Welcome to this next fireside chat with Immunome. I'm very happy to welcome Clay Siegall, the CEO, here today. Clay, welcome. Thanks for joining us this year. Thank you. So Clay, just to set the stage, could you just remind us of your overall vision for Immunome? Sure, so I am very interested in making a difference in the life of cancer patients, and that's been my career before Immunome and continues to be the same thing. So Immunome is, first and foremost, an oncology company dedicated to making a difference in the life of patients, and the vision is that we're going to use different modalities, but largely ADCs. So we're largely an ADC company, but we will be opportunistic in other areas to add targeted therapies that can make a difference in patients' lives, and much like what I built at Seagen for 25 years, it's largely an ADC company. But as you know, we developed a small molecule called Tukysa, which is on the market around the world, which is a great drug for women with breast cancer that have brain metastasis. So being opportunistic to help patients is always important and not just keeping blinders on. Right. Great. So before we talk about your ADC portfolio, I did want to touch on AL102, which is a drug that you licensed earlier this year. It's a gamma-secretase inhibitor. And so, yeah, remind us of perhaps what drove that licensing deal and what makes AL102 interesting to you? Drawing on experience from Seagen, at that company, it was first ADCs and getting ADCs on the market. So by the time we did diligence and looked at a small molecule or pill, which would be the best HER2 tyrosine kinase out there, buying Cascadian, Wall Street still thought of us as an ADC company. Now, with Immunome, we were building all our ADC efforts, and we ran into a small molecule that we really liked very much. And it came earlier in the history than what happened with Seagen. So maybe some folks got a little confused by that. But it was too good to pass up. What we saw was a great piece of chemistry in the gamma-secretase inhibitor with a company that was perpetually underfunded, that had no CMC to speak of, and no development pathway to really go and get the drug approved, and not the right leadership. They had multiple CEOs over time. And so you look back at Cascadian, and what we saw there was a great piece of chemistry, great phase II data, but perpetually underfunded with changing leadership and no CMC. So I mean, it's literally a carbon copy, but a different agent. So having seen that with the power of the gamma-secretase inhibitor and thinking best in class, just like the HER2 tyrosine kinase, Tukysa, was better than Tykerb and Nerlynx, we think this is best in class. We think that because the phase II data was done in three different arms, different dose schedules, and routes of administration. All the arms looked good. They all looked very productive. I've developed and commercialized a number of drugs. When drug companies tell you, "Well, I have a drug, but it only works on Tuesdays with people with one leg," it's not true. That means it's not a real drug. I'm talking about different dose schedules, whatnot. Real drugs like ADCETRIS worked with every dose schedule we looked at. It worked better. You could tweak it and find where it worked better. Real drugs work. They either work or they don't. This drug was remarkable to us because it worked in all the doses and schedules. One was the best schedule and dose. We used that one. Right. And I know you had some more data recently at ESMO. Can you just remind us of some of the takeaways from that update? Notwithstanding the exact data, the goal here is to do best by patients. I think that the work that SpringWorks did was fantastic. SpringWorks took a drug that was originally developed by Pfizer for neurologic disease. They got it approved for desmoid cancer, which is a type of sarcoma and with bone involvement. It was the first drug ever approved for desmoid cancer. They did a great job. The drug that we have is 250 x more potent. It's once a day at 1.2 mgm versus twice a day at 150 mg each. We use 1.2 mg a day. They use 300 mg per day. Our pharmacokinetics are excellent. The chemistry is very different. The potency is very different. When you look at the data, there are certain regulatory parts of the data, which you talk about, which are like PFS. And you have control arms, and they'll have certain amounts of PFS. And then you have your treated arm. And desmoid cancers don't progress rapidly. So the PFS in these are usually greater than a certain number. But what's really important is what the doctors look at. They want to know objective response rate. They want to know, in the patients that respond, how much of the tumor has really gone away? What's your level of that? And so that's really important. And they want to know the score. It's called the T2 score, which kind of shows whether it's a real tumor or it's not even a real tumor anymore. So there's a lot of excitement around the drug we're developing because we think, in the newest data, which really was just a little bit more than we previously thought, but it's not anything staggering. It was just an update, and more time has gone on and more follow-up. Patients stay on the drug for a long time, and I think that's one of the good messages, and one of the things that SpringWorks has shown is patients can stay on these drugs for years if they're benefiting. Right. So the real key here is what we're looking for is to do best by patients. And the objective response rate that was presented in their FDA approval package was 41%. And in our