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spk05: Good afternoon, and thank you for standing by. Welcome to Zencore's fourth quarter and year-end 2023 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. To ask a question during this session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1-1 again. Please be advised that today's conference is being recorded at the company's request. Now, I would like to turn the call over to your speaker today, Charles Lyles, Head of Corporate Communications and Investor Relations. The floor is yours.
spk06: Thank you, and good afternoon. Earlier today, we issued a press release which outlines the topics we plan to discuss today. It's available at www.zencore.com. Providing comments on the call are Basil Dahiet, President and Chief Executive Officer, Nancy Valenti, Chief Development Officer, and Dan Leone, Senior Vice President, Corporate Strategies. After the prepared remarks and presentation, we will then open up the call for your questions, and we will then be joined by John Desjardins, Chief Scientific Officer, and John Cush, Chief Financial Officer. Slides that we are using today should be visible here on the webcast and will be made available for download on the events and presentations page of our website. Before we begin, I would like to remind you that during the course of the conference call, Zencore Management may make forward-looking statements, including statements regarding the company's future financial and operating results, future market conditions, plans and objectives of management, future operations, the company's partnering efforts, capital requirements, future 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. With that, I'll pass the call over to Basil.
spk07: Thanks, Charles, and welcome, everyone. Today, we'll cover a few business highlights from 2023, briefly review our clinical pipeline, and provide a data update on Vudalimab and prostate cancer. You can refer to our press release for more information about the last quarter and full year. We focused our pipeline and discovery work on our T-cell engagers because of growing validation for their potential in solid tumors. Supporting this is the continued advance of Vidalimab and prostate cancer, where we'll provide an update today, and the start of a trial in frontline lung cancer for Vidalimab. And we've decided to reduce our investment in our cytokine drug candidates as part of this focusing. Our partnerships and licenses played a significant role for us last year, first with validating data for our XMAB 2 plus 1 CD3 platform from our partner Amgen with their xyloritmic data in prostate cancer, and And two phase one programs started in our CD28 bispecific collaboration with J&J. And we significantly strengthened our balance sheet with a partial monetization of our Ultimers and Mongevie royalties. As a result of that and robust milestone in royalty revenues, we ended 2023 with $697 million and expect runway into 2027. Now on to our pipeline. The focus of our clinical pipeline is bispecific T-cell engagers for solid tumors, an area with rapidly growing promise. Solid tumors have been challenging for antibody and cell therapies, but recent data, some of which we'll review momentarily, suggests that CD3 and CD28 bispecifics could play a role as therapies in a range of solid tumors. Key programs for us addressing this opportunity are XMAB819, an ENPP3 by CD3 XMAB bispecific for renal cell carcinoma, and XMAB808, a B7H3 by CD28 XMAB bispecific in prostate and other cancers. Both are advancing in dose escalation in Phase 1, and right behind them is XMAB541, a CLOUDIN6 by CD3 bispecific that we expect to start Phase 1 the first half of this year. For Vudalamab, we initiated a new study, its first frontline study, in non-small cell lung cancer, based both on our Phase 1 data in lung cancer and external data suggesting potential advantages against standard checkpoint therapy in this setting. And we've made progress with our metastatic castration-resistant prostate cancer studies, both in combination with chemo and monotherapy, and with encouraging monotherapy data we're going to present in a moment. Finally, we're wrapping up our Phase I work next quarter for both XMAVs 564 and 662, taking the PK, PD, and safety data in hand to establish initial product profiles and monitoring the field for further validation of these cytokines before we do any additional developments. Underpinning our T-cell engages our XMAP bispecific technology. It lets us address the solid tumor opportunity by engineering our antibodies with a format and affinities designed to give tumor selectivity in the context of each tumor target's particular expression levels and tissue distributions. Solid tumor targets in particular need a customized approach because they're distributed more broadly than heme tumor targets, which have already been successfully addressed by CD3 bispecifics in lymphoma and myeloma. Our plug-and-play antibody modules let us do this work rapidly, and as a result, we've got a growing pipeline of molecules with our 2 plus 1 design, which is particularly helpful with selectivity for solid tumors. And here is the first clinical proof of concept for our XMAP 2 plus 1 CD3 format, xaloridimig, which targets steep 1. Our partner, Amgen, presented very promising efficacy and tolerability data at ESMO last October in late Lyme prostate cancer, usually considered a cold tumor for immunotherapy. This target was challenging due to the limited accessible binding regions outside the cell membrane and non-tumor expression. So we're very encouraged to see this early data for the molecule in a 2 plus 1 format. Amgen's announced they are nearing completion of the phase 1 study and are planning additional studies in earlier lines of therapy, so we'll be eagerly awaiting their updates. Now, our own lead XMAB2 plus 1 CD3 bispecific is XMAB819, targeting ENPP3 and renal cell carcinoma. We chose ENPP3 as a target because it has exactly the kind of expression profile we want for a CD3 solid tumor target. Much higher expression on tumor than normal tissues and nearly uniformly high expression on clear cell renal cell carcinoma. Plus, it has potential for use in select patients and a range of other tumors. Also, we think renal cell carcinoma has a need for new mechanisms beyond checkpoint inhibitors and TKIs, and a directly cytotoxic antibody could be well-positioned. 819's design gives us selectivity we wanted in vitro, and we're continuing to advance in dose escalation with both IV and subcutaneous dosing, and expect to make significant progress this year toward target dose levels. I'll shift now to XMAB808, our new T-cell engager mechanism, CD28-targeting. The goal here is to activate T cells via the signal 2 pathway, which powerfully amplifies and sustains T cell responses. We designed 808's bispecific format and affinities to try to drive this activation in a tumor-specific way by requiring sufficient binding to its tumor antigen, B7H3, to turn on CD28 signaling. A key part of our approach is a lower-potency CD28 binding domain that we think could give us control of CD28 signaling and improve tolerability. We picked B7H3 because it offers high expression across a range of tumor types, creating an opportunity to potentially treat multiple cancers in combination with either checkpoint inhibitors or CD3 bispecifics. CD28 targeting has generated a lot of interest among clinicians and across the industry, and the current Phase I study in combination with pembrolizumab is progressing well in escalation. Now, our latest CD3 bispecific is set to enter the clinic imminently. XMAP541 targets Clouden 6, which is highly expressed on the majority of ovarian cancers and also on several other tumor types. Though it has a very promising expression profile, it is a selectivity design challenge because there are multiple closely homologous Cloudens. We think we addressed it with careful bindings main engineering and our 2 plus 1 format. XMAP541's IND is open, and we expect to be in patients the first half of this year. We're planning to apply lessons learned for solid tumor CD3 dosing from both internal and external programs to move the study quickly. Now I'm going to turn it over to Nancy for the Vidalimab update.
spk17: Thanks, Bessel. I'm excited about the encouraging new data we have to share from the prostate cancer monotherapy cohort. If we could go to the next slide. This cohort is part of the overall Vidalimab program, which consists of four studies. Based on the outcome of the phase one study, we moved into two tumor-specific expansions initially. The study 71704 in metastatic castrate resistant prostate cancer in combination with standard of care chemo and other agents. And study 71705 that included patients with gynecologic malignancies and a monotherapy metastatic castrate resistant prostate cancer cohort, which I'm going to further describe.
spk16: The next slide.
