All right. Well, welcome to this next Fireside Chat with Merus. I'm very pleased to welcome Bill Lundberg, CEO today at the Fireside Chat. Bill, welcome. Thanks for joining us. Thank you for having me. Before we jump into Q&A, do you want to just start out with some opening remarks? Sure. First of all, thanks to you and to the entire Guggenheim team for your continued support. It's a great partnership. We really appreciate working with you guys and the continued support we receive. For those not familiar with Merus, just a minute about Merus itself. We're an oncology-focused company with multiple clinical assets of our own and several with our partners and collaborators that I'll talk about, and we'll spend the entire time talking about. We are an oncology-focused company with a technology based in making bispecific and trispecific antibodies. These are complicated structures, and the strength of our technology platform is that we really try to simplify this to make these bispecific and trispecific antibodies essentially like monoclonal antibodies. What does that mean, and why should you care? The reason we do this is because we know how to make medicines out of monoclonal antibodies, and it greatly simplifies the process. We've been making medicines out of monoclonal antibodies for decades. So the more that we can rely on these tried-and-true approaches, a single cell produces essentially a single kind of bispecific or multispecific antibody, the more we can leverage things that have led to success already. So true high-throughput screens, letting the biology drive the selection of the clinical candidates, using process development, manufacturing capabilities that are for monoclonal antibodies, using global manufacturing capacity for our antibodies. And then because these are fully human IgG1 molecules, we can do all of the well-established engineering of these antibodies, like stealth silencing for T-cell engager approaches or enhanced ADCC capability. They've got reliable and predictable half-life in vivo and in patients and very low rates of immunogenicity. They basically behave really well. And while all of this doesn't guarantee success in the clinic, we think risk mitigating each of these little pieces does improve the chances that we can get really good drugs. And if you look across our portfolio, petosemtamab, which we'll spend the bulk of the time talking about, has really good clinical data in head and neck cancer. And zenocutuzumab, really good data in these NRG1 fusion cancers. Even MCLA-129, which we'll touch on just briefly, has very strong clinical activity. We believe it really derives from the foundational platform technologies that we use and relying on this concept of risk mitigating as much as we can to get the best possible drug to bring into the clinic. Great. Well, then maybe starting out with a question on petosemtamab. So you recently initiated two phase three studies, especially I think there's a lot of interest, especially in the LiGeR-HN1 study in first-line head and neck cancer, which just recently started, perhaps earlier than some had anticipated. So can you talk about what were the driving factors behind your ability to start that study so fast? Sure. Now, petosemtamab is our bispecific that's an EGFR x LGR5 bispecific that we discovered in a large high-throughput screen to really ask the question, what can we do that's better than just an EGFR antibody alone? We've shown really striking clinical data in head and neck cancer, both in the front-line setting with pembrolizumab, which you're speaking about now, and in the second-line setting as monotherapy. So across all of these, we've had really strong data for petosemtamab. We guided we would initiate a trial this year, and we started that trial actually at the end of the third quarter. And you've asked what's really helped bring that online. The first is the experience counts a lot. We brought on board Fabian Zohren as a new Chief Medical Officer earlier this summer, and he has thousands of patients' experience in getting up and running and executing on solid tumor oncology phase 3 registrational studies. We've strengthened our clinical operations team across the board. We really have the team now to drive this effectively, and I have to say also, we showed very impressive data at ASCO 2024, and we had a lot of momentum coming out of there and a lot of interest from investigators, from clinicians, from sites who really want to participate in the program, and that's helped a lot too. Great. And we'll talk about the ASCO data in a second. But just on the phase three study, just remind us how we think about timing here and how fast you expect to be able to enroll in the trial? So we've started this trial, which is a global phase three registration trial, which is our drug, petosemtamab, added to standard of care pembro in the first-line setting in recurrent metastatic head and neck cancer. And we haven't guided to timelines for enrollment, but we do point to the comparable of KEYNOTE- 048, which is a trial that enrolled in under two years. Great. And the interesting thing is you were able to get, I would say, FDA buy-in on using an accelerated path using overall response rate as a core primary endpoint. Can you talk about, yeah, how that really was enabled, perhaps by some of the discussions you had with the FDA? With our HN-1 trial, our first-line trial, it follows a paradigm that the FDA is really advancing, which is called Project Front Runner, which