Okay, welcome back. Hi, my name is Kelsey Goodwin. I'm one of the biotech analysts here at Guggenheim. I am delighted to welcome the MacroGenics team. Here with me, we have Scott Koenig, the CEO. And let's just dive right in. Maybe let's just start with a brief, you know, one to two minute overview of the company and your pipeline, and then we'll dive into each of the products. First of all, Kelsey, thank you so much for the invitation. Pleasure to be here, as always. Company right now, I'll just do quickly, is a little over 23 years old. I'm one of the co-founders of the company. The company was focused from its inception on developing alternative antibody-like molecules. We created three platform technologies, one around Fc engineering to enhance engagement of Fc receptors, one around bispecific, multispecific molecules, which we call DART molecules, and then ADC molecules. Company is about 350 employees. We're right outside of Rockville, Maryland, outside of D.C. We do everything from discovery and research, development. We have our own commercial manufacturing facility. In the history of the company, we've developed three molecules that ultimately got approved by the FDA, that are commercial now. The history of the company, we went IPO in October 2013. We've been very successful, bringing a lot of non-dilutive capital into the company, over $1 billion, since the IPO. Just for a point of fact, we've pointed out that, since mid-2022 to 2023, we've brought in $335 million in non-dilutive capital, to help fund the company. The company has enough capital to keep our programs going into 2026. As you know, we have multiple molecules in clinical development. We have a large preclinical portfolio, and we're, I would say, in the last year and a half, increased in emphasis on ADCs, with a collaboration. We have two ADC molecules in the clinic, collaboration, that we set up with Synaffix to have up to seven molecules, that using their technology, for new ADCs. We expect two of these to be in the clinic this year, and then we're working on targets three, four, five, et cetera. So- Mm-hmm. that's where we're at. A lot going on. Great. So there is a lot of focus, of course, in the first half here, on one of your lead programs, vobra duo. Remind us the construct of this asset and how we should think about the potential opportunity in B7-H3 positive cancers. Yeah. So as you know, Kelsey, we've been interested in this target for over a decade and a half. We were the first company to develop molecules targeting B7-H3. B7-H3 is a ligand in the so-called B7 family, structurally related to PD-L1, CD80, CD86, that's the family member. It's overexpressed on most solid tumors. It's expressed within a tumor microenvironment on dividing tumor cells, on the vasculature of the tumor, as well as T regulatory cells. Its expression correlates with poor clinical outcome, so we've been very interested in this target. And so when we first started out on this, we had over 50 antibodies to this target. We mapped a lot of different epitopes. We ultimately selected the one for the ADC molecule, vobra duo, based on its high tumor-to-normal tissue ratio and even a better incorporation than many of the other variable domains we had in our portfolio. So we think this is a superior variable domain for setup for an ADC type molecule. We then went and tested a number of different linker toxins. We ended up partnering with a company which is now called Byondis, which had a this cleavable linker toxin called duocarmazine. This is a DNA alkylating agent, so we had constructed this molecule with a DAR of 2.7. We had selected this based on, at that time, they only had phase I data with the same linker toxin targeting HER2. But ultimately, you know, they did a study called the TULIP study, with a molecule called SYD985, which they had a successful phase 3 study, but because obviously, the changing landscape in breast cancer, it hasn't been commercialized. But the fact that they showed a very good safety profile, their dosing at that time was 1.2 mg every three weeks. And then, obviously, the efficacy, that lends itself well, that we think we have a good linker toxin, and then, obviously, our own data, which has propelled us, so. Great. Yeah, I guess building on that, you've completed the dose escalation and expansion that was presented previously. Maybe just remind us what the clinical learnings have been to date for vobra duo. Yeah. So we were very excited when we originally did the dose escalation study. We started at 0.5 mg Q3, up to 4 mg per Q3. As early as initial patients at 2 mg per kg, we were starting to see significant anti-tumor responses. It was serendipitous that at 2, and then particularly at 3 mg per kg, we had patients in the 3+3 design that were enriched for prostate cancer. And what struck us is that we were seeing half or more of the patients having 50% reductions in PSA levels compared to their baseline values. So we said, "Uh-huh, we got something here. Something looks good, prostate." And before we even got to the 4 mg per kg, which was going to be our top dose, we said, "Let's go into expansion study." So we did a number of expansions between 20 and 40 