Afternoon, welcome once again to TD Cowen's 46th Annual Healthcare Conference. I'm Phil Nadeau, one of the biotech analysts, it's my pleasure to moderate a fireside chat with Crescent Biopharma. We have with us Joshua Brumm, CEO, Ellie Im, CMO, Jonathan McNeill, the President and COO. Maybe I'll kick it over to you guys to begin. Can you give us a brief state of the company, assessment? What are the biggest strengths, biggest challenges, and what is Crescent gonna do to create shareholder value over the next year?
Great. Lots of questions. I like it. Thank you, Phil. Thanks, Phil, for the introduction. Great to be here. I'm Joshua Brumm, the CEO here, at Crescent, and almost been a year since we started as a team. It's been a great run the last year. We inherited a company from Fairmount that is really focused on two real core strategic initiatives. One is to develop our PD-1 x VEGF bispecific, and the other is to develop our ADC sleeve of assets and then think about how we deploy those to create a matrix portfolio across combination strategies and synergies for oncology solid tumor indications. We closed out the year with a bang. We announced on the same day last December a major partnership with Kelun-Biotech.
As you probably know, Kelun's very well suited in the ADC space, has a great deal from Merck in the sac-TMT asset. We practically swapped assets. They gave us rights globally ex-China for an integrin beta-6 topo ADC, which added to our strength of our portfolio. In addition to our own ADC, we have a PD-L1 topo ADC that we're also developing. We've made a lot of progress over the last year. We actually announced about a couple weeks ago that we dosed our first patient with our CR-001 asset, so making a lot of progress quickly. That was about six weeks after we announced that we had our IND approved.
What this does for us in 2026, it sets up four studies that are started across three programs. We have started our CR-001 program, our phase I/II study there. Ellie can talk more about that. We have started in China with our Kelun-Biotech partner, our CR-003 study that they're running in China. We will this year file and enroll our first patients in our CR-002, the PD-L1 topo ADC asset, and then we'll have a very interesting combination study with CR-001 that we'll announce later this year through our Kelun-Biotech partnership that will start also this year, at least one combo study.
What that does for us, it sets us up in Q1 2027 to start putting out substantial data flow. We're less than a year away from that, and our first CR-001 readout will be around second-line plus patients, but also we've included a frontline cohort in non-small cell lung cancer. We wanna get the answers right away. We wanna start showing the effects of CR-001 in the frontline setting. We'll really set up well for a plethora of data readouts with the four studies starting this year, starting Q1 2027. Finally, in parallel with the Kelun announcement, we closed a $185 million PIPE. We're well-financed all the way through 2027 into 2028.
To dive into the CR-001 program, in a bit more detail, it was obviously designed to replicate avelumab and its cooperative binding. Can you talk about the preclinical data that you've generated?
Sure
suggests that was achieved?
Yeah. Thank you for that question. We had a publication at SITC last year sharing how CR-001 was creating cooperative pharmacology in vitro studies, but we also had in vivo study showing antitumor activity as well as PK data that is closely matching avelumab. That was a really great de-risking event for us from the preclinical stage, and of course, we intend to do that in our clinical stage that just started.
There are some modifications, subtle modifications in CR-001 compared to avelumab.
Mm-hmm.
Can you discuss what those are and the purpose of those?
For us, avelumab data, especially the ones that we've seen with the HARMONi-2 and HARMONi-6 data, the data was real, showing superiority compared to PD-1, and investigators who are treating non-small cell lung cancer patients all agree that that is clinically meaningful benefit. Given that this is IO space, we did not want to deviate too much from the drug that's already working from the efficacy perspective as well as a safety perspective, but what we could improve upon further is the stability.