spk17: The prostate monotherapy cohort required patients to have resist measurable disease, including visceral sites or lymph nodes, and the patients had to have progressed after all other appropriate therapy. Videlumab was given every three weeks as a flat dose based on our PK analysis of earlier studies. You can see that this study enrolled a heavily pretreated patient population that had exhausted available standard of care therapies. with a median of four prior therapies, 100% received prior antiandrogen therapy, all but one received prior chemotherapy, and 86% were ECOG1 performance status. As noted, the study protocol required patients with measurable disease at baseline, which is why we see a high rate of visceral metastases and high median baseline PSA. Reduction in target lesions and disease control are encouraging for such a heavily pretreated patient population, as you can see on the right, with a resist response rate of 35% and a disease control rate of 50%. And the spider plot shows we have several lasting responses and one patient with stable disease past 48 weeks. Deep PSA reduction was also seen in three patients, giving a PSA 90 rate of 25%, and a fourth patient with nearly a 50% PSA who is still on study. To describe one especially poor prognostic patient who responded well to venalamab, this patient had three liver mets, a total disease burden of 12 centimeters, and a PSA at baseline of 180 nanograms per mil, and achieved a confirmed PR, a PSA 90, and was in response for over 22 weeks. The treatment immersion adverse events highlight the tolerability has been generally well managed by dose modifications with only two treatment discontinuations. Unfortunately, there has been one case of grade five immune-related mediated hepatitis. The patient's treatment course was complex. And this is the only known grade 5 immune-mediated hepatitis event in over 240 patients that we've treated with Vudalamab to date. Reviewing specific immune-related adverse events, generally the events are what we'd expect with checkpoint inhibitor therapy. The rate of grade 3 events that you can see on the right were generally limited and specific to several patients. Overall, we are encouraged by the tolerability profile of the Q3 week flat dosing schedule with Fudalamab. In summary, we have observed encouraging single-agent activity in a heavily pretreated patient population. This is consistent with the data from the Phase I study in prostate cancer, where we had patients with 6- and 10-month duration of response. The Delamab safety profile is consistent with other checkpoint inhibitors, and we observed limited treatment discontinuations. Now I will turn this over to Dane to share comparative data to place these results in context.
spk13: Thanks, Nancy. As you can see on the next slide, these emerging data support us enrolling more patients into the monotherapy cohort. When you put the data into the context of the broader novel therapeutic landscape under development, it really is clear why we and our investigators during our discussion at ASCO-GU were so encouraged about continuing this study. When you compare the baseline characteristics of our patients versus our peer studies, the Vidalimab Bonn therapy cohort is among the most heavily pretreated and has the most advanced disease upon enrollment, as shown by nearly all having ECOG1 and all having measurable disease. Comparatively, only the xyloritmic dose escalation study has enrolled similar patients that are very late line and poor performance status. Despite the remarkably advanced patient population, patients treated with Adalimab have comparable resist response rate versus the peer studies in this table and experience DPSA-90 responses. Importantly, we think that resist response and DPSA response are required for translating into effective durability of response and ultimately survival outcomes for these patients. Regarding tolerability, using the Q3 week flat dose schedule of VudalMab has supported a manageable safety profile compared to our peers. Overall, considering the early nature of the VudalMab monotherapy cohort, we are encouraged by the clinical benefit for these advanced prostate cancer patients that have been treated well beyond current standard of care. And we look forward to evaluating a larger cohort of patients by year end. Now on the next slide, beyond prostate cancer, we are executing on the start of our frontline non-small cell lung cancer study of VidalMab plus chemotherapy. And we are excited that this study is underway with the first patient dose in the fourth quarter of last year. And with that, I'll turn back to Basil for a view of our corporate goals for 2024. Thanks, Dean.
spk07: Here's a look at our priorities for 2024. We're starting with a strong balance sheet, and as you can see, we're looking forward to this year really bringing the focus to our solid tumor bispecifics pipeline, where we have a lot going on for our CD3 and CD28 T cell engagers and for Vudalamab. Of course, we're doing discovery work on additional CD3 and CD28 bispecifics, and we'll select our next IND candidate later this year. Operator, we'll now open this call to questions.
spk05: Thank you. at this time we will now conduct the question and answer session as a reminder to ask a question you will need to press star 1 1 on your telephone and wait for your name to be announced to withdraw your question please press star 1 1 again please stand by while we compile the q a roster our first question comes from jonathan chang of variant partners our Lear Inc. partners. The floor is now yours.
spk08: Hi, guys. This is Dylan Drake from Upper Jonathan. Thanks for taking our questions. First of all, would you be able to comment on how investors should be thinking about when we might be able to see initial clinical data from the ENPB3 study?
spk07: Sure, I'll take that one. So we're not commenting on data just yet, and what we're trying to do is characterize with a sufficient patient number and follow-up the sort of outlines of the effective dose level as we pull together a dosing regime. These are CD3 biospecifics, so you want to have your priming and step-up doses. We've made great progress, and we really hope that this year we'll have a lot more knowledge about it. And then when we get close to having the decision to disclose, we will tell you. So we're not guiding anything there yet.
spk08: Great, thanks. If I could just sneak in one more. You guys set the stage pretty well with the comparative table there, but looking ahead to the go-forward decisions for both the mono and combination Zudalamab approaches, how would you guys set the bar?
spk07: Yes, I guess maybe the mono first. I mean, Nancy, Jane, do you guys want to take that? What's the bar for advanced comparables?
spk13: Yeah, sure. Great question. When we look at the patients that we've enrolled into the monotherapy cohort and will continue to enroll, These are patients that are as late line as you can get and have exhausted every standard of care therapy available to them. As such, what we've really decided to do in engaging the signal that we'll have as we hopefully get a cohort of 20 to 30 patients enrolled over the course of this year is look at some of the contemporary studies where cabazitaxel has been used as a control arm. And in those studies, namely the control arm for therapy or the very recently reported part two of Checkmate 650, you've seen a resist response rate for capacitaxel in that 11% to 24% range and a PSA50 response rate of 24% to 37%. This is why we're quite encouraged with what we're seeing in the cohort now with clinical activity of adalimab monotherapy. And hopefully with a larger cohort, more follow-up, we can then try and extrapolate what would be needed in terms of survival outcomes. And cabazitaxel, for reference, has generally come out around eight months for radiographic progression-free survival. And right now, based on some of the durability, it seems like we're in pretty good shape.
spk07: Now then, for the combo cohort, I guess, we've got different baselines there to look at.
spk13: Yeah, in the combination cohort with docetaxel, you really have to think about what docetaxel might be able to do in what would be post-angioreceptor inhibitor exposure for these patients. And again, the landscape will continue to change with Plavicto, but historically, if you're looking at the TAX-327 study, You'd be looking at a PSA50 response range of 40% to 50% and a fairly low resist response rate of somewhere around 10%. That said, the survival curves are a bit better for that line and that setting with dose-to-taxel monotherapy. But that's kind of what you have to think about when you're doing the combination study with dose-to-taxel at this point.
spk08: Perfect. Thanks so much. I appreciate it.
spk19: Thank you. One moment, please. Our next question comes from the line of Etzer Dorout from BMO Capital Markets.
spk05: Great.
spk11: Thanks for taking the question. I guess maybe on the safety profile of Delimab, if there's anything you can or will incorporate into the study to maybe kind of mitigate this autoimmune hepatitis, is this something that is just unique to this patient or if, you know, if there are other things sort of going on that you need to understand. And then also on XMAP564, just wondered the decisions to sort of pause that, was that data driven or, you know, whatever other contributing factors, if you could comment on that to pausing that study. Thank you.