is this notion that front-line or first-line registration trials often take a long time to read out to get to the ultimate overall survival endpoint and their interest in having potential accelerated approval at an earlier time in these large randomized trials. We've said previously that we do believe, based on the Project Front Runner documents, guidance documents, our conversations with the FDA, and other comments the FDA has made, we really do believe that there's an opportunity for a potential accelerated approval based on an early endpoint, such as overall response rate in this setting. The FDA, when they talk about overall response rate, they often talk about durable ORR, which means a response that happens that is also durable for a period of time. And they've also paused particularly at conferences like Friends of Cancer Research has made comments about the importance of understanding that the other endpoints, such as potential early look at overall survival, is also trending in the right direction in this regard. But we do believe that an early endpoint, such as ORR, really can support potential accelerated approval with confirmation of the benefit coming from the ultimate overall survival endpoint in the same trial. Right. And obviously, the phase two data at ASCO was extremely impressive, especially on overall response rate. But the data set was relatively immature, but still limited visibility on overall survival, for example. So what is your confidence that you will be able to succeed also on overall survival in the first-line setting, especially when we think about some of the experience with the LEAP-010 study? That's right. So we reported clinical data in the first-line setting in head and neck cancer with our drug, petosemtamab, combined with pembrolizumab. And in that report, we described the response rate in 24 evaluable patients. And it was early, so we didn't have a readout on PFS or OS. Importantly, though, it was looking very good. 14 out of 16 patients who were responders were still in response at the time of the report. So although we couldn't say what the PFS or OS was going to be, it looked very, very good compared to the historical controls. And I think there's a lot of interest now in seeing a potential follow-up data set to this or a follow-up look of this data set to understand what the time to event endpoints, PFS, OS may really turn out to be. But it looked very promising at the time. Right. And then maybe switching to your LiGeR-HN2 study, which is your second phase three study in the second-line head and neck cancer setting, which obviously started slightly ahead of the first-line study and presumably will read out results first. How do you, again, remind us of sort of assumptions for this study and how should we think about the control arm to perform, perhaps relative to what we know about Peto historically in the second-line setting? In the second-line setting in head and neck cancer, patients are typically treated with cetuximab or chemotherapy and often single-agent chemotherapy. And when you look at the trials that have gotten those drugs approved on the map or run with these control arms, what you typically see is response rates in the single digit to teens, and you see overall survival ranging from about 5-8.9 months. Our clinical trial follows exactly two prior registration trials where the experimental arm, in our case, petosemtamab, is compared to an investigator's choice of one of three different treatments: cetuximab, methotrexate, or docetaxel. And the reason we allow investigators to choose three is neither of them, none of them work very well, and investigators have strong feelings about or different availability of these three drugs. But when you look at that control arm cohort, you really see a median survival of only about five to eight, 8.9 months in one case. What we've seen already with petosemtamab, the data set we presented at AACR 2023, was a response rate of 37% and a median survival of 11.5 months. So we think it's also in a very strong position in terms of setting up for a registration trial in the second-line setting. Great. And then you obviously do have an update coming up for the new monotherapy phase two study at ESMO Asia in a month or so. Yeah. Can you just talk about expectations here and how should investors interpret the updated phase two results, perhaps with respect to the ongoing phase three study? So we've guided that we'd be providing a clinical update at ESMO Asia. The presentation is December 7th. And for those of you who are night owls, I think it's 2:30 A.M. local time. So you have the opportunity to stay up to watch it remotely or lie there to watch it live. It is a presentation of the cohort that was initially presented at AACR. And there, the response rate is well understood, but the duration, these time to event endpoints, were only moderately mature. And so it'd be good follow-up on those patients. We're also providing additional patients' data. We ran a Project Optimist-type dose comparison between 1,500 milligrams and 1,100 milligrams around 20 patients each. So in the 1,500 milligram case, we'll have a lot more data and we'll have a lot more follow-up, particularly of the patients who had been treated early on to give the investors a more robust sense of efficacy here. We'll also provide the dose comparison, how did 1,100 do? and why was it that we were able to so clearly support 1,500 as our go-forward dose. And so I think investors will