Study Update 2021

Sep 20, 2021

Press Release

Hello, and welcome to the TG Therapeutics IW CLL Investor and Analyst Virtual Event. At this time, all participants are in a listen only mode. A question and answer session will follow the formal presentation. If you'd like to ask a question, you may do so by using the raise the hand feature on your Zoom platform. We ask that you please ask one question and one follow-up and return to the queue. As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Jenna Bosco. You may begin. Good morning, and thank you all for joining us. My name is Jenna Bosco, and I'm the Head of Corporate Communications for TG Therapeutics. And I welcome you all to our virtual event this morning. Before we begin, I just wanted to remind everyone, that we anticipate making some forward looking statements based on our current expectations. These statements involve risks and uncertainties that can cause our actual results to differ materially from those indicated. For a description of these risks, we encourage you to review the disclosures on this slide, and also in our latest reports filed with the SEC, which are available on our corporate website at www.TGTherapeutics.com. With that, let's kick off with a quick overview of today's agenda. First, I'll briefly introduce our external speakers. Then doctor Barr will review the u two plus venetoclax phase one data presented this weekend, following which doctor Fuhrman will review the rationale and design of the Ultra V program. And finally, our CEO, Mike Weiss, will provide some data highlights from our other IWCLL presentations before we open it up to a q and a session. So to begin, I'd like to welcome and introduce doctor Paul Barr, associate professor of medicine and director of the clinical trials office for the Wilmont Cancer Institute at the University of Rochester. Doctor Barr is also the study chair of the phase one two u two plus venetoclax trial. Thank you for joining us, doctor Barr. Next, I welcome doctor Richard Berman, the Morton Coleman MD distinguished professor of medicine in the division of hematology and medical oncology at the Weill Cornell Medical College in New York. Doctor Fuhrman is also the study chair of the Ultra V program. Thank you, doctor Fuhrman, for joining us. With that, let me turn the call over to Doctor. Barr to review the phase one data. Thanks, Jenna. It's a pleasure to be here. I will briefly review the data that we presented at IWCLL yesterday. So just to remind everyone, this was truly a collaborative effort, this clinical trial. It was developed at our center in collaboration with the folks at TG Therapeutics as well as with input from the Cleveland Clinic in Northwestern. So we're very proud of this trial and its data. And here's the title. It's a phase onetwo study of umbralisibutuximab and venetoclax for patients with relapsed or refractory CLL. Just by way of background, I think everyone's aware that the novel agents are really changing how we treat CLL. And at the time of developing this study, the BTK inhibitors were quickly taking over first line use. So we really wanted to develop a regimen that would ideally suit relapsedrefractory patients and incorporate the other important classes for the treatment of CLL, namely PI3K inhibitors, CD20 agents, and BCL2 inhibition. So umbralisib is a novel small molecule inhibitor. We differentiate it from the other PI3K delta inhibitors because it is more specific to the delta isoform, has less gamma inhibition, and also uniquely inhibits CK-one epsilon. So perhaps for a variety of reasons, it has less impact on regulatory T cells and less autoimmune complications. Ublituximab is, I would say, more potent anti CD20. It's similar to rituximab in that it's a chimeric anti CD20, but it's glyco engineered, has a lower sugar content, and ultimately is more effective in enhancing EDCC, antibody dependent cellular cytotoxicity. As you also saw at IW CLL, this doublet, ublituximab and umbralisin, met its primary endpoint in the UNITY CLL study. So this particular trial was a multicenter phase one two study. We already completed the phase one and presented that data a couple of ASH meetings ago. We identified the phase two dose of umbralisib at eight hundred milligrams, the standard phase two dose, in combination with the fixed dose of ublituximab and standard venetoclax dosing. So it's important to point out that the phase one piece showed us that we can use the standard doses of all of these agents. The primary objective of the phase one component was to evaluate safety. What we're debt what we're showing now in these subsequent reports is the clinical efficacy, most notably by CR rate, progression free survival, and importantly, MRD rates. This is the study schema. We included a three cycle debulking period where patients received daily umbralisib and several doses of ublituximab. After those three cycles, patients started on venetoclax with the standard ramp up and received ideally nine additional cycles of venetoclax, umbralisib, and three more doses of ublituximab. At the end of the twelve cycle treatment period, patients underwent CTs, a bone marrow biopsy, and MRD assessments. Notably, if patients were undetectable for MRD, they were able to stop all treatment, which we think is an important concept in treating patients going forward. Patients who did have detectable cells were able to continue single agent umbralisib. These are just some of the key eligibility criteria. The study was really designed for patients who had previous treatments and had relapsed. We did attempt to enrich the trial for patients previously treated with BTK inhibitors. Otherwise, you can see some of the standard inclusion criteria below. So at this point, the pay