All right. We're going to go ahead and get started. I am Stephen Willey, one of the Senior Biotech Analysts here at Stifel. I'm glad to have with us in this next session the CEO of MacroGenics, Scott Koenig. Scott, I know we've done this a bunch of times before, but any opening comments you want to make before we jump into Q&A? I don't know if this is my swan song Stifel meeting or I'm going to squeeze another one in, but first of all, I want to thank you for all the years you've been covering us. You've been a real friend. You've always been professional. I love interacting with you on a personal basis. Didn't always get everything right, but having said that, it's really been great. Just a look back, you know, 24 years of the company. I think the company's in terrific shape, you know, aside from the market cap situation. If you really look at the full integrated company, we developed over the years three programs that got over the finish line and FDA approved. The company does everything from early discovery to late-stage development, but looking forward for new investors and even current investors, you know, we have three very active platforms. We'll have multiple readouts on phase II and phase I studies over the next three, six, twelve months. I could tell you our preclinical pipeline is chock-full of new opportunities using our proprietary platform. Going back to the history of the company, we raised over $1.5 billion of non-dilutive capital in the last 2.5 years, brought in $475 million of non-dilutive capital. Expectations are we will take advantage of both our platform and early-stage programs for additional deals. So I think we're in really good shape going forward. Okay. So I want to spend most of the time on the early-stage pipeline, but maybe we can just kind of get through some of the requisite overdue stuff first. So I know you're evaluating a few things here to ultimately make the decision what to do with this asset. I think you've indicated we're going to get mature rPFS data at some point early next year. That's one of the variables that is driving that decision-making process. I guess, you know, is there a threshold number in your mind that just makes you more positive on the overall risk-benefit at this point? So, you know, as you know, we provided an update at ESMO on the six-month landmark endpoint with an update on the safety. And as we indicated, is that all the patients that were enrolled as of July in the summer, no patients were receiving drug that the study would end after six more months. So you can figure out we're coming up to the end of the study very shortly. With regard to the specific number there, as you know, for standard of care therapy in the castration-resistant prostate setting, whether it be in the chemo-naive or chemo-experienced, you're running about eight months. So clearly, from an efficacy standpoint, we want to be in double digits. I'm not going to give you a specific internal house number of what we're looking at, but certainly that would be at least a baseline which you want to meet or exceed. With regard to the safety, as you know, we provided the update both on the side effect profile. You know that TAMARACK was designed to dramatically reduce particularly hand-foot syndrome and the effusions. We achieved that as we reported out with both 50% or greater reduction in hand-foot syndrome with lower grades there, a dramatic reduction in pleural effusions. What we observed is that because we were treating these patients for longer periods of time, that we were seeing some of the later timing of these pleural effusions. But in terms of the efficacy at the landmark endpoint, we were already at 8.5 months, which is what standard of care was doing with a confidence interval really for the upside there going forward with only 36% of the patients reaching an endpoint. So, you know, again, we're optimistic. We understand how the market has reacted to that. We said that we are not putting any new investment in that until we see what both the activity and safety profile there. And we'll assess that in the context of, is this an opportunity for a phase III in prostate? Is this an opportunity based on the activity and safety to go into another indication? And we'll let the data read out and come to a conclusion very shortly. Okay. I know one of the other variables that you've talked about in terms of what's driving the decision-making process here is, you know, your perception of the competitive landscape in prostate cancer. And you're obviously still leveraged to this via lorigerlimab and the ongoing phase II. Presumably, some of your B7-H3 targeting assets might be relevant here as well. What's your broader perspective on the competitive landscape in prostate cancer right now? Right. We're seeing approved therapies going further upstream. We're seeing new targets, new modalities entering downstream. And, you know, how complex of a landscape is this right now? And how much of a, how challenging is it, you know, that a trial that you plan and design and try to execute today might be competitively obsolete tomorrow? Yeah, I think that's a fair question, but let's just put it in perspective. This is the most frequent cancer in men. It's the second leading cause of death by cancers in men, so it has a great opportunity for anyone who's developing innovative drugs. We believe, and as we took a stand several years ago, we were attacking this at different lines of therapy, different mechanisms of action, and you're correct that, you know, current therapies, many molecules targeting PSMA with variations both on the radiotherapeutics or redirected CD3 dependent killing. You've got other classes of molecules coming through. You got the STEAP1 by CD3. You got Merck drug for the CYP17A1 molecule looking at the steroidogenesis, but we think that we can be very competitive with a number of molecules, and as you know, in the end, it's