All right, we're going to go ahead and get started. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us from Crescent Biopharma CEO, Josh Brumm, and the Chief Medical Officer, Ellie Im. We're going to have a discussion. If anyone has a question at any time, feel free to raise your hand. We'll get you acknowledged and your question answered. But maybe before we jump into Q&A, Josh, I know Crescent is maybe still a little bit new to the scene. So maybe you can just kind of give us a little bit of an intro statement around yourself, the company, its origination, and kind of the asset that everyone's really interested in, at least as of right now, which is CR-001.
Yeah. Well, first of all, thanks so much for the invitation. It's great to be here with Ellie, our Chief Medical Officer. Just as a reminder, we'll be making some forward-looking statements, so please refer to our SEC filings for more information there. When it comes to Crescent, this is a bold vision that we have as a management team. We came back together, added some key people like Ellie to really deliver on a bold vision of building the next world's leading biotech and oncology company. And really, we're going to do that with two distinct strategies, and then they kind of meet in the middle to really deliver the value. So you mentioned CR-001. That's our PD-1, PD-1 VEGF bispecific next-generation IO backbone therapy that we're working on.
It's been designed to replicate the cooperative pharmacology of ivonescimab, and we've shown that now with our SITC poster last week preclinically. And the real big step, next step for us is bringing that into clinic in the next couple of months, generating meaningful data, proof of concept data by the end of next year, early 2027. And that's well on its way to do that. That's been the milestone we've had out there on the CR-001 side of the business. I think as important to the next-gen IO backbone for us is the ADC part of our business, which is that second-focused strategy of really thinking about best-in-class synergistic combinations, because I think we believe that's where this space is moving. We believe this is where the real benefit for patients is going to be.
And I think we're going to leverage the way we intentionally designed CR-001 to be able to accelerate that development also in the clinic. And we're going to be really aggressive about our ADC strategy, both internally and externally. So we've developed, in combination with Paragon, our first ADC CR-002, which will be in the clinic mid-next year, so just a couple of quarters after CR-001 goes in. We've got some other assets in the pipeline. We have not disclosed those targets yet. I think we're getting ready to have that conversation. But also thinking about how then we can, again, leverage the way we designed CR-001 so that we can take other ADCs, whether they're late clinical development or approved, and rapidly use those in combination to really serve patients across a variety of indications. And so that's really the heart of what we're doing. It's a bold vision.
We have a wonderful team in place. We're well capitalized. We've got a lot of support, and we're pretty excited about what's in front of us.
All right. Great. So I think in the world of fast-follower biotechs, right, I think the effort there is to try to usually convince investors that their version of something is different from the first mover.
Yep.
You're kind of doing the exact opposite here, right, where you're actually trying to convince investors of the intentional similarities to the first mover. So I guess, how do you think about trying to deploy that strategy just from kind of a communication perspective, and how has it been received thus far?
Yeah, look. I think people are starting to understand that we've been here just over seven months now, and we've been building and executing on some key rallying calls for 2025 for the company, which is really around getting the IND filed, getting this CR-001 into patients, and then also working through our strategy on the pipeline, indication prioritization, building a complex matrix pipeline between the ADC sleeve of our business and the CR-001 backbone that we're working on. I think for us, having and explaining and understanding the leverage that we will get by showing the cooperative pharmacology similarities in the design of the molecule to ivonescimab while we did fix the stability and ability to be sub-Q in higher concentrations, which I think is going to be important long-term.
I think people understand that really because the big risk in oncology is always translation from phase II to phase III, and so now you've seen a bunch of phase III data, multiple indications in lung and patient populations. A lot of the questions have been answered. There's still the question around OS that people will have out there, but I think we believe that what we've seen, the clinical benefit we're seeing, and then also having the opportunity to think about how we properly design a study from the start, because we're going to be a global study ex-China, where everything else in the space has been China first. I think there's some significant advantages in there. I think we're going to be able to leverage those. We're going to be able to pave our way in the indications we want to go into.
And you start to think about how you leverage the phase III data that's already out there to accelerate our pipeline, particularly in the combination piece as well, and then having the confidence where we take CR-001 in mono or mono plus standard of care. It just provides so much leverage for us in de-risking. And so I think people are starting to understand that. We're starting to get the questions around competitors out there saying, well, IP and things of that nature. So we're starting to get on people's radars finally. And that just tells me that we're kind of doing the right things.
All right. So you talked about the cooperative pharmacology here. I know you presented that and some other translational data at SITC last week. I guess, is there anything within that presentation that you feel warrants a mention here?