the study is fully enrolled, 47 patients. It's 47 CLL patients. And we're just about at the point where the last patient is finishing his twelfth cycle. So soon we will have pretty mature MRD data for all the patients. We're just short of that in this presentation. Forty six patients were evaluable for efficacy. The median age was 64 years. These patients have received a median of two prior regimens, and more than half have received BTK inhibitors. We considered thirteen patients truly refractory to the BTK inhibitor. And in those thirteen patients, we were able to identify BTK or PLC gamma mutations in eleven patients. If you wanna gauge the overall risk profile of these patients, I think it's important to point out that almost three quarters, seventy two percent had at least one high risk molecular aberration. These are the AEs of all cause occurring at greater than twenty percent of patients. Infusion reactions were somewhat common but mild, and this just relates to how we administered ublituximab. We did observe cytopenias. Twenty eight percent had grade three or four neutropenia and were able to receive growth factor. Six percent had grade three anemia. Otherwise, there were mild GI effects that really didn't affect the treatment. You did not have to discontinue or stop therapy for these mild GI effects. And similarly, we had to take short treatment breaks for mild transaminase elevations. Otherwise, were two, in terms of the grade three or four AEs, there were two events of colitis. One tumor lysis event that occurred with the first dose of ublituximab, but none occurred with venetoclax. One rash as well. Two patients had to stop therapy prior to finishing the 12 cycles. The three cycles of U2 induction was very effective at reducing the tumor lysis risk, making it much easier to start venetoclax. Nearly all patients started their ramp up of venetoclax in the outpatient setting, which obviously saves a lot of resources. We saw a seventy nine percent relative reduction in the tumor lysis risk, and there were no events of tumor lysis syndrome during venetoclax. This is the big update that we provided at IWCLL as these patients mature throughout their treatment. All patients responded at cycle twelve, and actually all patients had responded by cycle seven. There was a thirty seven percent complete remission rate. And in terms of MRD data, ninety one percent were undetectable in the peripheral blood at cycle twelve, seventy two percent were undetectable in the marrow. So of the thirty four patients who have cleared cycle twelve at this point, only five continued omelicep. The rest stopped therapy. And with additional follow-up, you can see seventeen patients have completed cycle eighteen. Seventy six percent remain undetectable in the peripheral blood. Only a small number, seven patients, have completed cycle twenty four, seventy one percent are undetectable in the peripheral blood. We plan to watch closely how the different groups perform over time. So far, the patients previously treated with BTK inhibitors seem to be responding equally as well. You can see in the green box in the lower right hand portion of the slide, the MRD rates for the BTK refractory patients. They're pretty similar to the larger population. So far, have been a small number of relapses. The median follow-up is about two years, and the estimated two year PFS is eighty nine percent, pretty respectable for a relapse refractory population. So in conclusion, the three cycle induction is effective. It reduces the tumor lysis risk, notably in patients previously treated with BTK inhibitors as well. The response rate's a hundred percent at 12 cycles, and ninety one percent and seventy two percent are undetectable for MRD in the peripheral blood and marrow, respectively, at cycle twelve. And with additional follow-up, seventy percent or more remain undetectable following the completion of therapy. We're looking at retreatment strategies for the few patients who have progressed. And we're also studying this regimen in patients with Richter's transformation and mantle cell lymphoma. Both of those cohorts are currently enrolling. So this study is ongoing for those cohorts, as is the Ultra B study, which Doctor. Furman will detail shortly. I'll stop there and let, Doctor. Furman take over, and we'll have questions after. Thank you, Paul. I, those are very exciting data and data that I think will really help, you know, have set the stage for what we hope will be the next evolution in the therapy of patients, with CLL. So, you know, the BCR associated kinases really have been proven targets for treating CLL. And we've known this since Fosfamenatinib was first reported in 02/2008 at a national plenary session. So I want to go through just the three primary targets we have, and how they all fit together. So next slide. So the SYK kinase was the first one targeted. And as I mentioned, that was in 02/2008, at an ASH plenary session. We heard preliminary data that was actually incredibly encouraging. For a number of reasons, Fosfamenatinib didn't make it in the lymphoma world, but it's now approved for ITP. The second target to become apparent next slide was BTK, Bruton's tyrosine kinase. And we actually have three approved agents targeting BTK right now, ibrutinib, acalabrutinib, zanubrutinib, and a fourth one in late stage development, pure tobrutinib, I apologize, which is different. And I'll explain why later this is going to be a potentially helpful tool. And then finally, we have PI3 kinase, next slide, where we have currently four agents approved, idelisib, duvelisib, copanelisib, and umbralisib, which targets actually different isoforms. And I'll explain that in a moment. So while the B cell receptor pathway in the previous