the combinability of these molecules. It never is a single agent that's going to take it through. And so as we look at the molecules and the orthogonal mechanisms that we're trying to exploit here in parallel, how, you know, what line of therapy can we go in? And I think that we can both address the earlier stage disease or the late stage disease, depending on the activity and the safety profile of the drug. So right now, from our vantage point, we think we can be very competitive there. Okay. So I guess we'll find out what happens to vobra duo here in the coming months, but maybe we can kind of shift gears to MGC026, right? So this is another B7-H3 targeting ADC you have in the clinic, same vobra duo antibody scaffold, but a different linker payload. So maybe you can just kind of talk about how this new linker payload differs from vobra duo and then how you're thinking about those differences improving the therapeutic index of the molecule. Okay. So just to lay this down again is that the variable domain for both vobra duo and 026 is identical. And we selected that based on a lot of work we did to identify a specific epitope that had the best tumor target to normal tissue ratio. So that was a start. It actually hits a domain which has been the crystal structure of the IgG4 form has been identified and it binds to the so-called inhibitory part of the receptor. So we're hitting a good part of the molecule and has a good tumor to normal tissue ratio. And then the third part about it is we selected that because it's a great incorporator. It gets taken up to the cells most efficiently. And we did some testing side by side. For instance, we made the variable domain from the Daiichi molecule and it is superior in terms of cell uptake in that regard. So from all those vantage points, we thought that was a good variable domain. Now, with regard to the linker toxin, as you know, we have a collaboration with Synaffix where we have up to seven slots from them. We have publicly announced the use of this with their topo inhibitor, the SYNtecan molecule, which creates an exatecan molecule. We like this linker toxin technology because it's a site-specific conjugation to the glycan in the Fc domain. You can put a DAR4 onto the molecule. And so this seems to be a nice range in terms of activity. And then in addition, based on the data that Synaffix and others now have produced, it seems superior to deruxtecan and SN-38 in terms of its potency. It has a better MDR profile, less MDR than those molecules, and greater potency. So overall, we think that this from a topo 1 inhibitor class can be quite superior. Now, with regard to the comparison to the vobra duo story versus topo 1 inhibitor, as I've pointed out many times before, different linker toxins and the mechanism by which they work will induce different responses depending on the tumor types. And also the combinability will be different, as well as their side effect profile will be different. And so, for instance, as you are well aware, for the case of the Daiichi Merck molecule, their data with over 50 patients of data in late-line prostate cancer showed an rPFS value of 5.3 months. We've already told you that vobra duo is already superior to that at the six-month landmark. And I think there will be upside there likely in terms of the rPFS for vobra duo. I don't know if the SYNtecan version is going to make it so much superior for a topo 1 in prostate, but we'll have to see. But we also have data in other tumor types where vobra duo will work better than topo 1. So I think, again, getting back to your question is I think this will be tumor specific. We'll see what the activity is in particular tumor types and we'll look at the potential combinability here. But we think that we have gone about this in the right way in assessing how do we maximize the benefit of an ADC for B7-H3. Okay. And so you're currently dose escalating in tumor types that are known to express B7-H3. Absolutely. You know, we have a large number of tumor types. As you know, there's a wider range in terms of the percentages and that, but virtually most solid tumors express B7-H3 and all the ones we're including there do express B7-H3. And again, I think you referenced it, but this same linker payload tech, right, is also found on another clinical stage. Yes. It's the Innovent compound, the Claudin 18.2. Correct. That's now moving into phase III, I believe, in gastric cancer. But when you look at that safety tolerability profile, you know, how do you think that is de-risking? I know it's a different target, but when you look at the safety tolerability profile of that drug, where they are dosing it, what conclusions do you make in terms of the de-risking it may or may not provide in terms of MGC026? So obviously we looked upon that data favorably that there isn't a, oh God damn, there's a terrible platform-based toxicity that we were going to see because we didn't know how, you know, hitting that particular site in the Fc domain might, you know, lead to a bad safety. So having that check with that activity is great, but it isn't just the linker toxin. It's what's the target, what is the density of that target, what is the turnover of the target, what is the incorporation, where's the expression on normal tissues? So I think there are many factors that will ultimately determine, you know, whether a drug will be successful. But I am, you know, comforted by the fact that they had activity and they didn't have a, oh, we have a toxicity we would never have expected going forward. So I guess when you look at the Innovent non-human primate tox data for that compound, right? I think their HNTSD was 30 mg per kg. I think with MGC026 you were able to push that to 50. And so do you think that delta then reflects the target biology and is that translating to a higher TI for you? I think that that difference here to translate from a monkey study to a human is too