Hi. My name is Manoj. I'm an associate in RS team, and it's my great pleasure to introduce Crescent team. Maybe we can start with, so we are all back from ASCO. How do you view the HARMONi-6 data point at this point? It came slightly better than, in terms of overall survival. How do you view the HARMONi-6 data? Yeah, thanks. I think from our perspective, ASCO is very exciting across the entire portfolio and strategy for Crescent Biopharma. I think very validating for our view on really replacing first gen PD1s, with the new backbone therapy for IO around the bispecific class of drugs. I think that question was substantially answered with the historic data that Akeso and Summit put out with the HARMONi-6 data. I also think from a longer term strategy around our focus, which has been from the beginning around the ADC combination therapies, also the sac-TMT data was also very strong. From our perspective, it was a very exciting and validating ASCO for this year. In regards to the HARMONi-6 data, maybe Ellie, if you want to take a few minutes, just comment on our perspective. Yeah. Yeah. We thought that that data was really validating the class, and then answering some of the key questions that we've had. thus far. The first one was PFS benefit. Yep translating to OS benefit. PFS hazard ratio was 0.6. OS hazard ratio was 0.66. We are now seeing how PFS benefit is directly translating to OS benefit. What was also great was, regardless of a PDL1 expression. of the subgroup, the patients benefited across those levels. Yeah. In terms of safety, which is also important because some of the key concerns of this combination with the chemotherapy plus PD1/VEGF was coming from Avastin. Yeah causing a lot of bleeding issues, especially in squamous population. Now we are seeing that long-term safety data compared to last year's ESMO's data. Yeah comparable to what we saw at ESMO, and then overall Grade 3 or higher grade events compared to the two arms, PD1 arm versus PDL1. PD1/VEGF arm, we're not seeing major differences. Yeah. All those things, to us, is mainly a positive and huge validating point. for entire class. Maybe thinking about how. Yeah. Yeah. You can take off. Sorry. I got stuck in the elevator. How's it going, guys? It's going great. It's pretty good. We just finished talking about HARMONi-6. We're done. Yeah, exactly. I missed it all. By the way, I'm warning you guys already, I will go over. Wherever is the next one, I preemptively apologize. It's good seeing you guys. Yeah, same. We all just came back from ASCO. I wanted to maybe start off with, again, if we think about PD-1/VEGFs, class is real. I think the big takeaway, I think Manoj and I had, is really trial design matters. Yep. Yep. Can you hit on what were the big takes in terms of trial design that your team's going to be incorporating after we've seen some of the data sets we got from BioNTech and from Summit? Look, I think that's a very savvy point. We spent the last few days talking about just that point. The class of drugs now, I think, is completely validated. We started with that while you were getting out of the elevator. I think that the HARMONi-6 data validates the class of drugs. You have sac-TMT from ASCO that looked great. You had the CRC data from Summit as well, talking about label expansion from the first-gen PD1s, all on point for our strategy to company, right, and where we want to go. I think that even looking forward to the questions that Summit will need to answer around HARMONi-3, I feel like your point is exactly well taken. That's a Summit question. For us, the class of drugs and thinking about how we want to design our study, the lessons learned to be a fast follower to build- on our focus around developing CR-001 as the backbone therapy, best in class bispecific partner of choice. for this transformation and paradigm shift from first generation PD1s. is something that we're very excited about. There are some key lessons to be learned. from this data. Maybe Ellie could talk a little bit about that. Yeah. Yeah. Overall, we thought that this was really landmark data. We've been waiting for something that can do better than KEYTRUDA plus chemo in squamous cell- Yeah non-small cell lung cancer. It's been more than a decade. Finally showing PFS benefit translating to OS benefit. In overall AE perspective, everybody thought that it was acceptable safety profile. Overall, we are very encouraged by this data. The few things that we could draw from the results, of course, how to define inclusion/exclusion criteria. For safety perspective, who should be included because they can tolerate the drug, or who have a higher risk of immune-mediated adverse events or VEGF-mediated adverse events that we should not include. Right? What is the sample size we should use? What is the right benchmarking for the standard of care arm? Right? We were talking about median OS for the comparator arm. Would it be 19 months versus 24 months, right? If you now see