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

Greetings, and welcome to TG Therapeutics Webinar ASH 2020 Abstract Release Call. [Operator Instructions]. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Michael Weiss, Chief Executive Officer of TG Therapeutics. Please proceed.

Great. Thank you, conference operator, and good morning, everybody, and thanks for joining us. So like a regular presentation, I guess, I'm going to do some forward-looking statements. Before I get started, I just want to remind everyone that I will be making some forward-looking statements. And for those who are interested in TG, I do encourage you to read our public disclosure documents available on the -- online. Okay. So with that, let me start the call by just going through quickly the agenda for today. So first, I'm going to do a corporate update. The -- this will be in lieu of a quarterly conference call that we would normally host next week. So we're going to do some corporate housecleaning, do the updates and then get to the main event which is, most important, is going to be some presentations from our esteemed panelists on UNITY-NHL and UNITY-CLL. We'll follow that up with a really robust Q&A. I'll get back on to just to a quick, typical cleanup, go through some digital -- some programs again and what's coming up. So that's how we'll get [ started with ] the program. And let me just turn to the next slide and going through -- sure. Perfect timing. And let's go through the 3 major pivotal programs. So first, let's talk about UNITY-NHL. In particular, we're going to focus on our relapsed/refractory marginal zone and follicular cohorts. As we've stated previously, the primary endpoint for these studies was met, which is overall response. We've now -- also have the abstract data that was out yesterday. So hopefully, everyone had a chance to look at that. In terms of status of this program, we have filed a rolling submission. It's a [indiscernible] in August. This study -- the marginal zone portion of this is under breakthrough therapy designation, and that portion has been accepted for priority review with a PDUFA goal date of February 15, while the follicular indication has been accepted for our standard review with a PDUFA goal date of June 15, 2021. So chugging along, working toward those approvals, clearly, this is an exciting time for the company, and as we get closer and closer to, hopefully, bringing umbralisib after these years to patients in need. And of course, we are extremely excited to have the abstract data presented today by Dr. John Pagel of the Swedish Cancer Center in Seattle, who's a leading UNITY-NHL investigator. Okay. So let's talk about our UNITY-NHL trial and give an update there. Again, this trial is being conducted under special protocol assessment. And as many of you know, in early May, we did announce top line results that the study met its primary endpoint, that it had achieved statistically significant improvement in PFS. Again, as of yesterday, everyone got to see the actual numbers. Obviously, we're extremely excited about the results. And we have Dr. Alexey Danilov from the City of Hope Cancer Center here today, also a leading UNITY-CLL investigator, who will be on the line to review that data. Again, as many of you know, we've worked extremely hard over the years, working on getting U2 to this point and running [indiscernible] randomized trial for [indiscernible]. And we do believe that if approved, the U2 combination has the potential to be an important treatment option for patients with CLL. So again, very excited to review this data set with everyone shortly. And we're looking forward to submitting a BLA NDA for U2 in CLL as early as possible next year. And then our final pivotal program and certainly spoken about last here, but certainly not least, it's probably our largest [indiscernible] 1,100 patients enrolled is our ULTIMATE MS Program. So this is our ULTIMATE I & II Phase III trials. They're also being conducted under special protocol assessment. And this is in patients with relapsing forms of multiple sclerosis. Primary endpoint here is annualized relapse rate following 96 weeks of treatment, and it is designed to support a full approval of ublituximab in relapsing forms of MS. As I'm sure most everyone knows, these trials are fully enrolled, but we're just at the very end meeting for -- getting [indiscernible] so -- and as we've noted multiple times that we are on target to release that data in 4Q this year, which is this quarter. And we're targeting a data presentation in the first half of next year at a major medical conference. And similarly, we'll be targeting a BLA submission, also ideally in the first half of next year. So where does that leave us? Taken together, if we are successful, we could see approvals for umbralisib alone on the UNITY-NHL side. U2 -- so umbralisib and ublituximab together in U2 and UNITY-CLL, both in frontline and relapsed/refractory CLL. And we can see ublituximab in multiple sclerosis. So the potential of 5 approvals between '21 and '22. Now I'll say that would be an incredible accomplishment for any company. But for a company of our size, it's [indiscernible] that really need an incredible team of people. And I'd say we do have an incredible team of people here at TG. And I've always felt that the core strength at TG was our ability to design clinical and regulatory pathways, not just trials, but pathways, and then execute them with our own top-notch clinical team. We rarely use full-service CROS. We definitely use CROs for key support. But it's our internal clinical team that really gets the job done. And now as we approach the possibility of launching our first product, we're taking a similar approach to building a world-class commercial team. Similar to the clinical side, it starts with just a handful of great folks, and they attract other great folks. So at this point, almost every position on our commercial team is filled. Unbelievable. And I would say, filled, without the use of headhunters. This is all personal relationships because we brought in really great folks. So super excited about what's going on. Almost every position is now filled and the preparations for launch are -- for umbralisib are moving forward in earnest. And the key there and the goal is to make sure that if umbralisib is approved, we can have it available to patients immediately. So that's the goal, and [ we've put ] together a great team. So that is in motion, very much in motion. So with that, let me just say that there are companies that might be satisfied with 5 approvals over 2 years. But those companies would not be TG. Our clinical and regulatory pathways are designed to continue to strive for better outcomes for patients through additional combination trials. So I want to highlight just 2 of those programs next as they represent possible label expansion opportunities for us in chronic lymphocytic leukemia, and again, continue to be designed to provide best-in-class outcome for patients. So on the next slide, let's start with our U2 plus venetoclax program. That's the overall program. And then we have a Phase II trial which we refer to as ULTRA-V, which is a multicenter clinical study evaluating the safety and efficacy of the U2 combination with venetoclax. In this study, we have 3 cohorts. We have a relapsed/refractory CLL cohort, but we also have another cohort of relapsed patients who are BTK refractory, so specifically a group dedicated for BTK refractory, and then we have a frontline cohort. We're expecting to complete enrollment to this early next year. I can say that with -- I think we have 10 to 15 sites on this trial. These