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spk00: Good afternoon, ladies and gentlemen, and thank you for standing by. And welcome to the SEND course first quarter 2022 conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. Please be advised that this call is being recorded at the company's request. Now, I would like to turn the call over to our speaker today, Charles Lyles. Head of Corporate Communications and Investor Relations. Please go ahead.
spk12: Thank you, and good afternoon. Earlier today, we issued a press release which outlines the topics we plan to discuss today. The press release is available at www.zencore.com. With me on the call are Basil Dehiet, President and Chief Executive Officer, Alan Yang, Chief Medical Officer, John Cush, Chief Financial Officer, and John Desjarlais, Chief Scientific Officer, who will join us when we open up the call for your questions after prepared remarks. Before we begin, I would like to remind you that during the course of this conference call, Zencore Management may make forward-looking statements, including statements regarding the company's future financial and operating results, future market conditions, the plans and objectives of management, future operations, the company's partnering efforts, capital requirements for product offerings, and research and development programs. These forward-looking statements are not historical facts, but rather are based on our current expectations and beliefs and are based on information currently available to us. The outcome of the events described in these forward-looking statements are subject to known and unknown risks, uncertainties, and other factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements, including but not limited to those factors contained in the risk factors section of our most recently filed annual report on Form 10-K and quarterly report on Form 10-Q. With that, let me pass the call over to Basil.
spk11: Thanks, Charles, and good afternoon, everyone. Continuing with the approach we took last quarter, we're going to make a few brief comments before spending the majority of today's call on questions. So, you know, as I like to usually open with, we've used our array of modular approach and engineering tools to create a broad internal development portfolio in oncology and autoimmune diseases, which allows us to take multiple simultaneous shots on goal in the clinic. Our intent remains to use proof of concept data from these early stage studies to guide which programs we advance, which we terminate, and which we partner, so that we're most efficiently using our cash and our employees' time. In a moment, Alan is going to review our advancing clinical programs and upcoming plans. But first, today we announced our plan to terminate internal development of two Phase I programs, XMAB841 and Tidutimab, which focuses our resources on those clinical programs of ours with the greatest potential for success and makes room in our portfolio for the next wave of XMAB bispecifics and engineered cytokines. For Tidutimab, our SSTR2 by CD3 bispecific antibody and XMAB841, our CTLA4 by LAG3 bispecific antibody are After reviewing the data generated to date, we believe that neither program has a competitive enough clinical profile in their respective areas, particularly when compared to the programs we are currently advancing. So we're going to keep supporting patients currently enrolled in the study, including by continuing to provide study drugs. Now, a core piece of our strategy is leveraging our plug-and-play XMAP FC domain through licensing transactions, especially in therapeutic areas outside of our core focus on oncology and autoimmune disease. We wanted to highlight the recent FDA approval for Lexion AstraZeneca's Ultramiris for adult patients with generalized myasthenia gravis, its third approval in the U.S. Ultramiris, of course, incorporates our Xtend FC domain for longer half-life. We also bolstered a cash position with over $70 million in royalty revenue this quarter for the COVID antibody Citrovimab, which incorporates the same Xtend FC domain from our partners Veer and GSK. though because of the rapidly shifting COVID variants that keep emerging, we expect this revenue to drop very substantially next quarter and beyond. Now, looking at our partnerships for the XMAP bispecific FC domain and our T-cell engager toolkit, last quarter we highlighted encouraging early clinical data from Amgen's AMG509 program in prostate cancer, which in addition to being an XMAP bispecific, uses the XMAP 2 plus 1 multivalent format for T-cell engagement. Now, within the past quarter, Astellas' ASP2138, an ExMab Clouden 18.2 by CD3 bispecific antibody, has advanced into clinical development for patients with gastric, gastroesophageal, and pancreatic cancers. And we look forward to following this program, too. Now I'm going to turn it over to Alan Yang, our chief medical officer, who's going to briefly review our clinical programs and upcoming plans.