Avelumab is currently manufactured at 10 mg per ml, which is a relatively low stability. That's common with the scFvs. With our proprietary engineering, we introduced a new amino acid chain in the scFv domain, and we were able to push up to 150 mg per ml out in our preliminary run. We're also working on achieving higher concentration. What it means to us is that we have a lot of benefit in manufacturing capability of the drug. Our commercial vial size will be different. It can be a smaller volume that patients need to get. Of course, just like what Keytruda did recently with a patent life expansion with a SubQ change, that's another possibility that we can explore for CR-001.
I'm gonna just say the differentiation that we're going after, in addition to having more scalability and manufacturability with the asset is to leverage the cooperative pharmacology similarities that we showed ivonescimab, so that when we get into the clinic and get this phase I non-small cell frontline data readout, validates quickly that we said the drug does we thought it would do, how we designed it. We could rapidly then go into phase III, 2/3 accelerated approval studies. I think the real core strategic difference for us is, yes, we understand the bispecific class. It's really important for us to have that backbone that we own.
Mm-hmm.
That's what attracted partners like Kelun-Biotech, where we can quickly think about combinations, synergistic combinations where we can actually win and be best in class across any indication we really wanna go into leveraging the Matrix portfolio.
Mm-hmm
We 've been asked many times, do we think lung is still open? We say absolutely wide open, with the synergistic combination approach and our ADCs owning the rights to CR-001, we can have best in class in lung. We're not saying we're a lung company. We're not saying we're going into lung. We haven't disclosed yet where we're going. We're looking at eight different tumor types in our phase I / II study. We'll find our pathway and we're really thinking about, you know, kind of two things. One, where can we take CR-001 to have a beachhead, an opportunity, first in class opportunity, and how can we leverage our portfolio to have a best in class opportunity in something like lung, colorectal, or one of those, you know, larger indications.
To dive into the phase I in a bit more detail, can you remind us of the design of the study, in particular, what are those eight tumor types that are being recruited?
Yeah. The eight tumor types are coming from three therapeutic areas, non-small cell lung cancer, and then in the GI, colorectal, gastric, biliary, and HCC, and then gynecol indications, including endometrial, ovarian, and cervical. We've chosen these indications based on scientific data, clinical data, to make sure that there's a high probability of success coming from CR-001. We also thought about a market size opportunity, as well as a potential combination with our CR-002 and CR-003 based on the target expression of those ADCs, such as a PD-L1 and an integrin beta-6.
Among the eight, are there any tumor types that are higher priority than the others, or at this point is it too early and they're all relatively even?
We think that all of them have a great potential to provide a clinically meaningful benefit compared to currently available standard of care. What we will do in the ASCEND study is we generate comprehensive data as a monotherapy and with a combination with the standard of care. We also have combination studies that will be ongoing with CR-002, PD-L1 ADC, and integrin beta-6 ADC, and of course, working with Kelun-Biotech, potentially other ADCs as well. We will look at all those data and then, as well as a competitor's data in the landscape and carefully choose the indications that we will launch registration enabling studies.
We have highlighted the opportunity to generate first-line non-small cell lung cancer data, and that's not because that indication is more important than the others, but it is because that's the indication where ivonesimab and some of the other PD-1 x VEGF bispecific have the most data. Having first-line non-small cell lung cancer data as part of the ASCEND study will allow us to make an apples to apples comparison in first line patients to demonstrate that we are replicating that cooperative pharmacology. I would just say that we as a company right now, as a management team, are obsessing about generating as much data as we can as quickly as we can. I think the eight tumor types is a very large phase I, II study. The FDA allowed us to start at our highest dose we applied for.
We also allowed the FDA to dose first line patients, which was a win for us. I think it says a lot about the drug. Also through the Kelun-Biotech partnership, you know, all the data we could generate in combination. This is gonna really help us think about the path that we create. We've said this many times, there's lots of ways to win for Crescent. 40+ labels, label indications for PD-1s. All those can be retraded on new data with the PD-1 x VEGF bispecific class. We're thinking about just what path we're gonna go down, and we're gonna keep that to ourselves for a while, given the competitive nature of the landscape. There's lots of ways for us to win here, whether it's monotherapy plus standard of care or it's, you know, combination strategies.
