This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk06: Good day, and thank you for standing by. Welcome to the Zencore Q3 2022 conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Charles Lyles. Please go ahead.
spk03: Thank you, and good afternoon. Earlier today, we issued two press releases which outlined the topics we plan to discuss today. The press releases are available at www.zencore.com. With me on the call are Basil Dahia, President and Chief Executive Officer, John Desjardins, Chief Scientific Officer, John Cush, Chief Financial Officer, and Alan Yang, Chief Medical Officer, Ralph Zitnik, Executive Medical Director and Head of Autoimmune, will join us for Q&A. On our agenda, we will first review recent business news and financial results, followed by the presentation of results from the Phase 1 Single Dose Study of XMAP564 in Healthy Volunteers. This slide should be visible on the webcast and are also available for download on the Events and Presentations page of our website. We will then open up the call for your questions after both the prepared remarks and presentation. 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, 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. Section of our most recently filed annual report on Form 10-K and quarterly report on Form 10-Q. With that, I'll pass the call over to Pat.
spk02: Thanks, Charles. We'll focus today on our just-released XMAP 564 data and comment briefly on other topics. To frame the discussion, we've used our array of modular protein engineering tools to create a broad internal development portfolio in oncology and autoimmune disease and take multiple simultaneous shots on goal in the clinic. Our intent is to use proof-of-concept data from our early-stage studies to guide which programs we advance, which we terminate, and which we partner so that we use our resources on programs with the greatest potential for success and make room in our portfolio for the next wave of XMAP biospecifics and engineered cytokines. We're excited to share with you an important step along this journey, very promising biomarker data for 564, our second engineered cytokine program. But first, we'll briefly review upcoming data presentations for other programs and some business highlights. First, for Vidalimab, our Phase II PD-1 by CTLA-4 dual checkpoint bispecific antibody. It's enrolling a Phase II study for patients with metastatic castration-resistant prostate cancer after two prior lines of therapy. in combination with chemotherapy or a PARP inhibitor, depending on molecular subtype. It's an indication with a high unmet need and is currently without much checkpoint inhibitor use beyond MSI-high tumors, even though small studies of combination PD-1 and CTLA-4 inhibitions showed promise. Later this week at the Society for Immunotherapy of Cancer meeting, we will present some data from the first few handfuls of patients in the safety running portion of the study with a focus on patients receiving the combination of budalumab, a taxane, and a platinum agent. We're also conducting a second Phase II study with a more convenient every-three-week dosing schedule in patients with clinically defined high-risk metastatic castrate-resistant prostate cancer, which will allow us to study Vidaliband monotherapy in a specific population of aggressive prostate cancer where we saw confirmed partial responses in our Phase I study. We're also enrolling cohorts of patients with advanced gynecologic tumors. Now, for Plimodimab, our CD20 by CD3 bispecific, as you probably saw, an abstract was accepted for presentation at the American Society of Hematology annual meeting in December. We'll present updated clinical results from the expansion cohort in a Phase I study for patients with non-Hodgkin's lymphoma. We've observed that Plimodimab has remained generally well-tolerated with encouraging monotherapy activity. In addition, we've initiated a cohort to study subcutaneous dosing. We also continue to enroll patients in a Phase II combination study with tafacitumab and lenalidomide. Now, with that, I'll turn it over to John Cush to provide a brief financial update. Thank you, Basil.
spk18: GenCore's portfolio of collaborations and licenses with partners provides ongoing revenue streams to support investments in our research activities and our expanding pipeline of bivicivic and cytokine candidates. These partnerships provide upfront payments, milestones, cost-sharing arrangements for development programs, and royalty payments, including royalties from three marketed products. Total revenue for the third quarter in the first nine months of 2022 was $27.3 million and $143 million, respectively. Total reported revenue was primary royalty revenue from our Veer and Lexiana partnerships related to their sales of Citrobimab and Ultimaris, respectively. Total revenue proceeds that we received for the first nine months of 2022 largely funded our operations during the period. Total cash, cash equivalents, receivables, and marketable debt securities at September 30th totaled $564.6 million, which is just slightly less than the $664.1 million balance at the beginning of the year. We are updating our year-end cash position guidance and now estimate we will end 2022 with between $575 million and $600 million in cash, cash equivalents receivables and marketable debt securities. We continue to guide that we have sufficient cash and cash equivalents and marketable debt securities to fund our R&D programs and operations through the end of 2025. I refer you to our press release this afternoon and to our SEC filings for further details about our financial results. With that, I'd like to hand the call back to Basil. Thanks, John.
