TG Therapeutics, Inc. (TGTX) Earnings Call Transcript & Summary

Hello and welcome to the TG Therapeutics iwCLL Investor and Analyst Virtual Event. [Operator Instructions] 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 Dr. Barr will review the U2 plus venetoclax Phase I data presented this weekend, following which, Dr. Furman 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&A session. So to begin, I'd like to welcome and introduce Dr. Paul Barr, Associate Professor of Medicine and Director of the Clinical Trials Office for the Wilmot Cancer Institute at the University of Rochester. Dr. Barr is also the study chair of the Phase I/II U2 plus venetoclax trial. Thank you for joining us, Dr. Barr. Next, I welcome Dr. Richard Furman, the Morton Coleman, M.D. Distinguished Professor of Medicine in the Division of Hematology and Medical Oncology at the Weill Cornell Medical College in New York. Dr. Furman is also the study chair of the ULTRA-V program. Thank you, Dr. Furman, for joining us. With that, let me turn the call over to Dr. Barr to review the Phase I 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 is a -- 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 and Northwestern. So we're very proud of this trial and its data. And here's the title. It's a Phase I/II study of umbralisib plus ublituximab and venetoclax for patients with relapsed or refractory CLL. Next slide. Just by way of background, I think everyone is 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 relapsed/refractory patients and incorporate the other important classes for the treatment of CLL, namely PI3K inhibitors, CD20 agents and BCL-2 inhibition. Next slide. 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 inhibit CK1-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 glycoengineered, has a lower sugar content. And ultimately, it's more effective in enhancing ADCC, antibody-dependent cellular cytotoxicity. The -- as you also saw in iwCLL, this doublet, ublituximab and umbralisib, met its primary end point in the UNITY-CLL study. Next slide. So this particular trial was a multicenter Phase I/II setting. We already completed the Phase I and presented that data a couple of ASH meetings ago. We identified a Phase II dose of umbralisib at 800 milligrams, the standard Phase II dose, in combination with the fixed dose of ublituximab and standard venetoclax dosing. So it's important to point out that the Phase I piece showed us that we can use the standard doses of all of these agents. The primary objective of the Phase I component was to evaluate safety. What we're showing now in the subsequent reports is the clinical efficacy, most notably by CRA progression-free survival and importantly, MRD rates. Next slide. This is the study schema. We included a 3-cycle debulking period, where patients received daily umbralisib and several doses of ublituximab. After those 3 cycles, patients started on venetoclax with the standard ramp-up and received ideally 9 additional cycles of venetoclax, umbralisib and 3 more doses of ublituximab. At the end of the 12-cycle treatment period, patients under with CETs and bone marrow biopsy and MRD assessments. Notably, if patients were undetectable for MRD, they were able to stop all treatments, 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. Next slide. 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. Next slide. So at this point, the study is fully enrolled with 47 patients, it's 47 CLL patients. And we're just about at the point where the last patient is finishing his 12th cycle. So soon, we will have pretty mature MRD data for all the patients. We're just short of that in this presentation. 46 patients were evaluable for efficacy. The median age was 64 years. These patients have received a median of 2 prior regimens and more than half have received BTK inhibitors. We considered 13 patients truly refractory to the BTK inhibitor. And in those 13 patients, we were able to identify BTK or PLC-gamma mutations in 11 patients. If you want to gauge the overall risk profile of these patients, I think it's important to point out that almost 3/4, 72% had at least 1 high-risk molecular aberration. Next slide. These are the AEs of all cause occurring at greater than 20% of patients. Infusion reactions were somewhat common but mild, and this just relates to how we administered ublituximab. We did observe cytopenias. 28% had Grade 3 or 4 neutropenia and we're able to receive growth factor, 6% had Grade 3 anemia. Otherwise, there were mild GI effects that really didn't affect the treatment. We did not have to discontinue or stop therapy for these mild GI effects. And similarly, we had to take short treatment rates for mild transaminase elevations. Otherwise, there were 2 -- in terms of the grade 3 or 4 AEs, there were 2 events of colitis; 1 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. Next slide. The 3 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 is -- saves a lot of resources. We saw a 79% relative reduction in the tumor lysis risk, and there were no events of tumor lysis syndrome during venetoclax. Next slide. This is the big update that we provided at iwCLL as these patients matured throughout their treatment. All patients responded at cycle 12. And actually, all patients had responded by cycle 7. There was a 37% complete remission rate. And in terms of MRD data, 91% were undetectable in the peripheral blood at cycle 12, 72% were undetectable in the marrow. So on the 34 patients who have cleared cycle 12 at this point, only 5 continued on umbralisib, the rest stopped therapy. And with additional follow-up, you can see 17 patients who completed cycle 18, 76% remained undetectable in the peripheral blood. Only a small number, 7 patients, have completed cycle 24, 71% 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 seemed to be responding equally as well. You can see the -- 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. Next slide. So far, there have been a small number of relapses. The median follow-up is about 2 years, and the estimated 2-year PFS is 89%, pretty respectable for a relapsed/refractory population. Next slide. So in conclusion, the 3-cycle induction is effective. It reduces the tumor lysis risk, notably in patients previously treated with BTK inhibitors as well. The response rate is 100% at 12 cycles, and 91% and 72% are undetectable for MRD in the peripheral blood marrow, respectively, at cycle 12. And with additional follow-up, 70% 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 reduced transformation in mantle cell lymphoma. Both of those cohorts are currently enrolling. So this study is ongoing for those cohorts as is the ULTRA-V study, which Dr. Furman will detail shortly. Next slide. I'll stop there and let Dr. 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 -- have set the stage for what we hope will be the next evolution in the therapy of patients with CLL. Next slide. So the BCR-associated kinases really have been proven targets for treating CLL. And we've known this since fostamatinib was first used back in -- or first reported in 2008 on an ASH plenary session. So I want to go through just the 3 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 2008 at an ASH plenary session. We heard preliminary data that was actually incredibly encouraging. For a number of reasons, fostamatinib 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 3 approved agents targeting BTK right now: ibrutinib, acalabrutinib and zanubrutinib. And a fourth one in late-stage development, pirtobrutinib, 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 4 agents approved: idelalisib, duvelisib, copanlisib and umbralisib, which targets actually different isoforms, and I'll explain that in a moment. Next slide, please. So while the B-cell receptor pathway, in the previous slide, really looked like a very nice, neat, orderly process, this is an 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 multiagent chemotherapy or multiagent 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 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. And what really makes PI3 kinase unique is the different isoforms. And as it turns out, there's a p85 and a p110 subunits, with the p85 being regulatory and the p110 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 a phenotype of disrupted immune function in mice that have the delta knockout. Next slide, please. 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 idelalisib and duvelisib are actually marketed as mostly a delta inhibitor, with duvelisib having some gamma inhibition and copanlisib 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 CK1-e enzyme as well. Next slide. 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-2 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-2 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 as an important source of survival and nourishment and resistance to venetoclax. So you've already heard about the Phase I/II evaluating U2-Ven 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. And 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 U2-Ven 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. Next slide. And so just to talk about the need for combination therapies. These are data from the original Phase II study of ibrutinib, the 1102 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 route and really 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. Next slide. And so when we look at data from Ohio State University, these are 308 CLL patients that were treated on ibrutinib-based protocols, you can see there's 3 modes or 3 methods of progression. The first one is going to be basically 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 25% at 4 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 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 Dr. Barr may actually prove to -- might prove me wrong, which would be wonderful. But then finally, we have the CLL progression, which begins to rise at about year 2 and really hasn't peaked yet. And what we see is that at 4 years, there's 19.1% 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. So next slide, taking a look at the venetoclax data. These are data from the CLL14 study. You could see here that the -- while the data looks very good, the 4-year progression-free survival for venetoclax/obinutuzumab is 74%. And while this might sound great, there's a large number of these patients still getting to MRD negativity who were 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 karyotype and other high-risk mutations, you can see here that the median PFS is now 49 months. So 50% of patients are progressing, and these are treatment-naive patients with 17p and TP53 aberrations. Next slide. So with the need, we set out on the ULTRA-V Phase II trial, which looked at 160 patients that were treatment naive, previously treated and BTK refractory as 3 different cohorts. And patients in this trial received, as in the Phase I study by Dr. Barr, ublituximab and umbralisib for 3 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 4 through 6. Finally, umbralisib and venetoclax to complete 24 months of therapy. And those patients who are MRD positive we're going to go on to receive umbralisib continuously, and those who have undetectable MRD will come off therapy. The primary end point for this study is going to be the complete response rate as well as the overall response rate, with the secondary end point being rate of undetectable disease. Next slide. And our hope is that this really will be sort of the next step in evolution for treating our patients. So 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 non-overlapping toxicities. And we know that the one side effect of venectoclax that needs to be contended with is actually markedly reduced with the 3-cycle lead-in of umbralisib and ublituximab. 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 III trial is currently enrolling in treatment-naive and relapsed/refractory CLL. Next slide. All right. I'm going to pass it now back to Mike Weiss.