when the curves are separating, which you pointed out rightly so in your report, now we have a better understanding of. It should be for us to really detect the right amount of benefit that can be statistically significant and also clinically meaningful. Of course, last but not least is the stratification factors, what really matters, and how we can use the right stratification factors so that there's no critical imbalance between the two arms that can lead to potentially one or the other way. Yeah of results. Yeah. To that point, there's this interesting discussion which is, okay, well, there's a different dynamic in terms of elderly patients versus younger patients. Is that actually a false signal? It's actually more about ability to tolerate standard of care, and that it just happens that age is a stratification. When you think about, again, things that you would apply to your studies. Are you thinking is it an age cutoff? Are you thinking it's about prior lines of therapy in order to enrich for the patients who would be responsive with your drug? What's the right approach to amplify the right signal? Based on that question, which has been pointed out by the discussant. Yep heavily debated. Intimately. Right. Yeah. We actually looked at the HARMONi study, HARMONi-A study, HARMONi-2 study, and then as well as other monotherapy data and combination data in many different tumor types. Based on our knowledge, I think this is the only study that showed relatively big difference in hazard ratio of younger- Yeah or older patient population. The safety and tolerability perspective, I don't think there's any data to speak to that age 65 and older patients have a lot more toxicities. Right. I think it's more related to this study specific. Summit did a great job of explaining. There were two major factors that could have contributed to it. The tumor size, patients with the larger tumor size, and patients with brain metastases. There were a higher proportion of patients with such features were allocated to ivonescimab treatment arm in the age 65 or older groups. Yeah. Now we know this, and it looks like the Summit is already stratifying based on those two factors, which will potentially mitigate foreseeing such discrepancy in terms of. Yeah age affecting tumor benefit. Right. To you, it's less about the age, it's more about just how the older you are, the more severe you actually were with your cancer. Okay. That would make sense. I would just say, as people take time to digest and come back and start to look at the data. Yeah. Like the Chinese patient data versus the global data, those answers are existing in HARMONi and HARMONi-A. HARMONi-II. If you dig into the HARMONi-2, if you dig into those data sets, there's a lot to be gleaned there already. Understood. I swear, I didn't think I got a read. I figured I was going to leave ASCO and be like, "Okay, we're going to get a sense on how much alpha Summit spent on the HARMONi-3 readout." I don't know if I got one. If someone in the audience wants to chime in, it's fine. Did it have to be 0.6? Did it have to be 0.65? Did it have to be 0.7? There's a range of outcomes here. We're all dealing with this uncertainty, right? Yeah. When you think about, again, there could be a red flag where it's like, Hey, we are seeing, as we go into a global trial. that the data isn't one to one translating," which often happens. That doesn't mean it's not a real signal. It means it's not translating one to one. When you think about, okay, we got a four-month delta in squamous. If you are powering a phase III study today. what would be the absolute OS delta that you think should be the target in any well-controlled phase III trial in a more global population? How much wiggle room does four months give you? That's a really good question, and again, you pointed it out in your report, so I am glad that I have a chance to talk about this. We are looking at the shape of the curve. Right Between the two arms and how widely they're separating and in terms of reducing the risk of death. That's how hazard ratio is calculated. That was a 0.66. Median is just the one point of the number that's representing the survival benefit. Yeah. It's more of looking at the overall curve, how it looks like. Around month six or so, the curves started to really separate, and then the separation became wider with time. With the longer follow-up, this was a 38% data maturity for survival analysis. The longer follow-up might give us even better hazard ratio. Again, median is just a one point, that you are looking at one time point and see how long will the patients live at the 50% percentile. Overall risk reduction of this trial showed 34%. That's something that we need to look at, and also how the comparator arm is performing. Yeah. KEYNOTE-407, overall survival for the KEYTRUDA arm was 17 months. Here, the PD1 plus chemo arm was a 24 month. Depending on in which region and how your population is performing. that control