spk02: I'd ask the audience to advance to slide five. So the rest of today's comments will be presenting the top-line data from the Phase 1A study for XMAB564, a reduced-potency cytokine targeting regulatory T cells with the goal of treating autoimmune disease. Advance to slide six. 564 was designed like all of our XMAP cytokines, using the full range of our protein engineering tools. First, we engineered the cytokine's receptor binding profile to aim selectively for the particular receptor desired, in this case, CD25, and at the same time, reduce the molecule's potency significantly, often 100-fold or more, to improve two features. by avoiding overactivation of the immune system that results from hyper potent native cytokine administration. And second is to reduce how rapidly the cytokine is cleared due to receptor binding internalization. We represent this on the right panel of this slide showing a reduced toxicity activity peak, but a significantly extended duration, which we believe has the potential to create greatly improved therapeutic profiles. We then use our XMAP FC domains to serve as a stable scaffold and to ease manufacturing, plus extend half-life further. Advance to slide 7. Moving on to the Phase 1A trial, it's a single ascending dose study in healthy volunteers that showed subcutaneous XMAP564s well-tolerated and selectively expanded regulatory T-cells, starting at lower doses and reaching the highest reported levels we're aware of at the high dose. Particularly notable was the exceptional durability we observed, with the highest levels of Tregs after three weeks that we're aware of being reported. We're looking forward to exploring multi-week dosing schedules in our already started Phase 1b multiple ascending dose study and believe that longer dosing intervals are a potentially important differentiator for Treg targeting agents and in autoimmune disease generally. We're also pleased that 564 is the second XNAV cytokine to show remarkable target cell expansion in the clinic. Last year, we reported data from the Phase I study of XNAB306, our reduced-potency IL-5C fusion in oncology, where we also saw expansion of target cells, in that case, NK cells, and notably significant accumulation of NK cells upon repeat dosing across a range of dose levels. We'll be monitoring for similar pharmacodynamics in our multidose trial of 564, and, if present, assessing how that could potentially benefit dosing frequency. I'll turn the call over now to John Desjardins to describe in more detail the Treg targeting rationale and design of X9564. Thanks, Basil.
spk10: Let's move on to slide eight. Now, it's well established that Tregs play an important role in preserving immune homeostasis, and there's growing evidence that this balance is perturbed in autoimmune diseases. While there have been tremendous efforts to utilize low-dose recombinant IL-2 for autoimmune disease treatment, We believe our potency-reduced, long-acting IL-2-FC fusion can promote superior Treg expansion and selectivity, providing more robust and durable Treg expansion with better tolerability. On slide 9, the fundamental problem with IL-2 itself is that while it preferentially interacts with Treg, it's not perfectly selected. So at higher doses, it will also expand conventional T cells and other lipocytes. Its intrinsic preference for Treg is because Treg constitutively expressed CD25, the IL-2 receptor alpha, and that expression provides the highest affinity receptor complex for IL-2. So our engineering strategy here is twofold. First, we increased binding affinity to CD25, and second, we decreased affinity to the IL-2 receptor beta. With this strategy, we not only improved selectivity for Treg significantly, we also achieved the overall potency reduction we're looking for, to create a long-acting and tolerable IL-2. On the next slide, slide 10, here we show some of our preclinical characterization of XMAP564. The two plots on the left show the potency and selectivity profile of XMAP564, the plot on the top, versus wild-type IL-2. Note that due to our engineering, XMAP564 is not only more selective for activation of Treg compared to wild-type IL-2, it is also, and here note the difference on the scale on the x-axis, it's also considerably less potent as intended. And as predicted from a reduced potency hypothesis, we saw a nice extended PK profile for XMEN564 in non-human primates. Now I'll turn things over to Alan Yang, our chief medical officer, for a brief summary of our Phase Ia study.
spk11: Thanks, John. Before I begin with slide 11, I would like to recognize the XMAB564 team. We started this healthy volunteer study in 2021 during a time when the pandemic was creating many logistical hurdles and we have already completed the study and have started dosing in our phase 1B study in atopic dermatitis and psoriasis patients. The phase 1A study was a randomized double-blind study of subcutaneous XMAB564 that enrolled 48 healthy volunteers across six dose levels from 0.03 milligrams per kilogram to 0.065 milligrams per kilogram. Patients were randomized six to two, XMAP564 to placebo, respectively. The clinical primary outcome measures were safety and tolerability. In addition, TK and biomarkers, such as expansion of T cell populations like Tregs were examined. Important data that will inform our dosing strategies moving forward. Next, on slide 12. Overall, the XMAP564 was well-tolerated across all dose levels. All adverse events were grade 1 or 2 and self-limited. That is, they resolved without intervention. The most common AE was injection site reactions. There were no serious AEs, dose-limiting toxicities, or early discontinuations due to AEs. There were also no clinically significant abnormalities in laboratory values, vital signs, or EKGs. Some subjects had transit increases in eosinophils, though no eosinophil-related AEs were observed. We believe this laboratory increase might be related to the mechanism of action of CD25-targeted IL-2s. Finally, the terminal half-life is estimated to be 9 to 10 days at the lower doses and 6 to 7 days at the highest dose. This is consistent with the increase in CD25-target mediated clearance from the expanding Treg cells. Now I'll turn things back over to John to review the pharmacodynamic data.
