Okay, great. Welcome back everyone to the Citi Immuno-Oncology Summit. The next session is with Merus. I'm Yigal Nochomovitz, one of the biotech analysts here at Citi. I think most everyone on the call knows me. If you have questions for management, I'm happy to ask them. Just email me at yigal.nochomovitz@citi.com, and I will relay the questions. With that, welcome both Bill Lundberg, CEO of Merus, and Andrew Joe, the CMO. Thank you very much for taking the time. Bill, maybe as a place to start, for those that are a little bit less familiar with the company, you know, just give a quick overview of the company and the pipeline in brief, as well as, you know, how your Biclonics antibody platform is different from what else is out there. Obviously, there's a lot of different flavors of antibody platforms in the industry. Thanks, Yigal, and thank you for the opportunity to participate in the summit this year. Really appreciate it, and also really appreciate the continued support from the broader Citi team. Merus is an oncology-focused company developing multispecific antibodies and antibody therapies for cancer. These are bispecific and trispecific antibodies in the human IgG format, so like monoclonal antibodies. We have a robust clinical pipeline, which includes a number of clinical stage assets that have shown early evidence of clinical activity and a safety profile, and those include zenocutuzumab in NRG1 fusion cancers, petosemtamab, or MCLA-158, as it's been known, that is a bispecific between LGR5 and EGFR, and we presented data in head and neck cancer. MCLA-145, which is a bispecific that binds onto activated T cells with PD-L1 and binds onto tumor cells. I'm sorry, tumor cells with PD-L1 and T cells with the 4-1BB antigen, and MCLA-129, a c-MET EGFR bispecific. We believe we have leading multispecific antibody platform based on this common light chain technology. Our bispecific and trispecific therapeutic candidates for cancer are based on a common light chain format, and that allows us to make essentially monoclonal antibody, except that it binds to two different things with the two different arms. Coming out of one single cell, we produce essentially monoclonal antibody, and that allows us to leverage the immense power of monoclonal antibody technologies that have been developed over the past two decades or longer, and it enables large scale screening of hundreds or even thousands of these candidate molecules. It's a fully human IgG and usually IgG1 format. We have ease of manufacturing, grams per liter producer cell lines, low immunogenicity risk, durable, consistent half-life and predictable behavior in vivo, and the potential for ADCC enhancement or all the other engineering tricks of the Fc region of the antibody. It's all covered by a robust IP portfolio. We're well-funded to beyond 2024 and well through a number of value creating opportunities for our clinical stage pipeline. That's us in a nutshell. All right. Perfect. Well, let's dig in then. Let's start with the obvious one, with Zeno zenocutuzumab. That's the HER2-HER3 bispecific for NRG1-positive tumors. So as far as I understand, you are planning to communicate a clinical update in the first half of the year. So it would be super helpful if you could, you know, to the extent that you can comment, give us a sense as to what's gonna go into that update. You know, how many patients, types of data, what should be the expectations for investors for that? That's right, Yigal. Zeno is a bispecific between HER2 and HER3, and we like to say docks onto HER2 and binds to and blocks HER3 and prevents HER3 from getting together with HER2. We're targeting these NRG1 fusion cancers. NRG1 is the ligand for HER3, which can be an oncogenic driver, and the fusion of a strong promoter in front of NRG1 really is what makes these cancers grow as cancers. At ASCO last year, we reported early clinical data that Zeno, in this setting of previously treated cancers with these NRG1 fusions, led to an overall 31% response rate, including 42% in previously treated pancreatic cancer and 29% in previously treated lung cancer. This compares quite favorably, for example, to Onivyde, the standard therapy for patients who've progressed with pancreatic cancer. They would receive Onivyde in a 5-FU regimen, and that has a 7.7% response rate. Andrew can provide more color on the trial and where we anticipate presenting clinical update in the first half of this year. Great. Thanks, Bill, and thanks, Yigal and the Citi team for including us in this discussion. As Bill mentioned, last year at ASCO 2021, we reported on 47 patients that represented nine different tumor types, including non-small cell lung, breast, pancreas, and some others. In that data set, we showed