spk02: Thanks, Basil. Hello. So starting with our CD3 bispecifics and Pomodimab, our CD20 by CD3 bispecific antibody that we are co-developing with Janssen, we announced that the first patient has been dosed in a potentially registration-enabling Phase II study, where it is being evaluated in combination with tafacitimab plus lenalidomide in patients with relapse or refractory diffuse large B-cell lymphoma. Note, we are conducting this particular study ourselves, and our partners, Morphosis and Insight, are providing tafacitimab. The study has two parts, the first of which is a safety run-in followed by a planned randomization between the triple combination of tafacitimab, lenalidomide, with or without plimodimab. Later this year, we plan to present data from the expansion cohorts in the ongoing Phase I IV monotherapy study. In addition, we also plan to introduce subcutaneous dosing into this study. Also, for our CD3 platform, soon we anticipate dosing the first patient in a Phase I study evaluating our ENPP3 targeting CD3 bispecific antibody, XMAB819, in patients with renal cell carcinoma. We're particularly excited about 819, which utilizes the multivalent XMAB2 plus 1 format. In preclinical studies, we have shown this format preferentially kills tumor cells with high target antigen expression relative to normal cells. which may be of particular benefit against solid tumors. Moving on to our tumor microenvironment activator bispecifics, our most advanced is Vudalamab, which targets PD-1 and CTLA-4 double positive lymphocytes. We are conducting two Phase II studies, the first of which is enrolling patients with metastatic castrate-resistant prostate cancer. In this study, Vudalamab is being evaluated as a monotherapy or in combination regimen with standard of care depending on the tumor's molecular subtype. We're also initiating a second study in patients with certain gynecological malignancies or clinically defined high-risk metastatic castrate-resistant prostate cancer. And we're supporting additional signal-seeking investigator-sponsored studies as well. XMAB-104, our PD-1 by ICOS-specific antibody, is our second tumor microenvironment activator and is advancing now in the expansion portion of our Phase I study in advanced solid tumors, where we are evaluating it in combination with ipilimumab. We will be presenting a poster with the data of the monotherapy escalation portion of the study at ASCO in a few weeks from now. Moving on to our suite of reduced-potency cytokines, all engineered with our bispecific FC domain and incorporating Xtend technology, at the recent AACR meeting, we introduced two preclinical stage programs, a decoy-resistant IL-18 and a LAG-3 targeted IL-15, which is biased towards binding and activating LAG-3 positive T cells that are more likely to be tumor-associated. Clinically, our most advanced cytokine is XMAP306. a reduced-potency, long-acting IL-15SC fusion protein that we are co-developing with Genentech. XMAP306 targets NK and T cells for the treatment of patients with cancer. In the ongoing Phase I dose isolation, we observed high levels of sustained NK cell expansion and evidence of peripheral effector T cell proliferation, and we announced this last fall. Just recently, Genentech initiated an additional Phase I study to evaluate a combination with anti-CD3 antibody, daratumumab, in patients with relapse or refractory and multiple myeloma. We ourselves are planning additional studies with XMAP306 in combination with other therapeutic agents and look forward to providing updates in the near future. Next is our wholly owned XMAP564, reduced potency IL-2SC fusion cytokine, which we are developing in autoimmune disease. We're conducting a single ascending dose study Phase 1 in Healthy Volunteers, and later this year, we'll present our initial data from the study. In parallel, we plan to initiate a multiple ascending dose study in patients. Our third cytokine to enter the clinic will be the IL-12FC-xmab662, for which we anticipate filing an IND near year end. Finally, one additional exciting program we plan to advance into clinical development this year is our first CD28 bispecific antibody, XMAB808, which targets the broadly expressed tumor antigen B7H3. This new class of bispecific is engineered to provide conditional CD28 co-stimulation of T cells, activating them when bound to tumor cells. Now with that, I'll hand the call over to John Cush, our CFO, to review our financial results.
spk10: Thank you, Alan. Thank you, Alan. Zencore's broad FC technologies and the multiple partnerships that we have entered continue to provide us with opportunities to generate cash flows that strengthen our balance sheet and allow us to invest in our pipeline of biophysic, antibody, and engineered cytokine candidates. In the first quarter, we received $83.7 million of revenue from these partnerships. A breakdown of the proceeds includes $78.7 million in royalties and $5 million in expected milestone payments. We'd like to point out that approximately $70 million of the royalty revenue was from our VEER partnership and relates to sales of Sotrovimab. And given GSK's recent comments about anticipated Sotrovimab sales for the remainder of 2022, we expect that future royalty revenue on net sales of Sotrovimab will be substantially lower than first quarter amounts. As noted, we continue to maintain a strong balance sheet. As of March 31st, Our cash, cash equivalents, receivables, and marketable securities total $683.6 million, which is an increase over December 31st amounts of $664.1 million. We currently estimate ending 2022 with between $500 and $550 million in cash, cash equivalents, receivables, and marketable debt securities. Based on our current operating plans, we would expect to have cash to fund R&D programs and operations through the end of 2025. I will refer to you to our press release this afternoon and our SEC filings for further review of our financial results. With that, we'd now like to open up the call for your questions. Operator?
spk00: Thank you. At this time, I would like to remind everyone, in order to ask a question, please press the number one. Please press start and the number one on your telephone keypad. Your first question comes from the line of Jonathan Cheng from SVV Securities. Your line is now open.
spk08: Hi, guys. Thanks for taking my questions. First question on XMAB 104. Can you help set investor expectations for the upcoming data at ASCA?
