Okay, good morning, everyone, and thanks for being here. I'm Tara Bancroft, one of the senior analysts here at TD Cowen, and welcome to TD Cowen's 45th Annual Healthcare Conference. For this next session, we have Bicycle Therapeutics here for a fireside chat, and joining us today are Kevin Lee, the CEO, Alethia Young, CFO, Jennifer Perry, the Chief Strategy Officer and Head of Commercial. Thank you all for being here with us today. It's a pleasure to have you. I guess to start off, Kevin, maybe you could give us a general overview and update and lay of the land these days.
Sure. First of all, Tara, many thanks for the invitation. It's great to be here. Really looking forward to the session. Bicycle Therapeutics is a precision-guided therapeutics company. We have this unique technology that was created by our founder, Sir Greg Winter. Many of you know Sir Greg from his pioneering work in antibodies, for which he received a Nobel Prize. What Greg developed with this was this technology based on short peptides that create two loops around a central core of bicyclopeptides, hence the name bicycle. The idea Greg had was to really mimic the antibody paratope. His notion being that antibodies, while really providing enormous benefits in terms of antibody-targeted therapeutics, are not an optimal format for a precision-guided therapeutic system. They're too large, they spend too long in the circulation, and they have too many off-target effects.
Sir Greg created this bicycle technology. Bicycles are about 50-100 times smaller than antibodies, so they can fully penetrate into tissue. They have a very short circulating half-life, which should not be confused with intratumoral half-life. They have a very long intratumoral half-life, but a very short systemic half-life, and they have no off-target activity. They only bind to one target, which is the target that we target them to, if you like. We have this amazing technology. We're really focused in two areas right now: drug conjugates, where we target toxins into tumors, and radioconjugates. Our most advanced molecule is a molecule called zelenectide pevedotin, which is a Nectin-4 targeted Bicycle therapeutic. That molecule we're exploring across a range of different tumor types. We have an ongoing phase II, phase III potentially registrational trial in bladder cancer.
We've seen great initial activity in phase I, phase II studies. We also are using that molecule to target a range of other tumor types. Really focused on a very interesting observation we've made. The Nectin-4 gene is amplified in certain tumor types and requires an extensive frequency. We're using the amplification as a selection strategy in breast, lung, and across a range of other tumor types. Really exciting with zelenectide pevedotin. We have a range of other products that we're moving through various stages of clinical development.
Okay, great. I think a good place to start is in urothelial cancer with zelenectide pevedotin.
We can hear you.
Okay. You guys have presented several data updates from the Duravelo-1 trial. I know leading up to that and since then, you probably thought a lot about its positioning in the urothelial field. I just wonder if you could give us your thoughts on how it compares to the competitive landscape, especially as investors are doing versus PADCEV and different inferences you guys have made that maybe might be underappreciated by investors at this point in time.
Yeah, yeah. I mean, let me take a stab at that, and then maybe JP can follow up. One of the challenges is trying to compare an emerging data set with a mature data set and trying to compare a phase I study with a phase III study. We are continually doing these comparisons, and they are quite difficult to do. I guess the best, the best most mature data set that we have is in late-line bladder cancer. There we see very comparative efficacy. What we see, I think, is a really beneficial safety profile, much fewer, much lower incidence of the real problem side effects with ADC, such as peripheral neuropathy, skin toxicity with PADCEV. We are seeing very low incidence of that. What we believe that is translating to is a much longer duration of response.
In the last data cut that we did, that we presented at ESMO in September, we had a duration of response of 11.1 months, which compares with the, I think it's 7.3 or 7.4 months with PADCEV. We think that's a really strong data set. We think it could be transformational for patients. More recently, we've looked in the first-line setting, albeit in a very different group of patients, a much sicker, frailer population of patients. There again, I think we're seeing comparative efficacy and an overall better tolerability profile. That data is still very, very immature, I would say. JP, anything to add?
You know, it's interesting because right now we track the IQVIA prescription claims data. And when you're thinking about the market, it's complicated because we now have a leading combination with high efficacy and EVP. But right now they're at about 50% of total patient share. So when we query what's going on with the other 50%, that's still unmet need in our book. So anything that can improve upon that profile would be meaningful. Right now, the rest of that market's getting about half chemotherapy, half single-agent Keytruda or Opdivo. So something's wrong there in terms of not every patient being able to benefit from that combo. So our profile holding long-term in terms of the differentiation on those issues that usually cause people to have to stop or even not start EV are really important.