slide really looked like a very nice, neat, orderly process, this is in actuality more of what the reality is. And it's always amazed me as a scientist how any one agent could actually inhibit the entire B cell receptor pathway and have any efficacy in treating patients. And it's with this in mind that going on to multi agent chemotherapy, or multi agent therapy regimens, really has to be the rule. So in the interest of time, I can just speak to what the next couple of slides showed, which really is, you know, the key for all of our therapeutic targets is to have specificity. And while a lot of enzymes are expressed only in certain limited cells, PI3 kinase is actually present in every cell in the body. What really makes PI three kinase unique is the different isoforms. And as it turns out, there's a p 85 and a p one ten subunits with the p 85 being regulatory and the p one ten being enzymatic having actual different expression profiles. And the delta isoform seems to be uniquely expressed in lymphocytes and leukocytes. And therefore, we're able to knock out or target the delta isoform with minimal impact on the rest of the patient. And you can see here, that we really see just the phenotype of, disrupted immune function mice that have the delta knockout. So when we start looking at the different PI3 kinases, they really differ significantly in the inhibition relative to basically, the relative inhibition of the different isoforms. And what you can see here is that though idelisib and duvelisib are actually marketed as mostly a delta inhibitor, with duvelisib having some gamma inhibition, and copanalisib as a little bit more of a pan kinase inhibitor, they all really inhibit all the different isoforms of PI3 kinase, whereas umbralisib really is far more targeted to the delta isoform. Of note, as mentioned earlier, umbralisib also targets the CK1E enzyme as well. So basically, what is the rationale for Ultra V? We have a lot of effective agents for targeting CLL patients in the terms of BTK inhibitors and single agent PI3 kinase inhibitors. But the key and venetoclax is a BCL-two inhibitor. But the key is that we can do better, and we need to do better. So we know that inhibition of B cell receptor signaling is synergistic with inhibiting the BCL-two protein as well. And importantly, targeting the PI3 kinase may actually help prevent resistance from developing to venetoclax and vice versa. And a lot of this has to do with the ability of the PI3 kinase to lift the CLL cells off of the microenvironment and really deprive the cells in an important source of survival and nourishment, and resistance to venetoclax. So you've already heard about the phase onetwo evaluating U2VEN in the multicenter study. Our goal is to actually take this forward and to use this to be treating patients not just relapsed, but also treatment naive patients. When we look at the CAPTIVATE study, which looked at ibrutinib and venetoclax, we see incredibly effective therapy. The problem is that there are a lot of issues with tolerability. So the adage that we always like to follow is that if you can't deliver the therapy, the patients can't benefit. And so the hope with U2Ven was to establish a highly efficacious and a much better tolerated therapy that would really allow us to actually deliver the therapy to our patients. And so just to talk about the need for combination therapies, these are data from the original phase II study of ibrutinib, the 11/2002 study. And you can see here the treatment naive and relapsed refractory populations do quite well relative to everything else that we have at that time. But there is a continuous drop off in patients in the relapsed refractory group, and really, you know, patients that we need to do far better with. And a lot of these patients who are progressing are really progressing based upon the development of BTK, mutations and resistance to BTK inhibitors. And so when we look at data from Ohio State University, these are three zero eight CLL patients that were treated on ibrutinib based protocols, you can see there's three modes or three methods of progression. The first one's going to be, basically or not progression, but rather discontinuation. I apologize. So the most common and the earliest one is going to be a large number of patients who actually discontinue due to what's called an other event. And these were mostly adverse events. And you can see it's about twenty five percent at four years. And, of course, once again, these are patients who are being denied effective therapy. The second group are those patients who are transforming into a Richter syndrome. And these are due to the biology of the CLL, and it's something that I'm not really going to touch on, because our novel agents really are not efficacious in this setting. And we'll see. Hopefully, the Ultra V study by Doctor. Barr may actually might prove me wrong, which would be wonderful. But then finally, we have this CLL progression, which begins to rise at about year two, and really hasn't peaked yet. And what we see is that, you know, at four years, there's nineteen point one percent of patients progressing due to resistance to BTK inhibitors. And so this is really a large segment of the population that really needs an alternative therapy in forms of either PI3 kinase BTK inhibitors, but I think more appropriately, the combination. Taking a look at the venetoclax data these are data from the CLL14 study you can see here that while the data looks very good, you know, the four year progression free survival for venetoclax and binantuzumab is seventy four percent. And while this might sound great, you know, there's a large number of these patients still getting to MRD negativity who are then progressing. And