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

Greetings, and welcome to the TG Therapeutics Update Conference Call. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Jenna Bosco. Please go ahead, ma'am.

Good morning, and thank you all for joining us today to discuss the positive topline results from the UNITY-CLL Phase III trial. I'm Jenna Bosco, TG's Senior Vice President of Corporate Communications, and I welcome you to our conference call today. Following our safe harbor statement, Michael Weiss, the company's Executive Chairman and Chief Executive Officer, will review the topline results from the UNITY trial, and then turn the call over to Dr. Javier Pinilla, the Lymphoma Section Head and Director of Immunotherapy at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and one of our leading enrollers in the UNITY-CLL trial, who will reflect on today's outcome and provide an overview of his experience with the UNITY-CLL trial. Before we begin, I would like to remind everyone that various remarks that we make about our future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. TG cautions that these forward-looking statements are subject to risks and uncertainties that may cause our actual results to differ materially from those indicated. Factors that may affect TG Therapeutics' operations include various risk factors and uncertainties that can be found in our SEC filings. This conference call is being recorded for audio rebroadcast on TG's website, www.tgtherapeutics.com, where it will be available for the next 30 days. All participants on this call will be on a listen-only mode. Now I would like to turn the call over to Mike Weiss, our Executive Chairman and CEO.

Thank you, Jenna, and thanks, everyone, for joining us this morning. We apologize again for the delay getting in. There is apparently a lot of traffic trying to get into the call, which is obviously good news. Obviously, today is an extremely exciting day for us at TG, one we've been waiting for a very, very long time. We are thrilled to announce that the UNITY-CLL Phase III trial evaluating the U2 combination of umbralisib and ublituximab, referred to as U2, met the primary endpoint of improvement in IRC-assessed progression-free survival, or PFS, at the interim analysis. Based on the recommendation of the trial's independent Data Safety and Monitoring Board, DSMB, the study will be stopped early due to the superior efficacy observed. Also, as you may recall, the trial enrolled approximately 60% previously untreated or treatment-naive patients, and approximately 40% who were relapsed or refracted from prior therapy. And we are pleased also to report that the PFS benefit was observed across both patient populations. Interestingly, this marks the first time a PI3K delta-based regimen has successfully met its primary endpoint in a CLL Phase III study that included previously untreated patients. We believe this speaks to the differentiation of umbralisib. I want to thank a number of folks. First, I would like to thank Dr. John Gribben, our UNITY-CLL Study Chair, as well as the patients, their families, the doctors and their research teams who participated in this important study. And of course, the incredible team at TG, who helped to get us to this exciting and pivotal moment. As a reminder, the UNITY-CLL trial is a global randomized Phase III study, evaluating the combination of umbralisib, our PI3K-delta and CK1-epsilon inhibitor, and ublituximab, our glycoengineered anti-CD20 monoclonal antibody, compared to the combination of the chemotherapy chlorambucil plus the anti-CD20 monoclonal antibody obinutuzumab, and is being conducted pursuant to a special protocol assessment with the FDA. And of course, this preplanned interim analysis was under the SPA. Additionally, the U2 combination was granted orphan drug designation by the FDA for the treatment of patients with chronic lymphocytic leukemia. In terms of regulatory submission for the U2 combination for the treatment of CLL based on this data, we will be targeting the submission around the end of this year. Let me also note that although full safety data from the study is not yet available, as we have said previously, we have been encouraged with the outcome of numerous DSMB meetings over the course of the study, all of which have recommended the study continue without modification, the most recent occurring in April of this year, with approach presenting the entirety of the study at a major medical meeting, ideally, before the end of this year. Since our founding, we've been highly focused on developing combination regimens for patients with B-cell cancers, and we are incredibly excited to be one step closer to our first regulatory submission for the U2 combination. The U2 regimen in this study have been the cornerstone of our vision for many years, and we are thrilled to be able to announce the positive results today. We believe the treatment advances in the CLL landscape over the past several years have been incredible. However, many patients still do not tolerate or respond to existing therapies and CLL remains incurable. Patients remain in need of alternative treatment options that are tolerable, effective and easy to use, and we believe U2 has the potential to play an important role in the evolving CLL landscape, in which approximately 30,000 to 40,000 individuals will be looking for a new treatment option for their CLL every year in the U.S. alone. And as excited as we are today, we will continue to build upon our combination-based regimens and firmly believe the U2 backbone will be a critical foundation as we march towards triple and possibly quad combination therapies within our pipeline, as well as with approved agents, with the goal of developing the best possible treatment option for patients with CLL and other B-cell cancers. With that, we are extremely excited to have Dr. Javier Pinilla with us today, who is the Lymphoma Section Head and Director of Immunotherapy at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. Dr. Pinilla was one of our leading enrollers in the UNITY-CLL study, and he'll reflect on today's outcome and provide a little more perspective on U2's potential use in the current CLL landscape. Dr. Pinilla, thank you for joining us today.