that Zeno therapy led to responses in non-small cell lung cancer, pancreatic cancer, breast cancer, and cholangiocarcinoma. The trial is ongoing, and as of last September 2020, we reported we had enrolled over 80 patients. We'll provide that updated efficacy and safety information from this larger data set in the first half of this year. Okay. Very, very good. You mentioned a few other tumor types besides PDAC and non-small cell lung cancer. Which are the other ones where you believe you have a good chance of showing activity and potentially going into later stage development? All right. It should really be any cancer, right? If we're developing this in a tumor-agnostic way, the biology says that NRG1-positive cancers should respond. We've demonstrated responses in lung, pancreas, and the pancreatic cancer responses are very remarkable compared to standard of care in any disease setting. We've also demonstrated responses in breast and cholangiocarcinoma. These are pretty uncommon fusions that occur. We're now actively enrolling other tumor types to see where responses could be demonstrated. We're still working on this larger data set now. In terms of the relative prevalence of the NRG1 phenotype, can you just give us a broad sense as to how prevalent this fusion is across the different solid tumors? NRG1 fusions are generally more common in pancreas and lung cancers. Having said that, I'd say that they are rare events overall, with estimates in the several thousand new patients with this type of cancer in the U.S. each year. We've cited data that suggests that in pancreas cancer, it's between 0.5% or 1% and 1.5%, and in lung cancer, between 0.3% and 3%. Generally, among all other solid tumor types, such as breast, ovarian, cholangio, and other types, it's around 0.2%. A couple thousand, several thousand patients a year. We liken it around to around an NTRK type of opportunity. As you and others have put forth estimates and models around this range of numbers of patients as well. Importantly, from a patient identification and diagnostic standpoint, it's worth noting that these rare events occur specifically in subsets of particular cancer types that we focus on. Within lung and pancreas cancer, it tends to occur in patients whose tumors are RAS wild type. As you know, and it's gotten a lot of attention recently, the RAS-targeted drugs are specifically indicated for patients with tumors like lung or pancreas that have mutations in RAS. That's already a diagnostic algorithm which would identify the roughly 10 or 15% subset that have a wild type RAS and would not be eligible for those therapies. NRG1 fusions are overrepresented significantly in that subset of patients. We believe there's a path to a patient identification that's important for us here as well. That's very interesting. In terms of I mean, obviously, there's precedent for tumor-agnostic label, as you know, with Loxo, Ignyta, and so forth. Curious to know, you know, how much dialogue have you had with the FDA to this point on Zeno and the potential for a tumor-agnostic label? What do you believe might be the durability bar and the activity bar for a label, an initial label? We have had ongoing conversations with regulatory authorities, and specifically with respect to the FDA, we have previously received Fast Track designation for NRG1 fusion cancers. The FDA had previously indicated NRG1 fusion cancers could be a population of interest. With regards to our specific program, Andrew can provide some color on recent discussions with the FDA that we had shared an update about towards the end of last year. All right. Thanks, Bill. We did speak with the FDA last year on a potential regulatory path forward. They were highly interested in us pursuing a tumor-agnostic approach rather than tumor-specific development. We aligned on three important points that we will seek a tumor-agnostic development program and indication for Zeno in patients with previously treated NRG1 cancer. That the trial design, our main trial design, which we call the NRG trial, could support a BLA filing and program development. Thirdly, if the current rate of enrollment and efficacy remain consistent, we should have a sufficient number of patients by mid this year with sufficient follow-up to form a potential registration data set. Could it be? I mean, I remember with Loxo, I think it was only 55 patients, right, for the approval of the registrational data set. Is that the right sort of ballpark for how you're thinking about it? I think it's fair to say that, you know, Loxo's drug, larotrectinib, had a 75% response rate, which is the highest of all accelerated approvals in oncology over the past number of years. There is a robustness of that number allowed a more modest