what's more important in the next slide, when we start looking at patients who are higher risk, namely the 17p deleted and I suspect these data will also be translated into patients who are complex karyotyped and other high risk mutations. You can see here that the median PFS is now forty nine months. So fifty percent of patients are progressing, and these are treatment naive patients with 17p and TP53 aberrations. So with the need, we set out on the Ultra V phase two trial, which looked at one hundred and sixty patients that were treatment naive, previously treated, and BTK refractory, as three different cohorts. And patients in this trial received, as in the, Phase I study by Doctor. Barr, ublituximab and umbralisib for three cycles with the goal of debulking the tumor and making the addition of venetoclax safer. And then they received the ublituximab, umbralisib, and venetoclax for cycles four through six. Finally, umbralisib and venetoclax to complete twenty four months of therapy. And those patients who are MRD positive are going to go on to receive umbralisib continuously. And those who have undetectable MRD will come off therapy. The primary endpoint for this study is going to be the complete response rate as well as the overall response rate, with the secondary endpoint being rate of undetectable disease. And our hope is that this really will be sort of the next step in evolution for treating our patients. So, you know, we have the unmet need. So we do have patients progressing on single agent BTK inhibitors. And we do have patients who are unable to tolerate combinations of BTK inhibitors and venetoclax. Mechanistically, PI3 kinase plus venetoclax really meets the scientific rationale and has synergy that really should make both agents better than they are individually. Both agents have nonoverlapping toxicities, and we know that the one side effect of venetoclax at least to be contended with, is actually markedly reduced with the three cycle lead in of umbralisib and obblituximab. So the preliminary data, which you've already heard, really demonstrates a rapid and deep depletion of the tumor cells and affords our patients what would be a fixed duration of therapy. And so the Ultra V randomized phase three trial is currently enrolling in treatment naive and relapsed refractory CLL. All right. I'm going to pass it now back to Mike Weiss. Thanks, Rick, and thanks for all those great data and great presentations. I've got the easy job, and I'm going to spend just a few minutes just wrapping up, the remainder of the presentations at IWCL, just to remind everybody. So we did have a, ENCORE presentation of the phase three UNITY CLL trial. So again, for those of you who have not seen the original presentation, there's another opportunity to take a peek at the data. But again, at least it's significant outcome for the trial, both for the entire population and each of the subgroups of frontline and relapsedrefractory. We did I wouldn't say it was an encore. We actually for the BTK inhibitor, we took out from prior presentations and added some more updated information just on the CLL cohort. So for folks who interested, it's a pretty, I'm going say, busy poster. There's a lot of information on there. I do encourage folks to to take a peek. We think that this compound is coming along quite nicely. You can look at the AE profile, which we think is is kind of critical. The activity at the top, what you're looking at are basically just the CLL expansion cohorts at two hundred milligrams and three hundred milligrams. The darker bars are the three hundred milligrams. The lighter bars are the 200. In essence, whether it's two hundred milligrams or three hundred milligrams, nearly every patient responds to monotherapy. In the last bullet, you can see that every every one of the combination patients of u two plus seven twenty one also responded to the therapy. So in terms of activity, the activity is there. We're just really trying to spend as much time as we can trying to identify the right dose for the tolerability profile where we are seeking a best in class tolerability profile along with what is certainly comparable to the best in class activity. So keep keep following that compound, please. So this is a study that was was conducted by Doctor. Mehta. Pretty cool study. This is an early look at U2 plus p d one, PD L1 inhibition. This is U2 plus pembrolizumab. Most folks will recognize that we have our own PD L1 inhibitor fifteen o one or cozebelimab. You know, I think in terms of the overall response rate, you know, ninety plus percent, Probably, you know, small numbers. Hard to know if that's any different than you two alone. But there are some interesting aspects of of this trial, including the Richter's transformation patients. But one thing that's probably worth noting is the effect again, small numbers of patients, but just sort of continues to layer on top of what we've seen in other trials is that U2 alone works pretty well in BTK refractory patients here in the first three cycles. So similar to the venetoclax combinations, you give three cycles of U2 before we introduce the pembrolizumab. So in the three cycles of of U2 alone, we had four out of five of the BTK refractory patients responded. So, again, U2 doing pretty well in those BTK refractory patients. And then overall, they bumped up to five out of six responders for eighty three percent. So, again, interesting data. We're still trying to understand better how to incorporate PD L1s into CLL and Mb cell malignancies. But some interesting data, again, encourage folks to take a look at both posts. It's just a small snippet. But, again, today is really to focus on YouTube plus Venn. We've got two fantastic investigators here on the