Thank you, Mike. I'm happy to join this call, and I'm extremely pleased with the positive results shared today. I will keep my remarks relatively brief as I know there will be a lot of questions to get through. But I want to share my perspective on today's results. By way of background, I have been practicing in hematology oncology for more than 20 years, and I have participated in over more than 30 clinical trials. At the Moffitt Cancer Center, we see the third largest number of cancer patients per year in the United States. I have personally participated in CLL trials that led to the approval to several drugs in CLL, including ibrutinib, acalabrutinib and venetoclax. Additionally, it's worth noting that I run a large laboratory as well, focused on epigenetics of B-cells immunoregulation, and importantly, the role of the B-cell receptor inhibitors as the one that we are discussing today in the T-cell immune response or the effect in the T-cell immune response. I was excited to be part of the UNITY-CLL trial and to be able to treat my patients with a U2 combination. After review of the early data presented by TG, I always have been particularly interested in exploring the differentiation of umbralisib in my lab and investigating the unique inhibition of CK1-epsilon and its effects on the T-cell compartment. I wanted to better understand what differentiates umbralisib with the PI3K-delta class. This result was extremely exciting and has contributed to my understanding of the umbralisib as a unique delta inhibitor. And we are currently in the process of publishing the research very, very soon, hopefully, in the next month. Based on my lab and clinical experience with umbralisib and the U2 combination, I feel confident that umbralisib is a differentiated PI3K-delta. A question I get often is where would a regimen like U2, if approved and available as an option, fit into the treatment sequence of CLL. As Mike said before, first of all, I want to highlight that patients are always in need of additional treatment options, and most patients eventually progress, relapse or become intolerant to the current therapies we are dealing with incurable disease. If approved, there are a number of settings, where I think the combination could be an important option for CLL patients. For example, those patients who appear to be poor candidates to BTK therapies because many, many reasons that could happen, including those with certain preexisting conditions or have otherwise cell BTK therapy for toxicity or relapse. Also, many patients have comorbidities of high tumor burden, which may limit the use of certain available treatment options in the community settings where currently approximately 70% to 80% of CLL patients are treated. And this could be another important place for this combination. And as for more physicians use the U2 in the settings and to the extent they have a positive experience as I have in the UNITY-CLL, I would expect broad use beyond these examples that I mentioned. Let's keep in mind that there are over 20 new cases of CLL diagnosed this year in the U.S., with nearly the same number of patients or even more relapsing this year, and there remain a substantial amendment for those. If approved, I believe U2 will be available treatment option in the CLL landscape. The last thing I will note is that I'm excited about TG commitment to exploring combination built on the U2 backbone. TG has done a nice job developing data on the safety and activity of U2 in combination with a number of other agents also could potentially be using CLL. I'm looking forward to seeing additional data from ongoing studies, evaluating patients seeking time-limited therapy, something very, very important in the future, including the ULTRA-V trial of U2 on top of venetoclax, which I'm currently actively enrolling patients on. With that, I'll turn the call to Mike and look forward to participating in the Q&A session. Thank you.