population size. It's important to take into consideration what the response rate is that the drug is providing and what the error bars may be in terms of that. We're not providing specific numbers we aligned with the FDA on, but rather characterizing it in terms of what other comparables or benchmarks are that I could share with you. Importantly, we believe we will have reached the number of patients with sufficient follow-up by the middle of this year to support a potential BLA filing. Yeah. I think for the benefit of everyone listening, if you could quickly just highlight the benchmarks, that would be really helpful. The 11 most recent accelerated approvals in oncology, which include the five most recent tumor-agnostic approvals that are based on single-arm primary endpoint of overall response rate with a secondary measure of durability. The number of patients have ranged from 54 and 55 for entrectinib and larotrectinib, respectively, with very high response rates up into the 100, 120, 130, and perhaps a little larger for larger populations. Andrew led one of those registration-directed efforts in a previous company. With respect to the efficacy benchmarks, they've ranged from 15% for Tazverik in epithelioid sarcoma to 75% in terms of ORR for larotrectinib. You know, we believe we have a real opportunity here to have medicine that has efficacy and safety results well within the ranges of what the FDA has previously been able to support. Okay. We did align on specific benchmarks and thresholds for these numbers, and we're comfortable with those. Okay. And as far as, you know, line of therapy, are you thinking that this could be a frontline therapy in the NRG1 positive patients? Or for instance, with pancreatic and non-small cell lung cancer, would the expectation be that those with NRG1 positive tumors have to go through the standard therapies first? Yeah, it's an important point. Andrew, perhaps as our Chief Medical Officer, is better able to provide color. Okay. Yeah, it's a great question. Like I mentioned, the pancreatic sequence is really strong. It compares favorably, definitely in a second line, also front line. What we'll do for the tumor-agnostic approach in general is previously treated because we're gonna be using a single-arm data set. It becomes a lot more challenging to do a tumor-agnostic approach in the first line because many cancers have pretty good first-line therapy, chemotherapy response rates in the 50s and 60s. In order to continue a tumor-agnostic program using single-arm data, it'll be challenging in the first line. It depends on the efficacy signal. If the signal is sufficiently greater than the available first-line therapy, that could, you know, that could defend a single-arm approach. The other alternative would be to then pursue individual tumor-specific frontline strategies like pancreatic, for instance. The other thing that the FDA will wanna see is at least in the current data set, is if we have any frontline treated patients in chemotherapy naive. These are all the things that the FDA will use in considering a first-line label in addition to a tumor-agnostic previously treated label. It'll be like current sample size, current efficacy, what the other standards of care offer, and then an unmet need. That's a good question, though. Yep. Thank you. Not that you need to combine Zeno with anything, given it's what looks to be pretty good activity. Are you thinking about ways to combine Zeno with other mechanisms? If so, what might those be? Yeah. We're, you know, well, we are focused currently, as I said, on a tumor-agnostic approach in the previously treated setting. We are actively thinking about further additional lifecycle aspects of the drug, and these could include moving it into a different line setting or combining it with either immuno-oncology or chemotherapy. As Bill kind of alluded to, these cancers, the NRG1 cancers, tend to occur differently from cancers that have a driver mutation. We probably will not think about combining with a tyrosine kinase inhibitor, one of the oral agents. I think we will be thinking about combinations with chemotherapy and certainly IO. Okay. Bill, one- Yeah. One important characteristic worth noting is that the safety profile to date of Zeno in a large number of patients is really quite favorable. It allows us some latitude to consider combining with a wide potential range of therapies. Got it. Just a couple other questions which I think people might be interested in is, does anyone else have a HER2/HER3 bispecific that you know of? Is anyone else out there trying to develop something in NRG1 positive? I'm not aware of it. There have been other bispecific antibodies, mostly in research or preclinical development, in cancers. There