were enrolled extremely fast. The demand for the study was off the charts and continues to be off the charts. So very excited about this trial. Now when we look -- the subject of the ASH abstract that was released yesterday, it's that Phase I that led us into this trial. And that Phase 1 is being led by Dr. Paul Barr, again, who will present the full data from that study at ASH. Just a reminder that both the U2 venetoclax and the 1701 U2 abstracts went in several months ago. These are ongoing trials. So these data will be updated. So when I talk about the data and the data at the time of these slides, one should expect that the data will change and will be updated as we get to the conference. So on the Phase I U2 plus ven side, just quickly, from a safety standpoint, putting the 2 -- the 3 drugs together was not problematic. The combination was generally well tolerated. Grade 3, 4 AEs occurring in greater than 5% of the patients were limited to neutropenia, leukopenia and infusion-related reactions. There were no [indiscernible] concentration. From an efficacy standpoint, let me first remind folks that the critical endpoint here is at 12 months because we only check -- we only do bone marrow checks at the beginning of the trial and at 12 months. So in between, we can't really assess complete response or MRD status. So it's the first check at 12 months, which is critical for this trial. So we had 19 patients who had completed 12 months of therapy at the time of the abstract. We expect another 5 to 10 patients through that time point for presentation next month. And -- but in the 19 patients through 12 months that are in the abstract, I think the results are quite impressive. We saw a 100% overall response rate. We saw a 42% complete response rate. To put that into some perspective, obviously, it's a cross-study, but in the label for venetoclax plus Rituxan, the complete response rate is 8%. We also observed a 95 [indiscernible] disease, 68% undetectable MRD in bone marrow. So again, we're very excited about these data. We believe these are obviously encouraging, especially in these relapsed/refractory CLL patients. Many of these Phase I patients were BTK refractory. On the right-hand side of the slide, let me talk about our second triple program. This one is an internally developed one. So this is U2 plus our own 1701, our BTK. We've been working hard over the last year to identify the optimal single agent dose, and more importantly, the optimal U2 combination. So we identified activity for this compound at the very first dose level tested, which was 100 milligrams. We dose escalated all the way up to 400 milligrams without identifying an MTD, and then we backed down to 200 milligrams to start expansion cohorts. We did about 60 patients at 200 milligrams. So a really nice [indiscernible]. Now we're doing a 300 milligram expansion cohort. So we want to understand where we see what we call traditional BTK toxicities. Simultaneously, we've been dose escalating the U2 combination with 1701. And again, same thing, we're trying to identify where we can dose these compounds together to try, I say try, to dial down what are classically toxicities of each agent. So trying to get the best out of both and diminishing anything that you'd expect from these drugs. So that's the work that's been going on. We've had some pretty interesting data emerging from this trial already. I would just highlight the 200-milligram expansion cohort in patients with CLL as sort of a marker of the drug's activity. And we showed about an 85% overall response rate in those patients. So very nice results there. And then for the combination [indiscernible] BTK areas of activity, CLL on marginal zone 100% response rate. I can tell you, I believe, and you can double check all the data, but between U2 plus ibrutinib and U2 plus 1701, I don't think the combination, the triple combination, has been in a CLL marginal patient and they have not responded. And then also nice results in [indiscernible], and we did pick up a diffuse large B-cell responder [ one out of one ]. So some really nice early results. And again, these will be updated like the ven results at the meeting. So then lastly, before I move on to the panel, which again, is the most important part of the session today, I just wanted to do some housekeeping again. We're not going to do the quarterly conference call next week. So I did want to do a quick financial update, so -- on the next slide. So during the third quarter and into -- early into the fourth quarter, we were able to build on our balance sheet through the use of the ATM [indiscernible] cash flows of approximately $325 million as of September 30. And with the additional capital, we believe we are well funded well into 2022. And that does exclude the impact of any potential revenues from umbralisib, if approved. So again, we're hoping that we'll have approval of umbralisib, and that will start to diminish some of these or set off some of these R&D expenses. All right. So with that as the background, we've got everyone up to speed. We can get to the heart of the program today, which is the discussion of UNITY-NHL UNITY-CLL abstracts and then an open Q&A session. So with us today, we have 3 fantastic physicians. I know that most investors spend a lot of time with academic oncologists. And you won't be disappointed, we've brought out 2 of the finest in the land for you today. But [indiscernible] spectacular panelist, who is the Head of Research for one of the largest community practices in the country. So let me just briefly introduce each of these panelists. So leading us off today with our UNITY-NHL abstract will be Dr. John Pagel. He's a 2019 Seattle metropolitan area top doctor award winner. He is the Chief of Hematological Malignancies at the Swedish Medical Center in Seattle. And like I said, he'll be working -- he'll be talking about the UNITY-NHL abstract. Then not presenting but being available very importantly for the Q&A session will be Dr. Jim Reeves from Florida Cancer Specialists. Dr. Reeves is a Director of Research Operations for Florida Cancer. So Florida Cancer, I could say, the passion has been one of the most supportive and great partners to TG on [indiscernible] Dr. Reeves, critical [ point person ] in that effort. But just to give you a sense of the scope of Florida Cancer Specialists, there are 250 physicians, over 220 nurse practitioners and PAs. They have over 100 locations across Florida. So just think about the scope of that kind of an operation. But the key is, that's what the community is all about. They are actually in your community, you can be treated with great care close to home. And they treat over 16,000 patients a year. So really excited to have Dr. Reeves here. And he personally has been, I think, involved in almost every one of our trials. His team -- he and his team, I think, have recruited 150 to 200 patients into umbralisib and U2 trials. So a wealth of knowledge brought to the table today. And then coming in for us on the UNITY-CLL side, we've got Dr. Alexey Danilov, who is the Professor in Department of Hematology Transplantation and Co-Director of the Toni Stephenson Lymphoma Center at the City of Hope Medical Center. Dr. Danilov is an expert in CLL and other heme malignancies. He'll go through the UNITY-NHL trial. Dr. Danilov, again, like Dr. Reeves and Dr. Pagel, has been involved in a number of our clinical trials and has treated many patients, so again, brings a really nice experience base to the table so great for the Q&A. So with that as the introductions, let me turn the floor over to Dr. Pagel, who will run us through the UNITY-NHL abstract data.