In the phase I data that we get next year, can you talk a little bit about the endpoints that are going to be evaluated, what you're likely to disclose to investors, and give some sense of how to interpret it, what would be good, what would be disappointing?
Yeah. Maybe I'll start, and then Ellie can finish.
Mm-hmm.
We know that when we put the first line cohort in, right, and there's opportunity for more than just non-small cell, so stay tuned on other frontline indications that we'll look at within the way the study is designed. We knew that the, you know, the biotech data, the ivonescimab data, and the second line plus patient population was very messy.
Mm-hmm.
Right? We know those response rates are kind of anywhere from 12 to mid-twenties, on a percentage basis, and it depended on did you get a PD-1 before you went in.
Yeah
what number of patients came from what monotherapy. We didn't want to spend time dwelling in that arena. That's why we added the first line non-small cell data in there.
Mm-hmm.
I think, you know, from that perspective, if we can show better than 50% response rates, I think it's, you know, it checks the box for what we see from ivonescimab, and then we correlate that strategy, how we design the molecule, and we're kind of off to the races.
Yeah. In this study we have a dose escalation. As Josh mentioned, we are starting at 3 mg per kg. Considering how we designed this study, you can imagine that the next dose is 10 mg per kg and then 20 mg per kg. We will be getting to the clinically meaningful doses in just a matter of weeks of starting the dose escalation, which is a huge benefit for us. In the backfill, which is happening concurrently as we are clearing these dose levels, we have a tumor type specific backfill. For example, after clearing 10 mg per kg, we can open colorectal backfill patients up to 12 patients, and then non-small cell lung cancer backfill of 12 patients or so. This is an iterative process that's happening at each dose level.
You can imagine from this dose escalation and backfill that are happening at the same time, we can get very comprehensive PK pharmacodynamics, safety, as well as preliminary antitumor activity data of these specific tumor types. In the previously treated setting, as well as Josh mentioned, as monotherapy, front line non-small cell lung cancer, which will give us a pretty good confidence that this drug is really working, very similar to ivonescimab. We also have additional two cohorts. One is dose optimization cohort, which is very important for Project Optimus for us to determine the recommended phase II dose and have expansion cohorts. This is where we can test potential standard of care combination of CR-001 in other indications.
We are anticipating that in 2027 first quarter, the data will include dose escalation, backfill, and then some of the expansion patients, including safety tolerability, PK, receptor occupancy, as well as a preliminary antitumor activity data in previously treated patients, as well as a front line patients.
You've suggested in the past that you could leapfrog right from the phase I, II data, right to a pivotal study.
Mm-hmm.
Is that possible in all eight tumor types?
We will focus on generating quality data in the ASCEND study. We are in a great place because as a PD-1 x VEGF as a class, we believe it's a real chance of improving standard of care and replacing IO backbone. If our data shows that it has pretty close safety and tolerability and efficacy data to ivonescimab, and utilizing competitors' data that's out there's a chance that we can go into registration-enabling studies right after this ASCEND study. Because of how we designed the study of a tumor type specific backfill and dose optimization cohort as well as expansion cohorts, we have a chance to generate pretty comprehensive data without having to do any major amendment.
There's a lot going on in this trial. You'll get a lot of data. How will you prioritize which conditions to move forward in, which tumor types? Do you already have a rank order in your mind and you're just not telling us, or is it gonna be totally data dependent?
Well, I mean, I think it's gonna be data dependent for sure.
Mm-hmm.
I think we do have some ideas of where we'd like to go.
Mm-hmm.
I think we're also gonna monitor the competitive landscape.
Mm-hmm
Make sure that we have the right pathways in front of us.
Yeah.
I think, you know, there's a lot of time spent in the company thinking about, you know, do we go down a path of monotherapy or monotherapy plus standard of care?