isn't much there to speak of m ore relevant perhaps is efforts to pursue this specific indication, NRG1 fusion cancers with anti-HER3 antibodies, of which there have been a number of them. GSK had an antibody, HER3 antibody a while ago. Merrimack Pharmaceuticals had one, which is now seribantumab, which Elevation Oncology is developing. Hummingbird Bioscience has an anti-HER3 antibody as well. These are all much earlier efforts, and there are some of them, more than thirteen preclinical and clinical efforts to try to use anti-HER3 antibodies to block the HER3 ligand interaction. To date, they have not been successful. There are, you know, continued efforts to try to optimize those approaches. I would say that they were much earlier. In addition, when we've compared in a 2018 Cancer Cell paper, our bispecific to anti-HER3 antibodies in a variety of different assays, what we've seen is that this HER2/HER3 approach, docking onto HER2 and then blocking HER3, is much more potent in these in vitro NRG1-directed assays. I mean, it's interesting because you basically increase the probability that you're gonna bind HER3 by binding HER2 first as a lever. I guess that's the way to think about it. That is our approach. That's right. Okay. Sorry, Andrew, I interrupted you. Did you wanna say something? No. Okay. I mean, you can also know that, you know, NRG1 fusion, this is a new entity. With our ASCO data set last year, we demonstrated this is actionable. This is a target that occurs that we can target clinically. You know, the entity is becoming more recognized. That's why we see now other companies now looking at NRG1 cancers in particular. Very, very interesting. Okay, let's, unless you guys have any other comments on Zeno, let's move on to 158. So this one is also very interesting, as said, and I noticed in your recent press release it now has a name, so that's we guess we can call it Petos. So tell us about the data at the AACR-NCI-EORTC last year. That was really interesting data in head and neck cancer. Maybe just remind everyone listening about that data set. Peto or MCLA-158 is our bispecific that binds with one arm to the well-known cancer antigen EGFR and the other arm to LGR5, which is an antigen in the WNT pathway. It is primarily used in embryogenesis in development in utero, and it is very rarely expressed beyond embryogenesis. But where it's expressed, it can be expressed in some stem cells and importantly in cancer stem cells and then in particular cancer types like colorectal, head and neck cancer, gastric, esophageal, etc. We identified LGR5 as a potential partner for EGFR. Because our platform allows us to do large scale screening, we undertook a screening effort to ask what can we add to EGFR to try to get a more robust response. You know, most patients with head and neck cancer or colorectal cancer, their tumors express EGFR, but pretty consistently, the response rates to anti-EGFR antibodies is really only about 15%. There's a big gap there in our understanding mechanistically. That was the basic science that led up to the discovery and identification of this as a partner for EGFR. LGR5 is a partner for EGFR in this setting. I'll turn it over to Andrew to speak to the clinical data. All right. Thanks, Bill. We had a poster last year at the triple meeting, which is the AACR-NCI-EORTC meeting that occurred. At that meeting, we had a poster presentation or a slide deck where we showed Petos activity in seven patients with previously treated head and neck cancer. Of the seven patients, there were three partial responses. This is a small, very small data set, but we have been encouraged by that data so far. The poster's on the Merus website if anyone wants to refer to it. You had, if I recall, about a year ago, you did have some earlier data for 158 in, was it in colorectal? That didn't look as good. I guess the understanding was in head and neck, you just have a much higher expression of EGFR. Is that correct or no? Right. There you go. Yeah. You're referring to the ASCO. There was an ASCO GI poster in 2020- Yeah. where we described the dose escalation cohort for Peto, which is primarily patients with colorectal cancer. We also briefly described a gastroesophageal expansion cohort. We did mention that there were signs of activity. This is mainly a dose, an RP2D sort of poster establishing the recommended phase II dose and providing some initial safety data. As Bill mentioned, EGFR and LGR5 can be dysregulated in many different tumor types, including gastrointestinal cancers, and that's why we decided to look at Peto in gastroesophageal cancers. Okay. Got it. Just turning back to head and neck, what's the next steps for the program, and when could we expect to see a broader data set beyond