close to draw any conclusions. And again, back to the point of the variability on the density, the turnover, the receptors, all that may contribute. So I can't at this point speculate whether we're truly going to have a better TI. I could say that the toxicology data from the monkey studies was terrific. Not only did we have that for MGC026, but we also had that for what I imagine you'll ask questions about is MGC028, which is our ADAM9, has the same linker toxin. So having that experience now in monkeys and obviously the experience we have now to date with MGC026 in man gives us a lot of comfort going forward where we are. Okay. And so when you do declare tumor types for dose escalation or dose expansion, I should say, how does the selection of those tumor types, how is that selection process informed, I guess, if at all, by the I-DXd clinical footprint, which is the B7-H3 from Merck and Daiichi right now? Well, you know, again, this is becoming an exceptionally competitive landscape, as you know, in B7-H3. It's not only Merck, Daiichi, it's Hansoh, it's MediLink, it's all the 10 other companies that are now Duality, all the other companies that are following us. We were, as you know, the first company to go after B7-H3 into the clinic. In that vein, it's always nice to have a comparison to a tumor type that they may be pursuing. And that's why I thought the best data we had, at least for vobra duo, was on the prostate study for Merck, Daiichi. You know, given that many of these companies are focusing on small cell cancer, I'd like to have some comparison there just as that, not that we would go to compete in that indication. Because of the broad expression here in multiple tumor types, this is a great opportunity to look at other things that these companies might not be pursuing based on what we think might be the superiority of the linker toxin that we have for the molecule and the variable domain. I want to point out we think that variable domain has a superior profile. So we'll have to see what comes out of the dose escalation study. It's a cohort design. We have the opportunity to do many expansions when we see responses in the phase I study and then would obviously do a more expanded phase II development subsequently in that regard. Is there anything you can say about what you think the bystander effect of MGC026 is maybe relative to I-DXd? And I guess I asked the question, right? Because we know that the exatecan payload that's on MGC026 is more potent than the deruxtecan payload on I-DXd. And so I'm presuming that you need to manage that increased potency perhaps through the use of a more stable linker. And so given the stability of the linker, how does that then translate into comparable bystander effect? I'm not so sure we can extrapolate that at this point. Again, I think it's a lot to which epitope you're recognizing, what is the turnover there. Obviously, there, we go through waves of development of people wanting cleavable linkers versus non-cleavable linkers. I think it's just too early to, you know, come up with a conclusion about how important that will be at this time. Okay. Do you think that we're going to be able to sequence different flavors of topo derivatives in patients regardless of the target itself? I think the data to date says that is not going to be possible. I think that if you look at the data from the HER2 space with the toxins that were developed and it's irrespective of the target you go after, if you replicate the same class of molecule, there is very poor response subsequently in those patients that were pretreated with the same class of molecule because of resistance factors. I think we're getting the first look in the same thing with topo 1s here. So I am actually encouraged, and again this was part of our strategy and philosophy is to have different linker toxins that you could then go after a particular target because you would then obviate the resistance issue going forward. So I'm skeptical with everybody running into topo 1s that despite the fact that maybe some superiority went on that once a patient has progressed on that disease, you will not be able to go back with the same class of molecules. Okay, so that possibly has some interesting competitive implications for the entire drug development. I think so, and I think what it just says to you, it's not just the toxin alone. I'm back to the strategy I was espousing before. It's a combination story, so if you have the ability of orthogonal mechanisms and whether it's immune mediated or multiple different toxins with different mechanisms, whatever it may be, that I think will help to mitigate a lot of the resistance elements that we will contend with. Okay, and just timing on MGC026 dose escalation data, and I guess at that point, are you going to be in a position to communicate what the next development steps are? We're in the middle of dose escalation. From the timing perspective right now, all I'll say is, 2025 we should have the study done. I'm not going to give specifics on granularity of when we'll present the data, but sometime in 2025. Okay. You mentioned the ADAM9 targeting ADC again, kind of same linker payload. Why do you like this target, and you know, what, if any, learnings did you extract from the 50/50 development effort you had with ImmunoGen on the first iteration of this? Well, you know, again, back to the origins of our company, one of the goals with this company is to be a real innovator and go after targets that others have not pursued. We did that for B7-H3. We're doing that for ADAM9. We like ADAM9 based on the, again, expression pattern across lots of different tumors here. GI tumors, it's on prostate, it's on actually breast cancer and others. So we think that this has a broad opportunity in multiple solid tumors. We've picked again a variable domain based on a good tumor to normal tissue ratio. We picked one that is quickly incorporated