My name is Daina Graybosch. I'm a senior equity research analyst here at Leerink Partners. I'm excited this morning to welcome for the first time to the Leerink Global Healthcare Conference management from Crescent Biopharma or otherwise known as Crescent Biopharma, Ellie and Jonathan. In our 30 minutes we hope to talk through all three of their assets as well as a really interesting partnership that they did earlier this year. I think we'll start with your VEGF-A/PD-1 bispecific-
Mm-hmm
CR-001. If you allow me, you have a fast follower best-in-class strategy for your bispecific holistically as part of combinations. I wonder if you can help us understand how you believe you can succeed given you do lag behind the leading competitors, including several large US biopharmas.
Yeah. Thanks, Daina. Thanks for having us here today. Before we get started, just a reminder that we'll be making some forward-looking statements today, so please refer to our SEC filings for more information there. At Crescent Bio, we're focused on delivering next generation oncology therapies for people living with cancer. We're advancing a matrix portfolio across IO assets, ADC and standard of care combinations in our selected therapeutic areas, which includes thoracic, Gyn-Onc, GI, and head and neck cancers. If you think about our strategy, there are a couple key elements, some of which you mentioned. The first is CR-001, our PD-1/VEGF bispecific, which we believe has opportunity to be best in class and a next gen IO backbone.
Our ADC portfolio, which includes CR-002, a PD-L1 Topo ADC, CR-003, an integrin beta-6 Topo ADC, CR-004, an ADC against an undisclosed target, and importantly, novel combinations of CR-001, our PD-1/VEGF with ADCs. In December of last year, we announced a partnership with Kelun-Biotech, a leader in ADC development and commercialization. They developed sac-TMT and multiple other assets that are well known to those in the space. There's a couple key elements of this deal that we think are important about how we think about competing to win in this space. The first is that we in-licensed our integrin beta-6 Topo ADC from Kelun for all territories outside of Greater China. Kelun also in-licensed our internally developed PD-1/VEGF CR-001 to develop both as monotherapy and in combination with their full suite of clinical stage ADCs in Greater China.
As we think about the early innings of this $100 billion+ market opportunity, and as a reminder, there are no approved PD-1/VEGFs outside of China. We think that we have multiple ways to win based upon our differentiated assets, our partnerships, and our differentiated clinical development strategy. As Daina noted, that touches on where we are focused. The first element is first-in-class opportunities outside of China. There are 40-50+ indications where PD-1/VEGFs could be applicable in solid tumor indications, and the vast majority of those do not have any late-stage trials running outside of China. Similar to Ellie's experience at Tesaro and endometrial cancer, we have multiple opportunities to be the first-in-class program in solid tumors, both as PD-1/VEGF and in combination therapies.
That brings me to my second point of our strategy, which is best in class. We will not be the first to generate data in non-small cell lung cancer in Western patient populations as example, but we believe the opportunity in lung is wide open with best in class combinations of our CR-001 asset with ADCs that we either develop internally or access via partnership. You're seeing that in both our own pipeline and in our collaboration with Kelun. We feel like we're well positioned to execute on this strategy. We are on track to initiate more clinical trials in 2026, which sets us up for a number of clinical readouts across monotherapy and combinations beginning in Q1 2027. With our raise in December, we have cash into 2028, so we're well funded through those catalysts.
That's great.
Yeah.
That's a great overview.
Yeah.
Actually a quick follow-up on the Kelun partnership. They're gonna be combining the VEGF PD-1 bispecific with their own ADCs.
Yep.
Is there an official mechanism by which you could take some of that global if they get an interesting signal from ADCs you don't have partnered?
The notion of the way the Kelun partnership came about is that integrin beta-6 was high on our list of ADC targets. As we think about ADC innovation, once we identify an ADC target that we think is of interest, we make an analysis of should we develop this internally like we did for our PD-L1 Topo ADC or are there external assets that we could access via partnership or otherwise. For integrin beta-6, given Kelun's history of sac-TMT and other ADCs, that asset rose very high on our list. As we started talking to Kelun, we realized that they shared our vision of synergistic combinations of next gen IO plus ADCs, and they were looking for a PD-1/VEGF that mimicked the cooperative pharmacology ivonescimab. Their CMO was previously at Akeso, led the development of ivonescimab.