Yeah. I mean, look, I think this is a great chance for Ellie to maybe just quickly introduce yourself and talk a little bit about that data.
Sure. So thanks for the invitation. Ellie Im, Chief Medical Officer, so medical oncologist. I got to do Keytruda development and led the KEYNOTE-0 10 trial, which is the trial that led to global approval of Keytruda in non-small cell lung cancer as a first approval. And then I got to lead the drug development for Jemperli, which is the first PD-1 inhibitor to be approved in frontline endometrial cancer back then at Tesaro. And then after that, I did a couple of years of ADC development as well. So regarding our SITC data, so initially we shared in our corporate deck in vitro data of how we are replicating cooperative pharmacology of ivonescimab. So at SITC, we then shared additional in vitro data as well as in vivo data and then NHP PK data, how we are exactly replicating cooperative pharmacology of ivonescimab.
So we intentionally built this compound to match that functionality of ivonescimab as well as PK because in immuno-oncology, we know that preclinical data doesn't necessarily translate into clinical data or even phase II data sometimes does not translate into the phase III data. So ivonescimab now has successful randomized controlled phase III trials in four separate studies. And so we believe this data, and we intentionally kept the functionality while we are improving stability by introducing new amino acid chain in the scFv domain. So we are taking one step by step building this compound to match the key features of ivonescimab in vitro data, in vivo data, in the preclinical setting. Of course, the next step is then to dose our patients in first-in-human trial early next year, and then showing that we have matching clinical profile of ivonescimab.
So this first-in-human study, proof of concept data, then will help us get into the registration enabling studies with a high conviction, but also in a very efficient manner.
Okay. Yeah, maybe speaking of the first-in-human trial, and I think, as you referenced, you're probably a few months away now from dosing the first patient. You're obviously in a very unique position just from a strategic visibility perspective, right? There's been kind of a roadmap that's been laid out for you. But as you get into the phase I, how are you thinking about the balance between being thorough enough in terms of solid tumor signal detection, but also being efficient enough in finding a developable signal that you can move forward with?
Yeah. I mean, that's a really great question. So we are in a very fortunate situation with a lot of data from ivonescimab already validating the field. And then because we intentionally build a compound in that way, we will run our first-in-human trial in global setting, addressing that question about Chinese versus the rest of the world population if the data is translating. And the dose escalation data will be there, but we will also generate additional robust data to answer the questions about safety tolerability, PK, pharmacodynamics data, last but not least, anti-tumor activity data. So all this robust work will be done as part of our phase I trial.
And what that will allow us to do, a couple of key things here, finding the recommended phase II dose, and then doing dose optimization right, which is a key step for increasing probability of success for the registration trial, but also generating robust anti-tumor activity data in the late line setting as well as earlier lines of setting for us to utilize this data as well as competitors' data, then choose the indications that we want to go into. And of course, after that, we will explore various indications and options of combining CR-001 with the standard of care as well as novel therapeutic, including our ADCs or external ADCs.
Okay. I guess without knowing what the dose escalation schema will be, how quickly in that dose escalation process do you think this similarity to ivonescimab will reveal itself clinically?
Yeah. I mean, I would just, since we haven't given that schema yet or the doses that we'll be starting at and looking at, which we will look forward to doing that soon, the way I'd think about it today is that when we say we'll have data Q4 '26, Q1 '27, it'll be pretty rapid.
Okay.
Right.
You talked about the need to really ensure that safety tolerability is what you believe it to be.
Yep.
What supports your level of confidence that this kind of functional similarity to ivonescimab will largely mitigate a lot of the presumably predictable safety risks here?
I mean, I think there's just so much data out there now that gives us a strong level of confidence on the safety profile with the bispecifics. And I think we'll be able to kind of really check that box within the first year of dose escalation as we compare what we're seeing versus what we've seen from those that have been there before us. And I think everything we've seen to date gives us high conviction that this is going to replicate the same safety profile. And I think, obviously, with the preclinical data, I think we expect to have at least as good as efficacy.
Okay. So you have a pretty blank canvas ahead of you in terms of indication selection. As you think about those potential opportunities, what qualities of those opportunities either encourage you or discourage you from selecting one of them as an initial target indication?
Well, I mean, indication prioritization is something that we focused on this year since we joined. We've done an extraordinary amount of work on that. I think what it's going to come down to, first and foremost, is our own data, right? And then also, we're going to continue to monitor the competitive landscape. And that's why what we've said to date is that thoracic, GI, and reproductive are the areas that we're focusing on. And you'll probably see that carry through as far as tumor types in the phase I study. But we haven't ruled out others as well. We're going to follow the data. And we've designed the phase I study that we could have flexibility to add additional cohorts, backfills, etc., and really have a robust study.