Great. Thanks again, Dr. Pinilla, for joining us. That's great. And thanks again for hanging on for some Q&A, which will begin shortly. Before we jump into the Q&A, just given the pending UNITY-NHL submission completion and of course, the positive UNITY-CLL results announced today, I wanted to close my prepared remarks with just a few words on our ongoing commercial readiness efforts. Under the leadership of our Chief Commercial Officer, Adam Waldman, we have been able to build a stellar commercial team, with key hires across marketing, market access, legal compliance, many of whom have deep experience with commercializing billion-dollar products in hematology. Our small company is quickly evolving into a fully integrated commercial organization with an infrastructure to manage multiple launches both in the hematology side, but also on the MS side. And I'm extremely proud and awed by the strides we have made already. I want to again thank and congratulate the team at TG for everyone's hard work and dedication over the years. And with that, let's kick off the Q&A session, following which I will return to recap the upcoming milestones for the remainder of 2020. Operator?

[Operator Instructions] The first question is from Alethia Young, Cantor Fitzgerald.

So I do have a couple. So from our Zoom chat, we talked about kind of hazard ratio and how to think about that, a possible range of 0.3 to 0.7. We got the p-value at the [ crude date ], and I just wanted you to kind of help me think about because obviously, I'm not good at that. Should we think about that hazard ratio being kind of in that mid to lower range of that, is the first question. The second question is for Dr. Pinilla, and maybe also you guys might want to chime in. But I was just curious based on his own experience on the safety events like colitis and the bowel stuff or the inflammation, did he feel like or see there was any kind of differentiation? I know the control of study is blinded, but just like what kind of feel he got there. How or what color you guys can provide? Because I do think, so far, it looks differentiated, and that's important. And then my third question, I guess, is when you look at the data, especially on the anti-CD20 front and the MS coming out with second half of the year data potentially, does that increase your confidence there that basically these molecules continue to behave as you kind of expect them to behave? And should we make a read there on that?

Yes. So I'll go first on the hazard ratio. Again, we haven't given, obviously, any guidance on the PR exactly as the hazard ratio. We've put in the p as well -- we've put in a p-value for which -- that the study came out lower then, but we didn't actually provide any further guidance. The third question, Alethia, you lost me a little bit. Can you just restate that? And then we'll have Javier...

Do you think that the data that -- with the activity of the CD20 seen here in combination gives you confidence in heading into an MS readout later in the year?

Yes. I mean, obviously, we're confident in the MS readout regardless. I mean, it's hard to really know -- hard for me to extrapolate from this experience where you have the combination in CLL patients. I mean, we know that it's an active anti-CD20 monoclonal, but it's super potent. And we are highly confident. I mean, I think I've said that we were -- I was -- the 2 things I've been most confident about in this company that we'd be successful on the UNITY-CLL PFS. In fact, for those of you who remember, I said that if we weren't successful, I'd have to leave biotech. So I'm kind of happy I don't have to leave biotech right now. So I'm pretty happy about that. And we are obviously extremely confident with the MS and the likelihood for a positive outcome there. Javier, do you want to talk about -- answer the question or address the question that Alethia was asking?

Sure. Sure. Absolutely. More than glad. So for sure, we really believe, based on the experience that I have with the drug that is a completely different PI3K-delta for the one that we have in the market currently. I mean going back to the data, to the 2 current PI3K-delta that obviously show activity, I think the main downside, as you guys mentioned, Alethia, is this [ AE ] events that really, really comes from the true understanding of this immunological events, very similar to happen with this famous PD-1 inhibitors of immuno checkpoint antibodies. So we are really making the body react against patients, right, or against themselves with this form of colitis and hepatitis and pneumonitis. So this drug, and this is the reason that part of my research in the lab is a completely different story, thanks to the CK1-epsilon activity, which really compensate the deleterious effects on these T-cells that they are responsible for these problems, right? So -- and I think the key message here besides this very interesting laboratory finding is the story that those patients can continue on the drug for a very long period of time, something that is not being reproduced in or seen with currently other PI3K-delta inhibitors that although initially successful in terms of responses, that they are trying to really be discontinued because of these side effects, right? So I think I truly believe, or at least in my experience and the experience of many of my colleagues, we see a complete differentiation safety profile, which allow patients to be continuous on the drug for a long period of time, and at the same time, thanks to -- to be on the drug, to be -- live free of progression, right? So I think that's something that, hopefully, with more data that will be released and the one that we preliminarily have seen the Phase Is and an early experience in the Phase IIs, this will be confirmed in more rigorously way in future information.

The next question is from Matt Kaplan from Ladenburg.

Congrats on the positive topline results.