spk10: Thanks, Alan. Let's move on to slide 13. Okay, on slide 13, let's start with a look at the CD25 bright Treg population, thought to be the most suppressive Treg population. On the left, we show a time course of the absolute CD25 bright Treg counts over time for each dosing cohort. The placebo, in red, As expected, it shows a very low level of CD25 bright Treg that is consistent throughout the 20 days. Then, most notably on this plot, you see, starting with cohort 3 in the dashed green line and at higher doses, a very robust expansion of this Treg population with a strikingly high level of expansion for cohort 6 in magenta, peaking at about 150 cells per microliter. Now, these are averages shown here, but on the right-hand plot, we show the peak Treg fold increase for each subject across all dose levels. Here again, you see a consistent and statistically significant fold increase across all the dose cohorts. These are clearly significant increases in Treg with 10-fold and larger boosts starting at the 15 microgram per kilogram dose, culminating in a dramatic 117-fold increase at the highest dose cohort. You'll also notice a very large jump going from some of the intermediate doses to the high 65 microgram per kilogram dose. This is nicely consistent with our in vitro dose response curves, where at the serum concentrations we have for these doses, the in vitro dose response is just beginning to climb up rapidly toward the EC50. Finally, while there is clearly an overall dose-dependent trend, you'll notice a lower calculated fold increase for cohort 5. Digging into this, we find that these fold calculations can be prone to large variations in baseline values. Hence, normalizing to create the fold values can involve dividing by very low numbers of Treg observed at baseline. Let's move on to slide 14. One way of avoiding these baseline variability is to simply look at the Treg Tcon ratios. So here we're showing the time course and peak values for the ratio of CD25 bright Treg to conventional CD4 T cells. Again, we see a nice dose-dependent increase peaking around days 8 to 10. On the right plot, you can see the individual subjects, and now we see the consistent dose-dependent behavior more clearly. Notably, the ratio moves from almost zero to an impressive Treg-TCON ratio of 0.14 at the highest dose. I like this particular readout as it's generally thought that the Treg-TCON ratio is the most functionally important metric for immunosuppression. And again, you'll see here that big inflection from cohort five to cohort six, once again, consistent with our expectations for in vitro analyses. This is what we expect for the way we designed our molecule to be low potency and promote strong pharmacology near the bottom of the dose curve. Now, the other thing I want to emphasize in this data is the durability of this expansion effect. For the high dose cohort, you can see that our T-rate counts are still well above baseline value at the last time point, three weeks after dosing. Now, on slide 15, let's take a look at the total Treg population. On the left, again, is the time course, where, again, you see convincing increases in the absolute Treg counts from cohort four to six. And with the plot on the right showing fold expansions, which are, again, muddied by the baseline variability that contributes to the fold calculation, you see a strong eight-fold boost for the highest dose cohort. We believe this eight-fold boost in total Treg is as high as anything reported elsewhere. Once again, like we saw for the CD25 bright population, you can see on the time course that we still have elevated total Treg three weeks after dosing. Okay, so now moving on to slide 16, let's take a closer look at the durability. We show here the remarkable day 21 Treg counts for each subject with the CD25 bright subset on the left and the bulk Tregs on the right. We believe this maintenance of elevated Treg on day 21 holds potential for more convenient dosing. And we look forward to exploring a range of multi-week dosing schedules in our phase 1b. Finally, on slide 17, taking a look at non-Treg cell expansion, we see some evidence of a minimal increase in conventional T cells. But it's unclear at this point whether there is a real expansion of the NK cell population. I'll also note that the increases in the conventional T cells are generally not statistically significant. So we'll, of course, be tracking this as we progress to additional studies. Moreover, recall, as I showed you earlier, that our Treg-TCON ratios are also very nicely increased for all of our dose cohorts. Now, I'll turn things back over to Basil to wrap up the presentation and review our ongoing clinical progress and plans.
spk02: Thanks, John. Moving on to slide 18. To sum up, the Phase Ia study of XMAB564 showed that a single dose was tolerable and gave large and selective increases in T cell populations, which max or exceed previously reported engineered IL-2 programs, with particularly notable durability of these increases in our high-dose groups. We've already started our phase 1B multiple ascending dose study in atopic dermatitis and psoriasis, having recently dosed the first patient, and we'll use it to explore multi-dose safety and also assess the potential for multi-week dosing intervals by assessing T cell populations as well as looking at disease-modifying activity. We designed this study and selected the indications with the goal of advancing quickly, and I want to echo Alan's thanks to the entire 564 program team, from the molecule designers through to the clinical team. Now, advancing to slide 19, let's zoom out and look at our entire XMAP cytokine platform. 564 is the second clinical program, but it will soon be followed by XMAP 662, our potency-reduced IL-12 for oncology that we expect to start Phase I studies for in 2023. We're pleased that our approach of reducing potency and extending half-life has now resulted in two programs showing reduced toxicity compared to native cytokines, plus notable magnitude and duration of immune cell expansion. We're working on a number of additional cytokines and look forward to discussing our cytokine programs during future updates. We'd be happy to take questions now. Operator?
spk06: Thank you. At this time, we will conduct a question and answer session. As a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. Please stand by as we compile our first questions. Our first question comes from Edward Kentoff with Piper Sandler.
spk07: Great. Thank you very much, and congrats on the exciting 564 data. I really appreciate the way you're laying out this entire cytokine pipeline that's emerging. So I wanted to get a sense, you know, what kind of duration of dosing should we expect in the atopic derm and psoriasis patients? Is this going to be out to 16 weeks? Are you able to dose that long yet? And is this something where we could anticipate data in the back cabinet next year? And then just following up on this, it sort of fits outside of your oncology area of expertise. Is 564 a potential partnering opportunity, or do you ultimately have aspirations to really be in both oncology and autoimmune? Thanks a ton, guys.
spk02: Thanks, Ted. So I guess with regard to duration of dosing, we're just going to have to follow the data. We just don't know. We know there's some bogeys out there, you know, where the market leader depicts it in atopic dermatitis is every two weeks, and it's pretty firmly fixed there. It doesn't look like it'll ever be able to extend. But we know that in autoimmune disease, and particularly derm, the longer the better. So we're just going to follow the biomarker data as we go through this study and look to see if we observe accumulation like we saw with our IL-15 cytokine program in the clinic, and do the best we can. So, too early to say anything there yet.