be interested in that as well. Great. And then just maybe going back to your two ongoing phase 3 studies, which are both enrolling a broad patient population. I think it's PD-L1 positive patients in a first-line setting, all comers in a second-line setting. There's some discussion in the field about potential activity of EGFR inhibitors in context of HPV status. And you're obviously enrolling broad patients in your study. Sort of what's your confidence level that petosemtamab works broadly across HPV status? Yeah, it's biologically really interesting. The most important thing for everyone to keep in mind is that anti-EGFR antibodies don't work in cancers that are HPV-driven. They just don't work. Zero response rate across trial after trial after trial. And so when we're seeing responses with petosemtamab, especially as monotherapy, that's different. That's fundamentally different. And I think that was the first observation that said, wow, this really can work in HPV-positive cancers. What we shared at ASCO 2024 now is also in the first-line setting in combination with pembro, we saw a response rate of 75% in the HPV-positive subset. All of these data are really quite striking compared to what cetuximab would do alone and really provide a compelling argument that petosemtamab really does work in the HPV-positive population. Great. And then if we fast forward, assuming success in both studies, how would you anticipate petosemtamab being used commercially if approved in both the first- and second-line setting? So if petosemtamab receives approval in both the first and second-line setting, where I think there's opportunity for petosemtamab, potentially really meaningful benefit for patients in those two settings, I would imagine that the label in the first-line setting would incorporate patients whose tumors express PD-L1. So the PD-L1 negative tumors would potentially not be part of that label, which is arguably around 20% of patients with recurrent metastatic head and neck cancer. In addition, there are patients for whom oncologists still believe that chemotherapy, cytotoxic chemotherapy, will be important for those patients. And so we would imagine there may be some patients who receive chemo pembro regimen upfront. All of those patients would come through the second-line setting not having seen petosemtamab. And that is a substantial proportion of patients who could potentially benefit from petosemtamab in the second-line setting. Okay, great, and then we're getting an increased amount of questions about potential label extension opportunities for petosemtamab. So you recently started a phase two study in colorectal cancer, for example. Can you talk about the study and how you think about the potential of Peto in colorectal and perhaps other indications down the road? So for us, colorectal cancer is really interesting. And it's interesting because it is the disease in which the role of LGR5 positive cancer cells has been defined as this subset of cancer cells, the subset of cells within a large tumor that really drive the growth and metastases of cancers. Now, we didn't set out to make an LGR5 antibody. We asked the question biologically, what can we add to EGFR? And it turns out that having a binding domain against LGR5 is really what gives petosemtamab this additional benefit. So in colorectal cancer, it's really been the place where the role of these LGR5 positive cells as driving the cancer has been so well defined. And that's partly why we're so excited about testing our drug in colorectal cancer in earlier lines of setting. Now, you recall that we did dose escalation in colorectal cancer. We didn't see any responses. We were quite disappointed. Turns out fifth-line therapy, phase one patient population, heavily pretreated with cetuximab or panitumumab or having RAS mutations, probably not the right setting to look for robust clinical activity. So we're excited to test now in an earlier line setting, which is our drug combined with 5-FU chemotherapy in the second-line setting in colorectal cancer. And we're really looking forward to those results. Can you talk a bit more about how well chemotherapy performs in the second-line setting and sort of what type signal in your study would give you confidence to perhaps start phase three development? Yeah, so the colorectal cancer landscape is evolving. The traditional approaches have been chemotherapy, a 5-FU-based chemotherapy with a biologic in the front-line setting and in the second-line setting. Whether you use bevacizumab, Avastin, or whether you use cetuximab or an anti-EGFR antibody, they seem to be interchangeable, as is the use of oxaliplatin in the combination regimen or irinotecan, and there's a higher response rate in the front-line setting. Patients do respond appreciably in the second-line setting, and there is some variability in the numbers depending on the study, so you really have to look at the different studies and really understand what's the patient population, what were they treated with initially, how are they treated now to understand where those benchmarks may be. One other aspect of this is that it's not only response rate in colorectal cancer that matters, but also progression-free survival and overall survival. Ultimately, those will take longer to get to in terms of data readouts. Right. Okay. And are there other opportunities for petosemtamab beyond colorectal that are under consideration perhaps? Yeah, we're interested in a broad range of other