arm can be different. Right. How you consider that and choose the right sites and countries, and then also control the enrollment rate, and when is the right time to perform a analysis so that patients enrolled in the study have a sufficient follow-up to demonstrate the difference in efficacy, as well as a safety perspective. All those things are really great lessons for us. Yeah. We are here learning from all the great data that's coming out. Very encouraging, not just in non-small cell lung cancer, but from multiple tumor types. Yeah. We are executing and generating our own data of CR-001 ASCEND, which is phase I/II trial of our PD-1 x VEGF. We'll generate our own data and then learn from all the great lessons, and then that will give us chance to then decide on which tumor type and then what combination we should choose to improve a probability of success of our registration trials. Understood. Very helpful answer. Josh, this might be also a question for you. I think what the Summit management team, I think there's some very impressive team, there's no doubt about it. You have this kind of unique circumstance of You're competing with the big guys. You need to create catalysts. You need to raise money. That's something you're going to have to deal with as well. I can't help but think, I would be powering these studies for OS and just not messing around. Like no more PFS interims. Like we know this class works, that's fine. If you went and said, "Look, we are running our trials fully powered for OS. We are not spending alpha," because ultimately that's what, by the time we get on the market, that's what regulators are going to go for. That's really what we want to put forward. To your point, if the curves get wider over time. Mm-hmm, mm-hmm. they may have actually hurt themselves by doing an interim a little earlier than expected. Is that the right read? Right? Like how do you balance the need of a headline which could help with capital raises versus making sure these trials are powered correctly in your seat? Yeah, look, I think it's a great perspective. Our view is that this really is a unique position to be a very fast follower in the opportunity here. We're talking about, it doesn't matter who you talk to, what pharma you talk to, Summit ourselves, this is a $100 billion market opportunity paradigm shift. Our strategy and focus on the ADC synergist combination piece of this from the beginning, I think has been a clear differentiator in our clinical strategy. I think, our view is that we're learning rapidly from these studies. Again, I always say it's a great credit and bold leadership to open up this next class of backbone therapy. Yeah for IO. We'll learn from that. We will think about, is this OS only? Are we going to think about how we want to run these studies? It is such a massive opportunity. We're just talking about lung. Right? For us, as we think about this over the next couple of years, we're going to be able to generate a foundational piece of revenue out of this changeover paradigm shift with our CR-001 asset. I think what's unique to us is we own that asset, right? There's only a few people out there that have the opportunity to be a player in this next generation backbone therapy. CR-001, with the three buckets of data we're generating now, the Q127 monotherapy first-line non-small cell data that's coming again within 12 months here, within actually nine months. Within 12 months, that second bucket of data where we're going to take CR-001 and combine it with various standard of care chemo agents. We're going to see various tumor types, various reads across- being able to combine safely and efficaciously with various chemo agents. Leveraging the partnership we have with Kelun-Biotech to generate that third bucket of data, which is CR-001 combo with ADCs. As of this week, we now know that we're going to be able to be talking about the CR-001, SKB264 combo that our partner Kelun-Biotech's running in China. I'm shocked. plus additional ADCs. That was the ADC Kelun-Biotech. I had no idea. Right? The first of many. Yeah. We're very excited about being- Yeah In the middle of this entire field, generating data across all three of those buckets will allow us to be able to have a claim that we could be best in class partner of choice. How we think about designing these studies, where we go, how broadly we go, and how we go with partnerships. capital raise, et cetera, the data will give us the ability to generate that position of strength from a capital perspective and a partner perspective. I think we have some incredibly valuable assets. I think our strategy will pay off. I think being a very fast follower and the things that Ellie and the team are already thinking about implementing into our study design. are going to be incredibly powerful for us. Now, it's interesting. You look at the LENVIMA data, it's clear where Merck's head was at. You had an NSCLC backfill cohort. 