
Gotcha. How are discussions going with the FDA as regards to route forwards and-?
Sure.
accelerated approaches, et cetera?
Sure. I think, you know, all we can say on that front is, we've announced Fast Track. That of course is a great opportunity for us and, you know, helps facilitate discussions, and we're in active, ongoing discussions. Really appreciate FDA's collaboration and willingness to talk with us. Those discussions are ongoing, I think it's difficult for us to comment when you're in active dialogue. What we have said is that we'll be able to provide an update this year and look forward to doing that once our discussions conclude.
Perfect. Do you have any timing around that and then kind of the next meeting with the FDA?
I'm not sure that we're can kind of get into the latter question. I mean, we're in active, ongoing discussions right now. To your question about timing, Dave?
Just say, yeah, we've only said this year. We haven't been more specific than that.
Good. Okay. The expansion data, which is, I believe year-end, would that be for the 5 mg dose, recommended phase II dose?
In our update we said that we're focused on five. That's right. That's what you would expect.
Is there anything that we should be thinking about for the seven and a 0.5 mg dose? Will there be additional data there that we haven't seen?
We've shared the data from the phase I when we completed that trial. We've said we are focused on five. It's a matter of expediency. Obviously, we're very happy with the data that we've generated. We do have that second recommended phase II dose, so that is something that we can pursue. First and foremost, we're focused on advancing the molecule as quickly as we can. Right now you would expect to see the focus on that dose.
why have that second recommended phase II dose?
Well, I think there's a variety of reasons. It's an alternative on frequency. You know, we do want to make sure that we've pursued a wide range of doses, Project Optimist, that we've gone all the way up. We've looked, if you will, sort of sideways around different doses and frequencies and making sure that we've gone through and evaluated a wide range.
Yeah. That seemed to be a very expansive exploration of different doses and timing of doses, et cetera. Is that something you wanted to pursue yourself, or was that kind of a nudge from the FDA or?
I think it was important that we did it, when you come and engage with the agency that you've done a complete analysis and fulsome across a range. I think it was largely for that reason.
Gotcha. As we think about the expansion data, so is that year-end or do we also see kind of additional sets of that?
We haven't been more specific in terms of the timing. We haven't also been more specific in terms of what exactly. We should have quite a bit of data to choose from, it's a little bit early at this point to be more specific in terms of when, where, and what. We're very confident we'll have data to share from the expansion by year-end. I would just stay tuned on that.
Gotcha. Okay. I guess the normal process seems to be at the moment, kind of top line press release and then save data for a medical conference. Is that the same approach or?
I don't think so. You know, I think we're aiming to do everything at or around medical conferences. In terms of a top line press release, you know, last year we had promised investors that we'd have news to share by year-end. We did that. In the Q4, there was simply no medical conference that sort of made sense at that time. We did the Q4 top line press release, then we gave the full data set at ASCO GU. You know, it's not. That doesn't by rule have to be the sequence of events going forward.
Gotcha. Okay. Perfect. I guess as we think about the side effect profile of PADCEV's, you know, been well received, but, you know, when you dig into patient and physician comments, it's the side effect profile becomes the issue. Where do you think you need to be in terms of like rash, neuropathy or, you know, other components of safety that you think you need to control versus PADCEV?
Maybe just to clarify the question, where do we think we need to be going forward?
Safety profile. Would you be happy with-
Oh.
to compete against PADCEV?
Well, we're really encouraged by what we've seen. You know, obviously we'll have to generate more data and continue to do that. You know, amongst the 50 or so patients that we've shared, we're incredibly encouraged by low, fairly low rate of rash, you know, across all of the cohorts. Really, it's not an issue, both in incidence and severity there. We're incredibly encouraged about that and seems, at least so far, very different from what we've seen with the ADCs. Continuing to build on that, I think, would put us in a great place. Likewise on neuropathy, what we've seen both on the incidence and severity, which, you know, is important there too. Very encouraged by what we've seen.
It's notable that patients really are staying on therapy, and that really comes down to not only efficacy, but tolerability, ability to stay on therapy. In a patient population where the median prior lines was three, patients, when we gave our update, we said the estimated duration of response was 14 months. That's very compelling, and we think is great for patients being able to stay on drug and continue to see nice durable responses. We're incredibly encouraged by what we've seen. We recognize we have to build on this and continue to generate data. We're really confident that we will. Based on what we've seen, we're encouraged.
Got you. Do you think the side effect profile gets better, worse as you continue to expand and, you know, expand the number of patients on therapy?
Side effect profile of 8009?
Yes.
I think it's gonna depend on the setting. You know, if you're thinking late line, you're gonna be getting patients with, you know, higher baseline of various issues, including, you know, potentially neuropathy and other things. It could depend on the setting for sure. You think about in the front line, combining with a checkpoint like pembro, which you are adding two agents together. That's where we think that there's an incredibly compelling opportunity in that combining BT8009 with KEYTRUDA or another checkpoint inhibitor is an incredibly compelling opportunity when you think about combining a checkpoint antibody with an ADC. What we've seen is that the side effect profiles have increased significantly. We've seen the full cohort K data. Response rates have gone up for sure.
You know, certainly we've seen an improvement on that, but we've also seen an increase in side effects. This is where we think 8009 could have a very significant opportunity.
What's the timing around, I guess, seeing the initial data or starting trials in kind of first line with an anti-PD-1?