indications. There are areas both where we believe EGFR antibodies have played a role and where even other combinations of antibodies have played a role and where a potential LGR5 mechanism may be really interesting. Part of the challenge with being a relatively small company is our need to focus, and that's a theme we come back to, especially when we talk about the rest of the pipeline as well. And so getting our teams to focus on up and running with two phase three registration trials in head and neck cancer and delivering on our cohort in colorectal cancer has really been our primary focus, but we do recognize substantial broader opportunities with this mechanism or the mechanisms of action of our antibody. Okay. And then maybe shifting gears and asking a question about zenocutuzumab where you recently received a three-month extension of your PDUFA date from the FDA. Talk about how that may impact your partnering plans for the asset, which is something that you've mentioned in the past. Zenocutuzumab is our bispecific HER2 x HER3. It's in development for these NRG1 fusion cancers. NRG1 or neuregulin, also called heregulin, is the ligand for HER3. Our bispecific, again, it came out of a large screen of more than 500 molecules, is far more potent in blocking this pathway than simply HER3 antibodies alone. We've developed a clinical development set of programs to provide clinical data to support a BLA filing, which we announced we had filed and had been accepted by the FDA under priority review in May of last year. Just a week or two ago, we provided the information that the FDA had extended the review, as you described, to early February to be able to have additional time to review information that we had already submitted. Now, look, on one hand, I'm incredibly proud of our teams for we're a small company having actually taken a molecule all the way from discovering it ourselves all the way through clinical development and putting together immensely complex documents such as breakthrough therapy and this BLA filing, and to be able to do that as a small company together as a team is really quite an accomplishment. It is disappointing that the FDA has chosen to take additional time to review the BLA package, but we understand the process and we have to follow the process. I can tell you that we, well, as you know, we've talked about this for a long time. It's very important for us to have a partner to be able to make the drug commercially available because this is a modest opportunity, and again, our focus needs to be on petosemtamab. I can tell you that we're continuing to make very good progress with our partnering discussions. I'm excited about the progress we're making. Are there any specific type of strategic arrangements that you would consider for this? Yeah, I mean, zenocutuzumab is a molecule that's directed in a very molecularly defined or patient-specific type of oncology approach in lung and pancreatic cancers. And so a commercial partner that has capture or leverage in one of these areas would be really helpful for us, whether it's a personalized medicine approach or a diagnostic therapeutic understanding or a footprint in lung or pancreatic cancer. Those are the aspects that would be most helpful. Makes sense. And then before we wrap up, just a question on MCLA-145 and MCLA-129, which are two other pipeline programs. Can you just update us on current and potentially future development plans for those two antibodies? Again, we're faced with really interesting molecules and a need to really prioritize and focus our attention to petosemtamab. But let me say for MCLA-129, that is our EGFR x MET bispecific. It's like J&J's Rybrevant. Preclinically, we have reason to believe that it may be more potent than J&J's Rybrevant in certain areas such as MET-driven cancers. And this is where we have very strong clinical data in EGFR mutant lung cancer, in MET-driven lung cancer. And we've said that we could really benefit from having a partnership for this molecule to really put the resources, the mindshare, the commitment of the teams to be able to develop it effectively. Because this is a really active molecule in lung cancer. It's an exciting molecule. We just don't have the bandwidth and the capabilities to be able to deliver on that promise. For MCLA-145, this is our bispecific T-cell engager that grabs onto tumors with PD-L1 antigen and it grabs onto T cells with a CD137 or 4-1BB antigen. I will note that Genmab has decided to take their version of this molecule into phase 3 registrational studies in lung cancer, and here too, it's difficult for us to commit the resources. We're a company that's fortunate to have more assets than we have the ability to prosecute, and so we're open to partnerships there as well. Great, and you have a few discovery collaborations as well. Yes. Any updates you could provide on those? We have three major discovery collaborations originally with Incyte with up to 11 bispecific antibodies, which continues to move forward. The disclosures relating to all our partnerships really lie with the partner company, so they're not ours to speak about. We have a T-cell engager collaboration with Lilly, formerly known as Loxo Oncology Lilly, now Lilly. And we have a new Triclonics collaboration with several Triclonics programs with Gilead. Okay, so looking forward to hearing from those partners in the future potentially. So thanks. Well, with that, we'll have to wrap up. Appreciate your time. Great. Thank you.