those seven that we saw last year? Right. We're currently enrolling the patients. We wanna be really thoughtful about our regulatory strategy, including a possible pivotal study design. These will, of course, depend on things like efficacy in the population. Then when we define the population, you know, what are available standards of care? What's the unmet need? We do believe that so far, that if our early efficacy and safety signals continue in a larger data set, this could provide a single arm strategy, where the comparator would be cetuximab in the second-line setting. Of note, the response rates for cetuximab in this setting tend to be around 13%. This is something we're thinking about as seriously, and we'll have to figure this out once we see the magnitude of efficacy in the larger data set. Okay. Is it fair to say that the next study could potentially be that pivotal study comparing with cetuximab? I think that's fair. That's fair to say. We haven't provided any specific guidance around what the next study will be, and obviously, we wanna have the opportunity to look at data from a larger data set. Having a registration-directed opportunity as the next step, I think is an important component of this program. Yeah. I wanted to clarify. The pivotal data set in the comparison could either be in the same trial as a randomized trial, or it could also be a single arm trial with a historical comparison. Depending on the efficacy benefits. It can either be a singular approach or it could be a randomized trial against cetuximab. Okay. Are you doing anything in terms of LGR5, looking at the biomarker, looking at the expression there and correlating with activity, or is that not where you're going? I think the biomarker work is very important here. We have some very interesting, albeit very early data in head and neck cancer and important responses in a significant area of unmet need, where the historical comparison, historical response rates for cetuximab is 13%. So we really want to understand the characteristics of what is associated with responders. Obviously, LGR5 and EGFR expression are two very important components of that. To the best of our ability to get on study biopsies too, which is difficult from patients with cancer in these phase I or phase I/II studies, but to the best of our ability to get additional tissue, we'll really try to interrogate to understand the characteristics that correlate with response in the study. Where do you stand as far as MCLA-158 in gastric cancer? Are you gonna pursue that one or are you gonna pivot to the head and neck? We haven't talked about the gastric cancer cohort yet. We will provide a full update on the program, both the head and neck cohort and the gastric cancer cohort. We hope to be reporting a substantial number of patients when we do talk about that program later this year. Okay. Similar question as before on combinations. What are you thinking as far as what, I mean, you may not need to do this, but just if you were, you know, put your thinking cap on as far as what to combine it with, what would make sense? Obviously, not cetuximab because you already, that would be redundant, I assume. Chemo or other targets. Yeah. In the head and neck cancer setting, I think if we continue to have a strong signal of efficacy and safety in the second-line setting, there may be a straightforward path to developing the drug and seeking approval. The next immediate question would be in the front-line setting, where Andrew has commented that combination therapies in the front-line setting are generally the preferred way to go. Andrew, do you wanna provide some color there as well? Yeah, sure. Thanks, Bill. Yeah, again, depending on the signal, the strength of the signal, definitely monotherapy in a second-line setting. It's actually second or third line, depending on whether they get chemo and pembrolizumab in combination or sequentially. That would be the next step, whether we could do like what's occurred in lung cancer. You could either combine 158 with chemo and immuno-oncology with like a triple regimen, or you could try to do it with chemo only or IO only, or you could avoid chemotherapy. It'll depend on the strength of the signal. Okay. Makes sense. Good. Let's move on then. MCLA-145, which is your PD-L1 CD137 bispecific. I guess just first, operationally, what is the status of the phase I in solid tumors? How close are you to sharing some data there? That's right. MCLA-145, our bispecific that's designed to engage T cells on the 4-1BB antigen or CD137 antigen and bring them to the tumors that express PD-L1. We did report out early interim data at ESMO IO in December, where we showed clinical data on a number of patients in the dose escalation portion, and