spk11: Sure, I'll start with that. Thanks for the question on 104. It's going to cover our dose escalation portion of the study, and the study is currently in expansion, so it's going to go to the dose escalation of that agent where, you know, we're looking to see what kind of safe doses we could achieve. We know that there's been a history of ICOS agents that have had challenges there, and part of the whole goal of our design is by providing selective checkpoint inhibition and costimulation, we can provide a different kind of profile. And then, of course, whatever efficacy we can offer. It's in advanced solid tumor patients, as is typical in these studies.
spk08: Got it. And second question on Tudutimab and ExMab 841. Are you able to provide any more color on what you saw or didn't see in those studies that led to the decision to discontinue those programs?
spk11: Yeah, I'll open it, and then I can let Alan jump in. What we really are trying to do with our strategy that we've been executing now for several years is put a number of programs that have promising biology into Phase I and use the data to judge which ones could have the characteristics that we could develop and potentially create our own drug with. or partner in a way that we think is very valuable. And so we're always looking at the efficacy versus the competitive landscape, which is always shifting. And so this was done in the context of that and judging whether our resources could be better spent on other of our programs whose competitive profiles are more attractive. So it's about safety and efficacy in a particular context. I would say, I'll pass it over to Alan now, but in general, the efficacy bar for both of those settings is fairly high, and that tended to be what drove our thinking.
spk02: Yeah, Jonathan, I'd like to say, you know, probably the things to consider were actually outside the program. So if you look at XMAP 841, Abdulag, the BMS Lag 3 was approved. It was a pretty involved development program just for a relapse refractor, or excuse me, for melanoma. And so when you look at XMAP841, comparing it to our internal pipeline, we just thought we would deprioritize it. There are better things to invest in in our internal pipeline. Likewise, for Tidutimab, I think the key thing that changes, Amgen has AMG757 in small cell lung cancer, which is showing good clinical activity and a good safety profile. And then looking at our internal pipeline, again, we just can't compare what we want to invest in. So I think we decided to terminate that program as well.
spk11: I'll note that there's investigator-initiated studies that we expect for at least one, if not both, of those. And we'll certainly support those with drug supply and, you know, see if patients can benefit and if good experiments can be done. But from an internal investment perspective, it's really about where we get the most bang for the buck.
spk08: Understood. Makes sense. And just last question from me. Can you discuss the rationale for the XMAB306 plus daratumumab combination and multiple myeloma?
spk11: You know, sure. Why don't we let John Desjardins, our CSO, take that one? He's calling in remote. Johnny there?
spk03: Yeah, yeah. Happy to take that. Yeah, thanks, Jonathan. You know, I think what it comes down to is Darzalex you know, seems to have a pretty strong NK mediated activity against myeloma. But there's another wrinkle in it because there's, you know, some, a small amount of CD38 on the NK cells that actually takes a hit on the NK cells as well. And so the hypothesis is that with our ability with 306 to massively expand the NK cells, there might be additional synergy there on both fronts, right? Just having more NK cells to do the job, but also being able to replenish any of the NK cells that Darvila takes out.
spk08: Understood. Thanks for taking the questions.
spk00: Thank you. Thank you. Your next question comes from the line of Mara Goldstein from Mizzou. Your line is now open.
spk09: Hi. Hi. This is from Mara Goldstein. I have a question on the cytokine program. Basically, I'm curious to hear your thoughts on the cis-targeting approach for cytokine therapeutics. Now, you just showed the data on lactate IL-15 bispecific at the AACR. And, you know, whether you have enough evidence to say that this approach is potentially safer and more effective and could be incorporated into your clinical program in the near future.
spk11: I'll touch on how we're thinking about it from a development pipeline standpoint. It's in what we call our early development considerations. We're advancing a number of the activities we would need, and we've not yet publicly guided on expectations for timing of that being in the clinic. As to the scientific rationale, I think it's fantastically strong, and John can go over that in a second. But really, until you're in the clinic with these completely brand-new MOAs, you really don't know much.
spk03: Yeah, and, you know, on the SIS targeting, you know, the basic idea is we started with an IL-15 like XMAP-306, which is, you know, vastly potency reduced. And then when we format that arm into a single-chain IL-15 RL confusion and then target it with IL-15, it's a little bit further reduced. And so basically when we use that SIS avidity effect, the LAG3 targeting on those, the LAG3 positive T cells effectively restricts its activity only to that LAG3 positive T cell population. And the hypothesis, which is supported by all kinds of literature, including, you know, very recent papers from Steve Rosenberg's lab, is that LAG3 is a very good marker of neoantigen reactive CD8 positive T cells. And so if we could just selectively zero in on that particular population, that really could potentially open up a very strong therapeutic index for cytokine.