call, and I'm going to, turn this over for Q and A. Thank you. We'll now be conducting a question and answer session. Our first question today is coming from Alethia Young. Your line is now live. Hi. This is Emily on for Alethia. Thanks for taking our questions. Just confirming, can you hear me okay? Yes. How are you thinking about positioning when it comes to U2, U2 plus VEN, and also U2 plus your BTK inhibitor in terms of line of treatment? And do you feel that there's a place for all of these treatments to be used on the market, or do you think that one of the combinations would eventually take over from the others? And then maybe also with the profile that you're seeing so far with the u two plus ven combo, do you see a place for that in the treatment naive setting? And what do you think that you need to see in the phase two slash three study to show compared to BTK inhibitors or venetoclax alone for it to be used more widely? Thank you. Thanks. So can I ask doctor Barron, doctor Furman to tackle the second question first? I'll go through how we see the U2, U2 VEN, and BTKs, like where they fit into the marketplace. But the question is, what do we need to see in the phase twothree to see U2 plus VEN as a first line treatment? I'll start, if that's Okay, Rick, just based on our data. Obviously, our study was focused on relapsedrefractory patients. And to sort of touch on the impetus or the implications there, I personally think there definitely is a potential role for U2 Venetoclax in this patient population. The evolving landscape is changing very rapidly. And there is no longer one particular standard of care. It's very reasonable for patients to get a BTK inhibitor, to get venetoclax and binituzumab first line. So what you use in the relapse setting is very much dependent on what they got in the first line setting. And this three drug regimen would be very appropriate if patients fail BTK inhibitors. If patients got a year of venobinutuzumab and then relapsed. If patients on a clinical trial got the combination of the BTK inhibitor, venetoclax. So in my mind, the ability to use an agent targeting the BCR signaling pathway and the BCL2 inhibitory agent of limited duration really allows some flexibility and can address a large number of patients in the relapse setting. To the question of what we need to see in the first line study to see this moved up in the treatment sequence, I'll let Doctor. Furman touch on that more so. But ultimately, we need randomized studies showing us a clean side effect profile, superiority in terms of efficacy, generally speaking. But I think the ULTRA V study is a very good first step to showing this sort of feasibility initially. Just to follow-up on what Doctor. Barratt already mentioned. I mean, you know, as a relapsed regimen, this really fits the bill of coming in with different agents that would be non overlapping in terms of the resistance mechanisms and really provide excellent efficacy to most of those patients who are either getting venetoclax or BTK inhibitors as the frontline therapy. But I always believe in putting our best foot forward first. And so I do see this as a regimen for those patients up front with the idea that, you know, two years of therapy and then basically or eighteen to twenty four months of therapy and then giving the patients time to heal from therapy is really a better long term solution for our patients. And with the depth of responses that we're seeing at this time, the hope is that these could be very, very long durations of response. And so I do think I see this as an upfront treatment regimen. And primarily, the most important piece of data that we need to see beyond efficacy is going to be tolerability. And really, it's the number of patients who are able to actually receive therapy. Because, you know, as I mentioned, not being able to deliver the therapy means that these patients aren't going to be able to benefit from the therapy. And that really is a big issue when we start looking at BTK inhibitors. And you can see that from the data I showed from OSU, with over twenty percent of the patients not being able to continue therapy just due to adverse events separate from those who are progressing. So I think at this point in time, efficacy and tolerability are really the two most important things that we need to see from these regimens. Thanks. And I'll just from a corporate positioning standpoint, you know, we do see U2 as at the initial launch, while we're expecting or hoping for a very broad label, the idea is that we're pretty cognizant of landscape. We see U2 fitting in anywhere, in academic community, certain community in the third line setting. But we do see that there's earlier use available in community setting. So we think that in centers that are not using venetoclax, there'll be some frontline use in patients who are not good candidates for BTK. And in second line, again, in centers that aren't using venetoclax, anyone who's coming off a BTK inhibitor, we think, is an ideal candidate for you to do so across both the community. We see some first line use, but probably more likely a lot of second line use. And in the academic centers, some second line use, but primarily third line use for U2. As you've heard from the experts, as we move into U2 plus VEN, that changes the utilization of U2, potentially some frontline use in centers that are using VEN frontline as an alternative to VEN plus CD20. And then certainly, centers who are using VEN, anyone coming off of BTK is a perfect candidate for U2 plus VEN. With respect to our BTK question, was where does that fit in? So we do think that the market for BTK's is obviously going to continue to be quite robust, both in frontline and relapsed patients. We think that