Andrew can provide some color on what we provided there. Thanks, Bill. We had a poster at ESMO last year, sort of an update of where we are in the phase I/II study. Mainly this is a safety study. The safety presentation, we noted some hepatic and some neutropenia events that occurred, and these tend to be similar to other bispecifics like the Genmab compound, but also very similar to the 4-1BB drug. As Bill mentioned, 145 is a bispecific for CD137, which is also known as 4-1BB and PD-L1. The rationale is that the drug will bring the bispecific closer to T-cells by binding the PD-L1 on the tumor cells to avoid toxicity. We are seeing toxicity that looks very similar to the 4-1BB drugs, which has been challenging in that with respect to that area of development. Okay. How much, so to speak, how much more bang for your buck do you think you can get because you're, you know, you're hitting both PD-L1 and the 4-1BB as opposed to just the PD-1 axis? It's a very important question. With these drugs, we and others have shown that for bispecific antibodies that bind onto two different cells, including the CD3 T-cell engagers and others, there's an optimal amount of drug that you want. If you don't have enough drug, you won't get any complexes bringing T-cells to tumors. If you have orders of magnitude too much drug, you won't have any one antibody binding to both the T-cell and the tumor cell at the same time. There'll just be far excess antibody sticking everywhere. In that range of optimal dose or optimal exposure, it's sufficient or optimal to bring the T-cell to the tumor, but it's probably too low to fully block the PD-L1 axis. The original hypothesis of this drug was we can bring activated T-cells to the tumor. We can also take off the brakes of this checkpoint pathway. We and others, other companies developing these types of drugs, have come to the conclusion that we wanna first optimize the dose and the type of patients, which we've been doing and reported out at ESMO, and look for early evidence of clinical activity. We also really need to develop these drugs in combination with a PD-1 blocking antibody to get both effects. That is the original hypothesis of the drug. I got you. Just so everyone on the call understands, if the dose is too high, what you're saying is that on the immune cells, you're gonna saturate this 4-1BB with the drug, and then on the cancer cells, you're gonna saturate PD-L1, and you're just not gonna have any crosstalk between the two cells. That's right. Got it. Okay. Makes sense. I think we've answered the next question. What's the strategy then? I mean, obviously this mechanism is very general. It sounds like it could be in any solid tumor. Is there any reason to think that it could be better in certain solid tumors versus others or no? Let me touch on one operational aspect, and then Andrew can answer the where the drug may have efficacy and what are we doing next with the drug. That is, we announced several weeks ago together with Incyte that Incyte was returning the ex-US rights to us, and I wanted to make sure we touched on that. Mm-hmm. We had this drug in a partnership as one of our up to 11 bispecific antibodies with Incyte, and Incyte had elected not to continue to jointly develop this. They had a portfolio review. They looked at a number of their clinical stage assets. They chose not to move forward with a lymphoma drug, and they chose not to continue to move forward with this drug as a portfolio issue. Part of it was from the perspective of having the investment that they currently have with us but only having the ex-US rights commercialization opportunity. We now have regained global commercialization rights to the program. After a transition period, we also will now fully support or fund the program ourselves. I just wanted to make sure we touched on that and then Andrew in terms of next steps for MCLA-145. All right. Let's jump on here. As you mentioned, we're continuing our dose escalation study, and we are a global program. We have sites open both in the U.S. and the EU. What we're working on is the traditional dose escalation of a compound, MCLA-145 in this case. We are also considering combining with the PD-1, as Bill mentioned, and then other companies have also proposed. Okay. Actually, one other question, just another conceptual question I just thought of. Yeah, I mean, so you're binding PD-L1 on the cancer cell and CD137 on the immune cell. Does it really matter whether you go for a combo with a PD-1 versus a PD-L1? Is there any reason to think one would be better than the other, or it doesn't really matter? Our thinking is, you know, not all the PD-L1 sites are bound at the optimal concentration of, you know, so we, sorry, of 145, so we could use