spk07: Sure. So I'll talk, I'll go through the XMAP564, then maybe Nancy can take the question on the Vidalimab safety profile. So for 5, 6, 4, it was really driven by our, as much as anything, by our decision to focus on our T cell engages, our resources, our capital, and our people. And, you know, looking at how the class cytokines generally and IL-2 Treg driving cytokines in particular has evolved, there's still, I think, a lot of outstanding data coming in the next year from other companies about efficacy, about how much potential does this class have. And with our study having progressed and given us a reasonable look at our PKPD and safety, we think that that's the time to conserve resources and wait and see how the field evolves. We're well-positioned to ramp up again, but it's about focus now. And for 2024, pipeline focus is the key for Zencore. So it was really more just strategy-driven. With that, maybe Nancy, do you want to touch on the question on Voodalibet?
spk17: Yeah. So I'll go back to the patient with the hepatitis death, and that's the only immune-related hepatitis death we've seen across our program with more than 240 patients treated, both in the monotherapy and combination setting. The patient had responded to therapy but did have other treatment emergent adverse events, Before that, including diabetes mellitus and diabetic ketoacidosis, thyroiditis, hyperkalemia, lipase increase. So a bit of a complex course here. We have looked across the entire program, and we don't see anything concerning relating hepatitis. As far as the protocol and the investigators, We have emphasized to the investigators to be watchful for this and communicate it with them. The protocol does include the NCCN guidelines for treatment and it's also consistent with ASCO guidelines and other society guidelines like the gastric GI guidelines for monitoring and treatment. And so we do include screening at baseline for any diseases that might contribute to hepatitis. And we have frequent laboratory monitoring.
spk09: Great. Thank you for the color. Thanks, Heather.
spk19: Thank you for the question. One moment, please. Our next question comes from Gregory Rinza of RBC Capital Markets.
spk05: The floor is yours.
spk20: Hi. Thank you so much for taking our questions. This is support for Greg. Just to confirm, if this monotherapy data was from a particular molecular subtype, since I think that was how the trial used to be characterized, and if I may, secondarily, from the data comparison table, I think the PSA 90 looked competitive, but PSA 50 looked a little lower. Just curious if you have any hypothesis on why the data looks that way. Thank you.
spk07: So I'll touch on the specifics of the trial in the population. So I think just to be careful, there's two studies ongoing now where we're studying prostate cancer with Vudalamab. The monotherapy study, the one we discussed today, is not subdivided by molecular subtype. It's people with clinically defined high-risk disease, which includes extra pelvic and visceral metastases. So that's a population that's independent of molecular subtype in that regard. The other study, our combination with chemo study, that study is subdivided by molecular subtype. That's a different study. We didn't discuss data for that one today. We're enrolling still a crew of patients and more follow-up, and we hope to have a lot more clarity later in the year on that program. And also, I guess, first half of next year, really bring it all together. So I just want to make sure that this is not from the molecular subtype dividing study. Maybe on the comparison table, Dan, you want to answer that one on the PSAs?
spk13: Yeah, sure. That's a great question that we looked at. quite extensively once we had this data cut and were able to review the data with our investigators during ASCO-GU. What it seems to be is somewhat of an artifact of taking patients that are required to have measurable disease at baseline versus other studies that also include bone only. And as you can see on that table, most of our peer studies outside maybe one with a similar mechanism of action, is more of a mixed patient population. And what we see in those studies is you will get more PSA50s that don't necessarily correlate to a resist response, as some of those patients do not have measurable disease at baseline. In our cohort, to really get clinical benefit, those patients will need either a resist response or a PSA90. So I think there's two things there. One, is PSA 50 for patients that are this advanced in their disease course relevant for survival outcomes? Very debatable. But what is definitely needed is those resist responses and PSA 90s. Thank you.
spk19: Thank you. One moment for our next question. Our next question comes from the line of Kavari Pullman from BTIG.
spk05: The floor is yours.
spk03: Yeah, good evening. Thanks for taking my questions. My questions are mostly on Vidalimab. So first on the safety profile, can you tell us how the safety profile looks in comparison with epinephrine combination and how you are thinking about the dose that will be used going forward? And my second question is also for the no-go, no-go decision. How many patients do you plan to enroll in monotherapy and combination cohorts for that? And is efficacy the only factor you're considering to make these decisions? And the last one is also from the same trial. Any color you can provide on how many patients had bone disease, and were there any responses observed in those patients?
spk07: Thank you. Hey, thanks, Kavari. So that's a set of questions. I think maybe the one that's more just generically descriptive is your first one, Vidalmeb safety versus ipinevo, which is a broad kind of amorphous question, but, you know, we'll take a crack at it and what our dose going forward is. Nancy, do you want to jump in on that one?
spk17: Yeah, I mean, overall, what we've seen so far is a safety profile that looks similar to other checkpoint inhibitors. So we haven't seen anything that says that this is different, markedly different in some way that wouldn't be unfavorable to the product. But I guess I could say that overall. I mean, there's a lot of data out there on IPI, single monotherapy checkpoint inhibitors, as well as combinations. So broadly, we're similar to that. Do you want to?
spk07: Yeah, and on the dose going forward, note that in our lung cancer study, the newest study we started, as well as in the monotherapy prostate study, which was the second newest, we have switched to a Q3 week schedule using flat doses, and I think that's given us a good feeling that the Q3 week might have some benefits over the Q2 week weight-based dosing. With regard to ipinevo, even though we've got over 240 patients now, it's still hard to parse out those subtle differences. We don't see the kind of colitis that often bedevils IPI therapy at high doses. And note, we're giving much higher doses of our drug than the current sort of IPI regime of one milligram per kilogram. You know, so I think that's maybe the best we can say comparatively across such a range of studies and whatnot, but generally very checkpoint-like. And then on your second question, go-no-go number of patients that we'd hope to have for both the combo and the mono. So by first half of next year, we're looking at on the order of, I guess, roughly 30 patients in each of those settings. The chemo study in particular in the main cohort, which is our no targetable mutations cohort, which is our now docetaxel combo, and then on our monotherapy study as well. So in that, you know, we're aiming for 20 patients. Hopefully we'll get pretty close to that and be able to make decisions.
spk13: I think it would be helpful, maybe, Nancy, you could just explain the difference between measurable disease and nonmeasurable disease at baseline, because I think that might be helpful for everyone.
spk17: Sure. I mean, measurable disease means it has very basically two dimensions, and it's got to be a metastatic site in an organ. or a measurable lymph node, bigger than a normal lymph node. Non-measurable would typically be bone-only disease, or if a patient had bone-only disease. Our patients had measurable disease, and they could have also had bone disease on top of that. I can tell you two of the four responders had bone disease in addition to their other measurable disease. So we have seen responses in patients who had bony disease.
spk02: Got it. Yeah, that's what I wanted to know. Thank you. Thanks for the call.
spk19: Thank you for that question. One moment, please. Our next question comes from the line of Brian Chung from JP Morgan.
spk05: The floor is yours.
spk04: Hey, Basil. Hey, guys. Thanks for taking my questions today. Maybe the first one is just on the three confirmed responders, I think just kind of piggybacking on what was the question prior to this. What was the background of the three confirmed responders? Can you just kind of give us how many lines they have and kind of give us a sense of what their historical responses were? to prior AR or even, I see that they had, you know, some patients had radiation. So just curious, like, what were the responses like? And I have a follow-up. Thank you.