the market is going to, over time, shift to better tolerated BTK's, which is why we're so focused on making sure that we choose a BTK dose that is very well tolerated. Again, we're looking for ideally best in class tolerability profile as we develop that. So we think as a single agent BTK, we'll compete very nicely for the better tolerated BTK market, both frontline and relapse. And we're also working on very interesting combinations with U2 that also can change the positioning and the treatment landscape. So I think that's overall how we see the positioning for both U2 and then U2 and Tevin, consistent, obviously, with what Doctor. Barr and Doctor. Furman referred to it, with U2 VEN. Thank you. Our next question today is coming from Eric Joseph. Your line is now live. Okay. Great. Good morning, guys. Thanks for taking the question. Hope you can hear me okay. Just a couple from us on the Ultra V trial design. Given that you're looking at a a broader patient population looking at both acute naive and relapsed refractory patients. I'm just wondering if you could talk about whether there are any particular, you know, molecular profiles or risk factors that you're looking to enrich for this treatment naive patient population. And then similarly, when it comes to relapse refractory or in second line, are you second line plus, are you looking to exclusively enrich those who are BTK refractory? Would you expect any difference in either depth or duration of response with UT plus b if a patient was BTK refractory versus BTK relapse? Thanks. So I guess I can take this one. I think it's, you know, important to keep in mind that, you know, these are meant to be very broad, multicentered study, international studies, and we're really looking at trying to actually look at the population that's most representative. So I don't expect us to really be enriching, at least in the treatment naive, beyond the exception that, obviously, patients who have higher risk genetics and, more likely to progress on standard therapies are going to be more likely to seek out the clinical trials. So I do think there'll be some natural selection and enrichment for more aggressive disease, but we're not doing anything intentionally to elicit that. With regard to the relapsed refractory patients, you know, it's interesting. We really don't understand, BTK progressors as much as we do. And I think that this is a very important caveat, especially when we start talking about the reversible inhibitors. Because when patients progress on, covalent BTK inhibitors, you know, we see the variant allele frequencies for the cysteine forty one serine mutations really to be anywhere from three percent to fifty percent. And you really end up in a situation where, you know, we don't understand what's really driving the entire tumor to progress. And so, you know, in essence, we'll be looking at all those markers. But really, what we're going to end up looking at really are just patients who are progressing on BTK inhibitors. And that's really the clinical information and the clinical data that matters the most. Because as I mentioned, when we really start looking at all these individual subgroups, we really are possibly misleading ourselves into thinking that we really understand what's going on. And the only thing I'll add, Eric, is that in the enrollment in the Phase II, we did specifically look for a cohort of BTK refractory patients, which was about 20 that ended up in that portion of the trial. Okay. Got it. Maybe just one quick follow-up on, I guess, the balance of patients that you would be looking to I guess, numbers of patients that you're looking to recruit that are treatment naive versus relapse refractory and the base for the portion. Is there a sort of a target number of both that that you would need in order to, you know, satisfy statistical requirements to show, meaningful benefit in PFS? Well, the accrual goal is 200 patients in each arm in the treatment naive group and a 50 patients in each arm in the relapsed refractory group. Thank you. Our next question is coming from Matt Kaplan. Your line is now live. All right. I'm now unmuted. Good morning, guys. Thanks for taking the question. I guess for Doctor. Barr, can you give us a little bit more detail on the Phase III results with respect to what with respect to MRD negativity that you're seeing and how this compares with what you would typically see, I guess, with venetoclax alone? And then how how you use MRD negativity in your current practice. So I'll start with the second part. MRD testing, I would say, is still largely investigational when you use it in a predictive manner, meaning when you use it to direct therapy. Certainly, flow cytometry is regarded as a very reasonable thing to check MRD with. And the adaptive high throughput sequencing assay is now FDA approved. So MRD is going to be part of our standard of care. And it's pretty reasonable today to check it at the end of a fixed duration therapy to inform your patient, to have a discussion, to help them understand their prognosis. But it's less useful today to direct our therapy. So that's just a general comment about how we, in my mind, how we should use MRD. I do think with more and more studies, such as the ones you're hearing about, it will be more useful to help guide treatment making decisions. So that's just a comment on MRD. Regarding the data, so we use flow cytometry, again, readily available. We felt it was important to test this centrally in the phase one, two study so that the audience of those reading, watching the presentation, reading the ultimate paper, will have confidence that the results are reliable, so to speak. So this was done essentially at one particular lab, the samples being collected