Thanks, Matt.

Mike, can you walk us through kind of the -- now that you have the positive topline results from the interim look, the next steps for UNITY-CLL study in terms of the more detailed data and full picture of both safety and efficacy from the study. Walk us through that.

Yes. Probably a pretty short walk. We'll get the data put together as soon as possible. And I think our first opportunity to present, hopefully, it will be a live presentation would be at ASH at the end of the year. That would be the goal at this point. But yes, we just got to get the data to you. I mean, remember, this is an interim analysis. The company was completely blinded until late last night, and then we just got a very small piece of data because they only looked at -- there was a hurdle of which they needed to cross in terms of the p-value. And so there was very limited data that was even given to the DSMB in terms of the efficacy pieces. So there's still -- we haven't done a safety analysis. We haven't looked at any of the other secondary endpoints. So there's plenty of work to be done to get the study to presentation format. But obviously, the hurdle was the key here. We needed to meet that hurdle, and we did, and exceeded it for sure.

Great. Great. And then in terms of can you elaborate more on the DSMB safety looks? You mentioned that there was one just as recently as last month in terms of what they share and what they see and what they are analyzing there.

Yes. I mean, they -- I've never seen what they get. I'm blinded to all that information, I'm still blinded to it. But they get -- my understanding is they get a pretty full detailed safety assessment of the drug, AE tables, SAE tables, all that kind of data, I believe, is what they're seeing. So again, we don't know -- we can't be sure of, obviously, the incident rate of individual AEs, but we have to assume that there is no individual AE that was at a rate that was alarming for them to have made any changes across the trial. I mean, they've had access to 600 patients worth of data, I think, over 300 patients, of which were patients on umbralisib. I can't remember exactly close to that many number of patients in the frontline. So there's a lot of data that they have been seeing. Again, we just -- we can't -- we don't know what the precise numbers are. But again, we've always had the belief that they can't be seeing any individual or constellation of toxicities that would give them pause, for instance, to be treating frontline patients, whereas we know that one of the other PI3K results that the label specifically says not to be used in frontline patients. So again, we are gleaning the information from these interactions the way I assume that investors are as well. We have access to the complete profile of umbralisib single agent in lymphomas. And to -- I think, on average, folks would expect that the profiles would be somewhat similar. You wouldn't expect any dramatic differences in the profile between CLL and NHL. In fact, some have argued that perhaps the -- there are more toxicities in the indolent lymphomas than you would see in CLL patients. Again, not having seen any of our CLL data, I can't really speak to that now, but I can speak to -- that the profile that we're seeing in the compilation of our safety, we're building our integrated safety summary. The compilation of the safety database that we're building is consistent with the -- what's been historically presented, at least through the NHL, which includes, I think, that databases, the ISS database that will go to the FDA is somewhere between 500 or 600 patients. So we feel pretty good about, obviously, what the profile looks like. And again, it's, to our eyes, it's consistent with what we presented previously. And so we have to assume for the moment that there's no reason to believe that the CLL should look different.

Okay. And then just if Dr. Pinilla is still on the line, a quick question for him. In terms of -- given his experience with U2 and the UNITY-CLL study, how is he currently planning to incorporate U2 into his practice if it's approved and available?

Sure. I think I was really making some examples of why or where we can really use the combination. For sure, I mean there is other drug that have been used in combination. But I think this will be truly one that has a very long data or will have, hopefully, long data about the combination. So there is no doubt that the older population is well-fit for these kind of drugs, and definitely, we still are in the philosophy that treatment until progression, which is, in the future, very likely will start to shift after -- with time-limited therapy with further data and further combination. But for now, I think it's a very attractive combination for patients in the older population. Very likely with comorbid conditions that also is what really, really addressed somewhat the trial, mainly because the combination was always historically tested in this kind of population. So those patients that we are really targeting with this combination may have multitude of problems in terms of comorbid conditions. And definitely, for sure, people with cardiac, hypertension, even DDI with a need of PPI, they are really, really a good alternative for the ones, but also can even compete with the current ones. Obviously, we want to really have a more granulation on the safety profile. But as mentioned, in my experience, all the patients that I really enrolled on the trial are still on, and they have been -- really been there for quite a while with great durability and good response, right? So in my opinion, there will be another kind of tool and another really drug that we're going to really discuss with the patients as we discuss all the time. We have -- we are very lucky to have several options to the patient, and now more and more we try to customize with patients depending on comorbid conditions, depending on goals, depending on many, many things, which drug could be more efficacious, at least, which drug will fit better in the profile of each individual CLL patient that come to our clinics.