spk07: I'm sorry. I should have been more clear. I meant in terms of follow-up. How long will you be dosing patients? Apologize.
spk02: Oh, I'm sorry. I'm sorry. We'll be dosing patients for eight weeks as the study is designed currently. And I suppose we can amend as we observe the pharmacodynamic data and look at duration. I apologize for that.
spk07: No, no, no worries. And do you think that eight weeks should be able to do efficacy measures or is it still mostly going to be biomarker data?
spk02: You know, I think as designed right now, this is mostly about the biomarkers, but we can observe the data we see in the early cohorts and go from there, right? I would say that certainly top of mind for us is thinking about how extending cohorts and using expansion of patients in select cohorts is something that, you know, we do a lot in oncology, and I know that some of our competitors have done that in autoimmune disease. So we're very much aware of those approaches, and we'll absolutely be thinking about those. And to be clear, we are following efficacy in those patients. Yes. Oh, yes, yes.
spk07: Full measure.
spk11: Full efficacy measures.
spk07: Yeah. PASI scores.
spk08: And easy scores. PASI and easy scores.
spk07: Well, I think I asked more than my first question, so I'll hop back in with you.
spk02: That's great. Thanks, Ted. So I will address them, though. We'll guide a little bit later on as to our data timing expectations, but we are trying to move this program very quickly. As for partnering and the overall indication strategy, we want to chase the molecules that could be truly differentiated and offer ZenCorp something that's best in class. to move forward. If a partnership is something that can really accelerate the program and make it reach patients faster and more broadly, obviously, that's something we've done in the past and we would consider doing. But for now, I think we've got the right plan, and we're going to aggressively pursue it for a while.
spk06: Next question. Our next question comes from Mara Goldstein with Mizuho.
spk01: Oh, great. Thanks so much. Thank you, actually, for the slides. I appreciate that. Maybe you could spend a couple minutes just talking about 564 in relation to maybe Respeg, which is another drug in development with a not inconsistent mechanism of action. And then I also just wanted to get an update on the Pomodamab combination trials with lenalidomide and tafacetamib. And and just what that recruitment looks like?
spk02: So I'll address quickly the question of Plimodemab's phase two. We are recruiting patients, and now we've got the study opened up in a number of countries beyond just the U.S., which is where we started, and, you know, we're moving forward. We don't have any more granularity that we're offering on that. Now, going up to 564, there's so many ways to answer that question. So you're referring to a pegylated IL-2 that is CD25 biased. I will point out that, you know, our half-life of 9 to 10 days and then shifting to 6 to 7 days as you build up that antigen sink is very competitive with pegylated IL-2. I'll also say that our, you know, our dose response and the magnitude of both total Tregs and CD25 bright Tregs, the most immunosuppressive populations. And I think the whole field is really focusing on now. I think our magnitudes look really good in comparison. And you know, one interesting metric that I know is out there, the The multidose study in atopic dermatitis and psoriasis that were reported on earlier this year for that compound had about a 50-cell CD25 high, 50-cells per microliter CD25 high Treg count at about steady state, right? And, you know, note that with our single dose, we approach that certainly with our lower doses and greatly exceeded even at 21 days for our highest dose. So we think there's a lot of room here for us to operate and potentially have durability as well as magnitude of increases that could exceed competitive programs. Too early to say, but I think that the ground laid with this SAD study is very promising. Okay.
spk01: Maybe you could just indulge me for a quick sec. You know, the company has really talked a lot and put a lot of effort behind the cytokine pipeline, but clearly, right on the oncology side, that's been very, very heavy lifting as it relates to sort of IL-2 and even some of the other programs which are still early stage. So can you talk about sort of the risk-reward and how you're going about making those decisions? Sure.
spk02: You know, we we again go back to we follow the data that the risk or what I think comes down to how differentiated of a profile do you think you might have for any given compound? As you say, in oncology, it's a heavy lift because you're treating patients that are seeing the layers of immunotherapy typically. And in the cytokine case in oncology, you're essentially, maybe not entirely every case, but the vast preponderance of those of us making cytokine drugs across the industry are looking at them as ways to complement other immunotherapies. to increase NK cell counts, to increase T cell activation, et cetera. And so combination studies inherently are much more challenging, larger, more complex, and slower. I think in the case of autoimmune disease, the situation is a bit flipped on its head, where there you've got monotherapy activity that you would be looking at right out of the gate, right? And there's niches and slices of patient population, even naive to biologics, that are that are there and that have still a high unmet need. So it's a very different situation, but in all cases, we've got to look objectively at can we put our resources behind something that's got the best shot of being differentiated because an undifferentiated compound is one that is going to bite a small biotech, you know, in the behind if you put too much resource behind it.
spk01: All right. Thanks. I appreciate it.
spk06: One moment for our next question. Our next question comes from Jonathan Chang with SVB Securities.
spk19: Hi, guys. Congrats on the progress, and thanks for taking my questions. First question on 564, can provide any additional color on the details of the newly initiated Phase 1B study?
spk02: Sure. So maybe, I don't know, Alan, do you want to take that?
spk11: Yeah, it'll be a randomized double-blind placebo-controlled study in atopic dermatitis and psoriasis. We'll start at a higher dose than we started in our phase one, and the study will allow us to go higher than we've dosed in the phase one as well, since these are patients, if needed. We'll initially start at four doses given every two weeks and assess the PK and pharmacodynamic data as we go and optimize the potential longer dosing intervals as the data presents itself.