As he learned more about our CR-001 asset, there was a nice synergistic partnership here to be had where they could take our CR-001 asset in China as both monotherapy and in combination with their full portfolio of ADCs. That was a key element of this deal because they wanted to make sure that they had an IO backbone that they could apply across their full portfolio, and then we would develop their integrin beta-6 ADC outside of China. Again, we would also be combining that with CR-001 as part of our synergistic combination strategy. To answer your question, there's clear data sharing across the CR-001 and CR-003 assets, but I think one thing that's underappreciated about this deal is the opportunity for us in a very capital efficient manner to find signals of CR-001 with a plethora of ADCs.
You can look at Kelun's clinical stage pipeline to see what those are. That includes sac-TMT, includes HER2 ADCs. They have ADCs disclosed targeting Claudin and Nectin. All of those are available for combining with CR-001, and as Kelun generates that data, we have access to that data. Now, in terms of expanding the partnership for us to have rights to those outside of China, clearly that's an opportunity for us to have discussions with them on that topic. We have a very strong working relationship and, if we generate that data, there's clearly a lot of synergies to be had. There's value for Crescent. Frankly, regardless, if Kelun were to run, for example, a sac-TMT CR-001 study, even though we don't have rights to sac-TMT, there's clearly a lot of interesting learnings and value creation for us there.
Got it. I have to ask 'cause I cover Merck. Merck has licensed sac-TMT from Kelun, and I sort of guessed that we might get some data of sac-TMT in the novel bispecific that Merck's also licensed. Is there potential that we could see sac-TMT with a couple different bispecifics and start to get a sense of differentiation? Could be good for you.
Look, I can't speak to Merck's plans, but what I can say is that Kelun late last year put out a press release talking about a sac-TMT plus pembro study that they have run, and they said that it had very positive findings on a PFS setting, and was one of the first times that had been seen in first-line non-small cell lung cancer. We look forward to seeing more data in that space. One reason that Kelun wanted to partner with us is that they have the ability to use CR-001 across their full portfolio and have control of that asset in Greater China, right? There's a strategic value to them from a synergistic combination perspective. You know, we hope that they run CR-001 with as many ADC combinations as possible and look forward to enabling that.
What that means for Merck, you know, I won't speculate.
Yeah. One more question sort of regarding Merck. Merck sees Kelun as a pretty strong strategic partnership.
Yep.
It's not just like licensing sac-TMT . They've really spoken quite positively, which is good for you.
Mm-hmm
Clinical development capabilities in China and that they continue to work together.
Mm-hmm.
Why didn't Merck license the integrin beta-6? You know, can we read anything into that one came to you and not to them?
Do you wanna start and then I'll?
Yeah. Merck has their own ADC pipeline, right? They are prioritizing which ones should be developed in which indications. What they're doing with the, for example, sacituzumab tirumotecan and then B7H3 and CDH6. From our perspective, they have their own strategy of how to develop those ADCs and combine with the assets that they have. From their perspective, it probably have fallen out of those priorities of indications and then competing with the internal assets that they already have advanced.
In our point of view, when we assess the targets that are being explored from the ADC perspective and multiple indications that we have application to prosecute with combination with our CR-001, PD-1/VEGF , integrin beta-6 became a very attractive target because of its clear differentiation of level of expression in tumors, which is highly elevated, and then the normal cells, which is not that elevated. Looking at the competitors that have integrin beta-6 ADC, we could see the limitations of their assets and then how we can further optimize to increase the probability of success and going into the indications and creating a best-in-class profile. From that perspective, it really fit into our pipeline and our strategy. As Jonathan mentioned, our shared vision.
Yeah
Between the two companies and how we generate this data in China from their excellent operation and then from global perspective with the Crescent operation. Both companies working together, we also saw clear synergistic ways of generating the data and excelling our development of multiple assets.
Yeah. I would say there's
Yeah.
The goal here is a structured agreement that completely aligns incentives.
Mm-hmm.
That goes to data sharing, it goes to the ways of working. Kelun also speaks very positively of their relationship with Merck, right?
Yeah.