Thanks, Rick. I very much appreciate that. Sorry. Still can't handle my Zoom. 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 iwCLL. Just to remind everybody, on the next slide -- thank you. So we did have an encore presentation of the Phase III 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 we saw significant outcome for the trial, both for the entire population and each of the subgroups of frontline and relapsed/refractory. On the next slide, 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 -- it's a pretty, I'm going to say, busy poster. There's a lot of information on there. I do encourage folks 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 kind of critical. The activity at the top, what you're looking at are basically just the CLL expansion cohorts at 200 milligrams and 300 milligrams. The darker bars are the 300 milligrams. The lighter bars are the 200. In essence, whether it's 200 milligrams to 300 milligrams, nearly every patient responds to monotherapy. In the last bullet, you can see that, every one of the combination patients of U2 plus 1701 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 to try to identify the right dose for the tolerability profile. We are seeking a best-in-class tolerability profile, along with what is certainly comparable to the best-in-class activity. So keep following that compound, please. Next slide. So this is a study that was conducted by Dr. Mato. Pretty close study as an early look at U2 plus PD-1, PD-L1 inhibition. This is U2 plus pembrolizumab. Most folks will recognize that we have our own PD-L1 inhibitor 1501 or cosibelimab. I think in terms of the overall response rate, a 90-plus percent, probably small numbers. Hard to know if that's any different than U2 alone. But there are some interesting aspects of this trial, including the Richter's transformation patients. But one thing that's probably worth noting is the effect -- again, the 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 3 cycles. So similar to the venetoclax combinations, you give 3 cycles of U2 before we introduce the pembrolizumab. So in the 3 cycles of U2 alone, we had 4 out of 5 of the BTK refractory patients responding. So -- and U2 doing pretty well in those BTK refractory patients. And then overall, they bumped up to 5 out of 6 responders for 83%. So again, interesting data. We're still trying to understand better how to incorporate PD-L1s into CLL and B-cell malignancies, but it's an interesting data and again, encourage folks to take a look at both those. It's just a small snippet. But again, today is really to focus on U2 plus ven. We've got 2 fantastic investigators here on the call, and I'm going to turn this over for Q&A.