Great. Nice to be with everyone this morning. Thanks, Mike, for the kind introduction. That was probably over generous, but it's nice to be with everyone. I'm in Seattle. So it's early here, but it is a pleasure to be with you. I say it's a pleasure to be with you because it's exciting to present this data. I guess this is maybe the first presentation of this data. Of course, it will be at ASH, and you'll see that. Clearly, we're talking about umbralisib. It's an exciting new addition to a class of drugs that we've had established for quite a long time. But I think what you'll see -- at least I'll certainly express my enthusiasm for this agent as it is advancing the field and providing an agent that we think is really important for patients, with a reduced adverse event profile and, of course, a very high overall response rate in patients with indolent non-Hodgkin lymphomas in the relapsed/refractory setting. So this is the trial and the authors. You can see I'm buried in there somewhere I'm sure, but the point of that is to say that I do have significant experience with this agent and maybe I'll share a little of that as we go. So the next slide, please. It really just sets up quickly the design. I'm not going to go into a lot of detail about this. You know essentially how these things work, but this is a trial of patients with follicular lymphoma, primarily or marginal zone lymphoma, some small lymphocytics in there as well, small lymphocytic lymphoma. You'll see the data broken down for each of the different subgroups. The marginal zone lymphoma patient population, there were 69 patients who had failed at least one prior anti-CD20 antibody therapy. And for the follicular patients and small lymphocytic patients, they had failed 2 prior lines, including an anti-CD20 antibody, obviously, like a rituximab and an alkylating agent, which is, of course, the common approach to how we treat patients in the front line, primarily with follicular lymphoma in the United States. There were 117 follicular lymphoma patients and 22 small lymphocytic lymphoma patients who got umbralisib. It is an oral agent. It's taken once-a-day at 800 milligrams. And the primary endpoint is overall response rate that's assessed by an independent review committee. Of course, that we hope will be -- that will be the data reviewed, I'm sure by agency. And then, of course, you can see some secondary endpoints there listed. The next slide really introduces, I think, the major advance in this space, and that's the safety profile of this agent. Again, I have a lot of experience with all of these drugs in relapsed/refractory with lymphoma, not just, of course, in the PI3 kinase inhibitor space, but with other agents as well. We've always been impressed with the activity of the agents in the PI3 kinase class, but we've also mostly been cautious and limited as everyone, I'm sure, well knows on this call by the immune-mediated adverse event profile. This drug is an advance in that it has a much better tolerable adverse event profile in my opinion, and I think that's supported here by the data. You can see on the left, the most common Grade 3 or greater adverse events. You are going to get a little bit of neutropenia, it's reversible, of course. But very low rates of diarrhea or transaminitis, elevations in ALT or AST in comparison to the other agents. And I think on the right side here is most important, those immune-mediated adverse events of interest that we're definitely on our toes about with PI3 kinase inhibitors, and umbralisib is an advance in that we have low rates, relatively low rates of pneumonitis and colitis. These have kind of been dose-limiting adverse events for patients in this class. And umbralisib's showing us that this data will lead to the ability to treat patients and not have to perhaps discontinue therapy because of these problems that we've seen. And that's shown at the bottom. There were 31 patients who discontinued treatment, but that was about 15% due to an adverse event and relatively low rates of dose reductions as well, less than 10%. And that data is dramatically different than what we see with other PI3 kinase inhibitors -- I'm sorry, idelalisib, duvelisib, in particular, as well as copanlisib, where we've seen discontinuation rates due to adverse events of more than 30% and up to 50% with those agents. So this appears to be a very different profile. And I think, again, going to be a very important opportunity for patients. Next slide tells us and introduces the efficacy of the different subtypes or cohorts of patients in the trial. Looking at the response rate, the response rate is very strong in a heavily treated relapsed/refractory patient population and marginal zone. This is probably the -- about the best overall response rate we've seen with single-agent for that class of drugs, almost 