80% of your patients were PD-1, 1%-49%. Where have they not run studies in lung is the 1%-49%, of course, we'll get the Kelun less than 1% data in non-squamous shortly. Knowing that, and we think about your combination data set, and really, you also have a backfill cohort in first line lung. When you think about the data we've seen so far, and we're not just thinking about broadly first line, but we're thinking about subtypes, right? Where do you feel like the benefit of a PD-1/PD-L1 is best positioned relative to just pembro alone? Is it the 1%-49%? Is it less than the 1%? To your point, no, actually, we see across all subtypes, that's really where we're going to be enrolling for patients. When Kelun-Biotech does that trial, they're going to go for that really biomarker specific population, similar to what Merck did with LENVIMA. Ellie, Jonathan. Well, I would say first, we don't want to get ahead of our partner Kelun-Biotech around describing what the CR-001 SKB264 study is, and we'll be excited to share more about that when that's available. We're excited to generate that data because I think that will inform the question you asked, which is this applicable across all subtypes? What are the best tumor types for SKB264 and CR-001? More broadly, what are the right tumor types for other ADCs, such as the integrin beta 6 ADC that we also are partnered with Kelun-Biotech. We have rights to that outside of China, plus CR-001 as well, too. I think that we will make a database decision on that. The data to date and the data that Kelun-Biotech released at. ASCO suggests that it could be applicable across a wide variety of non-small cell and potentially other tumor types as well. That's something that our data and the field's data will guide us on. Understood. I don't know if you have anything, but. Yeah. No, we are looking at the data from monotherapy as well as a combination perspective of ADC as well as a chemotherapy. I think it depends on which strategy that we are referring to. One thing that has been really great to see with the PD-1 x VEGF as a class compared to PD1 antibodies is that regardless of PDL1 expression. Yep We are seeing similar degree of benefit. Having said that, maybe delta can be greater in patients who didn't receive a lot of benefit from PD-1. Yeah. Right? It makes it low. hint. Yeah. Right? It all also depends on are we doing it as a monotherapy, or are we combining with a standard of care chemo, or are we combining with ADCs. that have a specific activity in these tumor types and then PD-L1 expression. We have a lot of options of generating the data and then making decisions based on that. Now, not all chemotherapies have the same side effect profile. Not all ADCs have. Yeah same side effect profile. I think one of the things we see with sac-TMT is, A, that 4 mg/kg dose was kind of a breakthrough for them. I think they were higher dosing. Yeah. They were pre-dosing with G-CSF. Yeah. You had a lot of neutropenia. Yep. They found kind of a dose which balanced- Yeah I think, their AE profile. Can you talk about, again, less ILDs, but stomatitis, you have diarrhea? you have neutropenia. Why could sac-TMT potentially be the right side effect profile that would be combinable with the side effects that you get with a PD-1 x VEGF, right? Why is that maybe the right fit here? We are very encouraged to see what Kelun-Biotech and Merck had done to optimize their dose. I agree with you, the 5 mg per kg dose was associated with a higher number of greater 3 or higher grade events on those diarrhea, stomatitis. as well as other neutropenia and other adverse events. At 4 mg per kg, it was well-tolerated. We saw very low number of patients with a Grade 3 or higher grade AEs or AEs leading to discontinuation or death. Right? Based on that data, what we know from PD-1/VEGF versus PD1, immune-mediated adverse events perspective, the rates are similar. The VEGF-mediated adverse events perspective, most of them are Grade 1 or 2. Right. The Grade 3 or higher grade events are very rare. That gives us a lot of confidence that when sac-TMT was safely combined with KEYTRUDA, right, the safety profile of what we know of PD-1 x VEGF, also, we should be able to safely combine with the sac-TMT and provide that benefit. Okay. I'd like to add on that. I do think it is worth pausing and just acknowledging that there are a number of bispecifics in development. Yeah. Mm-hmm. They are not created equally. I do think that safety is going to be one of the key issues of can you really be a backbone therapy? If you're going to generate the next Tecentriq or the next KEYTRUDA, you need to be able to be combined across various agents safely. That's why these three buckets of data that we're generating that we'll have out middle of next year will be so impactful because it'll give people a look across monotherapy, multiple chemo agents, multiple ADCs in a very short period of time, and a solid number of patients. Is CR-001 safe and combinable across multiple