an anti-PD-L1 drug, but it also may compete. Yeah. MCLA-145 binding on tumor cell. That's why generally we're looking towards combining with a PD-1 blocker, so blocking this pathway on the T-cell side. Right. Very interesting. Okay. That's sort of fascinating. I'm looking forward to seeing that. All right, let's move on so we don't run out of time. MCLA-129, this is your c-MET EGFR bispecific, again, for solid tumors. Tell us about the rationale for combining c-MET and EGFR. Tell us about the status of the phase I/II, and your partnership with Betta Pharmaceuticals in China. Yeah, happy to. I can speak to two of those, and Andrew Joe can speak to the clinical trial. MCLA-129, a bispecific between c-MET and EGFR, was really developed around the time or started around the time that c-MET was being identified as a mechanism of resistance to EGFR inhibitors. The initial thinking was that if we bind to and block both c-MET and EGFR, maybe we'll be more effective at growth inhibition of the cancers that might use c-MET as a bypass pathway. We've developed this drug and along the way, we and also J&J, which have a similar drug in Rybrevant, have identified not only blocking ligand, EGF, EGFR, HGF to c-MET but also the importance of the host immune system, whether it's ADCC or ADCP or another mechanism, in really driving these cancers, eradicating or shrinking these cancers. I think we've found more anticancer effects as we continue to develop the molecule. Andrew, do you wanna speak to where we are with the clinical trial? We are currently enrolling our dose escalation portion of the phase I/II study. As you mentioned, Yigal, Betta also has a phase I study. We have a very strong collaboration with Betta, with the Betta team, and we're both conducting phase I studies. Their study is in China. Ours is global. We currently have sites in the U.S. and EU. It's been helpful in helping to understand both the drug characteristics, the efficacy of the drug. I think it'll be good in our plan to accelerate development. Okay. Are you near identifying a phase II dose? When might we see some clinical data? Andrew? All right. What we're planning, we're in dose escalation now, and we're planning to provide some data later this year. We're not gonna wait to have a data release based on anything from an expansion cohort. We will provide some data as soon as the recommended phase II dose has been determined. Okay. Obviously, another key question, an important question I think, is how does MCLA-129 compare with the competitive landscape and specifically with amivantamab? I'll speak to the mechanisms, and Andrew can speak to the clinical landscape. First thing to acknowledge is that they're very similar molecules. They're both IgG1 molecules that bind to the receptors and block ligand binding to the receptors. They're, of course, different antibodies, so they bind slightly different places, but mechanistically they're really quite similar in that way. They also both undertake engaging an immune response. They're both ADCC enhanced. One important difference, we believe, we understand, is that the amivantamab molecule, because of the way it's manufactured, may only be half ADCC enhanced. Our MCLA-129 is fully ADCC enhanced using the same ProBioGen low glucose technology. I think ultimately we'll have to see how that plays out in the clinic, but it is just an important distinction to note. Andrew, do you wanna speak to some of the clinical considerations around amivantamab versus MCLA-129? Yes, sure. You know, mechanistically, there could be a difference in efficacy. We'll have to see once we look at the MCLA-129 in a larger data set. We also think there could be an opportunity for a better safety profile and maybe drug administration. I mean, amivantamab has to be split into two days, and it's weekly doses given. I think there are many opportunities, safety, efficacy, drug administration, convenience for the patient. Many opportunities for differentiation. Okay, very good. I did just wanna remind listeners that you do have a partnership with ONO Pharmaceutical ONO-4685, that's the PD-1 CD3 for T-cell lymphomas. I know you can't really talk about it since ONO is controlling the program. Anything you wanna say there or did I summarize it correctly? You summarized it well. We have a partnership. We've licensed the PD-1/CD3 bispecific to ONO and if the program is successful, we receive milestones and royalties. Okay, got it. I think just to round out the session, it would be helpful if you could run through, just summarize the key milestones and catalysts for 2022, 'cause obviously everyone listening is super focused on the catalysts. For 2022, going down our clinical-stage programs for zenocutuzumab in NRG1 fusion cancers, we