Next question is from Chris Howerton, Jefferies.

And I'll also offer my congratulations. So a great, great news.

Thanks, Chris.

So for the -- I think one of the things that's popped up for us in terms of some of the discussions that we've had with physicians has been that, historically, this class has been viewed as toxic and unsafe. And obviously, we have had a bit of that discussion so far today. But from an outreach and education perspective, how do you expect to tackle that? And I guess, Dr. Pinilla, I'd be interested to see what your perspective is with respect to the rest of your colleagues and how they see this class and how we could convince them that perhaps this is an effective and safe therapy?

I mean, Mike, I can go ahead, right? I mean there is no doubt...

Yes, please. Yes.

Maybe it's a lot of education because as you mentioned, there is a myth around PI3K-delta and around the toxicity. The introduction or the penetration of these drugs in the market is quite low, right? I can really say for -- obviously, I can talk about me and about any of my colleagues who have really used this drug, that we all agree that it's a completely different story, as I mentioned before, right? So as happened in many of the drugs, I think it's very, very important to have a first-hand experience with a drug to really, really feel how different it is from previous drug. And this is a historical event that happened with other drugs in the market, right? People that really read some box warnings or there is something and they are really afraid. I think in this case, the advantage is we have a very, very important rationale or really, really deep rationale about why this drug is different. And I think it's a fundamental part of the story, right? Because we know PI3K-deltas that they are commonly available, delta or gamma/delta, they are very, very well studied in the immunological models. And we know why it happened when you really suppress this, what we call Tregs. But it's kind of complicated to go on to really explain the whole story. But the brief and the simple things that this dual inhibition between delta and CK1-epsilon really, really is the difference why we don't really see the same toxicity on the single delta. And I think it's something we have been reported in that platform. And hopefully, in the next month or 2, we believe that finally will be publication that will really explain in more detail this particular thing. How we can translate this in education? Well, it is a matter of really, really outreach out there and community practice and really have a good understanding and good really educational programs about why the difference. And I think it's something that, in my opinion, relatively easy, can be done by TG in the near future.

Yes. I'll just -- thank you, Javier. I'll just add that as we talk about and think about the community, the one thing that we did differently in this trial than any of the other larger studies is we had a very large participation from community-based oncologists in the U.S. In fact, this trial is the only trial that had over 50% participation by U.S. oncologists. And in the U.S., probably the majority of that was community-based enrollment. So we have a good group of clinicians who have used the drug in the community in the U.S., and we plan to leverage those positive, hopefully, positive experiences and expand from there. So I think we have a good starting point. We've got a great team in place. And as Dr. Pinilla mentioned, it's -- people who have used it, for the most part, have had a very good experience. And good experience is how we're going to be able to get people interested in using this compound -- this combination.

Great. Excellent. Okay, that makes sense. And I guess, as a follow-on to that, clearly, there's an opportunity for umbralisib with respect to marginal zone and follicular lymphoma maybe to do a bit of a preview for some of these same physicians. So I guess I'd be interested to hear how you think that could potentially pave the way or not for this combination in CLL.

Yes. So it is in the community. It is, for the most part, the same physicians who will be treating a marginal zone or follicular patient will be treating a CLL patient. So getting them comfortable in using the drug in marginal or follicular in anticipation of the CLL is, to us, we've always felt it's the perfect buildup into the CLL launch. So all of our efforts for marginal or follicular are not separate there. They're basically within the same office, same exact physician. And again, our goal is to get people to try it, have a good experience and there's no better way to get people excited. You can tell them how great things are, and you can explain to them how different they are, but hands-on experience, there's no replacement. So yes, our efforts out there with our team in marginal or follicular is the same folks that we will be talking to when the CLL label is available. Javier, any thoughts on that point?