Again, that was a benefit to us that they've had the ability to work with a large multinational pharma in a very productive way. This was an opportunity for us to take this as a lead asset, a strong strategic priority for us to generate data rapidly. In addition, there's economic incentives that are aligned as well. In addition to upfront some milestone payments, this is in our SEC filings. Kelun has a descending over time portion of any change of control that were to happen with Crescent, right? Why do we do that? We're not building the company to sell it today, but it was to completely align incentives for our success and Kelun's.
Wait, can you describe that again?
It's in our SEC filing. In addition to upstream, you know, the upfront payments and milestones, there is if Crescent's to experience a change of control.
Ah
Kelun gets a percentage of that transaction, descending depending on when the transaction happens from a low double-digit to low single-digit percentage that changes over time. Why did we do that? It's because we have seen assets in-licensed out of China, which then lead to a very quick change of control based on-
Yes
The generation of clinical data. Kelun had also seen that, and so to mitigate any concerns around that and to align incentives, we added this provision. I bring it up, not, again, not to say that we're building our company for a change of control. We wanna build a very leading independent company. It's how we align incentives, and again, it's something that we can offer that a large multinational pharma cannot.
That's interesting. It's sort of like what BioAtla happened.
Exactly
How could BioNTech turn that into a bigger deal that some of that would go to the BioAtla and in this case, to the Kelun shareholders?
Exactly. Yeah.
That's interesting. Actually, let's talk a bit more now that we're on the integrin beta-6. Can you talk about what the limitations are of the competitive assets? I know that we were just talking about one's gonna read out on phase III soon and how yours is differentiated, what that path was?
Currently, the most advanced asset in clinical development is Pfizer's integrin beta-6 with a MMAE payload coming from Seattle Genetics platform. Starting from phase I trial and studied in multiple indications, currently that asset is in phase III studies in one indication, that is non-small cell lung cancer. They've tested other indications. As far as we could see, there were no other advanced programs likely due to not being able to see the meaningful activity of those in those indications. In Pfizer's phase III study that is supposed to be reading out first half of this year, we are also seeing that they are exploring biomarker based on integrin beta-6 level expression if that is predicting the efficacy of the asset.
Looking at the overall safety and clinical profile of the asset, we thought that how we can develop an ADC that is optimizing safety and efficacy. From a safety perspective, going with the topo payload, we can avoid some of those class effect of MMAE, such as neuropathy. Topo payload ADCs tend to have wider therapeutic index. Depending on the linker, there's a better combination possibilities as well. Of course, with antibody perspective, be very specific to the target that is expressing integrin beta-6 to avoid any untoward side effect. Internalization is the key of ADCs going into the cells and releasing payload. All these aspects were optimized for Kelun's asset, and that's why we particularly chose this.
Specific binding to integrin beta-6 only, that activated sub-unit, and then the internalization perspective, not just the highly expressed cells of the integrin beta-6, but in the low expressed cells. Kelun did a nice job with that, and so showed that it has a superior internalization capability in lower expressed cells. Then the PK perspective, maintaining that conjugation in the system pretty much the whole time without releasing the payload, which can prevent any systemic toxicities. With all these optimized profile, we think that the CR-001, our own asset, can show clinically meaningful benefit in multiple indications. Even in the tumors that have highly expressed cells, some tumors can have a heterogeneous expression of integrin beta-6.
Overcoming some of those challenges and then preventing systemic toxicity issue with the improved linker payload technology will give us a chance to successfully combine with CR-001 or even other assets.
You know, with the upcoming Pfizer readout, that is effectively the only later-stage asset in the integrin beta-6 ADC space. Regardless of that readout, we think we'll learn a lot, right? If it's generally positive, it's further validation of the integrin beta-6 target, and we think that we have a potentially better asset based on all the elements that Ellie just said. If they see some negative readouts in terms of MMAE payload or otherwise, again, our asset's differentiated across antibody linker and payload. We think it'll be an interesting data point for us. There's also it's focusing increased attention on the fact that we both have an ADC portfolio and the PD-1/VEGF.
Mm-hmm.
You'll see maybe some correlation of integrin beta-6. You could be similar but different.
Yeah.
Yes.
Yeah. Yep. Let's go back and talk more about your PD-1/VEGF for a moment. Maybe way back. Mechanistically, what do you think is really driving the benefit of the VEGF-A/ PD-1 bispecifics?