50% response rate. And similarly, 45% -- there's 50% in the small lymphocytic lymphoma patients. The median durations of response, also very important, you can see that it's close to a year in follicular lymphoma space. That's very, very competitive with any other agent we have as a single agent in that space. Smaller numbers of patients with small lymphocytic lymphoma, but does appear to be encouraging with a median of 18 months for duration of response. And notably, the median duration of response in the marginal zone patients hasn't been reached, and it hasn't been reached with a median follow-up that is quite long, and that's the line above. The median follow-up for these patients is over 2 years in all the different cohorts of patients. That's impressive good follow-up, suggesting that these people are likely maintaining on therapy doing very well, maintaining their response for meaningful -- a clinically meaningful period of time. Median -- progression-free survival, also very similar. So the median time to relapse regression or death in the follicular space is 10.6 months. It's a little less than 2 years in the small lymphocytic lymphoma space. And again, with a 20 -- almost 28-month median follow-up in marginal zone lymphoma patients, that median progression-free survival wasn't reached, and the estimated 1-year PFS rate in those marginal zone patients is over 60%. So a patient population that's clearly benefiting, I believe, with a single agent umbralisib, and that's clearly the case as well in the follicular patients, in the small lymphocytic lymphoma patients, where you can see those 1-year estimates between 45% and maybe up to 60% or so. The next slide further just summarizes that data, again, showing that the response rate is on the order of around 50% for the different subgroups. You can see that there are some people having significant complete responses, almost 16% in the marginal zone lymphoma patients. But the point I want to make here really is that it's not just a response rate in this slide, it's really also including what you see in the gray portions of these histograms, and that's the stable disease patients. And I highlight that simply because in clinical practice where I take care of these patients every day, that's a meaningful portion of patients who are still benefiting from therapy. I'll show you that on the next slide further. But note that in a patient population where perhaps we're thinking about palliation, we're understanding that we don't cure these patients. They're older. They have comorbidities. Actually giving them some ability to just control their disease and help keep them happy and healthy and out of the hospital is certainly very valuable. And that's shown really on the waterfall plot on the next slide. I think the waterfall plot is quite impressive and looks excellent, with many patients achieving more than a 50% reduction in their tumor burden for the different histologic subtypes. But again, I want to highlight those patients who have down-going vertical bars that are under the 50% line. We can't call them a partial remission or an [ objective ] response, but clearly, they're benefiting from the therapy. Very few patients in this heavily treated population are actually showing progression. And so the waterfall plot suggests to me that most -- the vast majority of people are truly clinically benefiting from this therapy. The next slide really then just gives you this conclusion. I just will tell you, in my experience, this drug does give meaningful clinical activity in a patient population where we have unmet need. I think the unmet need is clear in TIG kinase inhibitors. I would argue that it's largely, of course, to improve on that safety profile, and we're seeing that here. That's been consistent with my experience and all of the data that's been shown with umbralisib to this point, with low incidence of immune-mediated toxicities and comparatively very low rates of discontinuation due to an adverse event. I will also note that I've used this drug in combinations many times. I have a lot of experience, especially with the U2 combination that Mike did discuss at the top. It's an exciting combination. Actually, just treated somebody with the U2 plus venetoclax combination yesterday, or I should say, earlier this week. So I think for me, this is an exciting drug that we're continuing to deliver to our patients that will have significant benefit. And then I'm not sure who's -- or I'm sorry, I should lastly say if you go back, please do note that this data will be presented by Dr. Pier Luigi Zinzani from Italy, Bologna. He will present that on the 7th of December at the Virtual ASH meeting, kind of how we do it these days. And please look for all of that data. Mike, does this come back to you? Or do we go to Dr. Danilov at this point?

