Welcome to the TG Therapeutics Update Call. At this time, all participants are in listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Jenna Bosco, Senior Vice President, Corporate Communications. Please go ahead, Jenna. Thank you. Good morning, and thank you all for joining us. I'm Jenna Bosco, and I welcome you all to our conference call today. Following our Safe Harbor statement, Michael Weiss, our Chairman and Chief Executive Officer, will discuss the regulatory updates announced this morning and then turn the call over to the operator to begin the Q&A session. Before we begin, I'd like to remind everyone that various remarks that we make about our future expectations, plans and prospects constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. TG cautions that these forward-looking statements are subject to risks that may cause our actual results to differ materially from those indicated. Factors that may affect TG Therapeutics operations include various risk factors that can be found in our SEC filings, including our most recent quarterly report on Form 10-Q. In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements. 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. Now I'd like to turn the call over to Mike Weiss, our CEO. Thank you, Jenna, and good morning and thank you all for joining us this morning to discuss the regulatory updates related to our pending Biologics License Application or BLA and Supplemental New Drug Application, or sNDA, for the combination of UKONIQ and ublituximab, referred to as U2, for the treatment of chronic lymphocytic leukemia. As highlighted in this morning's press release, we have received notification from the FDA that they plan to host a meeting of the Oncologic Drugs Advisory Committee, referred to as ODAC, in connection with its review of the BLA for ublituximab and the sNDA for UKONIQ. We have been informed that the potential questions and discussion topics for the ODAC include the benefit risk for U2 for the treatment of CLL and the benefit risk for UKONIQ in the current indications for relapsed or refractory follicular and marginal zone lymphoma. The date of the ODAC has not been determined, but the FDA indicated that they are preliminarily targeting the March-April timeframe. We look forward to hearing more from them on timing and content over the next few months. As a reminder, the UNITY-CLL trial is a global phase III randomized controlled clinical trial comparing the U2 combination to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment-naive and relapsed or refractory chronic lymphocytic leukemia. The trial randomized patients into four treatment arms, ublituximab single agent, UKONIQ single agent, U2, and the active control arm of obinutuzumab plus chlorambucil. A pre-specified interim analysis was conducted to assess the contribution of ublituximab and UKONIQ in the U2 combination arm based on overall response and allowed for the termination of the single-agent arms. The criteria for contribution, as set out in the protocol, was met, and accordingly, the UNITY-CLL phase III trial continued enrollment in a one-to-one ratio into the two combination arms. Approximately 420 subjects enrolled in the two combination arms and approximately 60% of the patients were treatment-naive and 40% were relapsed or refractory. The primary endpoint for this study was progression-free survival, PFS, and in May 2020 we announced that the trial met its primary endpoint, with U2 demonstrating a progression-free survival advantage over obinutuzumab chlorambucil. Full results were presented at the American Society of Hematology, or ASH, annual meeting in December 2020. Additionally, that PFS advantage was seen in both of the prospectively defined key subgroups, that is the treatment-naive group and the relapsed/refractory group. The UNITY-CLL phase III trial was conducted under a special protocol assessment with the U.S. FDA. The BLA and sNDA submissions of U2 to treat CLL were based primarily on the results of the UNITY-CLL trial. Now, while we originally did not think an ODAC would be necessary, the FDA recently determined that they would like to engage ODAC to provide guidance on the benefit-risk profile of the U2 combination in CLL and derivatively the benefit-risk profile of UKONIQ in relapsed/refractory marginal zone and follicular lymphoma. The FDA's concern appears to be centered around an early overall survival analysis from the UNITY-CLL phase III trial, which was provided to them in response to an FDA information request as part of the ongoing review of the application. Overall survival was a secondary outcome in the UNITY-CLL trial, and it was not specified to be analyzed in the primary analysis based on the study's statistical analysis plan, which was also agreed to as part of the special protocol assessment and was therefore not analyzed at the time of the interim analysis, which ultimately resulted in the end of the study, nor accordingly was it included in the BLA sNDA submission. While not explicitly stated, the overall survival endpoint was not