I personally think that the most important thing the company has to do right now is generate a very high-quality, robust, thorough, I'd say, pharma-ready, diligence-ready package of phase I dose understanding. If we get that right, because, again, how we design the molecule, I think we're going to be able to accelerate rapidly into a number of phase II, three areas and indications, and also think about then how we want to bring in that second sleeve of our business on next generation best-in-class combinations.
I guess, should that be the kind of initial phase I data update that we should expect to see at some point, maybe before the end of next year?
Yeah. We're going to be very clear here soon around what data is going to be generated, when we expect that data. As Ellie mentioned, we talk about the traditional second line plus patient populations you got to go through to do your traditional dose escalation data. Ellie also mentioned earlier lines of therapy. There's lots that we can do here with this global study ex-China to really check the box that we've mimicked the efficacy as well as what we've seen preclinically.
Yeah. And that'll be, I guess, one of the variables that will require consideration, right? The notion that you may be benchmarking to data generated in PD-1 naive patients, and you're likely to probably be enrolling a lot of patients who may be PD-1 experienced or is there a way to?
We have clearly thought through that discussion. We've seen that a lot of the better results have been in those that have not received a PD-1 prior. And so we're thinking through about how we generate data in both of those populations.
Okay. I know we've talked about lung as obviously kind of being an area of interest, just kind of given what's happening out there and the level of data visibility that we have at this point. But has it kind of become clear to you what is the most appropriate strategy within lung itself in terms of what would make the most sense for Crescent?
Yeah. Look, I mean, it's great. I get asked this question in every meeting like this. And it's the right question. And my response is the same. We think lung is wide open. So we are not telling you we're going into lung, but we're also telling you we're not going to shy away from it. We think that if we have an CR-001 strategy where we are looking at a first-in-class opportunity, the world would be a beachhead for us. Clearly, that's not going to be lung in the U.S. Outside of lung, everything else is open for that first-in-class opportunity. Fast follower in an area like lung in the U.S. where there are those that are ahead of us, second, third, or fourth, the market there is a massive opportunity in itself. So we understand that. But why do I think it's wide open?
I think it's wide open because the puck is moving to best-in-class synergistic combinations. And that's why it's important that people hear us when we say we are not just an CR-001 company, that we really do live this dual strategy of how we're building our pipeline and how we're leveraging the next-gen IO backbone in CR-001. And so our view is that there are ways to be best-in-class and win in lung through synergistic combos.
Okay. Does the selection of frontline colorectal by a couple of competitors recently, does that make that any more or less interesting to you now?
Validating in our thought process. It's very validating.
I guess when we go back and look historically at some of the development strategies that kind of the fast follower PD-1, PD-L1 sponsors have taken, are there any aspects of those development strategies that you think are transferable to the development of 001 and how you're thinking about it?
Yeah. You want to talk just about what we've seen in the studies so far and how we've learned from some of those and the strategy we're applying?
Yeah. Sure. So in terms of PD-1, PD-L1 inhibitors that have been developed, what I could see as a number of things that are critical. First is having a good drug because not every drug that got into clinic got to have an approval. So having a good drug is important. And that's where how we design the compound to match the key features of ivonescimab would pay off. And then the second part of it is compared to PD-1 versus PD-L1. PD-1 inhibitors had more indications of approval compared to PD-L1 inhibitors. So that's one of the things. And then the rest of it is when I look at the data, the timing of when they started clinical development mattered because it provided an opportunity to get the first-in-class approval in more indications. Last but not least is clinical development strategy, right?
That includes how to define the target population. You can do that with the inclusion-exclusion criteria, including biomarker, how to choose the dose, how to design the study, your regulatory strategy, and your execution strategy. So how Crescent is looking at the development of CR-001, I think it's a really smart one. And then I've been talking to a lot of investigators about this. And everybody is agreeing that this is really resonating with them. And they have been part of a PD-1 development because we have the compound that is matching key features of ivonescimab that has had already multiple successes in the phase III trials. And we are looking at how to then efficiently prosecute the first-in-human trial in the global setting to address that safety and efficacy PK aspect of it right ahead. And then we go into the registration enabling trials.
And instead of looking at the Chinese data and how that transferred in the global setting, we will do that from the get-go with the global patients and then working with the FDA and EMA, so that will help us to gain efficiency and also have a high probability of success, and some of the things that we are still talking about the HARMONi study, enrollment started in China, and then it expanded to the Western population, how that created a different follow-up time for the two populations, and then now they have to do longer follow-up and then have to provide additional explanations on the data, so that issue of starting in China and then going into global setting is not going to be the case for us, so we will have a seamless execution of the study and with quality of excellence.