Mm-hmm.
Do we think about combination strategies?
Mm-hmm
T hose indications? Given the depth and breadth of our portfolio, I mean, we really have built a pharma-like portfolio of oncology assets in less than a year. Thinking about how we prioritize those and how we leverage those is something that is a lot of fun to think about.
Turning to the collaboration with Kelun-Biotech, for those less familiar, can you remind us of the terms and what you got?
There's two elements of the deal. The first is CR-001, our PD-1 x VEGF bispecific Kelun-Biotech has the right to develop that in Greater China as both monotherapy and in combination with their full pipelines of ADCs. That's critical because Kelun-Biotech's an ADC leader globally. They developed sac-TMT, which is licensed to Merck and is in 15 registrational studies. The integrin beta-6 ADC, which we in-licensed from Kelun-Biotech in all areas outside of Greater China, builds on sac-TMT and is an enhanced version of its linker and payload with an integrin beta-6 antibody format. In our minds, there's two key elements of this deal. The first is the CR-001 data generation. We'll have the opportunity to leverage the data they generate in China.
That's particularly important in this space because there's been lots of discussion around the translatability of Chinese data, Western patient population data. That will never be a question for CR-001 because we will have both data sets developed concurrently. It will enhance our ADC development strategy more broadly because again, Kelun-Biotech can use their whole ADC pipeline and combine it with CR-001. They share our vision for synergistic combinations, so any of their clinical stage ADCs can be combined with CR-001 in China, and we will have access to that data to inform our own development strategy. We think it's a really innovative deal structure.
It's completely consistent with our vision of synergistic combinations being the key to this next generation of oncology therapies. We're very excited to work with Kelun-Biotech, who is truly a leader in this space.
Aside from CR-003, which we'll talk about next.
Yeah
What other assets does Kelun-Biotech have that you could be interested in?
I would say that they have... You know, you can look at their clinical stage pipeline to see what they've disclosed. Obviously sac-TMT is their most advanced ADC, which is approved in China. They've also publicly disclosed ADCs targeting HER2, claudin, nectin as well, and they have a number of undisclosed clinical stage ADCs. Any ADC that they've taken into the clinic is eligible to be combined with CR-001. We won't get ahead of Kelun disclosing what those are, but there's a reason they selected CR-001. It's because they think that it is a next gen IO backbone to be competitive in the Chinese market. They think their ADCs will need to be combined with the next gen IO backbone. We look forward to sharing more as that data is generated.
Great. Maybe turning to CR-003, can you talk a little bit about the target and why that's high value? I think investors are maybe a little less familiar.
Integrin beta-6 is the target of CR-003, and there are a number of reasons why that is a very attractive target for Crescent. Scientifically speaking, that's one of the targets that has a clear distinction in terms of the level of expression in the target indications of tumor types compared to normal tissue. That makes it a very attractive target. The second part is our Matrix portfolio. The indications that we are focusing on with the CR-001 and 002, which is a PD-L1 ADC. Integrin beta-6, when we look at the level of expression in the tumor types, it fits really well with our Matrix portfolio, and it complements further with our PD-L1 ADC. That's another great reason.
The third reason that why we are working with Kelun-Biotech is there's a clinical data from Pfizer's integrin beta-6 ADC. We carefully assessed the available clinical data and their preclinical data and see what types of optimization or modification do we need to make to CR-003 and create a clinically differentiated profile. We really liked what Kelun-Biotech did in terms of increasing internalization of a high expressed integrin beta-6 as well as a low expressed integrin beta-6 tumor cells, which will increase the number of indications that we can go after. It's a stable target, improve the PK, as well as a potent payload with bystander effect.
All those things gave us confidence that this is a pretty well made integrin beta-6 ADC, that we can create differentiated profile as a monotherapy as well as in combination with a PD-1 x VEGF bispecific .
In particular, why is Topo 1 the right payload to pair?