spk19: Got it. Thank you. And second question on Vudalamab, what would you highlight as key things to look for in the upcoming CITC presentation? Yeah, go ahead, Alan.
spk11: Yeah, so we'll have updated data at CITC. As we said, we have an abstract there. You know, Basil mentioned that we'll have a couple handfuls of patients. You know, this is the first time we've combined Bidalumab with chemotherapy, so I think we'll have the safety and tolerability of those chemo combinations. Got it. Thanks for taking my questions. Thanks, Jonathan.
spk06: One moment for our next question. And our next question comes from Brian Chang with JP Morgan.
spk00: Hey, Baseline, guys. Thanks for taking my calls. So a couple on 564. Just following up on your comments regarding the magnitude of Treg expansion, do you have any insights in terms of correlation of the magnitude of Treg that you need to see to see disease improvement in atopic derm and plaque psoriasis? And then I have a follow-up. Thanks.
spk02: So there's two directions of data you can take. At this point, only two. I think there's the ample data from the historic use of low-dose IL-2 that I believe increased Treg counts, bulk Tregs, total Tregs, on the order of about two-fold, maybe a touch higher, and in open-label small studies showed disease-modifying activity across a range of indications, from lupus to derm to even GI autoimmune disease. So that's one bucket, but very uncontrolled data, small studies, open-label academic studies. Then the other bucket we have is the data we referred to from a competitor data of a pegylated IL-2 presented in September at the EADV conference in both psoriasis and atopic dermatitis, where a multidose study, relatively short, I believe 12-week treatment, showed that when you increase the CD25 brights around to about 40 to 50, I think more like 40 cells per microliter absolute. And baseline, you're talking zero to three or four cells, right? So you can get a gleam sort of the magnitude of fold improvement. And in total, Treg is around 60 or 70 absolute cells. That was sufficient to have pretty promising activity, certainly in atopic dermatitis, with a remarkable durability post end of treatment. So I think those are the two metrics that give us a feeling that we're probably in a pretty good range right now with what we saw in the single ascending dose to come up with a potentially very attractive dosing schedule in our MAD, which, you know, the work's cut out for us. We have to do really careful work.
spk00: Great. And just a follow-up. So, you know, we went back to your presentation, I think, at ASH 2018-2019 on this molecule where you presented NHP data. A couple of questions on this one. So I think the impact on eosinophils is pretty much in line with what you expected and also the class as a whole. Just one quick question is whether you saw any impact on basophil, any impact on albumin that we saw back in the NHP models. And how do you think about, you know, whether these observations could probably come into whether that would impact your dose selection moving forward? Thank you.
spk08: We didn't see the .
spk05: We did not see anything in the albumin.
spk15: Yeah, and the basal fills or anything like that, no? Basal fills, nothing.
spk05: Yeah.
spk15: Except these samples, yeah. Great. Thank you, guys. Thank you.
spk06: One more for our next question. And our next question comes from Dane Leone with Raymond James.
spk13: Hey, how's it going? Congrats on the data, 564. Great to see that program moving along. I actually wanted to ask, just because I still can't get the website to work. Are you guys able to disclose what's in the abstract for the telomab at this point, given the technical issues that have been going on today?
spk02: As far as we know, we're not. I will say that our ability to communicate with SITC has not been any better than anybody else's that we've been aware of. I apologize for that.
spk13: All good. Do you guys have any idea when the issues might get resolved?
spk02: We don't, but I will say that our abstract is the data is almost entirely in our poster presentation, which I believe is coming out on Thursday a.m., and the abstract is really the setup of the study for the most part. So our abstract, we're a little less concerned about this bit of a, you know, the perennial sissy snafus on data releases for that society. Okay.
spk13: that's actually super helpful. So it's basically the abstract, which is like TIP, and then you'll actually have the data in the poster.
spk02: Essentially. Okay.
spk13: That's great. On 564, did you guys, you chose atopic derm and psoriasis just as a way of getting early clinical proof of concept. Is that necessarily indicative of what you want to do from longer-term drug development or what areas you want to go into um you know let me phrase it this way for you as you look at the landscape of autoimmune and inflammatory disorders um you know where do you rank uh atopic derm and psoriasis and and kind of disorders that could be mediated by dysfunction of t-rex like notably an ra right it's there there's been you know, good evidence of Treg dysfunction, but does that necessarily hold true in some of these other, you know, indications?
spk02: Maybe I'll address the strategic question, and I don't know if John wants to comment on the literature linking Treg to disease. You're right about the RA data being maybe the clearest. So, our goals for this Phase 1b for the indication selection was, first and foremost, how can we move fast getting a clear set of biomarker data that can help us understand schedule and dose, as well as have the potential to look for disease-modifying activity relatively easily. I think, in particular, psoriasis fits that bill for both. Atopic dermatitis is really honestly something we added because there could be potential, in particular, if you see this long-term remittive function that was observed with the pegylated IL-2 from a relatively small number of patients, there is absolute unmet need and potential there. So I'll say it's a maybe on atopic dermatitis. And then, you know, we're actively both looking at our competitors' clinical work. I think there's lupus data coming shortly from some competitors within the next 12 months. And then there is also work in ulcerative colitis still ongoing. We are, of course, looking at a number of other indications that we'll disclose in due time. You know, we just finished our phase 1A. So psoriasis for speed, atopic dermatitis, because there could be potential there. And we'll brief you more on that later. I don't know, John, I don't know if you want to comment on quality of data supporting indication choice.