Perfect. I think you did that for me. You transitioned to Dr. Danilov. Thank you, Dr. Pagel. It was really awesome and helpful. Dr. Danilov, it's your floor. Thank you.

Thank you. Can you hear me, folks? Can you hear me?

I don't see -- yes.

All right.

You look good.

Great. Well, first, congratulations to TG Therapeutics on this outstanding data coming up at the upcoming meeting of American Society of Hematology. And I will summarize the data which will be presented regarding the UNITY-CLL trial in patients with chronic lymphocytic leukemia, a large randomized trial, as you will see on the next slide. I do have extensive experience with umbralisib in chronic lymphocytic leukemia as well as its combination with ublituximab. City of Hope, my home institution, we also participate in ULTRA-V clinical trial, which combines U2 combination with the ublitux. So certainly a very exciting agent, very exciting combinations in chronic lymphocytic leukemia with lots of unmet need there despite all the advances. So to describe the trial, 421 treatment naive and relapsed/refractory patients with CLL were randomized to treatment with either U2 combination, which is [indiscernible] and give you the umbralisib plus CD20 antibody, ublituximab. And the second arm, the control arm included obinutuzumab, a CD20 antibody, with chlorambucil. And this is a control arm which has been used in many recent trials in chronic lymphocytic leukemia, including CLL-11, CLL-14, which studied the [ ublitux elevate TDN ], which studied [ like ] ibrutinib. So a very solid, well-justified control arm. The primary endpoint here was progression-free survival. But of course, secondary endpoints included other measures such as overall response rate, duration of response and ultimately, of course, safety. This study enrolled a broad population of patients with CLL representative of the population that we see in the clinic. So that included patients with deletion 17p, which represents between 10% and 30% of patients in previously [indiscernible] relapsed/refractory setting in our clinics. And the certifications were by deletion 17p and treatment status, where the treatment-naive versus relapsed/refractory CLL. And the [ relation centered ] these, of course, the subtype of CLL which is associated with inferior response to therapies. So as you can see, 10% of patients under study had deletion 17p, 56% had [indiscernible], which is also a high-risk factor, at the end, representative of what we see in the clinic. 57% of patients had not had prior therapies and 43% were previously treated. And the median age was 67, which is actually very close to a median age of diagnosis in CLL. So I'd say the study overall represents really well the type of patients with CLL that we see in the clinic. Next slide will show us the safety of U2 combination in comparison with chlorambucil and obinutuzumab. On the left side -- in the left column, you see the different duration of median 23 months with U2 regimen. And that has to do with the fact that in the study on this experimental U2 arm, umbralisib and ublituximab, will continue until progression or the adverse events or the patient had to come off for any other reason. And chlorambucil and obinutuzumab duration is 5 months, and that's consistent with getting 6 cycles of chlorambucil and obinutuzumab, and this is how we do it in this term of care. Discontinuation due to adverse events growth was 16.5% on this [ experimental ] U2 arm. And this is certainly a very, very positive, a very impressive number with PI3K inhibitors in particular, particularly where many patients had previously [indiscernible] disease. As Dr. Pagel had already mentioned, other drugs in this class, such as idelalisib, are associated with up to 50% discontinuation rate due to adverse events in patients with relapsed/refractory CLL, and could be even higher in patients with previously untreated CLL. So this number of 16.5% is [ comparatively ] encouraging. This is also a very good number in context of ibrutinib, where we see discontinuation rate of about 20% on patients enrolled in clinical trials of ibrutinib and up to 40% due to adverse events/discontinuations in the real world setting. So -- and if you look at the toxicities, Grade 3, 4 neutropenia was 30.6%, thrombocytopenia was rare, diarrhea was 12%, infusion-related reaction was 1.9%. And from my experience, they were easily managed. Elevated [indiscernible] function test abnormality is 8%, colitis 3.4% and pneumonitis 2.9%. Again, a very rare occurrence of those autoimmune complications that we watch out for in patients with CLL on PI3K inhibitors in comparison to what we are used to seeing with the [indiscernible] people on [ these ]. The next slide will show us the progression-free survival, which is the efficacy, essentially, of the regimen. So the green line demonstrates PFS of U2 regimen and we see clear, unequivocal separation of curves. The median follow-up here was about 3 years. And a median PFS for U2 regimen and sort of smaller in the table was 32 months, and chlorambucil with obinutuzumab was 18 months. And obviously, this was statistically significant. So again, very encouraging, clearly positive data for the U2 regimen. On the next slide, we'll look at PFS in the subgroups. And basically, this improvement in PFS was consistent in both treatment naive and relapsed/refractory settings. And given naive setting, U2 was associated with PFS of 38 months compared to 26 months with chlorambucil and obinutuzumab, and that's exactly what we expect with chlorambucil and obinutuzumab. So certainly, we see a significant improvement. And in relapsed/refractory setting, the PFS was shorter for both regimens. And that's certainly not unexpected as typically, these patients would have more biologically complex, difficult disease. And all the regimens that we have currently in CLL have slightly lower efficacy in relapsed/refractory disease compared to treatment naive disease. This is also really the first trial which has shown this data for chlorambucil and obinutuzumab in relapsed/refractory disease in patients with CLL. And again, U2 beat that data pretty handily. And on the -- on this next slide, we look at overall response rate. The U2 regimen was associated with 83.3% overall response, significantly higher than chlorambucil with obinutuzumab, 68.7%. And on the right side, this is a very important demonstration, but U2 regimen was also effective from patients previously treated with ibrutinib with an overall response rate of 57%, whereas chlorambucil and obinutuzumab was -- did not perform so well in this setting. Again, it is very difficult to [indiscernible] overall in response rate criteria in CLL, and the reality is more patients benefit than you see with response rates like Dr. Pagel mentioned looking forward with lymphoma stable disease or from all you need to achieve significant clinical benefit in our patients. And on this last slide, I believe, which the conclusions basically summarize that UNITY-CLL is the first randomized Phase III study in CLL of PI3K inhibitor versus human immunotherapy in patients with treatment naive CLL associated with very impressive data, well-tolerated safety profile, particularly in context with what we know about the PI3K inhibitors in CLL, but also in context of other drugs, such as BTK inhibitors. And there is clearly an impressive efficacy with an improvement of PFS versus standard of care immunotherapy in patients with both treatment naive and relapsed/refractory CLL. So this will be presented by John Gribben from the U.K. on December 7 and then [indiscernible] at ASH. Thank you.