spk09: Got it. And if you may just sneak one in on the 306 combinations, any additional color you could provide on that front in terms of, you know, indications or potential combination partners, any chance that you could, you know, you would explore a combination with NK or T cell therapy? Thank you.
spk11: So just recall that molecule, XMAP306, our engineered potency L15 is in a co-development collaboration with Genentech. You know, it's a 55-45 worldwide split, and both companies have the right to initiate studies. We plan on initiating studies, and we're in the stage of sort of really ramping one up right now to get going. We'll disclose details about that later. But I think both T-cell and NK-cell mechanisms are important to explore in both. We fully expect Genentech to expand beyond what they're already doing with the tesolizumab combos and now DARA combos, and you'll hear more from Zencore. As for the cell therapies, of course, that's an issue where we in Genentech have to have a basic meeting of the minds on what programs were are going to be advanced by the two companies. And so that's one where I think we're going to have to guide on that later on specifics. I think there's a great potential for these exogenous IL-15 and exogenous cytokine approaches with cell therapy. Scientifically, I just don't think we can talk about any kind of concrete plans yet. Got it. Got it. Thank you so much.
spk00: Your next question comes from the line of Dane Leon from Raymond James. Your line is now open.
spk15: Hi, thank you, and congrats on all the progress. Maybe I will use my question and focus on the expected initial data on Ludelimab in the back part of the year. So we saw interesting data in MCRPC, I think, last year, if my memory serves me correctly. And, you know, it seems like you guys established the premise that for what had been previously tested with, I think, PD-1, CTLA-4, and a similar patient population, you're achieving similar results, albeit maybe with less toxicity. What are you going to be looking for from this initial data from the Phase II study? And then as specific you can get in terms of, like, the scale and scope of of that data set, I think it would be helpful to set expectations. Thank you.
spk11: Yeah. Before I pass this to Alan, I'll say, recall, we started this study just very late last year. So by data cutoff for second half, and it was last year, we had the MCRPC data. By data cutoff, we should probably have about, I don't know, seven or eight months of accrual. And so it'll be it'll be on the order of a few handfuls of patients that we can show. And I think really key here is, like you alluded to, that safety-efficacy balance, because, recall, this study is in combo with chemo and potentially PARPs based on molecular subtypes. So can we start building on this as a backbone?
spk02: Yeah, Basil, not much to add. I'll just say that, you know, a lot of our work is sort of based on previous work from PEMBRO and NEVO, You know, I think the early data showed that there was a benefit in combining PD-1 with CTLA-4, but it's challenging to do that. And so we were very encouraged by our early data, you know, in our phase one, which we reported at CITSE, where we have a moderate response rate, even though it was a small number of patients. But moving forward, you know, I think the tolerability allowed us to sort of design a really novel study where we look at different molecular subgroups and then combine with the standard of care, right? So... you'll see that data with combination of 717 with aggressive chemotherapy or a PARP inhibitor or monotherapy in different subgroups. And that will hopefully bridge us to designing, you know, a registration enabling study.
spk11: Yeah, being able to go on top of chemo would, I think, be a big edge here relative to the limitations you might have faced otherwise. And so it should be, you know, with a few handfuls of patients, to get a read, start to get a handle on safety, see if there's any acute issues issues that arise. And of course, we'll show whatever efficacy data we have by that point. So I think it'll be a solid but pretty early look. And note, we are committed to prostate cancer. We're starting our second study, which is monotherapy in a clinically defined high-risk population as well, along with some gynecologic tumors in a different basket in that same phase too.
spk02: Yeah. And just to add a little bit more color on that, remember the The BMS program, when they looked at the Checkmate, I believe it was the 650 study, in combination of NEVO and IPPI, the combo was better. But in terms of their registration phase three, they're going with NEVO plus chemotherapy, just docetaxel as a single agent without the IPPI. So it sort of speaks to the challenges of combining PD-1 with CTLA-4, and that's what we're looking at. Maybe we can do it better.
spk15: Sorry, can I just clarify one thing with you guys? Are all three arms of the study, monotherapy plus PARC plus chemo, are those parallel?
spk02: So we'll have – so I'm trying to remember how much we've disclosed on clinicaltrials.gov, but we'll have a trials in progress poster. And there's five arms. I think three of them have chemo. One of them has a PARP inhibitor, and one of them is monotherapy, depending on the arm. Yeah, depending on the molecular subtype that's identified.
spk15: Then they're all in parallel. Correct. So you're expecting a handful of patients from each of the different arms of the study? Yes.
spk02: Well, so one of the arms, which is monotherapy, is the MSI, so the microsatellite instable. So that's going to be pretty rare. So I don't know how many patients will get in there. But some of the ones that are more easier to enroll in, like the biomarker negative group, it's sort of the ones that don't fit into the other categories should enroll a little bit more aggressively. So it depends on the arm and how rare it is. Okay.