We're doing some of that work now. We have the dose confirmation work going on, at 5 migs, with pembrolizumab. We just have to get through a few patients, confirm the dose, and then we have, within the 100 trial, the ability, you know, per protocol, we can go straight into that cohort, that combination cohort. We've said we'll have the 200 trial, the combo with blind study up and running this year. That's, those are very much on track. Do you have anything else to add around timing?
No, I think, you know, things are going well, especially that dose confirmation trial, which is, you know, critical as we look towards the initiating the combo trial. Do you think it eventually ends up that you'll have monotherapy late line PD-1 combination front line? Is that how we should think about it kind of in two years' time or so, that's where you'll be?
Well, we're doing both in parallel. We're working on, you know, late line, as we talked about earlier, in our chat here. In the expansion cohorts, we have late line, both mono, for naive and mono for monotherapy for Nectin-4 exposed. That data will, you know, we build on that data for late line and then as we're talking about all the work that we're gonna be doing in front line. They're not mutually exclusive, doing them both in parallel right now.
It seems very likely you could beat PADCEV on safety. Do you think you have to or can beat it on efficacy?
You know, I Not sure that we necessarily think about it in that, in that way. You know, that sort of gets you into sort of a head-to-head situation, which, you know, right now, first and foremost, we're just building on the data. We think that we have a very compelling profile when we think about what we've seen. First and foremost, continue to build on that, generate the data, get through the expansion cohorts, the 200 trial as well and, you know, phase III and commercial. We'll just basically continue to build on what we've done.
Yeah.
We think the profile we've seen is incredibly compelling.
You'd almost want like a, kind of a non-inferiority, at least on the efficacy side of things, but then you can drive better safety, which could potentially drive better durability. That.
Could be. I mean, there's different, you know, efficacy has a variety of different components. There's a response rate, there is durability of response, as you've just mentioned. You know, what we've seen so far, we believe that, you know, we're certainly, again, and it's not a head-to-head comparison, but you know, as good if not better on the efficacy side.
Gotcha. Okay. As we think about EphA2, why EphA2 and then kind of what should we expect? What should we focus on the expansion or escalation data in 2023?
Why EphA2? It's certainly been a target that a lot of work has gone into from an antibody and ADC approach, so using antibody approaches. They haven't worked. You know, there were significant toxicities, significant bleeding, etcetera, and we haven't seen any of that. Clearly, we're seeing differentiation on the Bicycle approach compared to antibodies, and that has been, you know, incredibly validating to see. We've seen efficacy in a couple of tumor types, based on the phase I. You know, that's exciting as well. Certainly, for those reasons why we advanced it. Dave, how about I think there was a question about timing.
In terms of update? Yeah. So we plan to give an update later this year, likely second half. We said back in November that we expected the initial enrollment of the cohorts in the expansion to be complete by year-end 2022. You can assume that that happened. At this point we're, you know, scanning patients and aggregating the data. We should have something second half of this year to share with investors.
That's for the escalation and then.
Correct.
The phase II expansion, kind of the timing we should think about then.
Oh, I'm sorry. Yeah, phase II. Yeah, I'm sorry. Phase II. The expansion later on in the second half of this year. Yeah.
Okay. Perfect. I guess the side effect profile looked encouraging, but there was some kind of grade three diarrhea and anemia. Is that manageable? Is that something you can kind of manage to drive, you know, low discontinuation rates? How should we be thinking about that? I know it's a small number of patients, etcetera, but.
I don't know to what You know, how manageable those conditions are. We, you know, if our CMO, Eric Westin were here, he'd be able to answer that more fulsomely. I think, you know, the one thing to point out about this trial, it was even more heavily pre-treated patient population than A double O nine. This is, you know, median prior lines of therapy were four. I think, you know, the fact that in general the side effect profile of the drug was, you know, sort of as clean as it was quite impressive given the number of prior lines.
The incidence of grade three events were fairly modest, particularly for a population like this. If you think about ADCs in some of the tumor types that we were exploring, there are some significant side effects. Certainly, you know, vis-a-vis some of the other agents that are moving forward and, you know, there's different issues that some of the ADCs have seen, whether it's ocular tox or pneumonitis. We really haven't seen that. Very nice to see that difference.
Yeah. No. Okay. We've seen some really interesting data and encouraging data with the Nectin-4 approach. EphA2, really intriguing as well. Kind of this bispecific, which kind of takes the platform kind of to another level as well. That's really intriguing, kind of why 137 and kind of what data we should expect to see from that phase I and what should we be focused on?
We really like the target. We're very excited about this. It's certainly when you think about the potency of CD137 as an IO target, we like a lot. As far as timing, Dave, what timing?
Timing, again, not to be a broken record, yeah, we're aiming for second half of this year. You know, that dose escalation's gone really well, we look forward to sharing data. We'll have more, you know, sort of we'll be more specific in terms of where and when.
Perfect.
Not just the future.
It was a good to hear a reiteration as opposed to broken record. I guess final question, just to kind of rephrase a question I've been asking the whole time is just like exposure to SVB plus kind of regional banks and these kind of non-bank lenders, kind of how should we be thinking about that?
Yeah. I think it's something the entire industry has been watching and, certainly on top of mind. You know, I think there are a lot of biotechs that have or touched SVB in some way and, you know, as did we. You know, there is some diversification and frankly, we haven't seen any disruption to operations whatsoever.
Okay. Does it make you think about which banks you pick? Is it... Have you kind of... Are you already banking with like a global bank or?
Is this where you're pitching Barclays?
It's a whale of a sorry. just that worry about regional banks...
Of course, Well, I think everyone, right, across the industry and probably broader than just our industry will be thinking about this.
Thank you so much.
Thank you.
Thank you.
Take care.