Thank you, Dr. Danilov. Appreciate it. Okay. So moving to the Q&A session. And so a big reminder, this slide, everyone can see who we've got on the call. So whoever, I guess, the conference operator is managing the Q&A session, how that will happen. So I'll shut up for 1 second and wait for the questions to come in.

Thank you, sir. [Operator Instructions]. Our first question today comes from Alethia Young of Cantor Fitzgerald.

I appreciate this review of the data, it's very informative and helpful. Maybe a couple for me. One for the physician. I guess I just wanted to get your perspective, especially in the community setting, on how you will think about kind of using UNITY-CLL data set as you see, whether it be in first-line or in later lines of therapy. That's one question. And then two, I just want to get one of your -- or maybe the whole panel's perspective on how to think about what we know about what kind of PI3 kinase CD20 toxicity from maybe the older generation drugs versus how we should look at this with U2 as well? And then maybe this is for the company. I just wanted to kind of think about what -- how you think about what the kind of potential -- peak revenue potential could be across the 3 indications based on now the data set that we're seeing here and the safety profile we have. Thanks.

Sure. So maybe Dr. Reeves, kick us off. I think the question came towards your direction?

Right. Yes. As you've heard, we have a lot of experience in -- here in treating patients in the community. Of course, in Florida here, we've got many older patients, patients who have other comorbidities. And we found both umbralisib in monotherapy and also in the combination with ublituximab to be very, very well tolerated. And I think there really is a differential between this PI3 kinase inhibitor, umbralisib, and the other PI3 kinase inhibitors that have been present up to this time. Depending on how the FDA approves it and in what line of therapy, I think that we'll see our doctors begin to use it. We've already got experience with it. And the first-line versus later lines question has as much to do with the FDA as it does with how we'll use it. But I think in our population, it's very appealing for those patients, particularly who are older, who have comorbidities. Atrial fibrillation is a big problem with the BTK inhibitors. This avoids that. And we're just not seeing the kinds of PI3 kinase toxicities that we've seen with the other drugs. Those drugs, we've done research trials with them too. So thank you.

John or Alexey? Anything further from your perspective as well?