No, I think you are right. Definitely it is going to help, hopefully, we have a pre, really, approval, hopefully, in the future of the drug and introducing in a low-grade lymphoma, that is the area, which I hope, we're going to see the drug solidify, right? So I think, as I said before, I think the main thing is that the use of this drug in the real life. And I think first experience of the drug, I mean, most likely it's going to be good. And this will really drive community physicians to really use these kind of drugs in the future, right? A good experience and really good durability and good efficacy on patients, right? I think it is a fundamental part.

Absolutely. Okay. And then maybe just a last one, if I may. So obviously, one of the interesting dynamics here would be the idea of a PI3K inhibitor versus something like a BCL2 inhibitor and the applicability or feasibility of those 2 treatment strategies within the community setting. So what, Dr. Pinilla, from your perspective, how do you see BCL2 inhibitors working in the community setting? And do you see an opportunity for them to widen their use? Or will it remain limited in your view?

I think the feel, as you know, is evolving, and there is no doubt that the BCL2 inhibitor is a very, very important new drug that is coming to our hands. And we are really using that, right? I mean, definitely, we are using combination and we are learning how to use this with the 2 main mechanism of action of the drug that we have, a BCL2 inhibitors and BCR inhibitors, B-cell receptor inhibitors. So many people, they see this contradictory. So I use one or I use another one. And this is the reality today, right? We use anti-progression with BCR inhibitors or time-limited therapy in the BCL2. I think the feel is going to evolve. And I think, number one, we're going to start to combine. We have already data with BCR inhibitors plus BCL2. We know they are really, really effective, and they will be combined. We mentioned that we are really testing the ULTRA-V, the U2 plus venetoclax. But I think the fundamental question at the end of the day is, which patients can be offered time-limited therapy and which patients can or should be on therapy for long or, at least, until progression. And this really coming back to the biology of each patient. And then once again, to the customization and that every patient is different. I mean, definitely, very -- I mean, CLL, we know that they come from very indolent to more aggressive. And the ones that are aggressive, they cannot really be without therapy. While the one they are very, very indolent, they can't really have repeated therapy in after a while. So I think this one, once again, is going to evolve over the next years which patients can be fit to really get limited therapy that, for sure, will include a BCL2 inhibitor, right, versus the one who really need to really have long-term therapy with anti-proliferative drugs such as BCR inhibitors, and this is what we are discussing today. So I think it's a little more complex, but you are right that today, long-term therapy versus fixed therapy, I think these things are going to really come together. But at the same time, they are going to be very, very dependent of the biology of each individual patient that come to the clinic, they get therapy, they relapse, so on and so forth.

Excellent. Okay. That makes sense. And it's great that you will have all those options to be able to do that. So excellent.

We have a question from Mayank Mamtani, Riley FBR.

Congrats, team, on the strong data. I have 3 questions, 2 on efficacy, maybe for Mike. Just on the process side, Mike, can you remind us, this is the prespecified analysis with the lower number of events as I think you discussed. Or these were some of the scans that you had in bolus given a lot of patients that enrolled towards the tail of the study. Could you just remind us from a process standpoint?

In terms of process for this interim, the events -- I'm sorry, Mayank, [ so what was the question ]?

Yes, the number of events. I know you're probably not -- can't quantify, but just curious, qualitatively. Obviously, it's encouraging for you to put out the p-value. I didn't see that in the press releases for other companies. But just curious any qualitative color you could give on the event number or patient split between first-line and relapsed/refractory or ORR? Any of those details?

Yes. We just don't have a lot of data at this point. So I can't really -- I can't share much because I just don't have much to share. But I mean, just in terms of the interim analysis and the way it was designed, obviously, it was, as you noted, it was less than the original number of events that we were predicting, was quite a bit lower than the original events to do this interim analysis. And yes, I mean, we were confident. When we were on the call in March, we were confident that we'd get the events because we knew we were extremely close to having the events required for the interim analysis at the time of that call, and we knew we had 1 or 2 months of scans sitting, waiting to be read. And typically, we always picked up 1 or 2 or 3 of those. So that would have put us in good shape for the interim. So yes, I mean, I think we did talk about that obviously there's a higher hurdle than obviously would have been expected for the final analysis. So I mean, I think it's easy to -- it should be easy to interpret that we are obviously pleased, what you've said, with the outcome. Not only did we get out of it, but I think we performed even better than expected.