required to be in the primary analysis because the study was not powered for overall survival, and those data were expected to be quite immature, with the number of overall survival events being too small to be informative. Accordingly, the overall survival endpoint was first analyzed as a response to a recent FDA information request. As noted in the press release, the data provided to the FDA for the overall survival analysis was as of a September 2021 cutoff date, and the results are subject to change as the data are further cleaned and of course, as additional time passes and additional survival events, event data are collected. In the ITT population as of September 2021, there was a hazard ratio of 1.23 in favor of the control arm, though this result is not statistically significant. One factor that we believe significantly affects the analysis of overall survival are deaths due to COVID-19, which account for approximately 15% of the overall survival events and disproportionately occurred on the U2 arm. When censoring, that is to say, not counting COVID-related deaths in the analysis, the hazard ratio to the ITT population in the UNITY-CLL trial is 1.04, essentially showing no difference in survival for either agent at this early time point with the data cutoff in this past September. The significance of the impact of COVID related deaths is a topic we expect may be explored at the ODAC. Now, importantly, I want to put that data into some context. We reviewed the data from the CLL14 trial, which many of you will know was the pivotal study for the frontline approval of venetoclax plus obinutuzumab in treatment naive patients with CLL. In this trial, at the time of approval of venetoclax in first line CLL, an overall survival hazard ratio of 1.24 was observed in favor of the control arm, which was also obinutuzumab plus chlorambucil. Again, the same control arm that's in our study. The overall survival outcome from this study was similar. We're at this point in this early stage, we're showing about a 1.23 for our ITT population, and of course, as we mentioned, 1.04 for the censored COVID analysis. Again, very similar to what was seen with venetoclax plus obinutuzumab at the time of their approval. No ODAC was required for the approval of venetoclax or obinutuzumab. I'd also mention that in terms of grade 3/4 AEs and SAEs, both data sets are reasonably comparable. Again, quite a bit of similarity on the certainly on the risk side of the equation, as we look at these trials and outcomes, again, cross-study of course being something to be wary about. Again, with the overall survival outcome for the CLL14 study looking quite a bit like what we've seen at this point, again at this early stage. Of course, the CLL14 trial was run prior to the COVID-19 era and so that is something that they did not have to deal with. Another important factor to note, and again, given the early nature of the look at that overall survival in CLL14 study, with additional follow-up in the CLL14 trial, the hazard ratio did go below 1. It was not statistically significant, but it does imply a potential survival advantage for VO, again with more time of follow-up and additional events. I think an interesting analog. Similarly, in the Alliance study, which evaluated ibrutinib monotherapy versus ibrutinib plus rituximab versus bendamustine rituximab, at the data cutoff for that primary analysis, a greater number of overall survival events were seen in both ibrutinib-containing arms as compared to the bendamustine rituximab arm. Again, while there are of course many other factors that contribute to an overall benefit risk determination, these examples illustrate that there is a precedent for approval of therapies without an ODAC that have underpowered overall survival analysis that seemingly favor the control arm in early follow-up. While we cannot be sure that the data will show what the data will ultimately show, UNITY-CLL may follow a similar pattern when the overall survival data are more mature, as may be expected based on the robust effect observed on progression-free survival. Recall, for the ITT population, U2 significantly prolonged independent review committee assessed progression-free survival versus the control arm of obinutuzumab chlorambucil. The U2 arm had a median of 32 months of PFS versus 18 months for obinutuzumab chlorambucil, has a ratio of 0.546, and the P-value was a very low point lower than 0.0001. Again, as you can see, we are, you know, we've seen a pattern in the past. We are quite comfortable with where we are with UNITY-CLL. Let me also note, as part of the benefit risk analysis, in addition to overall survival, we do anticipate the ODAC will include a discussion of the contribution of each of the components of the U2 combination, as well as the safety profile of the U2 regimen and the components, including adverse events, both serious and grade 3-4, discontinuations due to adverse events, and dose modifications. We plan to work closely with the FDA toward this ODAC meeting. We believe in the potential of U2 to