spk10: Yeah, I mean, and... ralph feel free to jump in here too i mean it's basically there seems to be an overall consensus that for most of the autoimmune diseases that the t-reg you know that disease is a deficit either in ratio or absolute counts of t-regs or in function of the t-regs and so that's that's why it's it's really encouraging to see you know cd25 bright population is a very suppressive population We see other markers of activation of the functional markers of that population. So super encouraging and potentially applicable to a wide array of autoimmune diseases. Ralph, do you have any more specifics you want to?
spk08: Well, you know, we're waiting to hear from Amgen and Lilly. Amgen has a big Phase II program coming in, and Lilly is going to present their data at ULAR in the spring. That's really interesting to us to look at. We're going to have a good load of data in the spring and as of late. The other programs, the ulcerative colitis, some of them are canceled and some of them are continuing, but, you know, that's a real good indication as well. RA, the only one that we heard about was Amgen. They had a lot of trouble with their phase 1B, but I think lupus ulcerative colitis and atopic dermatitis are probably our best options.
spk02: At the moment, there's still so much to be discovered about this mechanism and class of drug, and what we want to do is make sure we establish the most competitive, hopefully highly differentiated dosing regimen and biomarker activity that is the measure of how much immune modulation is this drug really doing. We think our design might really put us in the driver's seat there, and so we want to exploit it as best as possible.
spk13: Excellent. Thanks, guys.
spk02: Thank you. Next question.
spk06: One moment for that question. And our next question comes from Kaveri Pullman with BTIG.
spk17: Yeah, good afternoon. Thanks for the updates and congratulations on the progress. For 564, any insight into anti-drug antibodies? Are you testing those?
spk02: Yeah, Alan, I guess you want to touch on this one?
spk11: Yeah, we didn't see any evidence of ADA, and the PK data do not suggest any evidence of ADA as well. We are still early in the process of analyzing this data.
spk17: Got it. And my second question is for Udalimab chemo combination for prostate cancer. Can you tell us what drove your interest in choosing cabazotexel over other chemo agents like docetexel, which is also used for earlier lines of treatment, at least in a subset of patients?
spk11: Yeah, the current study allows both cabazitaxel and Taxol. And I think what we're doing is we're exploring both. You know, physicians seem to have a preference depending whether it's for whether they've seen taxane and pairs make them use a taxane and they go to cabazitaxel second line. So we're interested in understanding the activity in combination with both of those agents. either alone or in combination with a platinum.
spk17: Got it.
spk11: I believe. Yeah.
spk17: Yeah. I believe I just saw it on clinicaltrials.gov. But.
spk15: Yeah.
spk17: I thought that's really helpful. And maybe a last one on Flomodemab. So the abstract had a data cutoff date of July, I believe. Will you be providing updated data at ASH? And also, if you could just tell us about how you plan to introduce the subcutaneous formulation Do you plan to incorporate it into the ongoing pivotal trial?
spk11: So, a couple questions, so we will have incremental data more data at the time of the presentation in December. The plan for the sub queue is not to incorporate it into the pivotal study, which is our phase 2, but our current phase 1. so that was. Probably the most convenient and fastest way to accelerate the sub development. So we have an established group of investigators who have been working on this for a while. It's a phase one study that's open, and so it will be incorporated into the current phase one. So there'll be additional cohorts where we're studying our optimal IV dose and expansion cohorts, and then there'll be a cohort of sub-Q patients.
spk17: Got it. Thank you for taking my question.
spk06: Sure. One moment for our next question. And our next question comes from Etzer Barut with BMO Capital Markets.
spk20: Great. Thanks for taking the question and congrats on the 564 progress. Just, you know, I wanted to ask on some of the variability we see at the three higher doses, but obviously really robust and compelling expansion at these doses. Just wondered if this was just a phenomenon of small ends and how much confidence or weight you put on the high-dose data. And then, I guess, secondly, you mentioned the MAD study. Just wondered how many patients you'll dose in each of the indications, atopic derm and psoriasis, and whether or not, you know, sort of the placebo to drug-armed ratios will be the same as we saw for the single-ascending dose. Thank you.
spk02: Maybe I'll have Alan or Ralph touch on the Phase 1B patient allocation.
spk08: Eight patients in psoriasis, six and two, and 16 patients, and 12 and four. We're going to double the AD patients.
spk11: Yeah, and that's per cohort.
spk08: Per cohort, yeah.
spk11: And it depends on the number of cohorts we do will be dependent on the data we see. So, you know, it could be a few cohorts or it could be several cohorts.
spk02: Yep. And we're doubling the N on the atopic germ, of course, to see if there's, to have a better shot at looking at a signal, right? Now, going back to the variability question, you know, we have a lot of confidence in the data, even though it's a relatively small number, six patients on study drug in the SAD study, because of the consistency across multiple measures, in particular looking at Treg-Tcon ratios that don't involve that baseline variability when you look at fold measurements, as well as the consistency and just looking at absolute consistency. Treg counts, right, the real data, not the full data. So though there's jumpiness in the data because of the small numbers, I think the trend is quite clear. We're really replicating a dose-response curve like we saw in vitro pretty nicely, as John said. So I think that all those things point to a pretty high confidence in the data. And you can see the individual data points. Those are individual subjects. on those box plots and so you can see that the clustering is actually fairly consistent as well as the absolute cell count uh time course traces are very nicely consistent yeah and if i could add so you know i think the question was you know our confidence around the data
spk11: So the variability is really around the baseline. Because the baseline can be so low, that can have a huge effect on the actual fold increase. And we've tried to be very transparent here and go above and beyond. We're presenting the fold increase, the absolute increase, and then a ratio to conventional T cells. So we can be very clear on our data and help you compare it to other people's data.