phase II data, depending on dose and schedule, you could see response rates in the mid-60s. And the amount of tumor regression in the patients that respond, we had in the low 90s, and they had in the 70s. So you get deeper responses and higher response rate. Now, that's phase II, not phase III. So we have a phase III that's fully enrolled. It completed enrollment early this year. We are guiding that we will unblind it, based on it's an event-driven study. So we're guiding that we will unblind it in the second half of 2025. And it is something that we are really excited to do. Our plans are to commercialize the product. Right. So it sounds like you're still on track to disclose the top-line data in the second half of 2025. Absolutely. Great. And then, yeah, how do you think about the general market opportunity for 102 and desmoid tumors? And yeah, how do you think the drug will be used, perhaps relative to OGSIVEO? Yeah. So I think that the market is we're learning more about it with the launch of OGSIVEO. I mean, I think that that is really informative. And they've done a good job with the launch on there. And it's grown. And you could see patients staying on it. And there's a prevalence pool in the U.S. of slightly over 30,000 patients. The treatment pool that comes in each year has been something in the 6,000-7,000 range. And then there's about 1,600 new patients per year. And the numbers in Europe are pretty similar to the U.S. So it's a decent population. And one of the questions is, could you get more of the 32,000 patients into treatment if you had a really good drug that was easily used? We hear from doctors they would really like to see a once-a-day drug, which is what we have, not a twice-a-day drug. But that's not the reason why we undertook this. It was to do better and get better data for patients. So I think that once our data come out and provided that it's similar to our phase II data, I think it would be logical to see docs transitioning to that for the new patients coming in. For any patient that wasn't responsive, it would be logical to come in and get those, maybe more in the prevalence pool that are coming into treatment. For the patients that are responding to a drug, and this goes for any drug, if you're responding to a drug, doctors shouldn't take you off of a drug you're responding to. You should stay onto it. And that's the best thing for medicine. I think over time, depending on our data, we could command more and more and more of the market. Right. Makes sense. And then just one more. I know it's early still, but I know that you have global rights, presumably, to 102. Yes. We own it around the world. How do you think about capturing the rest of the world opportunity, assuming success in phase III? Right. So the clinical trial is US, Europe, Israel, Australia. So it's a global trial. And that's important. I've launched drugs around the world, as you know. And doing clinical trials in different countries is important because they want to see you have to do trials, and you have to be in Europe, and you have to be in Asia to get them to look at your data. And so we have a global trial. So that's the first good thing. The second thing is we hired a head of commercial a couple of months ago who is a star. I've worked with him for many years at Seagen. He was the head of two brands, ADCETRIS, which is now over a $2 billion brand, as you probably know, and Tivdak for cervical cancer. And so Roi Shahar is the head of commercial. He joined the company about two months ago from Pfizer. He stayed with Seagen to Pfizer and actually got promoted in a bigger footprint. But he's a superstar. And he knows how to launch drugs around the globe. In some areas, in territories, we would launch it ourselves and have our own salespeople. The U.S., especially the major parts of the EU, things like that. In some territories, we may choose to use distributors. And I did that at Seagen. We used distributors in a lot of Latin America and South America. We used distributors in other places. And you negotiate with them. And they come in, and they say, "Well, we want 50% of the drug, and we'll buy it from you." And then you negotiate. And if you end up at 65%, you're doing a good job. And they buy the drug for you and distribute it. It can work really well in some territories where it's maybe too cumbersome to launch a drug, especially if you only have one drug. If you have many drugs, it could be different. Right. Great. So maybe then switching over to ADCs. And so obviously, developing an ADC portfolio is a big focus area at Immunome. And maybe just talk about how you're leveraging your experience over the last several decades at Seagen to really build a new ADC platform, a new ADC company from scratch, more or less. Right. So thank you for reminding me that I've worked for decades, and I'm old. So I appreciate that. So I think when you look back at the founding when I founded Seagen, ADCs existed. They weren't called ADCs. I named them ADCs. But these targeted, empowered antibodies existed. And the one that was out there was Mylotarg. And that used a hydrazone linker. And the linker fell apart quickly. The vial itself, only half of the vial was naked antibody and half was conjugate because they didn't know how to conjugate to completion. So that was a pioneer. And I respect it as a pioneer. Now, it got pulled from the market because of other issues. But it was a great pioneer molecule. So now, how to do this? So at Seagen, I remember raising money. We were a private company before we took it public. People were like, "These don't work. Why are