fulfill an unmet need in CLL. Most importantly, we will always operate with the best interest and safety of patients in mind. To that end, if at any point during our analysis we feel that the U2 regimen does not have a positive benefit risk profile or believe the overall survival data needs to be to mature further to be sure of that benefit, then we will withdraw our BLA/SNDA and potentially refile at a future date. In working towards the ODAC meeting, we also plan to provide additional data and/or analysis to the FDA to support our thesis of a positive benefit risk of U2 in CLL. Given these new data and the FDA's plan to conduct an ODAC and the practical issues around scheduling and conducting the ODAC, we believe it is unlikely that a decision on the BLA/SNDA will be reached on or before the current PDUFA date of March 25th, 2022. Lastly, I wanted to touch on the FDA's derivative topic for discussion at the ODAC. That is to say, the benefit risk for UKONIQ monotherapy for the already granted indications of relapsed refractory marginal zone and follicular. The reason I say it's derivative is because based on what we know to date, the FDA's inclusion of the approved UKONIQ indications in the planned ODAC appears to derive from the same overall survival analysis from the UNITY-CLL trial. To our knowledge, is not related to any overall survival analysis of UKONIQ in follicular and marginal zone, for which we haven't even collected such data, nor related to any new information specifically related to UKONIQ in marginal zone or follicular. I will note, to date, the company is not aware of any unexpected safety issues or concerns reported in the post-marketing setting. To conclude, we want to thank the FDA for their continued diligent review of this application. We share the FDA's passion for patient safety and the challenges of balancing that with ensuring patients have access to novel medicines. CLL is a relatively well-served disease with newly approved novel agents. However, many patients are still in need of additional non-chemotherapy treatment options, even in the treatment-naive setting. U2 has what we believe is a well-characterized safety profile that we believe can be managed for patient safety with appropriate labeling around dose delays and dose reductions, as already exists within the current labeling for UKONIQ. We welcome the opportunity for the ODAC to critically analyze the UNITY-CLL data and believe we can be successful in addressing the potential questions for the ODAC regarding the benefit risk of the U2 combination to treat patients with CLL, as well as the benefit risk of the currently approved indications for UKONIQ monotherapy to treat patients with relapsed or refractory marginal zone lymphoma and follicular lymphoma. Before I turn the call over to the conference operator, I want to briefly mention our MS program. As most of you know, we are now 60 days beyond the submission date of our BLA. Yesterday, we received email confirmation that our BLA submission has been accepted for filing and that our filing communication letter, which will include details about the target PDUFA date, will be provided in the coming weeks. Once we receive that formal notification, we will issue a press release. As many of you know, we have been gaining increasing confidence and enthusiasm for our MS program. Our team is coming together nicely and our interactions with KOLs have been extremely positive. If approved, we believe the overall profile of ublituximab with the one-hour infusion every six months will represent an attractive option for patients with the relapsing forms of MS. We look forward to working closely with the neurology division of the FDA with the goal to bring ublituximab to market as quickly as possible. With that, I'd like to turn the call over to the conference operator to begin the Q&A session. Thank you. We'll now be conducting a question and answer session. If you'd like to be placed in the question queue, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing star one. One moment please while we poll for questions. Our first question today is coming from Alethia Young from Cantor Fitzgerald. Your line is now live. Hi, this is Emily on for Alethia. Thanks for taking our questions, a few from us. Is there anything from a long-term safety perspective that you've seen with patients on U2? And what is the longest exposure that you have in patients? And then secondly, given the ODAC analysis is looking at all the components of U2, which includes ublituximab, is there any potential for that to impact the MS review? And I guess, do you see any risk with that? And then lastly, how does this impact your guidance for 2022 that you gave previously? Thank you. Yeah, thanks for the questions. In terms of guidance, we've always said that guidance was contingent upon approvals on time. We can assume that we'll have to reevaluate the impact of this based on the timing of if and when the U2 gets approved. I think from a guidance standpoint, we were very clear about that originally. In terms of long-term