spk15: Understood. Thank you.
spk00: Your next question comes from the line of Charles Zhu from Guggenheimer Securities. Your line is now open.
spk13: Good afternoon, everyone, and thanks for taking my questions. First one as a follow-up to one of the earlier questions that was asked, perhaps. With respect to terminating bispecific checkpoint inhibitors due to, you know, uncompetitive early clinical data, have your internal benchmarks for these kinds of go, no-go decisions remained constant, you know, as you've brought these bispecific checkpoints, you know, through early stage studies. And by extension, should we expect that the XMAB104 dose escalation data set coming up could be comparable to the sort of readout we saw from, let's say, the initial Vudalamab data? Thanks.
spk11: So have our metrics remained the same? Well, in the sense that we're always looking at how the competitive landscape is changing, so that concept is constant, but as the competitive landscape gets more difficult and as the bar rises, our bar for data is going to rise. We also look at what indications you might be in and how the drug is going to be used. Recall that XMAB841, CGLA4, LAG3 bispecific, was intended for use in combination with PEMBRO, or Nevo, it tends to be used for a combination of PD-1, and so you're always positioning it as a combo agent, and so it has a different set of comparators, right? You'd be comparing that to Nevo-Ipi, to Nevo-Relatlamab, to Pembro-Chemo, as opposed to a monotherapy or a PD-1-containing agent like, say, our XMAV-104. I would say that we have not had expansion cohorts accrue enough to show data at ASCO for XMAV-104. So it's going to have just the escalation portion. And I recall at our... Actually, no, I take it back. Our first data look at XMAV-717 was just escalation with very little expansion. So it's going to look similar to that, maybe just a smidge less.
spk13: Got it.
spk11: In terms of the number of patients... the doses and so therefore how much you'll be able to glean from it.
spk13: Got it. Great. Thanks. That makes sense. And maybe just one quick follow-up. So regarding Vudalamab and prostate cancer as a follow-up to another previous question. So it sounds like you will have an early look across multiple cohorts, but the study itself will obviously continue to accrue patients and data beyond the near-term disclosure. You know, perhaps can you also provide, you know, a little bit more color around your thinking on how much patient data do you generally need to accumulate before making, you know, potential go-no-go decisions for registrational studies in prostate cancer? Thanks.
spk02: For go-no-go? Well, I think it depends on how good the data is and what the subgroup is. So remember, like, if you look at what Exelixis did in their, I think it's the Cosmic 21 study, you know, they had a a couple hundred patients of data, right? But they're looking at it as a big group for their CABO combination with the TISO. I think for us, you know, we're sort of breaking it down into sort of molecular subgroups. So there's aggressive variants, there's biomarker negative, there's PARP, sort of PARP responsive, and the MSI unstable. So if we go for a subgroup, we could probably use a lot less data. But if we go for a larger study going across all you know, castrate-resistant prostate cancer, we'll probably need more data to be confident and define the response.
spk11: And no, we define each of these subgroups based on what we thought the rarity of the tumor was, and the ones that are the aggressive subtypes are 20 patients per arm within this phase two for each subtype, and we think that would be adequate to make a go-no-go.
spk13: Got it. Great. Thanks for taking my questions.
spk00: Your next question comes from the line of Edzer Daruth from BMO Capital Markets. Your line is now open.
spk01: Great. Thanks for taking the question. So I have another one on XMAP 104. I guess, you know, on sort of the early plans here for expansion, if you could speak to any tumor types that look interesting at this point or could potentially be explored. And then I guess secondly, you know, we're going to see some data from other PD-1 CTLA-4 agents at ASCO, and maybe how we should think about, you know, any molecular differentiation or any potential read-throughs from a mechanistic standpoint that you would be looking to at these data sets. Thank you.
spk11: So, Ed, just to be clear, you had one question about XMAB104 tumor types that we might or might not be interested in, and the other one about molecular differentiation of our PD-1 CTLA-4 versus XMAB717 or Vudalamab. Is that right?
spk01: That's correct.
spk11: Okay, great. On the XMAP 104, we really can't comment on the tumor types until after we show our data at ASCO, and there will be information there that will that'll make it clear what tumor types we're going after in our expansion courts. We will define it.
spk02: Yeah, the expansion courts will be listed in our presentation.