Great. And just on median follow-up, obviously, with the April meeting that you had on DSMB. Can you just remind us how long on a median basis and from the last patient and patients have gone in the study? And maybe also an update on the MZL/FL study?

Yes. I apologize. I haven't mentally updated those median follow-up in last patient. But the last patient came in October of '17. So where does that put us exactly? I think you can do the calculation probably faster than me at this moment. But -- and the median is about 4 months longer than that. So that will give you some sense. But yes, I'm pretty sure we're plus 30 months probably for a total follow-up and close to 34 months of median or within that range. So really -- I mean, I think it's a robust follow-up period. I think we've had plenty of maturing of the trial. Certainly, the relapsed patient population, that's an incredibly long follow-up for a trial in relapsed patients and a very strong level of follow-up equivalent to probably just a little bit longer than the follow-up that was seen in ILLUMINATE, ELEVATE and I think even CLL-14. So I think we've got a good robust follow-up on the frontline patients as well. In terms of follicular or marginal zone, we continue to be extremely excited about that filing or that submission. We're hoping to complete that submission by the end of this quarter. And so far, I have no indication that we won't get that done. And fingers crossed, it's possible that we have Breakthrough Therapy Designation, and the FDA has been quite impressive in those turnaround times for those kinds of applications. So fingers crossed. If we get lucky, we could be approved for follicular and marginal before the end of the year. But hopefully, at least by the PDUFA date, which would assume -- presumably be in the early part of next year.

Great. And to just clarify all the detail on the -- even the lymphoma studies, including ORR and follow-up duration of response will also be at ASH. We you have to wait until ASH for that. Is that right?

Yes. We would like to present all that data at ASH. We hope there will be -- hopefully, there will be an ASH. Hopefully, there will be -- in-person ASH would be great. But yes, I think the goal would be to present the follicular and marginal zone data at ASH as well.

Great. And just one -- I think most of -- this question is answered by Dr. Javier, but I was just curious, this publication in a month's time that you are talking about, elucidating the effect of CK1-epsilon in the context of umbra's mechanism. Could you maybe talk about as you think about triplets and quads? And also, I think people think about cell therapy also in the context of attaining finite duration curative regimens. Can you just talk to mechanistically what we could learn in that paper, Dr. Javier?

Sure. Sure. There is no doubt that the paper will give you more details. But there is no doubt that the down-regulation of the PI3K-delta has a profound impact in Tregs, but, as you know, at the same time, can have really other impacts in other kind of immunotherapies. But at the same time, could be toxic, as we have seen with PI3K-delta. CK1-epsilon at least in our hands, it's been shown that increase on what the Tregs would compensate this mechanism. At the same time, there is a story that is still developing about the role in general of the PI3K-delta. And also, more importantly, in combination with CK1 and another important population is called PA-17, that is very, very fashioned in T-cells adoptive therapies and is something that we are actively also looking forward because if you're thinking that Tregs may somewhat be also increased by CK1-epsilon, there is a possibility that those population is what we call memory PA-17 population could also be expanding in patients treated with these drugs. And this could be in the near future some advantage for a future adoptive T-cell therapy. Something that is still in the works, something that has been published in the literature in somewhat with other combinations, but it's something that we're really actively looking forward to really dive deep on these possible mechanisms. And this comes, obviously, to your question, final question, is should we do once again long-term therapy versus time-limited therapy? And I think I will really reiterate what I say before, I think it's going to be very much dependent on the population that we are dealing with and then how aggressive, how genetically each patient, I mean, 17p, we know that even with venetoclax, they are not really do well, once we stop it versus another population of patients that may do very well for a long period of time. So at the end of the day, we're still looking for the cure, and I think the cure maybe in several combination of these drugs, maybe in addition with these new adopted T-cell therapies that may hopefully produce time-limited therapy, but also long PFS, including for T-cells cure in the long run.

Great. Mike, can I squeeze one more in? Can you talk to your EU strategy? I just got this EU strategy for filing for CLL. Could you just talk to that?