safety, I mean, we have patients. Honestly, I think from the first phase I, we still might have patients on trial. I'd have to check, but certainly well past five years and possibly approaching you know 8+ years of patients on therapy. But I can double-check the longest patient. In terms of MS you know obviously we have no idea. We don't think that this will impact MS. You know, it's a separate trial, separate you know separate division. It's ublituximab as a single agent. I think it'll be viewed on its own merits and not in relation to the U2 combination, where it does appear for the moment that the concern is more focused on UKONIQ, but again, it's hard to fully tell. Great. Thank you. Thank you. Next question is coming from Matt Kaplan from Ladenburg Thalmann. Your line is now live. Hi. Good morning. Thanks for taking the questions. Mike, could you talk a little bit about the maturity of the OS data that you have right now? You mentioned that you expect it to change over time. Are there certain cut points that you expect to take a look at the OS data for the study going forward? Yeah, the data are quite immature at this point. In terms of numbers of events, I think overall, combining the entire ITT population, we're give or take 20%. I think in terms of where you'd expect to see some sort of power, it would be probably closer to 66%-75% of events. Even that would be assuming the study were powered for an endpoint. For a powered endpoint, you wouldn't wanna stop the trial, let's say, as we... You know, to give some perspective on that, when we were looking at the PFS and we were trying to end the trial early because we were having trouble seeing events, we really couldn't get the FDA to agree to look at that prior to 75% of the expected events. So again, when you look at something like this, you know, we are at a very, very early stage of this analysis, and one would expect that the overall survival would be quite unstable. You know, I've talked to a number of experts, and they would say that, you know, you could expect to see, you know, if you look at this thing every several months, you could see the hazard ratio going up and down. It's just unstable when you have such a small number of events. It's a very early look. I think the answer is, yeah, we're probably gonna look at this thing every three to six months going forward, and keep an eye on the trend and what we're seeing in overall trial. Again, we might expect early on that it could be pretty unstable. Okay. That's helpful. Thank you. In terms of imbalances of side effects or issues, can you talk about what you observed in the treatment-naive population, in the UNITY study and, especially when we're thinking about UKONIQ and PI3K inhibitor? Yeah. Again, overall, the toxicity profile was similar between the frontline patients in CLL and the relapsed patients. Again, I think that is a point of differentiation from the other PI3Ks and their inability to be safely dosed in frontline patients. You know, I think, yeah, I mean, we're. I think generally we've shown the data where we compare grade 3-4 AEs and serious adverse events. Again, I think between the frontline and relapsed population, they're pretty similar. Okay. Last question, kinda related to that. In terms of infections observed other than COVID in the study, do you have any visibility to that in terms of driving, also driving OS? I don't. We've reported the infection risk and the grade 3/4 in the and I guess potentially even grade 5 AEs on that point. I don't have it at the tip of my tongue, but we've reported out certainly that data through the May 2020 timeframe. I could look into that. I don't have an answer. I don't know if there's any overall infection imbalance other than COVID. Nothing's been raised to me, nor have we looked at a separate analysis. COVID has been the primary infection that's been of concern. Okay. Thanks for taking the questions. Yeah. Thanks, Matt. Sure. Thank you. Our next question is coming from Chris Howerton from Jefferies. Your line is now live. Hey, thanks so much for taking the questions. You know, I guess, to refer to what you called it, Mike, the derivative of these OS data for follicular and marginal zone, you know, what is the status of the confirmatory study, and what can you tell us about, you know, kind of the path towards full approval in those indications? I've got to double confirm with my regulatory group, but I think the last interaction was we had filed the final protocol for the last review with the FDA. We're in the process of finalizing that protocol with the FDA before that gets started. Okay. All right. Sounds good. Maybe just a very quick question with respect to venetoclax. I know that you noted that at the time of their initial approval that there was an imbalance in the hazard ratio there as well. Did they also have an ODAC? I just don't recall. Yes. They did not have an ODAC. So no ODAC was required. Again, I think, yes, no ODAC was required for that. The overall survival was clearly in favor of the GC arm at the time of approval. Okay. All