spk11: With rationale. So that's coming. As the other one, molecular differentiation for other PD-1C to A4s at ASCO, our molecule is, I think, only one other molecule that we're aware of has a similar design, which is this design to create a molecule that really needs both both targets on the T cell to engage, right, rather than most of the designs where you've got a bivalent binding to both PD-1 and CTLA-4, so you're going to have high avidity binding to each. Ours are relatively low activity if you only have a PD-1 positive cell and very little activity with a CTLA-4 positive only cell, but good activity with both. The only other program we're aware of is AstraZeneca's, which just released some initial data, we recall, at AACR. So that molecular differentiation is, we think, at the root of our potentially differentiated safety profile. And so I think that's how we view our real competition.
spk02: Was the question around 717 or 104? 717 was the second one.
spk11: Okay, sorry. That's how we view our real competition because, again, how are you going to combine with potentially really toxic chemo regimens like we're exploring today and the DALAMAB Phase II, I think that's the way we're going to be able to use this kind of agent competitively.
spk01: Great. No, thank you.
spk00: Your next question comes from the line of Gregory Renza from RBC Capital Markets. Your line is now open.
spk06: Hi, this is for Greg. Thank you for taking our questions and congrats on the progress. Maybe first just a follow-up question on 104. Could you just expand a little bit on your earlier mention of that historical challenges of ICOs programs where you think 104 could potentially show differentiation?
spk11: Sure. So, hey, John, did you want to handle that one, or should we go for it here?
spk03: Yeah, I think I need that question repeated, though. I'm sorry.
spk06: Yeah, sure. I'm just wondering if you could, you know, expand a little bit on historical challenges of ICOs targeting programs where you think 104 could show differentiation.
spk03: Oh, yeah. Yeah, no, that's basically, I mean, Basil alluded to this earlier, right? So this is, you know, we know all the historical challenges of the ICOs programs, and this molecule was kind of magical when we, you know, when we put these two different sites together. This came out of an empirical screen of combining various, you know, PD-1 with various other co-stimulatory targets. And then all of our preclinical in vitro assays, the one of four was just the strongest in terms of activation of T-cells, you know, that included in vitro as well as, you know, our vivo mouse studies where we just saw, you know, raging hot activity on the T-cells. I'll confess we don't completely understand why this thing is different, but it was intriguing enough that we thought it was worth pursuing clinically. So it's a different beast than those other ICOS combinations.
spk11: Yes, it's a very different beast, and that also encouraged us that perhaps the central problem that the ICOS-targeting normal monospecific bivalent antibodies have was toxicity. They seem to be pretty toxic, and they were hard to use. The vastly different profile we have with our molecule, for example, it has no effect or function in the FC, so we wouldn't expect it to deplete eicos-positive cells. We are hopeful that that allows us to have a differentiated profile that maybe toxicity limited the efficacy because they couldn't get to enough dose, perhaps. of the historical molecules. So very different design, hopefully can overcome that toxicity limitation and see the activity there. That's what the rationale was for the program.
spk06: Great, thank you. And then maybe just another one on Clomodemab. Once you expect to see some initial data from the triplet study and also on the monotherapy, just wondering, if we could hear a little bit about your latest thinking around opportunity there and path forward. And, you know, lastly, just on the sub-Q formulation, how that will be phased into the expansion study. Thanks.
spk11: We're not guiding on our first data from the triplet plamo-tafacitimab lenalidomide study. It just started. We'll guide on expectations for first data later. Note that it is a triplet. safety run-in at two doses followed by ultimately the randomized phase if we go forward. So we will have some interim data, but we'll guide on timing for that at another point. You know, you want to comment on how we're going to phase in the sub-Q and what the monotherapy, the rationale for continuing in the expansion is?
spk02: Yeah, so a couple things. So the first thing about the landscape, you know, we are following that very closely. And I think one of the things is that CAR-T is definitely moving into second line, right? The data is very strong there. And so the landscape is changing. And, you know, one of the things I want to point out is that what is considered relapsed refractory diffuse large B-cell lymphoma has changed. And so what we're noticing in our studies is we're seeing a lot of CAR-T refractory patients coming into our studies, especially in the diffuse large B-cell lymphoma group. But we're still encouraged by our data. So in terms of sub-Q, you know, I think everybody suspects that, you know, using sub-Q will sort of change the the therapeutic index, you know, offer a better safety profile, allow you to escalate faster, and even higher in dose. And so as we introduce SubQ later this year, we're going to see how good it is and then make decisions on our current studies, which are currently IV. Do we convert them over to SubQ? But again, I think we need to see the early data first, but I think everyone is encouraged with that. And in terms of our monotherapy data, you know, we're planning to release additional monotherapy data from our IV study in our Phase I. That's in diffuse large B-cell lymphoma and follicular lymphoma. This will be IV. You know, I think that data, again, looks good. The study's designed in which way the data quality is good enough for registration, but would it be worth it since other companies are probably going to file IV sort of single-arm data in the near future.