spk07: Yeah, I mean, Nancy, you could take that. You know all the details. I'd say they were really, really heavily pretreated in rough shape when we got them.
spk17: Yeah, they had to be progressing through prior therapies. They had to have, you know, at least two prior therapies. You know, I'm looking at the background, and, you know, they had anywhere from three to, like, seven prior therapies, including XRT. I'm just looking at... Yeah, that's a lot of detail, Brian, so we're just picking up our notes. Yeah, yeah. So, you know, one patient had three prior therapies, not including any radiation. Second patient had three prior therapies. The third patient had six prior therapies, not including, so none of these are with radiation or counting that. And the last patient had two prior therapies. They all included one. They all included docetaxel, or one included carboplatin, two had prior radiotherapy. Let me just see. I can't really comment on their prior responses, but maybe in an upcoming presentation we could drill down into each individual patient?
spk07: Yeah, yeah, but suffice to say they've seen a lot of prior therapy, Brent.
spk04: Okay, and then a follow-up here is, you know, as you're looking at this data, and I think the last time we saw the combo data, maybe back in, let's see, I think back in 2022, how should we think about the low-hanging fruit piece? You know, what is the lowest-hanging subset of the MCRPC patients that investors should think of when it comes to a dial-up map? And is it high risk? Is it genetically defined? How do you think about the low-hanging fruit, either with combo or monotherapy? Thanks.
spk13: Yeah, I think it's a great question that we're obviously going to have a fuller answer to as we get these cohorts enrolled over the course of this year and can really look for a solution reliable signal, hopefully in 30 patients per cohort for monotherapy and for the combination. But the way we're thinking about it now is we just had an update on part two of TechMate 650 at ASCO-GU, where ipinevo was tried in every foreseeable combination relative to cabazitaxel. The emergent signal that we have in a small end right now is better than anything that was achieved in that study. in a comparable patient population, post-taxane patients. And, you know, so that's step one. We think we have something differentiated that hasn't been done with an IO therapy before in this heavily pretreative patients, even going back to the table that we have looking across all of our peer studies. And then step two is more of a question I think you're asking of how we see the treatment landscape evolving. As everyone knows, Pledicto is probably going to be used more and more. They had a good 2023 of commercial uptake in the United States. And so that has to be on our minds as we look through future development. But the interesting point here is the toxicity profile of Vidalumab is not overlapping with Pledicto. So that's one. And secondly, there's emerging evidence presented and published late last year that treatment Plavicto might actually sensitize the tumor microenvironment to checkpoint target therapy. And, you know, this all has to be proven out in the clinic within larger studies. And step one for us is still defining what we think the clinical profile is of Vudal MAD monotherapy for these heavily treated MADSAC patients with measurable disease. But once we understand that, I think there's a number of options how to move forward in an intelligent manner for development of this drug. So we're excited for what we're seeing. Again, early days here, so we don't want to, you know, get over our skis, but we'll look for a confirmation of the signal as we move throughout the year.
spk05: Great.
spk19: Thank you, guys. Thank you for your question. One moment, please. Our next question comes from the line of Alex Stranahan from Bank of America.
spk05: The floor is yours.
spk15: Hey, guys. Thanks for taking the question. This is John. I'm on for Alex. Just a first quick question. I think this was briefly mentioned before, but just wanted to check. I didn't catch everything. But what would be, like, a good benchmark or, like, a comparator for us to look at, you know, in comparison to the Vudalimab monotherapy data presented today? Okay. That's my first question. Second question on, you know, like quality of life data, you know, when can we expect to see some color regarding that if you're, you know, keeping track of it? And could you maybe provide some, shed some light on, you know, what you're currently observing in the clinic in terms of quality of life and, you know, like some patient reported outcomes? Thanks.
spk07: Thank you. Yeah, we're not collecting. Oh, sorry, Dan, you want to take both of them?
spk13: Yeah, I think, I mean, that question is really a question of when we have a totality of a cohort in discussion with our clinical investigators, is the clinical experience overall for these patients something that we should move forward? And, you know, so to that effect, the totality of the data is we don't know at this point, right? We want to see hopefully 30 patients in each of these cohorts, the monotherapy cohort and the dose-to-tax combination cohort, to have that conversation with our clinical investigators. So it's a great question, and that's really what we're hoping to answer. In terms of the first part of the question, that's why we provided the data table and the slides Because each of these studies that we're looking at, our peer studies, are exciting, right? We're excited about valioridomag and the clinical response there. But they're also limited in terms of their size and their scope and the comparability of the patients that were enrolled. So we don't want to make apples and oranges comparisons of novel agents for the treatment of these prostate cancer patients right now. But, you know, I think what we could say is a number of these programs, Zaluridimeg, I think, is undeniable, and hopefully our VodalMab monotherapy program as well, seem to be surpassing what you could probably expect for late-line chemotherapy from contemporary studies, as we mentioned, the cabazitaxel response rates. in the Checkmate 650 study and the therapy study. And then once you get to earlier lines of therapy, I think it is, you know, a toxicity profile. And again, you know, if it does seem that Plavicto is sensitizing the tumor microenvironment for IO therapy, we have a therapy that does not have overlapping heme tox and could be an interesting idea to explore down the road. All right. Thanks for the call, Eric.
spk19: Thank you for your question. One moment, please. Our next question comes from the line of Tara Bannecroft from TD Cowan.
spk05: The line is now yours.
spk18: Hi, good afternoon. So my question is more of a general question. So are there any other combos besides chemo that you're considering or really excited about that could increase the robustness of this data? And then specifically referring to the chemo combo, how do you think safety will look in that combination? Is there any update that you can provide on how that's going now in the 1704 study? Thanks.
spk07: So I guess on the first one, other combos other than the chemo, we think chemo is a very important one in this setting because it is the predominantly used therapy post-androgen still. I think it's really interesting to imagine post-plevicto treatment, maybe not in concert, given the intriguing immune priming activity that plevicto perhaps has from some small studies recently published, I think, out of UCSF. So I think those are the two top things on our mind now, but I think in the future, as we see our CD28 technology evolved. Our XMAB808 program is, of course, aimed partially at least at prostate, maybe even predominantly at the moment. And as that one evolves in combo with PEMBRO, we're certainly keeping our eye on how to maybe use that with Vudalimab if the stars align, right? So that's maybe the other big one that we're thinking of. You know, the future might hold combinations with CD3. By specifics with molecules like Fudalamab, I think that's something people are looking at. They're just starting to happen in the clinic now. I'm aware of some CD3 solid tumor molecules that are being tested with checkpoints. That's maybe a little bit further off in the future, though. And then I guess your second question was on what can we say about safety from the ongoing O4 study, given that we're not sharing specific data? So maybe, Nancy, do you want to comment?
spk17: Yeah, absolutely. So maybe I can share also that since we last presented data, we amended the protocol, the combination protocol in prostate cancer to remove the carboplatin and all but the aggressive variant. And we're really focused on the taxanes, specifically docetaxel as first-line chemotherapy. And so far, based on feedback from investigators, we seem to be seeing better tolerability with these new regimens than the prior one.
spk19: Operator?
spk07: Thanks everybody for joining us today and have a wonderful evening. We look forward to our next update.
spk05: Thank you for participation in today's conference.
spk19: This does conclude the program. You may now disconnect. Thank you. Thank you. Bye. Thank you. Thank you.
spk01: Thank you.