We've been using this new term of cooperative pharmacology, and I think that's a very smart way of describing because we know that giving PD-1 inhibitor and VEGF inhibitor together will not yield the efficacy that we have seen in HARMONi-2 or HARMONi-6 studies. From a safety perspective, we're also seeing less degree of VEGF-related adverse events such as bleeding and clotting and wound healing issues. Clearly what it tells us is that with the current structure of ivonescimab and then other agents that are out there's something that is happening with the. You know, currently the leading hypothesis include the daisy chain formation and then intensifying PD-1 signal. Of course, BioNTech has a slightly different ways to describe it.
PD-L1 is attracting the pumitamig in the tumor microenvironment, and there's an intensification of VEGF signal. I think we will learn a lot more about exactly what's happening in tumor microenvironment. Clinical data, as they emerge, we see that it is definitely showing better efficacy than PD-1 inhibitor or VEGF inhibitor were when they were given together. From the side effect perspective, we are seeing much better than when those agents were given together. I think that's why there's a lot of enthusiasm for the field that we're finally seeing an IO agent that can displace PD-1 inhibitor in a standard of care setting and provide better efficacy, and then the safety profile that is quite promising as well.
Do you expect that you'll eventually see differences between the PD-1 and the PDL-1 bispecifics in the clinic?
That's another very interesting and scientific question. Daina, I'm sure you know this, like, we've spent, I don't know, last decade plus talking about PD-1s and PDL-1s and which one's better. From the clinical data perspective, we know the number of indications that PD-1 inhibitors have been approved are more, right? There are some indications where PDL-1 inhibitors have done better, such as a small cell lung. We know that from, you know, monoclonal antibody perspective. As we are seeing, more data coming out from PD-1/VEGF or PDL-1/ VEGF, we start to see some indications, the safety and efficacy profile look different, but those are preliminary data.
With ivonescimab being only PD-1/VEGF inhibitor with multiple phase III study readout so far, we know what that agent did in terms of PFS benefit, and then OS benefit, which is maturing, and then the safety perspective. Pumitamig, which is a leading PD-L1/ VEGF, we are waiting to see more data with that asset. I think it is possible that there will be some difference in safety and efficacy perspective and how it's combined with different agents as well as the degree of benefit that we see with the PFS and OS in multiple indications.
Okay.
Yeah. That's one variable, but you'd have to control for the fact that many of the antibody formats are different too. If you start changing that.
Yes. Yeah.
Even if you have the same binding targets, then the behavior could be dramatically different, right?
Mm-hmm.
I think that that's something that we will increasingly see. You've started to see that across this drug class where, you know, not everyone is replicating the cooperative pharmacology that you saw with ivonescimab in larger trials. That's not, in my opinion, that's expected because-
Mm-hmm
...if you start changing antibody formats, you start changing binding affinities, effectively you're going to have different behavior in vivo. We've seen that across other drug classes. PD-1/VEGF will likely be no different. That's why we rationally designed CR-001 in the way we did.
Yeah. Is CR-001 similar enough to ivonescimab? We can pretty much assume any ivo proof of concept or phase three outcomes are basically a proof of concept for you?
Yes. I mean, we get that question a lot and how we intentionally built CR-001 is to looking at harmony two data and harmony six data showing 0.5 hazard ratio in PFS superior to pembrolizumab. We didn't want to create a lot of different aspects in terms of compound perspective and wanting to keep the functionality, including the PK. But we of course introduced the new ScFv amino acid to increase the stability of the compound. We have done our preclinical studies, including the in vivo studies in antitumor activity and then PK perspective and presented that data at last year's SITC, showing comparable data in all those aspects to ivonescimab. We are starting our clinical study, phase I/II study called ASCEND.
In that study, we are exploring safety, tolerability, PK, pharmacodynamics, as well as preliminary antitumor activity in eight tumor types that we are prioritizing. With that data, if that shows how ivonescimab did in terms of PK and pharmacodynamics and safety, tolerability, as well as in preliminary antitumor activity, we are generating not just the second-line plus, but frontline non-small cell lung cancer data. That is the data that will be cleanest in terms of being able to compare to ivonescimab as well as other PD-1/VEGF inhibitors that are out there because a previous treatment can affect antitumor activity of PD-1/VEGF. Once we have that comprehensive data in Q1 2027, we'll be sharing that data with the public.