Things like severe skin rash, grade two and above peripheral neuropathy, ocular toxicity, issues with hyperglycemia, those are things that right now limit the use of EVP. For us, that's places where we would love to be able to insert zelenectide into that combination.
Okay. Can you walk us through what updates you expect to provide for zelenectide this year and what our expectations can be for those? Like what types of data you're going to include in each presentation and what we should think of as the bar for those?
Yeah. Again, like the second half of the year is where most of the action is for the company again. I'll start with kind of the ones that are probably the most pertinent to investors. We're heading into dose selection for Duravelo-2, which is the phase II/III study. Effectively, dose selection is kind of akin to the end of the phase II part of the study where there'll be roughly about 120 patients. Remember, we were looking at a 5 mg per m² dose weekly and a 6.5 as well, which has an interval that's two weeks on when we draw, right? We have to get to a point where we decide what dose. This dose selection is actually very important for not only bladder, but the things we're doing in breast and lung.
What we've said so that everyone's very much on the same page is when we get to this point in the second half of the year, when we talk to the agency, our goal is to move as fast as possible into phase III of the data to sensitize that, right? We will be at one scan for a lot of patients and then line up where the market is currently. We probably won't give a response rate update until most of the patients are confirmed, right? We don't know the data yet, but that's where our base case is. I think you could easily see a situation where we say what dose and that we're moving forward. Obviously, implicit in that is that we feel the data have met a certain level of bar and standard.
Then probably later on, meaning probably up to a lot more time, we would then show the confirmed response rate for those groups. That is just truly in response to, I think the market wants us to show data that is very conclusive and very firm with not a lot of room for interpretation on what it means. That is the first update. There is another update for zelenectide in bladder and second line where it will be at a medical meeting in the second half of the year. That is what Kevin was talking about with the monotherapy where we had a response rate of 45% at the last ESMO meeting. Obviously, good duration of response as well.
At this point, we'll probably be able to show PFS there, which some people have been very interested in as the data mature to see how that looks relative to important PFS over time. I think that's obviously for us, it continues to bolster the profile and help the market also understand the profile of zelenectide . The third update is in first line, zelenectide , pembrolizumab. Essentially, it's the data that we showed in December and January. We'll show it at a medical meeting as our aspiration. A couple of caveats on that. Number one, we presented a fair amount of information in January. Our ambition is to go to a medical meeting, but we also made a strategic choice to try to help people understand the confirmed profile.
You can expect at this medical meeting that it'll be the same data cut that you saw in January, right? There's not going to be new data per- say. We may have incremental tidbits, but you're not going to be looking at a different time point in time. We'll be looking at somewhere in January, around January 3rd when we presented it. Those are the three kind of major updates that we framed for this part of the year. All of them are in the second half of the year.
Okay. I guess I can ask a couple of follow-ups for each one. Starting with the dose selection data, you have not presented any data, even safety data at six and a half, right? Are you going to be showing, even if you do not present ORR, is there a chance that we could get any PK data like MMAE exposure that will help us understand how it could translate?
You've seen some characterization in 2023 to R&D day of how the dosing curve looks for zelenectide BT8009. And you obviously know that the MMAE exposure for six and a half is a little bit lower. I think you will have to take the breadcrumbs, interpret what it means. I think all things being equal, we are all about patients and patient convenience, right? A dosing interval that's not weekly is preferred if you have similar efficacy and similar safety. I think there's going to be an interpretation to make. Again, going back to the premise that we're standing on right now, which is we present data when there's nothing swamped, when we go to a medical meeting, you would see not only the response rate, completely safety at that point.
I think also sometimes we get questions about is the chemical toxicity and all these things. I think the company's moved well past just showing PK. We need to show what the safety is with enough time point of follow-up that people are saying, "Okay, that's the profile of this drug.
Okay. The second line update, that is going to be mature enough that you guys are going to be able to present MPFS and other factors of durability, I guess. Where should we set expectations for that? What is the bar to be for that?