you doing this? Why are you raising money?" Now, there's more than 100 companies doing it. Raised a little bit of money to go forward with the concept of making better drug linkers. Antibodies were plentiful. There were lots of antibodies out there. In fact, when I incorporated Seagen was about eight months before Rituxan was approved. There was no antibody for cancer on the market, period, zero. It was obvious that the drug linker wasn't good for Mylotarg, which wasn't on the market yet. It was just a clinical agent. Making an empowered antibody, to me, was an obvious way to go. We needed better drug linkers. We worked and worked and worked really hard for years to develop a stable drug, a stable linker, and using a synthetic drug. Mylotarg used a natural product. So it's really hard to go get a natural product, conjugate it to a drug, and then conjugate it to an antibody. That's three major steps that it's hard to do manufacturing. So the concept that we had at Seagen was, let's take a synthetic drug with a synthetic linker, make that. So that's a one synthesis of chemistry. And so it's two steps. It's that synthesis combined with an antibody. And that was the magic dust, if you will, at Seagen, was coming to that and making a good drug linker. Now, 25 years later, half of the drugs being developed, maybe more, are the same handful of targets. It's not good. It's not productive. There's no way these are all going to get approved. There's no way to even show it. So if you take a drug and you want to beat an HER2, or you want to beat PFS, you're going to have to do studies that will be like 500 patients over four years. It's going to cost hundreds of millions of dollars. You could do phase ones. But to really get it approved is problematic when you have a really good molecule like a PFS. And it doesn't mean you can't get better. But wow, is it hard. And it's going to be hard to predict and hard to do it and expensive and long. So what we at Immunome look at now, and we say, really, what's it now? 25 years ago, it was, let's make a drug linker. Today, it's, let's use novel targets. And let's use novel targets to interrogate cancers and make new novel drug linkers. I think that's where the field is doing well. Now, we have a great toolbox. And we have great drug linkers to use. And they are great. And we keep on improving and improving them. Right now, our favorite drug linker is a topo with a novel linker. And it's a novel topo inhibitor. It's a derivative of exatecan and patented. And it has better properties than DXd. We just presented this at the Triple Meeting recently. It's not inhibited by multiple resistance pathways like DXd is. It's got different permeability. It's a shorter half-life. We think that could translate into more tolerable because the drug itself will leave early. You don't want the drug hanging out if it's not part of the drug conjugate or internalized. So it's got all the properties you would want: better linker, better agent, works well as a drug conjugate with a substantial DAR drug antibody ratio, and conjugates very well and is easily scaled. So we really like our drug linker as part of our toolbox. But the real key is all of these novel targets. And so we have collected quietly more than 50 novel antibody-antigen pairs. And we are working very hard to study them as fast as we can. And we've studied. Now I talked to my chief scientific officer yesterday. So we've studied about 20 of the more than 50 we have extensively. I think we've looked at more of them, but we've done extensive studies on 20. And with 12 of them having very extensive work done on it, including some of them with toxicology, some of them are entering into our development pipeline. You'll hear about them. And we haven't spoken about the novel targets yet because there are companies around the world in different places, like China. There's a lot of ADC companies that are doing excellent work. And if they see ADCs, they'll duplicate them quickly. And they're to be reckoned with. This is real companies doing good work. So you have to be careful and file a lot of intellectual property and come up with good packages. So we will be talking more and more about our ADCs and our novel ADCs when it's more appropriate. But the work is heavy duty. And we will go into clinic one after another after another. Now, the first IND is coming shortly. We've guided Wall Street first quarter, and we always try to beat that. But that's coming up fast, as you know, and that targets ROR1. ROR1, R-O-R-1, is a very interesting target because it targets both liquid and solid tumors. You may recall that there was a ROR1 from VelosBio, and it was a private company. I was looking at it very closely, and I wanted to buy the company when I was running Seagen for a number that was less than $1 billion. And it's where I thought it was, it should have been, and tried to make progress on that. The short story is Merck bought it for $2.75 billion, so it was a lot more than I thought it was worth at the time, and congratulations to Merck. Now, I think from the standpoint of Merck, now, while I am not Merck, certainly it's obvious that it has liquid tumor and solid tumor binding. And certainly, Merck saw a lot of the work, like with ADCs, of combining Keytruda with ADCs and how productive that is. So while I'm not Merck inside of Merck, it was easy to envision that they saw this as potentially combinable with Keytruda in liquid and solid tumors. But the original drug from VelosBio used an antibody that had modest internalization. And it had the Seagen drug linker on it, which has a DAR