have indicated that we would be providing a substantial clinical update in a medical conference in the first half of the year, updating where we are with the clinical trial, our data, and what are the next steps. We have indicated that we'd complete enrollment and follow-up for what could represent the clinical data to support a BLA. We haven't provided timing around BLA, but typically for companies our size, typically takes, you know, 6 months or so or maybe a little longer, 6-9 months, to file a BLA after that last patient, last visit. For MCLA-158, we have indicated we'd provide the next clinical update for the program sometime this year, and that would be both the head and neck cohort and the gastroesophageal cohort. We'll provide that. Our intention is here to provide it at a medical conference as well. For MCLA-145, we will provide a clinical update, but we haven't provided any timeline there. We obviously want to undertake the completion of the recommended phase II dose determination and a potential trial with a PD-1 in combination with a PD-1 agent. Those are two important clinical activities for the program. For MCLA-129, we will report out when we reach recommended phase II dose in our clinical data to date at a medical conference. We won't wait, as Andrew indicated, for the expansion cohorts to enroll. We haven't said exactly when that is, but we are well aware that this is a, this time is of the essence. We are in competitive position with respect to the J&J molecule, so we're keen to provide that. As we get a little further into the year, we'll provide a little bit more granularity on the timing of these things. One other question I should have asked earlier, I suppose, is can you talk at all about what's going on in your, you know, early stages research efforts, other combos, other bispecifics that you're working on, that are coming closer to an IND? We have a robust set of research molecules in the pipeline, both through our collaborations with Lilly, Loxo Oncology at Lilly. We have up to three T-cell engagers that we are working on together with them. We have up to 10 now bispecifics with our major partner, Incyte, across a variety of different cancer indications. We haven't disclosed where any of those are in terms of the process for where, what the timeline is to IND. The communication also is coordinated with Lilly and Incyte, respectively. We have our own internal pipeline of both bispecifics and trispecifics. We've spoken a bit about our trispecific technology. Our bispecifics, particularly our CD3 T-cell engagers and our CD3 panel at research conferences, but we haven't provided any specific guidance around the IND timeline. We've really been focused in terms of our external communication around our clinical stage assets. We have a number of research programs and molecules moving forward. You mentioned trispecifics. That's interesting. Does that mean that you have to deviate from the, you know, the IgG format? Or how do you do a trispecific? With our technology, with our Triclonics, we essentially make one of the two heavy chains of the bispecific, just extended by one more binding domain. Oh. Because we use a common light chain for all of these binding domains, we can still essentially make a monoclonal trispecific in a single cell. We have the same ability to do large scale screening and the same characteristic manufacturing, leveraging all of the technology and what we know about monoclonals. Then ultimately, our ability to clinically develop these is much like monoclonals. We think it's a real advantage and a real opportunity. For the third target, for the trispecific, do you engineer that so that it's only on one arm of the antibody, or do you put it on both arms? If you follow what I'm saying. Yeah, it's on one arm of the antibody. One arm. Okay. An image of this is on our corporate deck, which is on our website. All right. Very good. Just for the benefit of everyone listening, can you just remind us in terms of the financial health of the company, you know, where you guys are in terms of runway and so forth? At the last quarter update, we had $333 million of cash at the end of the third quarter last year. We did a raise of approximately $110 net. That puts us around $440 plus, and then we've spent a quarter's worth of cash. What we say is we have cash beyond 2024, and sufficient to take us well through a number of these really interesting and important value inflection opportunities across our pipeline. Okay. Thank you. Well, thank you very much, Bill, Andrew. Appreciate the time. Very interesting conversation. Best of luck with the progress on the pipeline and I'm sure we'll be chatting again soon. Appreciate your support. Thank you, Yigal. Welcome. Thank you. Thanks.