Well, I'll just say a word. Just real quick, Alexey, and then I'll let you --. I think what Dr. Reeves said is true and the proof is kind of in the pudding, so to speak, meaning that patients are staying on umbralisib or the U2 combination therapies for long periods of time with low rates of discontinuation. That really tells you that there is a role for -- in my opinion, a role for this combination, U2, where the community physicians have not been enthusiastic about using these agents just because of those adverse events and the discontinuations due to those adverse events. So we've been seeing. But if you think about the data, really maybe one of the most meaningful pieces of data are the low rates of discontinuation due to an adverse event. And I think the nice thing, too, is that we're seeing that in the combinations as well, not just obviously U2 as a combination, but in combination with venetoclax. So maybe one of the questions was around CLL, and Alexey, since you're the CLL expert here, maybe you'll answer that portion.

Well, yes. Well, I agree with the other doctors. I would say that if you think of front-line setting in CLL, chlorambucil and obinutuzumab, or the obinutuzumab by itself, is still a valued regimen which many of us continue to use. And in -- the other options include BTK inhibitor, ibrutinib. And not every patient is a great candidate for ibrutinib, really. As you know, there is up to 20% rate -- frequency of atrial fibrillation in -- particularly in older patients with CLL treated with ibrutinib there is hypertension, a significant complication, with up to 10% or 11% of major cardiovascular events through hypertension. And then we have venetoclax, which is an effective agent. However, the issue is tumor lysis syndrome monitoring, which requires frequent visit and visits. And there are certainly risks associated with that and some inconvenience. So there is a very clear niche for the U2 regimen in patients with CLL, many of whom are older and have comorbidities, which give us a pause in terms of using some of the other drugs that I mentioned. The other great thing about umbralisib is really lack of drug-drug interactions. It seems to be the case that up to 23% to 30% of all investments in oncology, if not more, are related to drug-drug interactions. And umbralisib does not interact with other drugs overall. So that's a really good thing. And in terms of relapsed/refractory setting, the field is really changing, where in the past, we lead with chemo-immunotherapy era, where most of our relapsed patients have progressed after bendamustine or [indiscernible] or some other sort of chemo-immunotherapy. In this current era, the relapsed patients are those who progressed after, say, venetoclax combinations or BTK inhibitors. And believe it or not, there has become rapidly an unmet medical need where options are becoming -- are quite limited. So there is a very clear role for U2 combination in relapsed/refractory CLL as well, say, after patients progress on venetoclax CD20 antibody combination. I absolutely could see use of those agents, as well as you have seen efficacy in patients who have received prior BTK inhibitors, whether they were intolerant or whether they experienced progression. Again, there is a clear role there as well.

Thanks. Thanks to all. So Alethia, just to answer your question quickly because I don't want to take time away from other questions to the physicians. But from a company side, obviously, we believe that the data is absolutely supportive of everything that we're trying to accomplish for patients, which is provide a treatment option that can replace, for those who are not good candidates for BTK, so something to sit alongside for those patients who are not good candidates for BTK and also to come after BTKs and venetoclax. And that's what we feel is sort of the current unmet medical need, and then the future is part of this triple therapy combination expansion where we see U2 later being used in combination with U2 plus venetoclax and U2 plus BTK. So to us, the data absolutely is on target and supports all of that. In terms of peak revenue sales, we save that for another time. We obviously are excited about the data and what we can do for patients.

The next question is from Josh Schimmer of Evercore ISI.

Congrats on the data. I guess a question for anyone who may be able to address it. First, the waterfall plot showing the patients with progression in UNITY-NHL. Is there any reason to think that there may be a pseudo progression phenomenon going on, like we see with checkpoint inhibitors? And then a second question for the specialists who addressed Alethia's question about utilization of umbra or the U2 combination practice. I guess in theory, and what we're seeing is that umbra can be added on to many regimens, including a venetoclax or a BTK inhibitor regimen. So if you think a little bit more forward as the data evolves, given the fact that umbra could be added across the board frontline in relapsed/refractory, who would you see as not candidates to have that addition? Who are -- which patients are very well served by the current treatment options that you wouldn't consider umbralisib add-on down the road?

Why don't we do the last question first, and then we'll go to the waterfall plot. So we won't forget the last question. I remember the first one now. Pull that aside. Go ahead, folks.

I'm sorry, Mike, you talk about the -- yes, the last question. Go ahead, Alexey.

I guess from -- I will talk from the perspective of CLL. The problem with, say, some of the regimens that we currently use is lifelong therapy, and we are trying to get to time-limited regimens and achieve responses and potentially cure M-CLL. And you're right. So umbralisib lends itself really well to combinations, again, but because of lack of significant drug/drug interactions and [indiscernible] toxicities without either BTK inhibitors or venetoclax. So I struggle to -- if you are thinking of deepening responses and designing new regimens, which say, will stop after 2 years or 3 years or what have you or we could -- or detail them based on the length of the regimen, will be tailored based on the depth of response, I really struggle to think of a patient who wouldn't be a good candidate for something like that. I'd say all patients will be great candidate for a combination which achieves deeper responses.