[Operator Instructions] Our first question today is coming from Alethia Young.

This is Emily on for Alethia. 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 is 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 U2 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 II/III study to show compared to BTK inhibitors or venetoclax alone for it to be used more widely?

Thanks. So can I ask Dr. Barr and Dr. 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 II/III to see U2 plus ven as a first-line treatment?

I'll start, and then -- if that's okay, Rick, just based on our data. Obviously, our study was focused on relapsed/refractory patients. And to sort of touch on the impetus or the implications there, I personally think that there definitely is a potential role for U2/venetoclax in this patient population. The evolving landscape is changing very rapidly. And there isn't -- there is no longer one particular standard of care. It's very reasonable for patients to get a BTK inhibitor, to get venetoclax and obinutuzumab 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 3-drug regimen would be very appropriate if patients failed BTK inhibitors. If patients got a year of obinutuzumab in the 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 BCL-2 inhibitory agent of limited duration really allows some flexibility and can address a large number of patients in the relapse setting. So the question of what we need to see in the first-line study to see this move up in the treatment sequence, I'll let Dr. 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 Dr. Barr had already mentioned. I mean 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 upfront, with the idea that 2 years of therapy and then basically or 18 to 24 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 were seen 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 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 20% 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 2 most important things that we need to see from these regimens.

And I'll just, from a corporate positioning standpoint, we do see U2 at the initial launch, while we're expecting or hoping for a very broad label, the idea is that we're pretty cognizant of the landscape. We see U2 fitting in anywhere, both an academic community -- certain community in the third-line setting. But we do see that there's earlier use available in the unit setting. So we think that in centers that are not using venectoclax. 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 is coming off a BTK inhibitor, we think is an ideal candidate for U2. 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 then frontline as an alternative to ven plus CD20. And then certainly, in centers that are using ven, anyone coming off of BTK is a perfect candidate for U2 plus ven. With respect to our BTK question as far as that fit in. So we do think that the market for BTK 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-tolerating BTKs, 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 relapsed. 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 into ven consistent, obviously, with what Dr. Barr and Dr. Furman referred to it, the U2-Ven.

Your next question today is coming from Eric Joseph.

Just a couple from us on the ULTRA-V trial design. Given that you're looking at a broader patient population, looking at both treatment naive and the relapsed/refractory patients, I'm just wondering if you could talk about whether there are any particular molecular profiles or risk factors that we're looking to enrich for the treatment-naive patient population? And then similarly, when it comes to relapsed/refractory or in second line, are you -- the 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 U2 plus v if a patient was BTK refractory versus BTK relapsed?

So I guess I can take this one. I think it's important to keep in mind that these are meant to be very broad, multicenter 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 trial. 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, 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, we see the variant allele frequencies for the cysteine 41-serine mutations really to be anywhere from 3% to 50%. And you really end up in a situation where we don't understand what's really driving the entire tumor to progress. And so 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. 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 relapsed/refractory [ base for the portion ]. Is there sort of a target number of [ vote ] that you would need in order to satisfy statistical requirements to show meaningful benefit in PFS?