into cells. So we like the variable domain. The issue that came up with the collaboration with ImmunoGen is we actually looked at their next generation at that point, a maytansinoid, the DM21. It turned out to be an exceptionally potent molecule, but with it came the toxicities that one sees in that class, which was the ocular toxicities. And we could never achieve the dosing that was, we believe, necessary to get the therapeutic efficacy. So when ImmunoGen was taken over by AbbVie, we both agreed that that would not be pursued. But given that we had full rights to the variable domain, we said, let's take advantage of a different linker toxin. And that's what led to the IND that we announced that we filed on it. Okay. Let's shift gears to lorigerlimab. Yeah. So this is currently in the phase II LORIKEET trial, I think in combo with docetaxel, pre-taxane setting, prostate cancer. I know that you think this is a differentiated molecule. Given the history of, you know, IO-focused drug development in prostate cancer being pretty unspectacular, I think we'd probably both agree. Well, a comment though, but go ahead. Oh, finish your question. No, so I'm just curious as to why, you know, why choose prostate, why choose the LORIKEET trial as kind of a proving ground to interrogate, you know, this differentiation of this drug? This is a classic story of looking at what was out there, looking at the data, looking at how does one fix the problems that were encountered that resulted in the failure, so when Bristol did ipi nivo combinations in prostate, they actually had a signal. They missed their endpoint, but there was activity of that molecule. As you know, Bristol tried very hard to get the right dosing and the right exposure, and they never were able to get more than 1 mg per kg of ipi in combination with 3 mg of nivo and only had to limit it to four doses, and so we believe that number one, by not having a CTLA-4 component beyond the four doses of exposure, limited the ultimate efficacy there. To address the toxicity issues, we made the hypothesis that if we could design this molecule with a superior bispecific profile and we made this tetravalent bispecific, you would get a higher avidity to co-expressing cells, which are enriched in the tumor microenvironment of the exhausted cells. And then by making this an IgG4, you wouldn't knock out the T-reg cells, which control many of the GI toxicities going forward. And that has actually turned out to be what we have observed, is that when we went through the monkey studies with dose escalation expansion studies, we were not seeing this overwhelming GI toxicity that there. And if you look at the phase I data, we did an expansion of 42 patients in prostate cancer and over 126 patients overall in different tumor types. This was. We was. We were able to dose these patients at six mg per kg every three weeks. And some of these patients in the prostate study were on over two years. And then if you then looked at the efficacy of that data in that phase I study, we saw PSA50s in 29% of the patients and objective responses in 26% of the patients. And at the exact same meeting, Merck showed the ipi nivo data of 9.3% objective response rate and 13.8% PSA50s. So we have a molecule that we can give much longer, better safety profile, and more activity. So we then went into LORIKEET and said, hey, let's move up the line of therapy to chemo-naive prostate patients. Sure enough, what we have announced on our recent earnings call is that we'll finish enrolling 150 patients studied, two-to-one randomization in androgen receptor targeting experienced patients who are chemo-naive. That will fully enroll by the end, within the next quarter, by the end of the year or beginning in 2025. That's a lot of data to be able to look at that. And that, you know, the fact that we're going to finish this enrollment says that the combination with docetaxel, which is, you know, has its toxicity unto itself, can be combined with a PD-1 CTLA-4 and given repeatedly, I think gives a nice profile there. And it's compared to all the other PD-1 CTLA-4s, we think we have a superior molecule going forward. So we'll wait for the data and we'll see where we are. But I can tell you that we are planning additional tumor types as well to pursue. Okay. Have you spoken to the magnitude of the rPFS benefit that you're powered to show in LORIKEET? We have not spoken to that. Obviously, we have internal views, but I've already spoken to that in the context of vobra duo, what standard of care is. The beauty of that, the study we have is we have 50 patients there being treated with docetaxel alone. So as I said to you, the standard of care is about eight months. We'll see if our patient population mimics what the historical data is as a control population. Okay. And then just the expansion of lorigerlimab and other tumor types beyond prostate, is that best done through a MacroGenics-specific endeavor or do you think that that's best done with a strategic partner on board? We're open to both. The plan would probably be exploring based on obviously our cash and where our other programs are to obviously move forward in that. But we're certainly open to having partners work with us to take advantage of what we think is a superior molecule. And I, which is, I should say also is that we have a great partnership with Incyte around retifanlimab. And the fact is, is that the variable domain, the PD-1 is the exact same one in lorigerlimab as in retifanlimab. All right. If there are no further questions, Scott, really appreciate it. I think I was going back through my notes the other day and I think it's been almost 15 years that we've been interacting. So have enjoyed all of those interactions. And if this is indeed your last Stifel fireside, then I wish you nothing but the best. Thank you very much, and again, I appreciate everything that you've done for us. Thank you, Scott.