Pfizer is using MMAE payload. We carefully assessed which payload might be the best. Some of the clear benefits that topo payload provides is, like with the stable linker combined, lack of cytopenias, which provides a better chance of combining with additional agents and then a higher Bystander effect. Again, a chance of working in multiple tumor types, as well as a lack of certain side effects such as a peripheral neuropathy. Last but not least, with the superior PK profile and how that mechanism action is of a topo payload, we are seeing the wider therapeutic index compared to MMAE. All those things made sense to us why that's the right way to go.
This is also an opportunity for us to be leaders in the synergistic combination space. Kelun-Biotech released a press release last year, they have not shown the full data, saying that sac-TMT, which is a Trop-2 with a topo payload that's very similar to the payload we're using in our integrin beta-6 ADC that we in-licensed with Kelun-Biotech. It had positive PFS results in first-line non-small cell cancer when combined with pembrolizumab-.
Mm-hmm
... in a Chinese market. I bring that up because not only do we think PD-1/VEGF has the opportunity to be superior to pembrolizumab from a next-gen IO agent, but also shows the potential to synergize IO with a topo payload. We think that as this field evolves, this is a reason that we have an opportunity to be a leader in this space.
Mm-hmm.
It really does open us up across many different solid tumor indications.
Mm-hmm.
You referenced the phase I that Kelun just started. Can you go into a bit more detail on the design of that study? Which tumor types are in it, and what data could be released next year?
Not quite yet. We rely on our partner, Kelun. It's registered in ClinicalTrials.gov. It's around solid tumors.
Mm-hmm.
More to come from them. We're very excited about that data. You can imagine the typical dose escalation. Again, one reason we're working with Kelun is because they've taken a number of ADCs into clinic in China, and we're very excited to share that data as it comes in 2027.
Mm-hmm.
What are the plans to file an IND in the U.S.?
Yeah. we're gonna evaluate their phase I data.
Mm-hmm
Then decide when the timing is right for us to leverage that data and potentially advance that filing into a later stage study off of that phase I data. We haven't disclosed that yet, but we're gonna wait to see that data.
Got it. Will you, would the next trial be monotherapy, or could you do a CR-001 combination with CR-003?
Yeah, I mean, we're definitely thinking about oh one oh three combo.
Mm-hmm.
Start that at some point. As well, we could also consider monotherapy.
Great. Maybe turning to CR-002, can you give us a brief background on that compound?
That's a PD-L1 ADC internally developed with a topoisomerase payload. Again, we didn't want to take any biologic risk, we wanted to go with a target that has a clinical data. There are a couple of PD-L1 ADCs that are out there that have generated a pretty exciting early clinical data. We thought about how can we further improve upon the clinical profiles that they have generated. With our antibody part, we improved internalization as well as potent cytotoxic cell killing ability of the ADC. By using stable linker, we are hoping to provide better safety profile for the patients.
We have used the topo payload with the excellent bystander effect, which should help us generate antitumor activity in multiple indications that we are aiming for.
Yeah. I'll just say that CR-001 and CR-002 have both been internally developed. It's been developed through our partner with shift with Paragon, which is run by Fairmount. They've been great partners to us as well.
What tumors are you prioritizing for CR-002 ?
We have a list of indications that we have, we built in our corporate tech as part of it. As you can imagine, we use the information that's been generated by multiple companies on the PD-L1 expression, and then how topical payload worked in those indications, and then potential ability to combine...
Mm-hmm
... with the PD-1 x VEGF . That includes lung, head and neck, GI indications, as well as gyn-onc indications. Again, we have chosen these targets of ADC very carefully so that it fits our Matrix portfolio.
You've got it to the start of a clinical study in the second half of this year. What remains to be done to file the IND and get the trial going?
Just your typical steps towards IND. Lots of regulatory writing, medical writing. We're well on track to deliver on that timeline.
Mm-hmm.