The accrual goal is 200 patients in each arm in the treatment-naive group and 150 patients in each arm in the relapsed/refractory group.

Our next question is coming from Matt Kaplan.

I guess for Dr. Barr, can you give us a little bit more detail on the Phase I/II 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 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 where 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 thought it was important to test this centrally in the Phase I/II 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 centrally at one particular lab. The sample is being collected from all the sites. And as such, goes down to a level of 10^-4. So when I say undetectable, it's less than 1 in 10,000 CLL cells. And then in our presentation, we also use intermediate. That means the cells are being detected between 10^-2, 10^-4, and positive will be greater than 10^-2. So just general arbitrary cutoffs that are agreed upon internationally for determining the level of CLL cells in the peripheral blood and marrow. As you can see at the end of 12 cycles of treatment, 91% were undetectable, less than 10 or minus fourth, less than 1 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, BCL-2 combinations, other studies with triplet combinations. Numerically, our results look better. And this is in a relapsed/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 Dr. Furman and Dr. Barr. I guess given the high rates of discontinuations that you see with ibrutinib for various reason, whether patients progressing or not being able to tolerate. What's -- 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 the ultimate issue, of course, is to always put our best foot forward first, as I already said. And the idea would be to start with those -- with the U2 or the U2-Ven 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, it will be a relapsed situation that these agents will get used. I do expect that to sort of evolve over time as the 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 relapsed 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 relapsed/refractory setting.

Our next question is coming from Mayank Mamtani.

Thanks for the detailed presentation. So maybe just a couple of quick follow-ups for Dr. Barr and/or Dr. Furman. In terms of the threshold for MRD, from a regulator -- from an FDA standpoint, for instance, I mean, do you guys think there is a different bar for a finite duration combination regimen versus maybe also thinking about -- you commented on other regimens, but also thinking about cell therapy modalities that are progressing? And how might those things differ when you think about frontline relapsed/refractory and particularly BTK refractory patients? Is there a number that I can push you on MRD that maybe 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 EHA -- 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. 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 improving therapy. 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. So when we talk about MRD, the data that I find most helpful are Peter Hillmen's data, which actually gives us a target of 10^-8 as potentially being 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.

And a quick follow-up for Dr. Barr. On the patients refractory on U2 and now on umbra monotherapy from the Phase I trial. Do we know anything about the resistance mechanisms? And I'm just curious if there are any learnings to apply in the larger ULTRA-V study. And I just have a last quick follow-up for Mike after.

Yes. It's too early at this point. There literally is 2 patients about to start single-agent umbralisib. 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. And Mike, just remind us what officially qualifies as the formal confirmatory study that have been able to see accrued meaningfully as it gets ready to grant U2 accelerated approval in first quarter next year? Does ULTRA-V qualify for that?

Yes. The ULTRA-V Phase III portion would qualify either as a confirmatory trial or as a registration trial in itself. I think your question to help some others [ at you ] a little further. Basically, if we're able to utilize the Phase II data for accelerated approval, would the Phase III be useful as a confirmation? I believe the answer is yes. If we can't use the Phase II for accelerated approval, I believe the Phase III could stand alone as a registration trial.

Our next question is coming from Ed White.

So maybe a general question, thinking about the community setting and the use of venectoclax. 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 U2 the answer to that to get venectoclax 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 of 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 a 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 U2-Ven strategy makes it much easier. [ When you deal with ] 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 -- 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 an 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. And maybe a question for Mike. Just curious as to maybe if you have any thoughts on the timing of when you identify which dose, the 300 or the 200, for 1701 you will move forward with? And then just a question on the U2 and pembro study. 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-1, the 1501 product? When do you move over and start using that in combination?

Thanks, Ed. Yes. So I'm going to use -- I'll 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 our pivotal program around the first quarter of next year, so we hope to have that result. 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 keep you posted there. In terms of follow-on to the pembro study, there's a few aspects of that. 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 were some early data, and we need to sort of get it out a little bit more of that. The use of the PD-L1 enabled certain patients in that study or the PD-1 in that study to come off all therapy and stay in remission 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 a 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 Dr. Mato and some of the other investigators and try to see what the next best step is for that type of program.

Thank you. We 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 thank Dr. Barr and Dr. Furman for taking some time this morning to be with us. Dr. Barr to share the data and Dr. Furman to talk about what's coming up, hopefully, by the middle of next year, some fulsome Phase II data from the ULTRA-V trial. But again, thanks to the investigators for all their hard work and their patients, of course, who joined these trials. To the investors, if you have any further questions for us, you know how to reach us. And hopefully, 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.