In that case, the roadmap has been laid for what not to do.
There's a lot of paving out there of roads that we probably won't follow, yes.
Okay. You mentioned HARMONi. What are just kind of some of your high-level thoughts on the phase III IVO data that we've seen to date? And I guess maybe specifically, what did you think of the HARMONi- 6 data that was presented at ESMO?
So, HARMONi-6 data with HR 0.6 PFS in squamous cell population. And that is, of course, compared to PD-1 containing chemo combination. Overall, we thought that it was really encouraging data. And then KOLs seem to share the same opinion about the study. And on top of that, now we are seeing the safety data of ivonescimab containing arm showing immune-mediated adverse events that are similar to PD-1 arm. And then everybody was worried about VEGF side effects because that's how Avastin did not get to be developed in squamous cell carcinoma with especially hemoptysis. But overall, VEGF-related adverse events frequency was much lower than Avastin. And especially the high-grade events, grade 3 or high-grade events were less than 5% in general.
So robust efficacy data in PFS combined with favorable tolerability data, I think everybody is very excited about what ivonescimab was able to do in that population. And of course, we will wait for the OS data and see how that looks like.
What was, I guess, your internal theory for the changes that were made to HARMONi-3? From a protocol perspective, right, where you kind of decouple the squamous and the non-squamous, upsize each of those cohorts, what did you take away from that decision that someone made?
We think it's the right decision because in non-small cell lung cancer, non-squamous versus squamous, they use different chemo backbone. And when we look at the PD-1 combination trials, the squamous versus non-squamous patients have responded differently, right? So the degree of benefit was different. And so it made sense to split the two populations and then redesign the study. And increasing the sample size for both will allow them to have more comprehensive data to assess efficacy and safety, as well as probably that will increase the probability of success of hitting PFS and OS signal as well. So in general, we thought that it was the right decision.
Yeah. It was a good change and the right change to correct a non-optimized study design from the beginning.
I guess, is there an opportunity that you see kind of based upon what Summit's been doing and experimenting with to kind of propose a more optimal phase III design within the setting of lung that doesn't necessarily require an N that is 1,600 patients spread across two histologies?
Yes.
Yeah. Yeah. I mean, so we are not the first company to develop this drug. But the great thing about us is that we are learning. We are studying from what Summit has done, what Akeso has done, and what biotech has done so far. So we are studying these studies and the results. And as a community, all of us are learning how to best develop this class of drug in multiple indications and what is the best combination partners of a PD-1 VEGF and what is the right way to design the study, what is the right PFS and OS assumption, and how to execute it from operational perspective. So yeah, we are very grateful for the learnings that we get to have. And we'll definitely utilize those learnings to improve our probability of success for the studies that we run.
Yeah. I would say going to the long term, it's not my natural MO to be fast follower, right? So it's a different strategy than I've used in the companies that I've built. But I do think that there's so much benefit. And we're so early in this baseball game, if you will. We're in the top of the first. There's so much space. There's so many ways to win. There's so many indications to go after. Everything we can do to learn and be right on the heels of being the first really global study ex-China. There's just a lot of benefit from that. And so we are grateful. We appreciate that. And I think the other thing I'll say on that note is that the U.S. sites are super excited to get going. They really haven't been engaged because it's been all ex-China or ex-U.S. and China.
So the enthusiasm there, we have our pick of the sites that we want to work with and great partners. We've matched our sites with our areas of indications where we're interested in. So we can go deep as needed. And it just feels like that momentum for us is really building.
Yep. Yeah. We did a lung cancer panel yesterday. One of the physicians was quite excited to get involved in these, so.
Yeah. Yeah. For sure.
I know there was a lot of investor discussion and perhaps debate just around the evolution of the OS signal that we've seen for IVO thus far in lung. What kind of supports your confidence that's going to continue to trend in a positive way?
Look, I mean, I think investors always take both sides of the bet, right? That's just kind of what the market does, and so I think we are excited that investors understand the space. They're paying attention to the space. They're making their best on either side. I think strategics have been ahead of investors in this one, right? You see the size of the deals that have been done. We feel the interest on our side significantly, and that's why I think all molecules aren't created equal here, all bispecifics, and I feel like how we developed ours is going to ultimately pay massive dividends for us as we go through this development program and think about partnering in BD and building the company that we want to do in our bold vision.