patients. The prostate cohort, which was approximately 40 patients, again, we were seeing very exciting data, with about half the patients having PSA 50 reductions, similar to what we were seeing in dose escalation. But then, what we observed is that a lot of these patients were having their doses reduced, or interrupted, or completely stopped, despite the fact that they were having objective responses against their tumors. And the four main side effects we were seeing were typically fatigue, which it wasn't particularly discomforting. We were seeing marrow effects, mostly manifested by neutropenia, but this was more of a laboratory observation, in that we weren't really dropping their neutrophils down to levels that would induce increased infections or febrile neutropenia. It was more of a laboratory finding, and that was obviously managed mostly by holding the drug, in rare cases, giving some G-CSF. The things that were most discomforting to the patients were patients who developed Grade 2, which was hand-foot syndrome or palmar-plantar erythrodysesthesia. When you have a Grade 1, you get sort of redness and swelling in your hands and feet. When you get Grade 2, you get pain in your extremities. And particularly, patients that were exposed to taxanes, which have higher incidence in neuropathies, this seemed to be much more problematic. And so patients, despite the fact that their PSAs were dropping or they were getting tumor reductions, would come off the study. So we knew that that was something we'd like to get better. The other one was we were seeing fluid increases peripherally. We were seeing some evidence of patients, again, pleural effusions, mostly Grade 1, 2, and that was usually picked up on a scan when they were getting their tumor evaluations. There were some patients that obviously had thoracentesis to get their fluid removed, but that was a much rarer occurrence in those cases. So again, we wanted to see if we could fix and then continue having good activity and reduce these side effect profiles. So we did a full analysis of the data from that study. We looked at the PK of the free drug, we looked at the conjugated drug, we looked at the side effect profile. And what we observed is what you would expect when the majority of the patients either have dose interruptions, reductions, or stoppage, is that they never saw a 3 mg/kg every 3 weeks. They saw much lower doses. So when we calculated those doses, what they really saw, we kind of bookended them, and that came out to the dosing, which we're testing in TAMARACK, which is 2 mg every 4 weeks, or 2.7 mg/kg every 4 weeks. And if you really analyze this, it's not that great a change from the doses what we were doing. We're just giving a little bit easier administration. So if you, for instance, evaluate what 3 mg/kg every three weeks means in terms of dose, exposure, and a 2.7 mg/kg every four weeks, that's only a 28% reduction, assuming you got full doses for each. If you look at the 2 mg/kg, that's about a 47% reduction. So the fact is that if we actually are able to deliver to the majority of the patients 2.7 mg/kg every four weeks, we're probably delivering more than we delivered when they got in that other study, and obviously, with 2, we would be somewhat lower. So we think we're in this, hopefully, Goldilocks range... of allowing the patients to be exposed longer, which should lead to a better, you know, responsiveness, which we would measure from rPFS or duration of response, overall. So that's the objective of TAMARACK. As you know, the study was enrolled in about a six-month period of time. We got the majority of the patients in mid-year. First patients came in in the second part of the second quarter. We got a bolus of patients in the third quarter, and we were shocked, because as we got to the hundredth patient, we had all these patients still in screening. And so we had, you know, said that, "If you're in screening and you pass screening, we'll let you in." And as we announced to J.P. Morgan, we have over 150 patients in the study. That turned out to be very serendipitous for us, because the enrollment criteria allowed for patients who had up to one previous exposure to docetaxel. They had to have progressed on an androgen receptor targeting agent. So it turned out where, which was a surprise to me, is that a lot of patients came on that had not seen a taxane. So now we all of a sudden have two very sizable populations to evaluate the data, those that have seen taxanes and those who have not seen taxanes. And so we'll be able to look at this both in terms of safety, activity, and as we've said, we will have the first cut of the data either at AACR or ASCO. Okay, great. Yeah, that's a lot of information. Maybe to just dive in a bit on, you know, this having seen a taxane and not, how should we think about the efficacy benchmark there, especially kind of in the context of what you said that we've seen in the phase 1 dose expansion? So if you look at the last three studies which used docetaxel as a control, and as you know, we're doing another study called LORIKEET, which is using docetaxel as a control, the rPFS is about eight months. I mean, they were it was, like, right on eight, 8.1. So obviously, for the taxane-naive population, we like to see greater than eight months. Mm-hmm. The story on a post-taxane will is often dependent on what is the extensiveness of disease, how much bony disease they have, how much visceral disease they have, how much lymph node, how much combination thereof, and that's a little bit all over the place. It can go be anywhere from 4 months to 8 months. Obviously, Pluvicto saw even higher in their post-taxane. CONTACT-02 just was recent, came out data at ASCO GU. That was a Cabo plus plus Atezo versus a second ARAT. That was a 6.3 months versus a 4 and change. So my sense, and, CARD was about 8 months, so I'm, you know, I'm thinking about anything north of 6. 