of approximately four. So what I think you'd want with that, and ROR1 is expressed in high amounts of liquid tumors but low on solid tumors. And their biggest issue, what they were focused on, was solid tumors with Keytruda a lot. So what I think is what you want is if you make a really good ROR antibody, you want to screen a panel, which was not done for that one. That was an individual antibody, and screen a panel looking for rapid internalization, especially if you have low antigen density like you do in solid tumors. You need rapid internalization. The antibody we have, rapid internalization. You also need a high DAR because you need potency if you don't have a lot of receptor. We have a DAR of eight. So you have a high DAR. You have rapid internalization. You have a stable linker. And then you do the preclinical work. And the drug link, the ADC we have is much more effective than the one from VelosBio that Merck has now. So we're excited to go into clinic. We're going to be filing IND shortly. We'll test it in both liquid and solid tumors. I think for liquid tumors, where Velos had shown it worked and Merck has continued that, showed that it worked for liquid tumors, I think it's a no-brainer that we should work very well because it works better. In solid tumors, we don't know. We're going to test it for sure. Preclinically, it looks much better than what was there. The question is, is there enough receptor coming in with a better antibody, faster internalization, high DAR, and I think we have a great shot at it, but certainly, as a liquid tumor drug, it could be a very important drug. Right. Right. So great. Thanks, Clay. So maybe just a couple of follow-up questions on maybe just on your payload first. So I think you're referring to this HC74 payload, right, where you had some data at the Triple Meeting g. So I know you know DXd tech very well, maybe too well. What are the shortcomings of the Daiichi technology? And how does your new payload perhaps address some of that? The Daiichi did good work on this. I mean, look, when I was at Seagen, I flew to Japan and went to Daiichi and showed them the technology and taught them about ADC. So that's there. And I think that's what you were referring to. But given that, they did a great job of developing it in the clinic and making it HER2 using the technology. And DXd was a linker that was very similar to the Seagen linker. And instead of using monomethyl auristatin E and antimitotic, they used a topo inhibitor. And it was an Exatecan derivative. And they call it DXd. And in the patents that Seagen has, it says, here's the type of linkers that are in there. And then it describes antimitotics and topo inhibitors and all sorts of stuff. So it's taught in that patent. And it teaches that. So what they did was they did some great clinical development. And what we have doesn't get blocked by resistance mechanism. So you put it into various cell types that have resistance to different cancer drugs. It is not blocked like DXd is. So I think it's more user-friendly. And it'll treat a broader array of diseases. It's also clearance is quicker, the drug. And so that could portend to better safety. It has different permeability. We have also a different linker with very good stability. So I think that the payload linker, the drug linker unit, if you will, is a serious improvement from DXd. And it shows it in all our preclinical work. And so that's what's going into clinic with a number of our ADCs. We also have work on novel drug linker units that are even further improvement. And we haven't talked about those yet. But in the future, we could do that. But we're very excited about our drug linker, our drug payload, drug linker right now. OK. Maybe just two quick follow-ups. So one is on your antibody pipeline. So your target pipeline, you mentioned there's 12 of them that you've sort of prioritized for now. I know you don't want to share the targets. But can you just talk in general terms about how you went about target selection? Is it market opportunity? Is it validated targets? Is it new targets? How do you prioritize those targets? So I think that the vast majority of them are novel targets. There are a few of them that are old targets that had failed for certain reasons. And now we have an antibody that binds or internalizes differently. Like an example, I'll draw an example from Tivdak. That was an ADC targeted to tissue factor. Tissue factor was studied by a lot of companies. They used antibodies that bound in certain ways. And what's really important with an antibody is they're all different. And they bind to different epitopes. So people think of an antibody as a receptor is a cup. And an antibody binds a receptor. That's it. That is far from the story. Inside that cup, there are thousands of dots. And those are epitopes. So each antibody has a different way it binds and it traffics. And some of them bind, and they bind in different ways. And the antibody that's in Tivdak is a unique tissue factor antibody that binds very differently and has different cross-reactivity with things like blood vessels where you see staining. And so you had to find an antibody that was different. And that's what Tivdak did. And that's where it separated itself from the previous ones. So at Immunome, we are bringing in antibodies in many different ways, many different configurations. We have discovered some on our own. We have in-licensed some. We have partnered with some. But we've amassed more than 50. And that's the same playbook at Seagen, basically. We didn't have antibody discovery. We amassed them through our.