spk11: Yeah, we don't think monotherapy ultimately is the long-term play, or even, frankly, the medium-term play in CD20, CD3s trying to get into the B lymphoma landscape. Monotherapy data simply is, I think, not going to compete against the myriad of combinations that are proceeding, some of which have already shown glimmers of good activity from early studies, whether it's chemo combos, We're very excited by our chemo-free regimen. So the monotherapy opportunity, as much as anything, is about continuing the studies. It's not about thinking that there's a great opportunity there, but more about establishing that baseline of data and bringing forward enough data to make sure we can, you know, demonstrate the rationale for our further studies. Exactly right.
spk06: That's very helpful. Thank you very much.
spk00: Your next question is up from the line of Zeke Yangshu from Virenburg. Your line is open. Great.
spk05: Thanks very much for taking my question. So two from me. First, on the discontinuation to do the MAD, I guess the SSTR2 is the risk target in neuroendocrine tumors, and you show some activity there. What was the reason for this continuing in that particular indication? Has it, does it have anything to do with the commercial opportunity or is it really because you learned something about the city that TISA engaged in this knowledge release? And second question is a quick one. Can you help us understand the IL-2 program you are developing with that data there and should we be able to see the data? Thanks very much.
spk11: So on the Tidutimab stop in neuroendocrine tumors or NET, I think it was as much as anything, not so much the commercial opportunity per se, but rather the very, very long clinical trials you would have to do to achieve them where Historically in NETs, and I think Tadutimab would face that as well here, there are long PFS and OS studies that are long to accrue and very long time endpoints, out past two years in many cases. So we looked at the timeline for how that might go, and it didn't seem like something that made sense. And even in NETs, there is a shifting landscape. That was really the driver for not wanting to pursue NET. And then Alan mentioned for why the challenge in small cell lung cancer, a potentially great opportunity, didn't make sense anymore based on what we were seeing. Could you repeat your question about our IL-2 at NCATCHAT?
spk05: Yeah, just kind of can you update us with the status right now? I don't know.
spk11: Oh yeah, so the status of the study is we are currently in the phase one single ascending dose study in Healthy Volunteers, and we expect to have data from that study later this year that is essentially going to be your trifecta of safety tolerability, The biomarker data, you're looking for regulatory T cells to go up and for T effectors to not go up, really, and how long that lasts, right, the durability of it. That trio of biomarker data, duration, and tolerability is going to tell us how we stack up, I think, against that same sort of correlated similar data that was released after SAD studies by some of the competition groups. And it'll also allow us to really be well set up to start our multiple ascending dose trial, which we're currently in preparation for, and we'll also start this year, and we'll give the details about that later.
spk05: Great. And just a quick follow-up on the titunumab abazole. Since you mentioned it's sort of long trial duration, are you thinking maybe potentially I'll license these two programs as you did for some others you discontinued? Thanks very much.
spk11: You know, we're always open to finding ways for molecules we make to potentially benefit patients and, you know, accrue value to the company. So I would say everything's on the table. I'm not going to guide to that. I would say it's not a high priority for us for these two programs to find partnerships where I think we've got other fish to fry. But never say never.
spk05: Great. That's helpful. Thank you.
spk00: Your next question comes from the line of Peter Lawson from Barclays. Your line is now open.
spk07: This is Cheyenne for Peter. Thanks for taking the question. Just to follow up a little bit more on the discontinuation, for your CTLA-4 by LAG-3, is there anything in that Phase I data that you had developed so far that pointed to you being more negative on the approach of a CTLA-4 LAG-3, or do you think it was just more based on the molecule you had and would you want to revisit making another CTLA-4 LAG-3? And then just also a little bit on the Vudalamab, just in light of the discontinuation, what is it that you're actually looking from that second half data that would point to you that you want to go forward? And then further, do you think that this will be a substantial enough update in second half for you to make that decision?
spk11: Thank you. First of all, the Vudalamab, it's not going to be enough data for the go-no-go. It's going to be an initial look at safety and whatever efficacy we can see from that few handfuls of patients that across these different molecular subtypes. The tolerability in combination with aggressive chemo is, I think, a very important thing to look at. It really shows the potential, but we don't anticipate efficacy go-no-go in this year's update. We'll have been less than one year since the study started. Obviously, safety data can give you a go-no-go at any time, whether you like it or not, but we're optimistic that we can provide an update and fully expect to continue the trial after that update. But it'll give people a read on what is really the potential for this new way of targeting this pair of receptors. Going back to the CTLA-4 by LAG-3, is it the molecule or the target pair is essentially what you asked. I will say I don't know if anybody can address that given that I think there's only one of these that's ever been in the clinic and it was ours. I can say that we don't plan on going back and making another one because as much as anything I think the landscape of competition has moved, and it's very different from what, you know, we all expected it to be three or four years ago because you never know what it's going to be. So we would not plan on making a new one, but I don't think that reads on whether it's the target pair or the specific molecular design choices we made. I wish I could answer that.