I mean, effectively, isn't the bar always what's going on in the commercial landscape? PFS are important now.
Okay. Front line, going to be too early to present.
I mean, I don't see anything different than what you saw, so there's nothing really to consider. I mean, I think people, if you look at what we showed, people have the feedback we've gotten in the last month or so is that we had a very high rate of ECOG- 2 patients, 46%, right? Okay. That obviously seemed to be a little bit of a drag on the response rate, but still showing efficacy in that population, very notable and profound. For us, we believe the next update is probably a duration of response. I mean, even if you had a month more of time, remember all these medical meeting cutoffs for abstracts are generally early, meaning if you were trying to hit most of these, you're kind of in this arc now, you probably still wouldn't have enough maturity.
I think the right time to show that again is when we have median duration and there are things to conclude, right? I think the response rate with one patient left is what it is, right? I think there's not a lot of debate on that. Now it's the other parts of it or understanding what an ECOG-2 population of people potentially look like.
Okay. I do want to talk about other tumor types, but I want to do that after. I want to stay on the topic of urothelial right now. Maybe we could talk about Duravelo-2 now. Can you tell us about how enrollment is progressing? Can you give us a percent enrollment that you've achieved so far?
We gave the update at JP Morgan. I think we have over 150 sites activated. At that point, we were at 188 patients on trial, very close to the requisite number for the interim analysis one, the dose optimization. I mean, we're very pleased with the recruitment. It's been from a standing start about this time last year, we've opened more than 150 sites across about 26 different countries. Incredible interest from investigators around the world. I think we've exceeded our expectations. I think that's testament to how good the drug is in the hands of these physicians. They really like it.
Yeah. I think that's a really good update. Because one of the concerns that investors have is does front line PADCEV limit the enrollment at all? Could you give us some more feedback on what they say on that interest and whether your enrollment is shifted more towards ex-U.S. versus U.S. community versus academic centers?
I think we're seeing good recruitment across the board, whether it's the first line or the late line. I think we don't see a bias towards any particular geography. We're seeing, I think, really strong recruitment. We brought together around 250 investigators at the end of last year to share learnings, etc. I think people believe that the molecule has a very differentiated profile to ADCs. That's the general perspective. The toxicity isn't as profound. It's not as hard for patients. There is a reversibility to it. I think they find that really exciting. Anything to it?
I think it's a reminder, I would say, that for EV-3 or 2 itself, the population was 23% in the U.S. and 77% ex-U.S. I mean, I think that speaks for itself. I mean, the mix probably will be something in that neighborhood over time, which shouldn't be shocking to anyone. Obviously, the ex-U.S. is going to have more minimum because there's not as much reimbursement for the medicine. People are very confident in the profile of a Nectin-4 in combination with PD-1. I think that being said for the U.S., and JP can go into it a little further, it's a lot more complicated than what people expect it to be once the drug starts being used beyond academics.
Yeah. I go back to the numbers I just quoted. We hear a lot in the community setting where people have had less experience with EV. How do you manage it? It's different from chemo. Chemo is all they've had for a very long time in terms of them considering it standard of care. Uptake there has been slower. We are aware of obviously a lot of push from Pfizer to try to penetrate into the community, even things like making sure just get someone on a low dose and try to keep them on. That same academic kind of fervor around get that high response rate is a little bit different. We see that pull through in our market research where community practitioners basically say a quality of life play for them matters as much as the efficacy.
There is still opportunity in places where that chemotherapy is being used, obviously where we have single agent KEYTRUDA being used, that you would have placement of a study like DV2 in the U.S.
That makes sense. Other than the preference for quality of life, like you said, are there particular types of baseline characteristics that doctors that you've spoken to specifically say, "I would not give PADCEV in this population for whatever reason," and would those patients then be eligible for zelenectide?
You said that one.
Yeah. So funny, as recently as a couple of weeks ago, Dr. Enrique Grande put out what they call the EVITA criteria, and that's EV ineligible criteria. It's controversial because obviously there's folks in academia who feel like, "Just let me manage it. I'm a clinician." There is a lot of concern, like I just said, about EV going into community settings and people not knowing exactly how to manage it, especially things that are irreversible like neuropathy can really be damaging to patients. What's often quoted for why people don't give it and also outlined in those criteria are things like ECOG performance status two, grade two peripheral neuropathy, the hemoglobin A1C, eight and above, or uncontrolled hyperglycemia. There is some guidance in there also around renal function.