spk05: Good afternoon, and thank you for standing by. Welcome to Zencore's fourth quarter and year-end 2023 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. To ask a question during this session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1-1 again. Please be advised that today's conference is being recorded at the company's request. Now, I would like to turn the call over to your speaker today, Charles Lyles, Head of Corporate Communications and Investor Relations. The floor is yours.
spk06: Thank you, and good afternoon. Earlier today, we issued a press release which outlines the topics we plan to discuss today. It's available at www.zencore.com. Providing comments on the call are Basil Dahiet, President and Chief Executive Officer, Nancy Valenti, Chief Development Officer, and Dane Leone, Senior Vice President, Corporate Strategies. After the prepared remarks and presentation, we will then open up the call for your questions, and we will then be joined by John Desjardins, Chief Scientific Officer, and John Cush, Chief Financial Officer. Slides that we are using today should be visible here on the webcast and will be made available for download on the events and presentations page of our website. Before we begin, I would like to remind you that during the course of the conference call, Zencore Management may make forward-looking statements, including statements regarding the company's future financial and operating results, future market conditions, plans and objectives of management, future operations, the company's partnering efforts, capital requirements, future 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. With that, I'll pass the call over to Basil.
spk07: Thanks, Charles, and welcome, everyone. Today, we'll cover a few business highlights from 2023, briefly review our clinical pipeline, and provide a data update on Vudalimab and prostate cancer. You can refer to our press release for more information about the last quarter and full year. We focused our pipeline and discovery work on our T-cell engagers because of growing validation for their potential in solid tumors. Supporting this is the continued advance of Vidalimab and prostate cancer, where we'll provide an update today, and the start of a trial in frontline lung cancer for Vidalimab. And we've decided to reduce our investment in our cytokine drug candidates as part of this focusing. Our partnerships and licenses played a significant role for us last year, first with validating data for our XMAB 2 plus 1 CD3 platform from our partner Amgen with their xyloritmic data in prostate cancer, And two phase one programs started in our CD28 bispecific collaboration with J&J. And we significantly strengthened our balance sheet with a partial monetization of our Ultimers and Mondravie royalties. As a result of that and robust milestone in royalty revenues, we ended 2023 with $697 million and expect runway into 2027. Now on to our pipeline. The focus of our clinical pipeline is bispecific T-cell engagers for solid tumors, an area with rapidly growing promise. Solid tumors have been challenging for antibody and cell therapies, but recent data, some of which we'll review momentarily, suggests that CD3 and CD28 bispecifics could play a role as therapies in a range of solid tumors. Key programs for us addressing this opportunity are XMAB819, an ENPP3 by CD3 XMAB bispecific for renal cell carcinoma, and XMAB808, a B7H3 by CD28 XMAB bispecific in prostate and other cancers. Both are advancing in dose escalation in Phase 1, and right behind them is XMAB541, a Clouden 6 by CD3 bispecific that we expect to start Phase 1 the first half of this year. For Vudalamab, we initiated a new study, its first frontline study, in non-small cell lung cancer, based both on our Phase 1 data in lung cancer and external data suggesting potential advantages against standard checkpoint therapy in this setting. And we've made progress with our metastatic castration-resistant prostate cancer studies, both in combination with chemo and monotherapy, and with encouraging monotherapy data we're going to present in a moment. Finally, we're wrapping up our Phase I work next quarter for both XMAPs 564 and 662, taking the PK, PD, and safety data in hand to establish initial product profiles and monitoring the field for further validation of these cytokines before we do any additional developments. Underpinning our T-cell engages our XMAP bispecific technology. It lets us address the solid tumor opportunity by engineering our antibodies with a format and affinities designed to give tumor selectivity in the context of each tumor target's particular expression levels and tissue distributions. Solid tumor targets in particular need a customized approach because they're distributed more broadly than heme tumor targets, which have already been successfully addressed by CD3 bispecifics in lymphoma and myeloma. Our plug-and-play antibody modules let us do this work rapidly, and as a result, we've got a growing pipeline of molecules with our 2 plus 1 design, which is particularly helpful with selectivity for solid tumors. And here is the first clinical proof of concept for our XMAP 2 plus 1 CD3 format, xaloridimig, which targets steep 1. Our partner, Amgen, presented very promising efficacy and tolerability data at ESMO last October in late Lyme prostate cancer, usually considered a cold tumor for immunotherapy. This target was challenging due to the limited accessible binding regions outside the cell membrane and non-tumor expression. So we're very encouraged to see this early data for the molecule in a two plus one format. Amgen's announced they are nearing completion of the phase one study and are planning additional studies in earlier lines of therapy. So we'll be eagerly awaiting their updates. Now, our own lead XMAB2 plus 1 CD3 bispecific is XMAB819, targeting ENPP3 and renal cell carcinoma. We chose ENPP3 as a target because it has exactly the kind of expression profile we want for a CD3 solid tumor target. Much higher expression on tumor than normal tissues and nearly uniformly high expression on clear cell renal cell carcinoma. Plus, it has potential for use in select patients and a range of other tumors. Also, we think renal cell carcinoma has a need for new mechanisms beyond checkpoint inhibitors and TKIs, and a directly cytotoxic antibody could be well-positioned. 819's design gives us selectivity we wanted in vitro, and we're continuing to advance in dose escalation with both IV and subcutaneous dosing, and expect to make significant progress this year toward target dose levels. I'll shift now to XMAB808, our new T-cell engager mechanism, CD28-targeting. The goal here is to activate T cells via the signal 2 pathway, which powerfully amplifies and sustains T cell responses. We designed 808's bispecific format and affinities to try to drive this activation in a tumor-specific way by requiring sufficient binding to its tumor antigen, B7H3, to turn on CD28 signaling. A key part of our approach is a lower-potency CD28 binding domain that we think could give us control of CD28 signaling and improve tolerability. We picked B7H3 because it offers high expression across a range of tumor types, creating an opportunity to potentially treat multiple cancers in combination with either checkpoint inhibitors or CD3 bispecifics. CD28 targeting has generated a lot of interest among clinicians and across the industry, and the current phase one study in combination with pembrolizumab is progressing well in escalation. Now, our latest CD3 bispecific is set to enter the clinic imminently. XMAP541 targets CLOUDIN6, which is highly expressed, on the majority of ovarian cancers and also on several other tumor types. Though it has a very promising expression profile, it is a selectivity design challenge because there are multiple closely homologous cloudins. We think we addressed it with careful binding domain engineering and our 2 plus 1 format. XMAP 541's IND is open and we expect to be in patients the first half of this year. We're planning to apply lessons learned for solid tumor CD3 dosing from both internal and external programs to move the study quickly. Now I'm going to turn it over to Nancy for the Vidalimab update.
spk17: Thanks, Bessel. I'm excited about the encouraging new data we have to share from the prostate cancer monotherapy cohort. If we could go to the next slide. This cohort is part of the overall Vidalimab program, which consists of four studies. Based on the outcome of the phase one study, we moved into two tumor-specific expansions initially. the study 71704 in metastatic castrate-resistant prostate cancer in combination with standard of care chemo and other agents, and study 71705 that included patients with gynecologic malignancies and a monotherapy metastatic castrate-resistant prostate cancer cohort, which I'm going to further describe.
spk16: The next slide.