from all the sites. And as such, goes down to a level of 10 to the fourth. So when I say undetectable, it's less than one in ten thousand CLL cells. And then in our presentation, we also use intermediate. That means the cells are being detected between 10 to the minus second, ten to the minus fourth, and positive would be greater than 10 to the minus second. So just general arbitrary cutoffs that are agreed upon internationally for determining the level of CLL cells in the peripheral blood marrow. As you can see at the end of 12 cycles of treatment, ninety one percent were undetectable, less than 10 to the minus fourth, less than one in 10,000 cells in the peripheral blood, 71% in the marrow. I will say that if you make the somewhat unfair comparison across other combination studies, this level of negativity is at least as good as what you've seen with BTK, BCL2 combinations, other studies with triplet combinations. Numerically, our results look better. And this is in the relapse refractory setting, not in the first line setting. So it's convincing me that we're seeing deeper levels of response than we've seen in some of the other studies. Again, I'm comparing across clinical trials. So at the very least, I think it's reasonable to say our results look as good as other combination studies. So pretty long winded answer there. Hopefully, I answered your question. No. That's very helpful. And maybe just a follow-up for Doctor. Furman and Doctor. Barr. I guess given the high rates of discontinuations that you see with ibrutinib for various reasons, whether patients progressing or not being able to tolerate, what's how do how do you handle those patients currently? And then what are your thoughts on potentially incorporating U2 or U2 plus V in that patient population? Well, I really think, you know, the ultimate issue, of course, is to always put our best foot forward first, as I'd already said. And the idea would be to start with those with the U2 or the U2VEN regimen first in place of, once we really establish the better tolerability and efficacy. And I think that's really what it comes down to is, right now, because BTK inhibitors are already so prevalent and are the more common or the most common first line regimen being used by patients, you know, it will be a relapse situation that these agents will get used. I do expect that to sort of evolve over time as regimen does move to the upfront setting. Right now, how are we managing these patients? It's currently primarily with just single agent venetoclax. And in the relapse setting, we do see a significant number of treatment failures. And so it's important that we once again have a combination regimen to be used in the relapsedrefractory setting. Thank you. Our next question is coming from Mayank Mankami. Your line is now live. Good morning. Thanks for the detailed presentation and appreciate you taking our questions. So maybe just a couple of quick follow ups for for doctor Barr and or doctor Furman. In terms of the threshold for MRD from a regulator from a from an FDA standpoint, for instance, I I mean, do you do you guys think there is a, you know, a different bar for a finite duration com combination regimen versus maybe also thinking about you know, you commented on other regimens, but also thinking about cell therapy modalities that are progressing. And and and how might, you know, those things differ, you know, when you think about frontline relapse refractory and and and particularly BTK refractory patients? Is there a number that I can push you on on MRD that maybe, you know, the regulators are willing to, think about for these different, modalities? So let me, start first. I think it's important to recognize that there are significant differences between the FDA and the EMA, sorry, regarding how they're approaching, MRD as an approval tool. And I think one of the things that we often forget is that we currently don't have any data on making treatment decisions based upon the MRD assessment. And so that's what we're really looking here to establish, is that MRD can be a useful tool. And I do think MRD will be a useful tool. We just need to figure it out first. And currently, the FDA has not been using MRD as truly a measure for approving therapies. So even though they've approved the next generation sequencing MRD assessment as a tool, it's really not with any clinical without its use in clinical management. And that's sort of an interesting aspect of all that. You know, when we talk about MRD, the data that I find most helpful are Peter Hillman's data, which actually gives us a target of 10 to the minus eight as potentially being, you know, where we might consider someone to be cured. Other than that, PFS really has to be the guidepost. And I think that's really the most important aspect of all data that's going to be generated long term from an approval pathway. But as a clinician, looking to use MRD to sort of try to predict the future is something that I'm hopeful will at least allow us, we will have as a tool in the near future. Thank you. And a quick follow-up for Doctor. Barr. On on the patient refractory on YouTube and now on Umbra monotherapy from the phase one trial, do we know anything about the, you know, the resistance mechanisms? And and just curious if there are any learnings to apply, you in the larger Ultra V study. I just have a last quick follow-up for Mike. It's too early at this point. There literally is two patients about to start single agent unrelacin. So it's a good problem to have. There haven't been many relapses. So hard to say much about molecular characteristics at relapse or timing and whatnot. So more to come. Excellent. Thank thank you. And and, Mike, just, remind us, what officially qualifies