spk07: Great. Thank you for taking the question. Congrats on the quarter. Okay.
spk00: Your next question comes from the line of David Dye for SMBC. Your line is now open.
spk04: Great. Thanks for taking my questions. So one question on Vidalimab. So we saw in SITC data that there were some modest level of equivalent to rash and pruritus, around 31% to 46%. So could you share with us the physician feedback on the tolerability profile, especially in the context of the combination in various different prostate cancers?
spk11: So just to make sure we heard your question right, you were commenting that the most common AE we presented at CITC for Vudalamab last year at CITC was rash at around 30%, and you're wondering how that might work, what might happen with chemo in terms of synergistic tox? Is that what you're asking?
spk04: That's correct. Yes, that's correct. You know, would you expect C is for a higher... tolerability or safety issues when you combine with different combinations.
spk02: So, yeah, let me just sort of generally talk about the tolerability of 717, which we are very impressed with. I mean, remember when you give a PD-1 CTLA-4 combination with the two drugs independent like NEVO and IPI, you know, a third of patients develop colitis and have to discontinue, so much so that they usually just give the NEVO, and then they give the IPI for a short period of time. Four courses, I think, is the latest thinking right now. So when we looked at our data from CITSE, you know, we had a GI sort of diarrhea rate around 10%, which was very tolerable, much lower, and rash was the most common AE, and, you know, for oncology patients, rash is not a huge, it's not an important toxicity. It's not going to cause you to discontinue. Now, whether you would expect to see synergy with chemotherapy for that toxicity profile, probably not. I mean, it's still early, but if you think about it, you know, rashes are often treated with low doses of methotrexate depending on the type of rash. So I Yeah, for autoimmune diseases and so forth, and psoriasis. So that's the old days. So I don't think we'll see synergy in terms of toxicity, but we don't know. It's still early. I think that was your question, right, David?
spk04: That's right. Well, thanks so much for the answer. And then another question on 104, maybe just help me understand some of your biomarker strategies to identify the responding tumor types for the program.
spk11: I think our strategy for identifying the responding tumor types is really about response. It's about resist response. I think we have to be stringent about that. We've obviously characterized the biomarkers because understanding the mechanism can help you glean insights into dose selection, the rationale for maybe if you see some kind of activity or toxicity in certain patients. But, no, it's about the kind of tumor response you see, not really the biomarkers. Thank you so much.
spk00: Your next question comes from the line of David Naring-Martin from Red Bull Securities. Your line is now open.
spk14: Hey, thanks for taking the question. Maybe we'll just switch to Playmo for a second. Speaking of competitive profiles, it's a pretty competitive space. What do you think you need to hit with the triple combination in terms of a response rate to consider advancing the program further?
spk11: Yeah, I think that it's still really hard to say from most of the studies because I think there's only one study we've seen a significant number reported. It was just top line from the recent AbbVie release where they had about a 60% OR and a 40% CR rate for that relapsed refractory DLBCL population. I think that sort of sets the minimum bar, honestly, for it because it's a similar population. And so how much you can go from there? We know that tapacitamab and lenalidomide starts with about a 40% CR rate and about a 60% OR.
spk02: Yeah, and I think there's a couple things. So, you know, the L-MIND study is probably a good benchmark of what we'd expect to see with just tap and len by itself. Granted, the landscape is changing a little bit, but what's nice is, remember, we'll have this run-in, so... If we think the study may be underpowered, we can adjust the size or change strategy in the second part of the study.
spk14: And maybe a quick follow-up. I mean, you know, not to give too many hypotheticals, but, you know, is pushing those patients to CR more important to you, or is it, you know, kind of generally the overall response rate that's more important to you when you assess the prospects?
spk02: Yeah, it's a good question. I think that's more of a qualitative answer. I think CR is always important, right? So, you know, I think you'll get responses, but, you know, when you look at the competitive landscape, I think the power of the CAR-T has been they've been able to push patients into CR that are durable, right? And the question is, can bispecifics do something similar to that, right?
spk11: Yeah, and that's why we think that the potential for for additive or maybe synergistic activity with a CD19-targeting NK cell-recruiting high ADCC antibody is something that just adds another avenue that avoids the tox of chemo that maybe lets us move that needle. Right.
spk00: Got it. Thanks. Thank you. There are no further questions at this time. I would now like to turn the call over back to Basil Dayak.
spk11: Thanks very much for joining us today, everybody, and we look forward to updating you again in the near future. Bye-bye.
spk00: This concludes today's conference call. You may now disconnect.
spk11: Thank you.
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