spk17: The prostate monotherapy cohort required patients to have resist measurable disease, including visceral sites or lymph nodes, and the patients had to have progressed after all other appropriate therapy. Videlumab was given every three weeks as a flat dose based on our PK analysis of earlier studies. You can see that this study enrolled a heavily pretreated patient population that had exhausted available standard of care therapies. with a median of four prior therapies, 100% received prior antiandrogen therapy, all but one received prior chemotherapy, and 86% were ECOG1 performance status. As noted, the study protocol required patients with measurable disease at baseline, which is why we see a high rate of visceral metastases and high median baseline PSA. Reduction in target lesions and disease control are encouraging for such a heavily pretreated patient population, as you can see on the right, with a resist response rate of 35% and a disease control rate of 50%. And the spider plot shows we have several lasting responses and one patient with stable disease past 48 weeks. Deep PSA reduction was also seen in three patients, giving a PSA 90 rate of 25%, and a fourth patient with nearly a 50% PSA who is still on study. To describe one especially poor prognostic patient who responded well to venalamab, this patient had three liver mets, a total disease burden of 12 centimeters, and a PSA at baseline of 180 nanograms per mil, and achieved a confirmed PR, a PSA 90, and was in response for over 22 weeks. The treatment immersion adverse events highlight the tolerability has been generally well managed by dose modifications with only two treatment discontinuations. Unfortunately, there has been one case of grade five immune-related mediated hepatitis. The patient's treatment course was complex. And this is the only known grade 5 immune-mediated hepatitis event in over 240 patients that we've treated with Vudalamab to date. Reviewing specific immune-related adverse events, generally the events are what we'd expect with checkpoint inhibitor therapy. The rate of grade 3 events that you can see on the right were generally limited and specific to several patients. Overall, we are encouraged by the tolerability profile of the Q3 week flat dosing schedule with Fudalamab. In summary, we have observed encouraging single-agent activity in a heavily pretreated patient population. This is consistent with the data from the Phase I study in prostate cancer, where we had patients with 6 and 10 months duration of response. The Delamab safety profile is consistent with other checkpoint inhibitors, and we observed limited treatment discontinuations. Now I will turn this over to Dane to share comparative data to place these results in context.
spk13: Thanks, Nancy. As you can see on the next slide, these emerging data support us enrolling more patients into the monotherapy cohort. When you put the data into the context of the broader novel therapeutic landscape under development, it really is clear why we and our investigators during our discussion at ASCO-GU were so encouraged about continuing this study. When you compare the baseline characteristics of our patients versus our peer studies, the Vidalimab Bonn therapy cohort is among the most heavily pretreated and has the most advanced disease upon enrollment, as shown by nearly all having ECOG1 and all having measurable disease. Comparatively, only the xyloritmic dose escalation study has enrolled similar patients that are very late line and poor performance status. Despite the remarkably advanced patient population, patients treated with Adalimab have comparable resist response rate versus the peer studies in this table and experienced DPSA-90 responses. Importantly, we think that resist response and DPSA response are required for translating into effective durability of response and ultimately survival outcomes for these patients. Regarding tolerability, using the Q3 week flat dose schedule of VudalMab has supported a manageable safety profile compared to our peers. Overall, considering the early nature of the VudalMab monotherapy cohort, we are encouraged by the clinical benefit for these advanced prostate cancer patients that have been treated well beyond current standard of care. And we look forward to evaluating a larger cohort of patients by year end. Now on the next slide, beyond prostate cancer, we are executing on the start of our frontline non-small cell lung cancer study of VidalMab plus chemotherapy. And we are excited that this study is underway with the first patient dose in the fourth quarter of last year. And with that, I'll turn back to Basil for a view of our corporate goals for 2024. Thanks, Dean.
spk07: Here's a look at our priorities for 2024. We're starting with a strong balance sheet, and as you can see, we're looking forward to this year really bringing the focus to our solid tumor bispecifics pipeline, where we have a lot going on for our CD3 and CD28 T cell engagers and for Vudalamab. Of course, we're doing discovery work on additional CD3 and CD28 bispecifics, and we'll select our next IND candidate later this year. Operator, we'll now open this call to questions.
spk05: Thank you. at this time we will now conduct the question and answer session as a reminder to ask a question you will need to press star 1 1 on your telephone and wait for your name to be announced to withdraw your question please press star 1 1 again please stand by while we compile the q a roster our first question comes from jonathan chang of variant partners our Lear Inc. partners. The floor is now yours.
spk08: Hi, guys. This is Dylan Drake from Upper Jonathan. Thanks for taking our questions. First of all, would you be able to comment on how investors should be thinking about when we might be able to see initial clinical data from the ENPB3 study?
spk07: Sure, I'll take that one. So we're not commenting on data just yet, and what we're trying to do is characterize with a sufficient patient number and follow-up the sort of outlines of the effective dose level as we pull together a dosing regime. These are CD3 biospecifics, so you want to have your priming and step-up doses. We've made great progress, and we really hope that this year we'll have a lot more knowledge about it. And then when we get close to having the decision to disclose, we will tell you. So we're not guiding anything there yet.
spk08: Great, thanks. If I could just sneak in one more. You guys set the stage pretty well with the comparative table there, but looking ahead to the go-forward decisions for both the mono and combination Zudalamab approaches, how would you guys set the bar?
spk07: Yeah, so I guess maybe the mono first. I mean, Nancy, Dane, you guys want to take that? What's the bar for advanced comparables?
spk13: Yeah, sure. Great question. When we look at the patients that we've enrolled into the monotherapy cohort and will continue to enroll These are patients that are as late line as you can get and have exhausted every standard of care therapy available to them. As such, what we've really decided to do in engaging the signal that we'll have as we hopefully get a cohort of 20 to 30 patients enrolled over the course of this year is look at some of the contemporary studies where cabazitaxel has been used as a control arm. And in those studies, namely the control arm for therapy or the very recently reported part two of Checkmate 650, you've seen a resist response rate for capacitaxel in that 11% to 24% range and a PSA50 response rate of 24% to 37%. This is why we're quite encouraged with what we're seeing in the cohort now with clinical activity of adalimab monotherapy. And hopefully with a larger cohort, more follow-up, we can then try and extrapolate what would be needed in terms of survival outcomes. And cabazitaxel, for reference, has generally come out around eight months for radiographic progression-free survival. And right now, based on some of the durability, it seems like we're in pretty good shape.
spk07: Now then, for the combo cohort, I guess, we've got different baselines there to look at.
spk13: Yeah, in the combination cohort with docetaxel, you really have to think about what docetaxel might be able to do in what would be post-angioreceptor inhibitor exposure for these patients. And again, the landscape will continue to change with Plavicto, but historically, if you're looking at the TAX327 study, You'd be looking at a PSA50 response range of 40 to 50% and a fairly low resist response rate of somewhere around 10%. That said, the survival curves are a bit better for that line and that setting with dose-to-taxel monotherapy. But that's kind of what you have to think about when you're doing the combination study with dose-to-taxel at this point.
spk08: Perfect. Thanks so much. I appreciate it.
spk19: Thank you. One moment, please. Our next question comes from the line of Etzer Dorout from BMO Capital Markets.
spk11: Great. Thanks for taking the question. I guess maybe on the safety profile of Delimab, if there's anything you can or will incorporate into the study to maybe kind of mitigate this autoimmune hepatitis, is this something that is just unique to this patient or if, you know, if there are other things sort of going on that you need to understand. And then also on XMAP564, just wondered the decisions to sort of pause that, was that data-driven or, you know, whatever other contributing factors, if you could comment on that to pausing that study. Thank you.