spk10: Yeah, and just to be clear, the ratio is really nice because there's no dividing by a low number in the baseline. You're dividing the Tregs by the conventional T cells. And so I think that's consistent with what Alan is saying, that it's really those low baseline numbers that give you most of that variability.
spk20: Got it. Thank you. Congrats again on the update.
spk06: One moment for our next question. And our next question comes from David Dai with SMBC.
spk04: Great. Thanks for taking my questions, and congrats on the update. So one question on the ExMAP A19 in the renal cell carcinoma. I understand we will see the initial look at the data in the phase one trial data at CISI next week or this week. If you could help us assess some expectations ahead of data readout, what kind of efficacy bar should we be looking at here?
spk11: Yeah, I just want to set expectations. You know, we just started enrolling the patients over the summer.
spk02: Yeah, I think you're mistaken. We've never guided we would have EXPAB 819 data this year at all. Yeah. Oh, there's a trials in progress abstract at CIPSI, though. Yes. That just describes the trial design in high detail, not data. Thank you.
spk04: Got it. Okay. That's helpful. I just want to get some clarification there. And then just another question on the 564 data. The safety looks fantastic so far in the health volunteers. Maybe just share some insights in terms of whether any difference between the healthy volunteers versus any kind of all the immune patients that could factor into any kind of differential safety profile we're seeing in the patients. Any thoughts on that?
spk08: Ralph, that's... It's hard to say. Normal volunteers are very different, of course, and what we're going to see in the psoriasis patients and AD patients.
spk02: I will say from the limited competitor data presented, For granted, CD25 directed IL2s that are designed very different from ours, but that limited competitor data didn't show really any new signals. Got it. That's really helpful. Thank you, guys.
spk06: And one moment for our next question. And our next question comes from Gregory Renza with RBC Capital Markets.
spk16: Hi. This is for Greg. Congrats on the data, and thanks for taking our questions. Maybe just a follow up on 564, just wondering how does the inflation reduction act play a role in your thinking around indication selection for this program as well as the impact on market opportunity? Thank you.
spk02: Sure. So, 1, I'll note that. Actually, 564 is a biologic drug, so it has the longer time on market prior to being subject to Medicare negotiations. I would say that we're going to chase what we think is going to have the biggest patient impact and try to help establish a new class of drug with a new mechanism of action. I don't think the IRA, Inflation Reduction Act, is really entering into our thinking at this point much yet at all.
spk15: Great. Helpful. Thank you. I think we lost you.
spk06: Yes, if we could have, coming in from Gregory Renza, if you want to hit star 1-1 to come back in, we can follow up. We have your follow-up question. And so our next question will come from Charles Zhu with Guggenheim Securities.
spk21: Hey, guys. Thanks for taking the questions. I had a quick one on the blood eosinophils. Not sure it was addressed earlier, but how should we think about – it still seems early and extremely mild and transient, but how should we think about what this could look like as you go into multi-ascending dose cohorts, and how does it benchmark so far relative to some of the other C25 programs out there? Thank you.
spk02: From what I know about the other CD25 programs, I don't know that we have a lot of detail from any of them. In fact, we don't, except everybody reported in limited ways the way they reported it, transient increases and very limited clinical consequences. We didn't see any clinical significance. We're just going to watch out, right? Keep track of clinical signs and symptoms and do the lab work and just follow it.
spk21: Got it. Got it. Great. And maybe one question on IL-12. It looks like you guys are starting up the phase one next year. You know, how should we think about, you know, the potential similarities and differences in the IL-12 program relative, you know, to what you guys are going through on IL-15? Thank you.
spk02: You know, I think John is the best equipped to address that question about the different cytokine MOAs. You want to go at that one, John?
spk10: Yeah, absolutely. First of all, XMAP662, that's our IL-12 FC. We followed the same general principle that we used for the XMAP306 and XMAP564, and that was to reduce potency pretty significantly, approximately 100-fold for IL-12. And in our preclinical studies, we saw kind of like we expect for a potency-reduced cytokine. We saw what looks like better tolerability. We're able to dose it a lot higher. We see improvements in the half-life in non-human primates because of that potency reduction. And then I think most importantly, what impressed me the most about the data that we saw in the non-human primates was that we had a much better control of the pharmacodynamic response as we dosed, you know, from low doses to higher doses with the potency reduced version. And I think that bodes really well for getting through dust escalation in our phase one study. As for differences in MOA, I think of the IL-12 as promoting more cytotoxicity and an interferon gamma response from natural killer cells and T cells, whereas IL-15 has some of that as well, but also is really a lot about proliferation, particularly the NK population.
spk05: Great. Thank you.
spk06: And one moment for our next question. And our next question comes from Peter Lawson with Barclays.
spk09: Great. Thanks for taking my questions. Just a quick clarification. question initially, Basil, just on budelumab. Do we get initial efficacy data this year, and kind of what's the bar for success, and at what point do you think you have enough data to make a good comparison to additional data sets out there?