We believe that data will give us a lot of confidence approaching late stage development. Because of the intentional design of our compound compared to other bispecific antibodies that have different moiety or affinity PK or binding affinity. We believe we will have high confidence and then can potentially share that probability of success that ivonescimab demonstrated. Of course, from clinical development perspective, the great advantage that we have is we are starting with a global study, and so we will be addressing that question right ahead. It's not Chinese data and how is that going to translate in the Western world. We'll be generating the Western data, but Kelun, our partner, is also generating their own data.
In this way, we have a very efficient way of generating quality data, and then will help us making the decision and working with the global regulatory agencies from the beginning to increase that success in an execution, for the late stage development. Right now we are seeing that Summit Therapeutics and BioNTech constantly trying to refine their clinical study design, endpoint, and sample size. I think one great advantage that we have, we are closely following them, but we also have advantage of generating that Western data and working with the FDA and EMA from the very beginning. With our strategy, we'll have a smooth transition going into the late stage development.
It's really interesting that you're gonna be having data internally.
Mm-hmm
and also from Kelun.
Yep.
Is Kelun gated by this phase I too? Then how should we expect-
No
'Cause things happen really fast there, how should we expect to see data with your asset coming out of China?
Yeah, I mean, well, we can talk about our own study in the sense that we cleared the IND, we announced that in January, and we were dosing a patient within six to seven weeks, right? We're moving quickly in the U.S. to generate patient data. Kelun has said they are going to initiate a monotherapy study with 001 in China in parallel.
Mm-hmm.
They can of course leverage the data we've generated both pre-clinically and clinically to inform that. It will be parallel data generation, and the reason Kelun's running a monotherapy study in addition to their interest in generating monotherapy data is that will enable them to accelerate their combo studies that they can run with our own and their ADC portfolio as well in China. I think the way we think about it is as a standard, we have a joint steering committee for the broad collaboration. We'll be sharing clinical data. It really does create an opportunity to accelerate both our programs and Kelun's programs with this parallel data generation in both outside of China and China.
Can you talk about, I think a key part of your strategy is the ADC combination. Will you be pursuing only ADC combinations? Were you looking at traditional chemo? Like, how critical is that?
Mm
Is that to your strategy?
Our strategy is creating next wave of anti-tumor agents that are providing best benefit to the patients. Our current pipeline includes PD-1/VEGF bispecific as well as ADCs with the topo payload. In our phase I study, we will do monotherapy data generation to find the recommended phase II dose, as well as exploring combination with the standard of care. Our ADCs will have a clinical stage programs this year, so we will also explore that combination. Given the safety profile of PD-1/VEGF , what's great about it is that it opens the door for us to also looking at other combination opportunities.
With our development strategy as well as a business development strategy, we can see what other agents that are out there that provides excellent probability of success and then meaningful data, and then we'll explore multiple ways to generate potentially best-in-class profile.
Last minute, we haven't talked about your PD-L1 ADC. Interesting ADC. It's Topo, whereas Pfizer's again is MMAE. I guess the most interesting thing for me is how much of your activity is on PD-L1s expressed on tumor cells, PD-L1 is also expressed on suppressive myeloid cells, and sort of how do you expect the Topo to differentiate, given the PD-L1 expressed on both those cell types versus MMAE?
With our strategy, we wanted to again optimize this ADC to have differentiated efficacy and safety profile compared to Pfizer's MMAE-based ADC. Binding affinity of the antibody as well as internalization capability that leads to cytotoxic cell killing is the focus of our antibody optimization. The linker and payload perspective, we thought that it is important for us to have stability of the linker and using the payload, the Topo payload to differentiate again therapeutic index, as well as systemically using stable linker will reduce the toxicity. Going into the tumor that it releases carefully by internalization, with the potent bystander effect producing that cell killing.
The way that we have optimized this profile can potentially broaden the cell killing in tumor cells that have a heterogeneous expression of PD-L1. Those were the things that we focused in optimizing this antibody, and we believe this will provide us a great chance to generate the data in multiple indications as a monotherapy as well as in combinations.
Got it.
Well...
I think that we're through time. That was a lot.
Great.
Thank you very much.
Okay.
It's a real pleasure.
Thank you.
Thank you.