You've disclosed one other candidate, I believe, CR-004, but we don't know anything about it. What can you tell us anything about that candidate?
We have a comprehensive strategy across all elements of ADC design, so antibody, linker, and payload. You can imagine that it's a candidate that we'll reveal as it approaches clinic and later-stage development. As we think about our broader ADC strategy, there's both internal development and external development, and our goal there, as you saw with the Kelun partnership, is to continue to augment our existing pipeline, so to be either to synergize with 001 and also have power as monotherapy beyond which we have with our current PD-L1 and ntegrin-6 targets.
Yeah, I mean, one thing I'll say is that as we de-risk and mature and grow as a company, our initial strategy on the ADC side was not to take risk around novel targets. As we start to think about having more stability, more success in our development programs, you know, novel targets may be on that list. We always have our shopping list of things that we're excited about and focused on. It just shows our dedication to our dual strategy between next generation IO therapeutics and our ADC sleeve of our business. We really do believe in the synergistic combinations approach, and we think that's how you win in this space long term. We always are thinking about what that next partnership might look like, maybe even continuing to think about other things we can do with Kelun-Biotech.
We're very focused on that.
Broadly, what is your business development strategy? Would you take 001 all the way through to the market? Do you intend to partner with a bigger biotech or pharma company?
Yeah, go ahead.
I think, look, there's 40, 50 indications that we could take CR-001 through. Clearly, you know, we're not gonna run all those registrational trials in parallel most likely. That being said, from a BD perspective, we think it's most important for us to generate meaningful clinical data as we've guided to before we enter into a large partnership, right? That's right for shareholders, it's right for us to optimize CR-001 . The answer to your question is, there's a world in which we do entertain that partnership after clinical data. That being said, there's also a world in which we do that for select indications, and we do take CR-001 forward ourselves, either as monotherapy or in combination with our own pipeline in select indications.
I think it's not a one-size-fits-all strategy, and that just speaks to the breadth of opportunity we have, but we are focused on generating clinical data before entertaining those partnerships.
You referenced perhaps bringing things in from external into your own pipeline. How much capacity do you have to do that? What, what would be interesting to supplement your pipeline with given all that you already have?
Well, I think what's most interesting is data generation. I just continue to go back to we're kind of obsessive about the data we could generate and the speed at which we can generate high-quality data that can create value for stakeholders, first and foremost, patients. As we think about types of deals we could do, I think the Kelun-Biotech deal is pretty creative for a company our stage. I think again, the credit goes to the quality of the CR-001 asset. I don't know if you know, but the CMO at Kelun-Biotech developed ivonesimab at Akeso.
Hmm
You know, Kelun-Biotech got to see all the Chinese bispecifics, all the things that are out there, and they picked ours, for that reason, which is very validating for us. I think we're gonna apply that creativity we had in the Kelun-Biotech-type deal to think about how can we generate data more quickly, how can we generate combination data more quickly, and how can we win in this space through synergistic combinations? I think that's where this is going. I thought it was great last year in the November timeframe, Pfizer started talking about that. Biotech's been talking about that. We couldn't say anything because we'd had this deal to announce, and we've been thinking about this for over a year now, and that's kinda how the company was founded. We really are behind that strategy.
It's really about data generation.
On your balance sheet, can you remind us, Zip, of your cash balance and the runway that that affords you?
Yeah. We have runway into 2028. We feel good about that. That's through all the clinical value-generating milestones we've talked about across the monotherapy and at least one combination study as well.
Yeah, I think we just announced earnings, $213 million in cash.
Great. I think you've answered all my questions. Anything I should have asked you that I didn't that is important for investors to know as they look at Crescent?
No, we're having a lot of fun. It's great to have the team back. It's really a fascinating space and, you know, it's a big task for a company like Crescent. We love the competition. We love being in the middle of it. It's just a great place to work, so...
Great. Well, thanks for coming by the Cowen conference.
Yeah. Yeah. Thank you.
Okay.