spk02: But we'll report efficacy data for the patients that were reporting on safety, them, to the extent they've had their efficacy assessment, which I think nearly all or almost all would have had. So, of course, we'll be completely transparent. That goes without saying. I think that these are relatively small numbers. We've guided a couple of handfuls as we go through the safety data. run-in period. So I don't think that's going to really be able to give you a read in any kind of quantitative way on competitive positioning against sort of what you see with the chemo regimens, which are the standard of care here for the non-PARP-sensitive patients, which I think run about a 30% or 40% OR, but durability being rather a challenge. You know, we'll guide more on timing later, but certainly nothing this year.
spk09: Gotcha. And then When do we see combination data for Delamer?
spk02: The combination safety run-in data is going to be this year with whatever efficacy we have in that couple of handfuls of patients. And that's the study that's farthest along relative to the monotherapy. So it's really going to be about the combination with the chemo, platinum taxane or PARP.
spk09: Gotcha. Will we have enough of those PARP combinations? patients to kind of start telling the story, or is that much less?
spk02: No, that's a less common grouping, so we're getting a lot more of the chemo combo, and the poster is going to focus mostly on those.
spk11: Yeah, and just to remind you, Peter, of the study design with the PARP, we have those that are both PARP refractory and then those that are PARP naïve. So.
spk02: And the PARP refractories get the chemo combo, PARP naives get the PARP as their co-drug with VUDA.
spk09: Thank you. And then for Plumotumab, the triplet data, what's the timing around that data set? And what do you need to see to, I guess, find a position in that pretty crowded space?
spk02: Or you meant the phase two? Yes. We haven't guided yet on timing for that. Go ahead, sorry. Yeah, we haven't guided yet on timing for that. I will say, without getting into specific numbers, the bar for efficacy there is not saying it's going to be high, which is why we went after a triple regimen with two completely distinct MOAs and different targets. But we are going to be setting a high bar because we only want to pursue something if there's really potential.
spk09: Gotcha. And when would that kind of go – No-go decision. Would that be in like a, that's a late 23 kind of event?
spk02: You know, we'll guide on that as we move further along. We haven't chosen our guidance statements on that yet. Good. Okay.
spk09: Thanks for taking the questions. Appreciate it.
spk06: One moment for our next question. And our next question comes from Zhaixing Xu with Barenburg.
spk12: Great. Thanks for taking the question. First one on 564. First one is around the dose. I guess two parts. First is in your dose escalation, single dose ascending dose study that you haven't seen, you only see grade one and two and no SAE. I wonder if you have considered those even higher and explore even more potent activation of Treg. This is part one. And I guess part two on the dose part is when you look at the full change, it looks like there is no clear dose-dependent change, but really the highest dose has the most significant upregulation of the Treg. Is there any mechanistic explanation for this?
spk02: Yes, so first on the SAD, we're not going to be going higher doses in the single ascending dose because it's in healthy volunteers, and that's the limit, right, for healthy volunteers. However, in our multiple ascending dose, we do have the go-ahead and could explore higher doses in the multi-dose setting because that's in patients, and the risk-benefit is obviously better. So we have that option. We don't know whether we're going to do that or not. With regard to the fold change, you know, as we discussed, when you're normalizing each individual against their baseline number, and that baseline number is going to range from zero to four, normalizing can create a lot of scatter. We think that even so, there is a clear dose-dependent trend when you look at absolute cell counts, when you look at Treg-Tcon ratios, and even with the fold changes. And I think in particular, you should you should consider, as John said earlier in the call, the dose-response curve we saw in vitro. Now that we're seeing concentrations that are starting to climb up that curve at the top two doses, you're seeing that uplift pretty much mirrored. So I think the explanation is a very simple potency of how the molecule was designed and the drug concentrations.
spk10: Yeah, Basil, I'll add, I think the caller should should take a hard look at slide number 14, which has the peak ratios on there. And again, the ratios are not subject to this division by low baseline numbers. It's really the cleanest way to look at the data. And there we see significant, statistically significant increases of the Tregs starting all the way at the lowest dose level at a very nice looking dose response throughout the different doses.
spk12: Okay, great. And then the second question is around kind of how you look at this competitive field. You know, a few names were mentioned. They either pharma or large cap biotech. They get their IL-2 asset in autoimmune quite early in the development. And I guess for you, as a small biotech, as you mentioned, how do you plan to compete in this field? Are you actively looking for a partnership to
spk02: We're not looking for partnerships right now. We have the right plan right now to build value in this program. And, you know, if we feel like the time is right and that would be when you have the vision that you could greatly accelerate the program and move it faster and more broadly with a partner, we would consider that. You know, we don't just partner things off willy-nilly. Okay, great. Thank you.
spk06: One moment for our next question. And our next question comes from Ted Tenthoff with Piper Sandler.
spk07: Great. Thanks. Just a quick follow-up on IL-15. What kind of expectation should we have for updates from you and Rose? Thanks.
spk02: That we all certainly update on a new study, new studies that we're going to start in the near future. We'll guide on that when those studies kick off. And I can say that Roche is very busy with the program, and I would not be surprised to see new studies from them announced soon. On data from that study, because, of course, that's really at Roche's discretion. Fair enough. Thanks, Ted. Great. Thanks a lot, Ted.
spk06: I would now like to turn it over to Basil for closing comments.
spk02: Great. Thank you so much, and thanks, everybody, for joining us today and spending the time on the call and going through our new data update. We'll really look forward to updating you again in the near future. Thanks, and have a great evening.
spk06: Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
Disclaimer