I guess I'd just like to add that, again, here in South Florida, we do see some patients who simply by age or comorbidity might not be good candidates for a combination of U2 plus venetoclax or U2 plus a BTK, but still may benefit a lot from monotherapy with umbralisib. So I can kind of envision that, but I agree completely, and we're very excited about the combinations with U2 plus other drugs to come forward. I think we'll see continued improvement in this disease.

And I would argue that the difficulty is not using U2, the difficulty is adding BTK inhibitors now, if patients is on anticoagulation or have fully-controlled a-fib or hypertension, yes. But that's the problem with BTK inhibitor, not U2 really. So it's the other way around.

Maybe I'll address the -- yes, maybe I'll address the first question if -- then -- which was the waterfall plot in the UNITY-NHL. And the question, I think, was around pseudo progression as a possibility for those progressors. I think that's highly unlikely. It has been described, I think, a couple of times with PI3 kinase inhibitors, but it's generally not something we see with PI3 kinase inhibitors. And in fact, here, I can pretty much assure you that that's probably not the case, given the length of follow-up that we see with these patients. Pseudo progressions, if it's going to happen, it was going to happen right away early, usually with the first dose of any agent like a PD-1 inhibitor, as you mentioned. Here we've got longer follow-up, and we have objective measurements that really are calling those as true progression. So I think that's -- these are not pseudo progressions, most assuredly.

The next question is from Mayank Mamtani of B. Riley Securities.

And again, appreciate this comprehensive review. So my first question for Dr. Danilov, could you speak to how the chemoimmunotherapy arm performed in context of what you may have seen from other studies? And I'm thinking chronologically, that number has been evolving. So could you just comment on what you may have expected and how that has come through here for both first-line and relapsed setting?

Yes. So for the first-line therapy for the first-line regimen, chlorambucil and obinutuzumab performed almost exactly like it performed in CLL-11 study. I believe in that study, PFS was also on the order of 26, 28 months. So it really -- it's basically exactly what we expected. In the last refractory setting, if you look at regimens like bendamustine, rituximab, you would expect a PFS of actually 13, 14 months across multiple studies that has been shown. So again, I'd say obinutuzumab and chlorambucil maybe even overperformed a little bit compared to what I expected. But I'd say that overall, both -- in both settings, it's overall as expected. So it's a very solid control arm in both settings.

Great. And maybe staying with you, Dr. Danilov. So as you think about triplet regimens and you sort of try to figure out how to go first-line and obviously, you have the option with ibrutinib and venetoclax. So what are the things you want to see going forward in the next study that will help us get to that finite regimen that you're talking about? Again, I understand also looking at the liability is the consideration with the BTK that we have, which is dose escalating.

Yes. So I really do like the design of the ULTRA-V study, which is in combination with venetoclax in an effort to achieve these responses. So at this point, this is, I believe, a single-arm study, meaning that there is not a competitor arm right now. But I think that's a great start, both on patients with previously untreated and relapsed/refractory CLL where we [indiscernible] regimen could be used.

Yes. Maybe I can just say a word around that. Just as further to say, the advance in the front line in CLL, as Alexey just mentioned, is to get to time immunotherapy. But it's not even just that where you can stop treatment, which patients like, but it's actually to keep them off of treatment for as long as possible. So we'll see what the data ends up showing over time, but I highly have a strong suspicion that we'll see an advance there with the addition of venetoclax in the U2 combination. That's going to take some time. But clearly, that's our big goal there.

Great. And maybe on the FL and [ NDL ], as you know, you think about the full approval study there. How are you thinking about the -- as you try to move earlier lines? Like what sort of comparator arms that you're considering as you think of designing the full approval Phase III study?

Mike, do you want to mention? I mean I don't want to step on the company there.

Yes. We haven't given out full details yet, but obviously, it's going to be a randomized trial of U2 plus ven versus a control arm. I think we haven't made a final decision. We haven't disclosed too much, but my guess is that the control arm will likely be U2 as well.

For [ NFL ] and [ NDL ]?

No, for CLL.

What about FL and [ NDL ]?

So in terms of -- for the follow-on to the UNITY-NHL cell trials? Yes, so the confirmation trial we have not discussed yet publicly, but that will come out at some point.

Okay. Great. Final question, maybe for you, Mike. As you think about the incremental what efficacy and also safety for rituximab on top of [ umbralisib ], how should we think about -- again, I know it's a oncology-focused conference call, but obviously, the MS [indiscernible] is extremely critical. Anything you learned at the conference about the safety of ublituximab that gives you confidence going into the IPEMED study readout before the end of the year.

I don't think so. I mean I think in terms of the safety profile of ublituximab in our oncology studies, that would translate into something for MS, is that what -- you lost me there, I'm sorry.