Those are people sometimes where just clinicians feel will not do well on the medicine or do not feel they can even start them on the medicine because of the fallout from the EVP side effect profile. If our profile stays differentiated as we go through DV2, we would expect a couple of things. One, that you would be able to have potentially more people start on drugs who would be not eligible. If you think about ECOG performance status two, we now have this data where they did well, not just from efficacy, but also from safety that clinicians may consider using in that population, but they'll also be able to stay on longer. I would add on there eye tox, skin rash, neuropathy, performance status.
Those are all things that limit people not being able to tolerate the EVP combination long and often coming off of EV. Our goal would be able to get them on Zele P, keep them on better efficacy for longer because of that tolerability.
If you had to put a percentage to it, what percent of the population do you think that encompasses?
In terms of the, I can only go back to our market data. You're saying how many people would be right now not getting EVP?
I think the question of how many people are not getting EV right now is different than what the addressable population could potentially be that aren't eligible. That is more so the latter is what I'm asking.
Gotcha. Absolutely. We want to do an aggressive switch strategy. We want to replace EV in the combo of EVP.
We're not trying to take what's left over. We want physicians at point of care to make a choice. That's what our market research backs up, that at accelerated approval with immature OS and PFS, they would pick the Zele + P profile over EVP three times more often. If you actually move forward and think about mature PFS and OS for Zele + P at full approval, they'll pick it 20 times more often in terms of utilization in our market research. That just shows us that there's opportunity to actually take a large part of that market in terms of not just the 50% who aren't getting EVP, but actually being able to replace a significant amount of people choosing this drug as their first line therapy, maybe saving EV for some other opportunity behind Zele + P .
Thank you. Yeah.
I guess similar question for the second line then. How many patients do you think will funnel through to the second line in need of treatment and then be eligible for Zele ?
Yeah. We know that from first line to second line, you obviously have people just drop off overall because of fitness and other reasons they don't get treated. We use a number of about 70% move from first line to second line. Some clinicians would argue it's even less than that. In that setting, though, if you're thinking right now that half of the population in first line aren't getting EV, those are all eligible for Zele + P because we do have combo in DV2 as well as Zele monotherapy in second line.
For us, that's still an opportunity again to capture market where they've not been exposed to a Nectin agent or exposed to an MMAE toxin. Still opportunity. We look at this as a first line play. We're not looking to niche Zele + P or zele in second line. The second line portion is to show basically contribution of component in DV2, as well as I want to label from a commercial standpoint on par with PADCEV, right? You want to have all lines in your label.
Okay. I think we can move on from urothelial because I do want to get the chance to spend a substantial amount of time on other tumor types because I feel like in all the focus on UC, that kind of gets forgotten to some extent.
Could you recap just very briefly what you guys showed at the San Antonio conference and what were the key strengths of the data that you felt like?
Yeah. I mean, about four years ago, we at Bicycle Therapeutics identified that the Nectin-4 gene in certain tumors is amplified. That work was followed up by a number of academic groups, most notably Niklas Klümper at University of Bonn, who's actually a member of our advisory board. What we've shown now is that in tumor types such as, I think most notably, breast, all comers breast actually, and lung cancer, the Nectin-4 gene is amplified. The frequency is about 30%, which if you think about triple negative, Nectin-4 is amplified to a greater frequency than HER2, which I think has really not really been picked up by people. What we did was we took our open label phase I study data where we examined zelenectide just in all comers, non-selected.
We retrospectively looked to see how patients have performed on zelenectide based on the amplification. When we looked in the all comers group, we found that the response rate, very similar to what EV has reported, was 14%. If we went and looked in the Nectin-4 amplified population, that went up to 60%, 100% disease control. These are patients who have had six prior lines of therapy. They have been on TRODELVY, etc., and they are responding very well to our molecule. We continue to expand that dataset as well as build now a selection assay and to instigate a study of pre-selecting patients based on Nectin-4 amplification. That is all moving forward very rapidly. We guided that we would open a breast cancer study this quarter, a lung cancer study next quarter, and a multitumor study the following quarter.