spk07: Sure. So I'll talk, I'll go through the XMAP564, then maybe Nancy can take the question on the Vidalimab safety profile. So for 5, 6, 4, it was really driven by our, as much as anything, by our decision to focus on our T cell engages, our resources, our capital, and our people. And, you know, looking at how the class cytokines generally and IL-2 Treg driving cytokines in particular has evolved, there's still, I think, a lot of outstanding data coming in the next year from other companies about efficacy, about how much potential does this class have. And with our study having progressed and given us a reasonable look at our PKPD and safety, we think that that's the time to conserve resources and wait and see how the field evolves. We're well-positioned to ramp up again, but it's about focus now. And for 2024, pipeline focus is the key for Zencore. So it was really more just strategy-driven. With that, maybe Nancy, do you want to touch on the question on Vudalibet?
spk17: Yeah. So I'll go back to the patient with the hepatitis death, and that's the only immune-related hepatitis death we've seen across our program with more than 240 patients treated, both in the monotherapy and combination setting. The patient had responded to therapy but did have other treatment emergent adverse events, Before that, including diabetes mellitus and diabetic ketoacidosis, thyroiditis, hyperkalemia, lipase increase. So a bit of a complex course here. We have looked across the entire program, and we don't see anything concerning relating hepatitis. As far as the protocol and the investigators, We have emphasized to the investigators to be watchful for this and communicate it with them. The protocol does include the NCCN guidelines for treatment and it's also consistent with ASCO guidelines and other society guidelines like the gastric GI guidelines for monitoring and treatment. And so we do include screening at baseline for any diseases that might contribute to hepatitis. And we have frequent laboratory monitoring.
spk09: Great. Thank you for the color.
spk05: Thanks, Heather.
spk19: Thank you for the question. One moment, please.
spk05: Our next question comes from Gregory Rinza of RBC Capital Markets. The floor is yours.
spk20: Hi. Thank you so much for taking our questions and support for Greg. Just to confirm, if this monotherapy data was from a particular molecular subtype, since I think that was how the trial used to be characterized, and if I may, secondarily, from the data comparison table, I think the PSA 90 looked competitive, but PSA 50 looked a little lower. Just curious if you have any hypothesis on why the data looks that way. Thank you.
spk07: So I'll touch on the specifics of the trial in the population. So I think just to be careful, there's two studies ongoing now where we're studying prostate cancer with Vudalamab. The monotherapy study, the one we discussed today, is not subdivided by molecular subtype. It's people with clinically defined high-risk disease, which includes extra pelvic and visceral metastases. So that's a population that's independent of molecular subtype in that regard. The other study, our combination with chemo study, that study is subdivided by molecular subtype. That's a different study. We didn't discuss data for that one today. We're enrolling still a crew of patients and more follow-up, and we hope to have a lot more clarity later in the year on that program. And also, I guess, first half of next year, really bring it all together. So I just want to make sure that this is not from the molecular subtype dividing study. Maybe on the comparison table, Dan, you want to answer that one on the PSAs?
spk13: Yeah, sure. That's a great question that we looked at. quite extensively once we had this data cut and were able to review the data with our investigators during ASCO-GU. What it seems to be is somewhat of an artifact of taking patients that are required to have measurable disease at baseline versus other studies that also include bone only. And as you can see on that table, most of our peer studies outside maybe one with a similar mechanism of action, is more of a mixed patient population. And what we see in those studies is you will get more PSA50s that don't necessarily correlate to a resist response, as some of those patients do not have measurable disease at baseline. In our cohort, to really get clinical benefit, those patients will need either a resist response or a PSA90. So I think there's two things there. One, is PSA 50 for patients that are this advanced in their disease course relevant for survival outcomes? Very debatable. But what is definitely needed is those resist responses and PSA 90s. Thank you.
spk19: Thank you. One moment for our next question. Our next question comes from the line of Kavari Pullman from BTIG.
spk05: The floor is yours.
spk03: Yeah, good evening. Thanks for taking my questions. My questions are mostly on Vidalimab. So first on the safety profile, can you tell us how the safety profile looks in comparison with epinephrine combination and how you are thinking about the dose that will be used going forward? And my second question is also for the no-go, no-go decision. How many patients do you plan to enroll in monotherapy and combination cohorts for that? And is efficacy the only factor you're considering to make these decisions? And the last one is also from the same trial. Any color you can provide on how many patients had bone disease, and were there any responses observed in those patients? Thank you.
spk07: Hey, thanks, Kavari. So that's a set of questions. I think maybe the one that's more just generically descriptive is your first one, Vidalmeb safety versus ipinevo, which is a broad kind of amorphous question, but, you know, we'll take a crack at it and what our dose going forward is. Nancy, do you want to jump in on that one?
spk17: Yeah, I mean, overall, what we've seen so far is a safety profile that looks similar to other checkpoint inhibitors. So we haven't seen anything that says that this is different, markedly different in some way that wouldn't be unfavorable to the product. But I guess I could say that overall. I mean, there's a lot of data out there on IPI, single monotherapy checkpoint inhibitors, as well as combinations. So broadly, we're similar to that. Do you want to?
spk07: Yeah, and on the dose going forward, note that in our lung cancer study, the newest study we started, as well as in the monotherapy prostate study, which was the second newest, we have switched to a Q3 week schedule using flat doses, and I think that's given us a good feeling that the Q3 week might have some benefits over the Q2 week weight-based dosing. With regard to ipinevo, even though we've got over 240 patients now, it's still hard to parse out those subtle differences. We don't see the kind of colitis that often bedevils IPI therapy at high doses. And note, we're giving much higher doses of our drug than the current sort of IPI regime of one milligram per kilogram. You know, so I think that's maybe the best we can say comparatively across such a range of studies and whatnot, but generally very checkpoint-like. And then on your second question, go-no-go number of patients that we'd hope to have for both the combo and the mono. So by first half of next year, we're looking at on the order of, I guess, roughly 30 patients in each of those settings. The chemo study in particular in the main cohort, which is our no-targetable mutations cohort, which is our now-dose-to-taxel combo, and then on our monotherapy study as well. So in that, we're aiming for 20 patients. Hopefully, we'll get pretty close to that and be able to make decisions.
spk13: I think it would be helpful, maybe, Nancy, you could just explain the difference between measurable disease and nonmeasurable disease at baseline, because I think that might be helpful for everyone.
spk17: Sure. I mean, measurable disease means it has very basically two dimensions, and it's got to be a metastatic site in an organ. or a measurable lymph node, bigger than a normal lymph node. Non-measurable would typically be bone-only disease, or if a patient had bone-only disease. Our patients had measurable disease, and they could have also had bone disease on top of that. I can tell you two of the four responders had bone disease in addition to their other measurable disease. So we have seen responses in patients who had bony disease.
spk02: Got it. Yeah, that's what I wanted to know. Thank you. Thanks for the call.
spk19: Thank you for that question. One moment, please.
spk05: Our next question comes from the line of Brian Chung from JP Morgan. The floor is yours.
spk04: Hey, Basil. Hey, guys. Thanks for taking my questions today. Maybe the first one is just on the three confirmed responders, I think just kind of piggybacking on what was the question prior to this. What was the background of the three confirmed responders? Can you just kind of give us how many lines they have and kind of give us a sense of what their historical responses were? to prior AR or even, I see that they had, you know, some patients had radiation, so just curious, like, what were their responses like? And I have a follow-up, thank you.
spk07: Yeah, I mean, Nancy, you could take that. You know all the details. I'd say they were really, really heavily pretreated in rough shape when we got them.