Yes. I mean we're going to sit with the team and get a plan going for an EU filing as well. We believe the data should be supportive of an EU regulatory submission. PFS endpoint seems to be a pretty reasonable approach for the EU. So we don't have a time frame, but I assume it will come after the submission for the U.S., but perhaps not too far after. I think we can do a little more work and nail that down.

We have a final question from Ed White, H.C. Wainwright & Company.

Mike, sorry, I was -- had trouble getting on before. So I hope this question wasn't asked, but, just wanted to ask with the pandemic and update on ULTRA-V. And what you're seeing as far as venetoclax in being used during the pandemic?

Yes. Sure, Ed. Thanks for calling, and sorry about the hold-off in getting in. And I think a few people had trouble as well. In terms of the ULTRA-V trial, it's an interesting question. So we have heard that, obviously, if any patient that needs to be hospitalized, there's definitely been concern. I don't have any real-time feedback on whether that's actually happened. I know we had a chat with investigators and said, "Look, if you don't want to bring people in that you need to keep in the hospital, that you should certainly just keep them on U2 until you feel comfortable administering the venetoclax." I guess probably more interesting might be to hear Dr. Pinilla's view of how it's going with venetoclax out there right now, whether it is problematic, given the need for some patients to be hospitalized. Javier any thoughts on what's happening with that?

Sure. Absolutely. Number one, I will say that it's extremely unlikely, and I didn't have no patient I need to hospitalize for the venetoclax today. So thanks to the debulking strategy. We do 2 patients that are completely in low-risk intermediaries, and those patients never been hospitalized, okay? We never really have done even in previous experience. Definitely, it's part of the experience of the investigator, but there is not really a reason why we should hospitalize those patients. Besides that, and obviously, it's a very, very evolving and dynamic issue that we are dealing. I mean it's very, very dependent of the geographic area that you are dealing with. I mean in Florida, in the beginning, we were very scared, and we were really ready for everything. We never really stopped anyone. And in fact, we enrolled a couple of patients on the ULTRA-V just in the beginning of the pandemia. And we have not been having trouble. So I think, obviously, it's patient preference. Some patients may be more reluctant, more concerned about the potential issues. Obviously, we have been following. And once again, in our institution, we are extremely lucky that we were really completely ready for the worst, but the worst didn't come, and now we are slowly coming back to the normal, but we are really continuing to really treat patients. So there may be a completely different story in areas like New York or L.A. or in other places where people -- well, they are really, really concerned and the cases are continuing to go up or at least they stabilize, right? But again, I think patients need to be followed in the clinics, for sure, with labs. And I think it's an important part, fundamental part of the protocol, really to really be careful. But at the same time, it's unlikely that we're going to have any complication based on the fact that after this debulking strategy, the risk for any potential complication is minimal.

Okay. I think that is the end of the Q&A. So why don't I just finish off here with some concluding remarks. We are getting late into the opening of the markets. So again, let me just thank everyone for joining us this morning, and thank you very much, Dr. Pinilla, for taking the time out of your busy schedule to be here today. Let me wrap up with some key upcoming goals and objectives, which -- most of which were covered in the Q&A. But first, we are targeting completion of our rolling NDA submission for patients with previously treated marginal zone lymphoma and follicular lymphoma later this quarter. Then heading into the second half, we are targeting topline data from our ultimate Phase III trials in relapsing MS. So big data coming for that as well, lots of exciting news on the horizon. And then, of course, based on the results announced today, we're going to be targeting a regulatory submission for U2 for the treatment of patients with CLL as well as the presentation data from the UNITY-CLL trial by year-end. And as I mentioned, fingers crossed, so we get -- catch a little bit of a break. We can possibly get the approval of umbralisib as a single agent in marginal and follicular by year-end. Finally, we expect to continue to advance our early pipeline candidates, including 1501, 1701 and 1801 as single agent and also very important in combination with U2. And we look forward to potentially presenting data from those trials in an upcoming medical meeting, either virtually or in-person. Hopefully, that will happen sooner rather than later. So on behalf of all of us at TG, we want to thank you for spending time with us this morning to discuss these exciting results. It's truly been a long time coming, and we are thrilled, very thrilled by the positive outcome of UNITY-CLL trial. I want to, again, thank our investigators and their patients, as well as our employees and shareholders for their continued support. Thanks, again, everyone, and have a great day.

This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.