as the, you know, the formal confirmatory study that FDA will need to see accrued meaningfully as it gets ready to, you know, grant, you do accelerated approval in first quarter next year. Does Ultra V qualify for that? Yeah. The Ultra V phase three portion would qualify as either as a confirmatory trial or as a registration trial in itself. I think your your your question to help help some others out, you went a little further. Basically, if if we're able to utilize the phase two data for accelerated approval, would the phase three be useful as a confirmation? I believe the answer is yes. If we can't use the phase two for accelerated approval, I believe the phase three could stand alone as a as a registration trial. Thank you. Our next question is coming from Ed White. Your line is now live. Good morning. Thanks for taking my question. So maybe a general question, thinking about the community setting and the use of venetoclax. Maybe we can just get the doctor's opinion on what's going on there. Is venetoclax, in your opinion, becoming more widely used? What can help it become more widely used? And is you too the answer to that to get venetoclax more widely used in the community setting? It's a good question, Ed. And you'll probably get different answers from different investigators based on where we practice. In Rochester, New York, there are a number of smaller community sites that are relatively spread out, may not have tremendous resources for intensive monitoring, and not a lot of experience treating relapsed refractory patients. So I'll give you a couple examples. We have a number of sites around us that have never used venetoclax, and we help start patients and then transfer them back. Whereas little larger sites, say in Syracuse, that are very comfortable using venetoclax in the relapsed refractory setting. So one of my comments earlier is we need a variety of strategies to treat CLL patients. There is no more one particular standard of care. So personally, I think a you to then strategy makes it much easier. You develop the patient, you can keep them outpatient, and it's very easy to monitor the laboratory studies. You know you're not going to run into tumor lysis. That makes it feasible at some of the larger community sites that again are comfortable as an outpatient. But there will be some sites, some smaller centers that are, you know, some physicians seeing one CLL patient a year, that venetoclax just isn't going to be something they reach for very often. And this goes back to Mike's comment about using the U2 regimen in some of those community patients as opposed to VEN. So kind of a answer that isn't very directive. But I honestly think that's the landscape. We need to have a variety of options for our patients. And I think this program addresses some unmet needs. Okay, thank you. And maybe a question for Mike. I'm just curious as to maybe if you have any thoughts on the timing of when you identify which dose, the three hundred or the two hundred for seventeen oh one, you will move forward with. And then just a question on the U2 and pembro study. You know, when do you how should we be thinking about this study progressing? And when do you move over as you mentioned that you have your own PD-one, the fifteen oh one product, When do you move over and start using that in combination? Thanks, Ed. Yes. So I'm going to use take the easy question first, the dose for BTK. We would hope to have that resolved by the first quarter of next year. So we're hoping to start a pivotal program around the first quarter of next year, so we hope to have that resolved. And, again, for us, it's more about the tolerability profile and really dialing out as much as possible of those BTK toxicities. So we'll we'll keep you posted there. In terms of follow on to the pembro study, you know, there's a few aspects of that. We're we're probably more keen today on trying to explore our PD L1 in more aggressive B cell malignancies like diffuse large B cell. There's some there was some early data, and we need to sort of vet it out a little bit more of that. The use of the PD L1 enabled certain patients in that study with PD-one. In that study to come off all therapy and stay in remission for for years. So there was this concept about T cell surveillance that we definitely need to do further work on. So I think that's an interesting tie in. And, again, when we're trying to move into limited duration therapies, if in fact you can get add a PD L1 for a certain amount of time, and it will help keep patients in remission due to some T cell surveillance that is ongoing after the fact, that would be quite interesting and quite useful tool for treating these patients. So the second question about the pembro next steps, still yet to be determined. We need to work with Doctor. Mado and some of the other investigators and try to see what the next best step is for that type of program. Thank you. We've reached the end of our question and answer session. I'd like to turn the floor back over to Mike for any further or closing comments. Yes. So thank you very much. I want to thank everyone for joining us. I want to particularly Bars and Doctor. Furman for taking some time this morning to be with us. Doctor. Barna shared the data, and Doctor. Furman talked about what's coming up hopefully by the middle of next year, some fulsome phase two data from the Ultra V trial. But, again, thanks to the investigators for for all their hard work and their patience, of course, who who joined these trials. To the investors, if you have any further questions for us, you know how to reach us. Hope everyone has a very nice day. Thank you. Thank you. That does conclude today's webinar. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.