8 is better, 10 is even better, higher is better. So we'll have to see, you know, where we come out there. Got it. That's great. And how should we think about a registrational path forward? How are you thinking about that, and, you know, when will you meet with the FDA? When will phase 3 begin? And, yeah, how should we think about the potential design? It's still too early. I don't know the data. Let me say that again, I don't know the data, so I can't give you what direction. Obviously, we'll have to see what the effect size is in the taxane naive versus the taxane experience. That will determine the size of the study. The presumption is we could do both populations. You could do either one or the other. We'll have to see where that is. If it's taxane alone, it would probably be a control against docetaxel, as I just said. Mm-hmm. If it's post chemo, what we're finding is there's no perfect things. As you know, PSMAfore had crossovers with a second antigen receptor targeting agent. Cohort 2 had a second antigen receptor, but investigators don't like us to do that. So in the end, it may be picking a couple of sorts of opportunities, an ARAT, a chemo, something x, but we'll have to see. With regards to the timing, my sense is we probably will not have enough follow-up to get what the rPFS is by mid-year. It may be second half of the year when we have that, but we should have a good sense of safety, and general activity, PSA 50s and response rates, early in the year, so that if it's looking like it's moving in the right direction, we would then talk about operational way of doing a phase 3 study, meet with investigators, and, you know, get their feedback in that regard. And, you know, plan if, you know, again, if we get the activity and safety for a 25 phase 3. Got it. Great, and I guess what would be considered a win in terms of the safety profile as we kind of think about, you know, hand, foot, and pleural effusion? You know, what kind of- Numbers ... feedback have you gotten? Yeah, have you gotten from KOLs or, yeah. You know, I think in any study, I mean, if you go back and think about what happened with the T-DM1s, when ILD first came out, it was going to be the killer of bad things. Obviously, ILD, what's that? It's we can deal with that. When in HER2, it obviously is a blockbuster drug. I think what has happened is that even with the side effects we had and the experience we have, people are now more comfortable that these side effects can be managed. But our goal is taking those grade 2s on hand-foot to bring it to grade 1s, but also potentially decreasing the incidence. Same story, if we can get the fluid incidence down, again, grade 2s to grade 1s, et cetera, like that, that becomes- Mm-hmm ... better. What the absolute number is, we haven't defined that yet. Okay, got it. And then looking forward, what other solid tumors are of interest for this program later this year? So what we have said is that we are planning right now to go into probably 5, 5 or so additional tumors for expansion. These will likely be cohorts of, you know, 20-40 patients. What specific tumor types? We'll provide in near term the updates of the specific tumor types... Clearly, we haven't had experiences in. We had 1 patient in dose escalation with small cell. Given the Daiichi data and the Hansoh data, we'd like to see probably some cohort of small cell. We historically have discussed activity in a number in our other expansions, melanoma, for example, lung cancer. We had, you know, responses. What we ultimately end up with, we'll define it in the near term. Okay, great. Moving on to lorigerlimab. So you-- like you mentioned, the phase II LORIKEET trial is ongoing. Maybe just remind us of kind of how that was designed and what, what to keep in mind as we get initial data there, and when-- how that will kind of inform the next steps for the program, what the plan is for that? We're very excited about the prospects of this PD-1 CTLA-4 molecule. You know, this was designed to have as good or better activity than Ipi-Nivo combinations with a better safety profile. We were particularly focused on mitigating the GI toxicity associated with that combination. And I think the data to date has borne that out with activity which is at least very encouraging. So the way we designed this molecule is a tetravalent bispecific, two binding sites, the PD-1, two, the CTLA-4. You have full occupancy of any PD-1 positive cell at 1 mg per kg