And so I do think that for me, it's the engagement from strategics, their conviction, coupled with what we're seeing from investigators' reaction to the data that's already out there. That gives me the conviction that we've seen quite a bit already, although being mainly lung from Summit. I think this is clearly a class of drugs, right? And then if you start to correct for some of the things that Ellie talked about in study design, powering, patient populations, I think these next fast followers that I put us in that bucket of with the right drug, I think we're going to benefit and see better results from a trial design perspective.
From a trial design perspective, and again, I know it's early, but is there a collaborative structure that you've seen in the space? It doesn't necessarily have to be PD-1 or VEGF-A, but is there a structure out there that you find to be appealing, and would you want that kind of strategic or collaborative structure to allow you to be involved in the decision-making process and the profitability part of it?
Yes. I think there's obviously like the Pharmacyclics deal having been there, one of the best deals ever done, I think, in our space for Biotech, showing how to lead with pharma. I think that a balanced relationship like that is probably the best way to go. I think it has to be like-minded people, right? I think, as you know, biotech is responsible for 70% of all drugs that are on the market. And so I think pharma understands that. And so it really comes down to the mentality between the two companies. That said, I think that for us, as I mentioned earlier, to get ourselves in that strongest position to have that type of relationship, the phase I design, nailing the dose and a very robust, you can't take shortcuts in this business, getting that done right. Ellie's done it a couple of times already.
Couldn't be a better person to lead us through that. So let's get that done right. Then we'll entertain those more seriously around the type of valuation we should get for a partnership in this space and how we find somebody that really is like-minded. I think that on the other side of the phase I data, there's multiple options for us to be successful. We get asked about capital, very capital-intensive strategy here, thinking about the cost of these studies. But look, table stakes in my mind is it's a Tesaro-type outcome, right? We can go find an indication, be first-in-class. We can win there. It was a $5 billion+ outcome.
We can then take another path where we want to deliver on our bold vision of building the next Celgene and doing a massive partnership and getting broad across multiple indications and really driving that strategy home with our combinations as well, or somewhere in between, and so I think that it starts with getting the phase I study right. We're well capitalized. We'll continue to be well capitalized going into that readout, and I think we're going to have great options on the other side to build the business we want to build.
Okay. Maybe just quickly on the ADC side, obviously, we're not going to be talking about targets just yet. But how would you characterize the targets in terms of where you're kind of stepping out on the risk curve?
So what we said about our ADC targets and again, looking forward to seeing more soon, we aren't taking biology risks. So these are not novel. The initial wave is not a novel target. But we had a lot of experience with conjugates of Dyne, very similar here. We brought Yun Peng from ImmunoGen who leads up as our CSO that part of our business. We understand best-in-class antibodies, best-in-class linkers, best-in-class payloads. And we're really building a best-in-class ADC for that ultimate best-in-class synergistic combination. So that's how we'll compete and win without taking biology risk initially. I think as we grow and develop and mature, of course, we'll be open to more novel risk and thinking about doing some things that are taking on that biology risk. But there's no need for us to do that now.
There's so many ways and so much excitement in some of these known targets that if we optimize, that we feel like we're going to be in a really strong position.
Okay. The linker and the payload, were those externally sourced?
We'll come back and talk about that stuff.
Okay, and just given this kind of emphasis on potential combinations, I don't know if you can speak to the extent in which the design of the ADCs was kind of intended to maximize TI because we know a lot of these ADCs tend to suffer from a TI issue, and then maybe coupled to that, obviously, going in combination in an earlier line of therapy kind of avoids all of the second line plus topo ADC sequencing questions that everyone's going to be running into, so we'd just be interested to kind of hear your comments in terms of how important you think that TI is and whether or not the drugs were designed specifically to widen that.
I think that is one of the key things that we have focused while we are building our ADC and optimizing antibody part and linker part and payload part, how many to put in, right, and then the potency of it to make sure that there's enough TI for us to go up and down and then optimize a safety and efficacy profile, and then also, as a monotherapy, it has to have activity and then provides that combination potential with our IO backbone, PD-1 VEGF, and then last but not least, applicability in broad indications. So all those things we have carefully considered when we put together our CR-002 and CR-003, which are ADCs. So we are very excited about speaking more to those drugs in the near future.
Okay. Great. Maybe last question, just balance sheet and what it allows you to execute on?
Yeah. Cash, $133 million is the last quarter, gets us through 2027, gets us through the big readouts in Q4 2026 and Q1 2027. So well capitalized, great group of investors, like-minded, sharing our vision to build the company we're trying to build. And we're excited about what's to come here in the very near future.
All right. Josh and Ellie, really appreciate it.
Thanks a lot.
Thank you.
Appreciate it.
Thanks everyone.