agents? That's why we're designing the study this way, because we are positioning this to be the best-in-class backbone. Understood. I want to stake one more question on your partnership with Kelun-Biotech before we'll end on V6-A. Look, Kelun-Biotech, and we've gone to Shanghai, we've gotten to know that management. It's a very remarkable organization. They have great science. The more we meet them, we really do think they're super impressive. They think about novel payload delivery, whether it's even RNAi. steroid delivery. I mean, degraders. some pretty interesting stuff. What is your relationship with them? You have two ADCs you're sharing. I can't help but think, A, I think a lot of things people don't understand about the deal you did is they actually now kind of have some skin in the game in terms of if there's something strategic with your company, they have an ownership stake. You're going to get data not just with sac-TMT, but there's a ton of ADCs they have in their portfolio, nectin-4, and some with Merck, some not. Would I be surprised if, let's say, we generate some of that data and then you in-license, or you have the ability to actually bring those products into the United States, right? Is that possible that we shouldn't just think about the Kelun-Biotech partnership on the PD-1 x VEGF and these two assets, but actually something that could be more expansive? I'll ask Jonathan to talk a little bit about that. First, I'll just say that we couldn't be happier with our partnership with Kelun-Biotech. Dr. Gao, their CEO, and I personally have become friends. We have a very shared vision across both companies. to really become leaders in this field. I think there's many things that we expect we could see that will build upon this first initial collaboration, and we couldn't be happier with that relationship. Yeah. I would only add that, as you alluded to, we designed the economic incentives and the structure of this relationship to truly align that as we generate meaningful clinical data, the value we create is shared together. We see that as a foundation for what could be a relationship that expands further as we continue to advance our assets across not just 001 and sac-TMT, but 001 and the integrin beta 6 ADC, and then potentially other ADCs as well. Okay. Yeah. That is interesting. All right. Last thing to hit on here, obviously we got the Pfizer announcement. Sounds like the decision was made months ago. OS ITT, no more V6A high, V6A low, we're going to go for it. I want your just gut reaction. When you heard that, what was your first thought? Again, there's two ways to think about it. These guys missed on their PFS. This is their last shot of hitting on OS, and it's going to be a modest effect size. The other read is, I look at that publication they had a month ago. They talked a lot about dose optimization. We're seeing with these ADCs, actually PFS understates sometimes the OS benefit, especially if you're going head-to-head against chemo. The longer you stay on the drug, again, with longer time, that actually ends up being a good thing. These guys are making a smart decision. Those are the two thoughts in my head. Jesus. What was your team's internal read on that Pfizer announcement? Yeah, look, I think we take Pfizer for what they said, right? They said this is something they've been discussing for quite some time. That they haven't seen the data, and that they are obviously committed. They've made a number of changes to the protocol here throughout this study. They're very committed, obviously, to the integrin beta 6 target with the first-gen program that's reading out as you're talking about, but also the second-gen program they have. We really do think that this is an interesting target. It was top of our list. It was one of the reasons that the Callidion deal got done. Mm. Mm-hmm. I think we'll let the data speak when they're ready to let it speak, but I think they're clearly committed to it. They're excited about it. They've seen a lot of data. We're just going to let that be and see when the data comes. I would just say we'll learn from that data just like we will from. Yeah in terms of biomarker strategies, trial design. If it is positive, that's wonderful for the field. It's also wonderful for the opportunity we have to have a best-in-class integrin Beta6 ADC. If the data shows some MMAE-related toxic liabilities, again, we have a very different molecule across antibody linker and payload. Although that would be unfortunate, we'll learn from that. As long as it validates integrin beta 6 target, we're full steam ahead. Understood. I will say Albert, he had a fireside chat with our CEO. He said V6A could be the biggest drug in Pfizer's pipeline. It's great. on that note. Great. Again, guys, I apologize for being stuck in the elevator. Apologize to the management team, too. Oh, we're good cleaned it up at the end. Yeah. Hey, thanks so much. Yeah, thank you very much. Thank you. Thank you.