I think this is really, really very exciting, one because we're getting really good response rates. Two, I think this gives us a lot of optionality when we think about where we can take zelenectide . I think it means that we can make really good decisions on the dataset that we get in the interim analysis as well. We're not forced to go one way. We can look at that data in a really objective way. Is this data strong enough that we believe there's a real market opportunity in that bladder setting, or does it make sense to pivot into these other tumor settings? Or they do both. We have the wherewithal to go in any direction we choose.
We're really going to be looking at, is it best in class, second to market in the bladder population, or I truly believe we're first in class in breast and lung and all these other tumor types. Actually, if you look at the addressable population just in breast or in lung, that's as big as the bladder population. We've really opened up this drug to bring so much more benefit to so many more patients. I think we're really excited about this. As the discoverers of the amplification, obviously, we have the patents around the use of the amplification assay, etc. What we've done over the last couple of years is really build a very strong patent portfolio, which I think, again, is very challenging for others to try and circumvent.
Okay.
We're quickly starting to run out of time, but I do want to get into what the market is on this. I know you touched on it very briefly just there, but can you talk first of all about KOL willingness to adopt a new companion diagnostic for this, and then how you more quantitatively would look at the opportunity in these other solid tumors, maybe even in relation to urothelial?
Yeah. I'll let JP go with the commercial. We've held a number of KOL ad boards now, and the excitement and the pull is I've not seen anything like it, to be honest. There's an incredibly excited group of I mean, you've got to remember that in the breast population, we have a drug that causes very little alopecia, for example. And this is something the KOLs picked up on.
This could be remarkable for these relatively young, healthy young women. We think this is a huge opportunity. The KOLs are similarly very excited, and you should talk about it.
Just to start with the testing. In lung and breast, the comments in our kind of market research have been I'll summarize as saying we're okay to chase small populations through testing to drive efficacy. You see that happening in breast cancer where you had TRODELVY, and right now TRODELVY is being outperformed by HER2 through testing, as well as they continue now to expand from high to low to ultra low. For them, they've started testing at point of care decision. You have HER2 on the panel, and that's been quite powerful. Our intel for Gilead is that that has been quite hard for their commercial teams to circumvent.
Now, TRODELVY is something discussed after the fact, and if they're HER2 positive, they're going to get HER2. In breast, rapidly evolving to adopting testing. Lung, though, as you know, they've been testing because of driver mutations. Half the population in non-small cell lung cancer are getting tested, or they're getting tested, half will have a driver mutation. The other half usually gets single agent IO, and that's obviously, it's not as effective. People are usually progressing less than a year. For us, in lung, kind of a slam dunk for testing. In breast, certainly now Inher2 has changed that landscape very rapidly for testing. As Kevin alluded to, just to give you a feel for the size of the treatable populations in those areas, bladder is about 20,000-25,000 in first line, second line plus.
If you look at breast, HR positive, HER2 negative, TNBC, which is where our study is, that's about 30,000. Lung is about 26,000. Both of those amplified metastatic populations for breast and lung alone dwarf basically or size up over bladder at this point. For us, all of that is white space. There's no Nectin agent there. We're not behind anyone, and we now have a selection strategy to drive efficacy where other people have not been able to do that with their Nectin agents.
I'm hearing we need to pay a lot more attention to other tumors.
Yeah.
Speaking of other things besides zelenectide and UC, I know we are basically at time right now, and unfortunately, we didn't get to the rest of the pipeline, which has a tremendous amount of activity.
I guess the last question I want to ask is, from the other pipeline, what do you want to highlight for us that has an update this year that you want us to keep in the forefront of our minds this year?
I mean, I think where we've put a lot of investment and where we're growing, I think in a really aggressive and really exciting way is the radiopharm. I think you'll see more data from us this year, imaging data, as well as updates on how we're building our capability. I always find it fascinating everyone forgets about our FRNA2 molecule, which is in phase II, and we're super excited about that, and we'll share more data towards the end of the year. Completely white space there. No one is able to actually target it other than a bicycle technology, it seems.
Yeah, we're really, really very excited about what's to come.
Okay. Great. With that, I want to thank the entire Bicycle team and everyone here for listening.
Thank you so much.