spk17: Yeah, they had to be progressing through prior therapies. They had to have, you know, at least two prior therapies, You know, I'm looking at the background, and, you know, they had anywhere from three to, like, seven prior therapies, including XRT. I'm just looking at... Yeah, that's a lot of detail, Brian, so we're just picking up our notes. Yeah, yeah. So, you know, one patient had three prior therapies, not including any radiation. Second patient had three prior therapies. The third patient had six prior therapies, so none of these are with radiation or counting that. And the last patient had two prior therapies. They all included one. They all included docetaxel or one included carboplatin. Two had prior radiotherapy. Let me just see. I can't really comment on their prior responses, but maybe in an upcoming presentation we could. drill down into each individual patient?
spk07: Yeah, yeah, but suffice to say they've seen a lot of prior therapy, Brent.
spk04: Okay, and then a follow-up here is, you know, as you're looking at this data, and I think the last time we saw the combo data, maybe back in, let's see, I think back in 2022, how should we think about the low-hanging fruit piece? You know, what is the lowest-hanging subset of the MCRPC patients that investors should think of when it comes to a dial-up map? And is it high risk? Is it genetically defined? How do you think about the low-hanging fruit, either with combo or monotherapy? Thanks.
spk13: Yeah, I think it's a great question that we're obviously going to have a fuller answer to as we get these cohorts enrolled over the course of this year and can really look for a solution reliable signal, hopefully in 30 patients per cohort for monotherapy and for the combination. But the way we're thinking about it now is we just had an update on part two of TechMate 650 at ASCO-GU, where ipinevo was tried in every foreseeable combination relative to cabacidaxel. The emergent signal that we have in a small end right now is better than anything that was achieved in that study. um, in, uh, a comparable patient population, uh, post-taxane, uh, patients. And, um, you know, so that, that's step one. We think we, we have something differentiated that hasn't been done with, with an IO therapy, uh, before in this heavily pretreated patients, uh, even going back to the table that we have looking across all of our peer studies, uh, Uh, and then step two is, is more of a question. I think you're asking of how we see the treatment landscape evolving. Um, as you know, everyone knows Plavicto is probably going to be used more and more. Uh, they had a good 2023 of commercial uptake in the United States. And so that has to be on our minds as we look through future development. But the interesting point here is, uh, the toxicity profile, the dialed map is not overlapping with Plavicto. Uh, so that's one. Um, and secondly. There's emerging evidence presented and published late last year that treatment Plavicto might actually sensitize the tumor microenvironment to checkpoint targeted therapy. And, you know, this all has to be proven out in the clinic within larger studies. And step one for us is still defining what we think the clinical profile is of Vudal MAD monotherapy for these heavily treated MADSAC patients with measurable disease. But once we understand that, I think there's a number of options how to move forward in an intelligent manner for development of this drug. So we're excited for what we're seeing. Again, early days here, so we don't want to, you know, get over our skis, but we'll look for a confirmation of the signal as we move throughout the year.
spk05: Great.
spk19: Thank you, guys. Thank you for your question. One moment, please. Our next question comes from the line of Alex Stranahan from Bank of America.
spk05: The floor is yours.
spk15: Hey, guys. Thanks for taking the question. This is John. I'm on for Alex. Just a first quick question. I think this was briefly mentioned before, but just wanted to check. I didn't catch everything. But what would be, like, a good benchmark or, like, a comparator for us to look at, you know, in comparison to the Vudalimab monotherapy data presented today? Okay. That's my first question. Second question on, you know, like quality of life data, you know, when can we expect to see some color regarding that if you're, you know, keeping track of it? And could you maybe provide some, shed some light on, you know, what you're currently observing in the clinic in terms of quality of life and, you know, like some patient reported outcomes? Thanks.
spk07: Thank you. Yeah, we're not collecting. Oh, sorry, Dan, you want to take both of them?
spk13: Yeah, I think, I mean, that question is really a question of when we have a totality of a cohort in discussion with our clinical investigators, is the clinical experience overall for these patients something that we should move forward? And, you know, so to that effect, the totality of the data is we don't know at this point, right? We want to see hopefully 30 patients in each of these cohorts, the monotherapy cohort and the dose-tactic combination cohort, to have that conversation with our clinical investigators. So it's a great question, and that's really what we're hoping to answer. In terms of the first part of the question, you know, that's why we provided the data table and the slides Because each of these studies that we're looking at, our peer studies, are exciting, right? We're excited about valioridomag and the clinical response there. But they're also limited in terms of their size and their scope and the comparability of the patients that were enrolled. So we don't want to make apples and oranges comparisons of novel agents for the treatment of these prostate cancer patients right now. Um, but, you know, I think what we, we could say is a number of these programs, um, uh, value red omega, I think is undeniable. And, uh, hopefully our Vidal lab monotherapy program as well seem to be surpassing, uh, what you could probably expect, uh, for a late line chemotherapy from contemporary studies, as we mentioned, the capacity tax or response rates, um, in the Checkmate 650 study and the therapy study. And then once you get to earlier lines of therapy, I think it is, you know, a toxicity profile. And again, you know, if it does seem that Plavicto is sensitizing the tumor microenvironment for IO therapy, we have a therapy that does not have overlapping heme tox and could be an interesting idea to explore down the road. All right. Thanks for the call, Eric.
spk19: Thank you for your question. One moment, please. Our next question comes from the line of Tara Bannecroft from TD Cowan.
spk05: The line is now yours.
spk18: Hi, good afternoon. So my question is more of a general question. So are there any other combos besides chemo that you're considering or really excited about that could increase the robustness of this data? And then specifically referring to the chemo combo, how do you think safety will look in that combination? Is there any update that you can provide on how that's going now in the 1704 study? Thanks.
spk07: So I guess on the first one, other combos other than the chemo, we think chemo is a very important one in this setting because it is the predominantly used therapy post-androgen still. I think it's really interesting to imagine post-plevicto treatment, maybe not in concert, given the intriguing immune priming activity that plevicto perhaps has from some small studies recently published, I think, out of UCSF. So I think those are the two top things on our mind now, but I think in the future, as we see our CD28 technology evolved. Our XMAB808 program is, of course, aimed, partially at least, at prostate, maybe even predominantly at the moment. And as that one evolves in combo with PEMBRO, we're certainly keeping our eye on how to maybe use that with Vudalimab if the stars align, right? So that's maybe the other big one that we're thinking of. You know, the future might hold combinations with CD3. By specifics with molecules like Fudalamab, I think that's something people are looking at. They're just starting to happen in the clinic now. I'm aware of some CD3 solid tumor molecules that are being tested with checkpoints. That's maybe a little bit further off in the future, though. And then I guess your second question was on what can we say about safety from the ongoing O4 study, given that we're not sharing specific data? So maybe, Nancy, do you want to comment?
spk17: Yeah, absolutely. So maybe I can share also that since we last presented data, we amended the protocol, the combination protocol in prostate cancer to remove the carboplatin in all but the aggressive variant. And we're really focused on the taxanes, specifically docetaxel as first-line chemotherapy. And so far, based on feedback from investigators, we seem to be seeing better tolerability with
spk16: these new regimens than the prior one.
spk19: Operator? Do we have any other questions?
spk07: No, that looks like that's clear. Great. Well, thanks, everybody, for joining us today, and have a wonderful evening. We look forward to our next update.
spk05: Thank you for participation in today's conference. This does conclude the program. You may now disconnect.
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