or higher. And if it expresses CTLA-4, it then obviously has a great avidity advantage to bind there on those co-expressing cells, which are enriched in the tumor microenvironment and tend to be the most exhausted cells. So the other way we improved upon this is that we surmised that a lot of the GI toxicity was due to ipilimumab is an IgG1, which can mediate ADCC activity. And as you know, a large percentage of Treg cells are CTLA-4 positive, PD-1 negative. And so we were surmising that a loss of those cells could lead to significant GI toxicity. And sure enough, when we dosed up to 100 mg per kg in monkeys, we did not see the GI toxicity that Ipi-Nivo seen. We dosed up to 10 mg per kg in our dose escalation in phase I. Again, did not hit the maximum tolerated dose. And then when we went into expansion and the data we presented a year ago at 6 mg per kg, Q3, we had 1 Grade 3 colitis. So it, you know, and this was giving the drug every three weeks. As you know, ipilimumab is given only for four doses at one mg per kg, and then, Nivo is given, Q3 weekly. So that study, as you know, had very outsized responses in castration-resistant prostate cancer. We saw 26%, confirmed objective responses, 29% PSA fifties. Every one of the nine of the 35 patients with objective responses that were confirmed had PSA nineties to hundreds. Two of those patients are still on drug every three weeks, two years out. So the tolerability there is terrific. Obviously, we have a big window if in combination, we need to reduce the dose, because, as I told you, saturation occurs at 1 mg per kg, and we were seeing Ki-67 upregulation on CD4s and CD8s at that range, as well as ICOS upregulation on CD4s. So we're now doing the LORIKEET study, which is a—we said, given that positive data, given that there is no approved checkpoint in prostate cancer, and given that the Bristol data at the same meeting showed a very inadequate response in a similar population, we said we'll go a one line higher in chemo-naive patients. So we're doing a 150-patient study, 2-to-1 randomization. 100 will get docetaxel plus lorigerlimab, and 50 will get docetaxel. We will start enrolling fourth quarter. We will enroll this study this year, and what I've said is if we get it enrolled by mid-year, then we'll have some data late this year. If we don't, if it takes longer, it'll be sometime next year. Um- We're looking at other indications as well. Mm-hmm. We will announce another tumor type, which we will start, likely later this year. Got it. And for... I guess, how should we think about, you know, this program in the context of also pursuing vobra duo, also in prostate cancer, and then the combination trial for the two? What's kind of the development path there? Well, I think we're putting a big footprint down in prostate. Mm-hmm. So the two studies I just described, obviously, we'll see where Vobra ends up, whether it's pre-chemo or post-chemos, but it's in sort of mid or late-line therapy. We think that LORI, which is now mid-line, could actually go earlier based on the safety profile. We'll see with VOBURDUO how early it can go. And as you know, we have a third molecule, enoblituzumab, or Fc-engineered B7-H3. That will start a study this quarter, it's called the HEAT study. This is basically an IST in neoadjuvant prostate cancer in patients Gleason essentially 8-10. There will be allowed some sevens in. This is a 219-patient study, 2-to-1 randomization. We're excited about the prospects here, but that's gonna take a couple of years, obviously, to get the readouts, and it's gonna be very heavily translationally focused in terms of T-cell activation, scannings, and everything in that regard. Great. Well, a lot to cover, and we didn't even really make it to a lot of the other programs. But I guess maybe in the last minute or so, is there any other pipeline program that you wanna hit on, that you're excited about, that we weren't able to cover? Yeah, I mean, as you know, we're taking advantage besides the checkpoint bispecifics, we have a next generation version of our, T-cell redirected killing mechanism. We have a partnership with Gilead there. And that's the middle dose escalation CD123 by CD3. We have a second program with that. Obviously, that's an option-based deal. We'll see where that goes. I mentioned already the new ADCs, the two that'll be in the clinic, this year. You should also keep an eye on the two molecules that we outlicensed, have... You know, there's over $1 billion of milestone potentials on these two approved products. Sanofi has indicated they have interactions that they'll update with the regulatory agencies on, on the new onset Type 1 diabetes. Obviously, that a positive result there could be valuable to us from a financial standpoint. The same thing with the Incyte relationship on our anti-PD-1, which is approved, ZYNYZ, which is approved in Merkel cell. There are two phase 3 readouts this year, one in front line lung cancer and one in anal cancer. If either one of those hits, that's obviously of value to us financially going forward. Great. Well, with that, we will wrap up. Thank you, Scott, for joining us. Thanks, everyone, for joining as well. Great. Thank you!