right. Thank you very much. Thanks, Chris. Thank you. Our next question today is coming from Eric Joseph from JP Morgan. Your line is now live. Hi. Thanks for taking the questions. I guess having seen data with longer follow-up, I'm just wondering if you're seeing a change in the relative rate of death prior or without progression between the two arms. I'm also curious to know whether you're seeing a meaningful difference in treatment regimens adopted following progression on either of the arms in the UNITY study. Uh- You had the question of whether, you know, imbalance in subsequent or post-progression therapy might be contributing to an imbalance in OS. Yeah. That's a great point, Eric. We are working on that. We've got, as I mentioned in the prepared remarks, I mean, we're doing a lot of additional analysis. Again, this, you know, we kind of put together the overall survival data in as a response to a request by the FDA. You know, we did the best we could to gather that data. Again, it was not a primary focus of our efforts. It wasn't, you know, in the primary analysis. Again, we did our best to put it all together. We got it to them. Then, there was some time between when we got it to them, and then them saying, "Well, we're uncomfortable." Right? They want it, "We want more information." Yeah, we're now digging in hard into the data. Again, we looked at the data, you know, in context and thought it was an early OS and was not problematic. Then obviously, there was a difference of opinion on that is why they wanna vet this at the ODAC. Again, yeah, to answer your question, I don't have the answer today. We are digging in deep into this data to understand all of those facets of where we are with the overall survival and any of those factors that may be impacting it. Okay, great. Thanks for taking the questions. Yep. Thank you. Our next question today is coming from Mayank Mamtani from B. Riley. Your line is now live. Good morning. Thanks for taking our questions, Mike. Just a follow-up to the prior conversation. Is there any other form of OS data cut you may have looked at beyond the hazard ratio, like, you know, 12-month OS analysis or, you know, first-line versus relapsed refractory? What I'm trying to gather is like how far we might be from, you know, that final hazard ratio number from CLL14, which was I think 0.85. Just curious, you know, from a cutoff standpoint, from a follow-up standpoint, where do you think we are with the study and with the events relative to, you know, when we learned about the CLL14 hazard ratio earlier this year? Yeah. I mean, again, it's hard to go apples to apples, since, you know, the numbers we've given you are a combined group of patients at frontline and relapse. Theirs is a purely relapsed population. But I think if you look at and so to answer your question, yes, we have looked at frontline versus relapse. As many of you know, the PFS benefit seen in the frontline population, we gave those hazard ratios out. I think the hazard ratio for the frontline population for PFS was below the 0.5 mark. I think it was somewhere between 0.45 and 0.47. Again, I don't have the exact in my head, but give or take. So there was 0.48. There was definitely more. Thank you, Mayank. Appreciate that. There was a little bit more of a robust effect in the frontline patients on the PFS, and that has translated so far into an advantage in overall survival between the frontline and the relapse. Again, can't go apples to apples exactly, but if you just look at the frontline population, with a similar level of maturity to the VO, our frontline population is already below one. Okay. looks like the UKONIQ incrementally- And that- Contri- Mayank, just to be clear, the hazard ratio for overall survival for the frontline is already below one. That's, I believe, independent of COVID as well. It's pretty solid, HR at this point for OS for that frontline population. Oh, that's great. Maybe actually a good segue would be, is there a more refined labeled population you could kind of target as you think about ODAC? Looks like you know, this incremental contribution of UKONIQ is sort of top of mind from what I could gather from your prepared remarks. Is there again a way you could you know, sort of narrow down a particular patient population but make sure you know, that's the best risk-benefit that particular patient population gets as you think about discussion at the ODAC? Yeah. I think everything's on the table, Mayank. Yeah, if you know, if the FDA were to be comfortable with, you know, in this particular example, you know, one of the patient populations like the front line, and they wanted more information on the relapsed refractory, I don't think we would be opposed to going down that path. Again, if that were to be a subject of conversation at ODAC again, that would not be, you know, a terrible outcome for us either. Yeah, I mean, look, we wanna make sure that everyone is comfortable with the risk-benefit of the U2 regimen in all indications for CLL. We certainly, you know, we'll certainly work with the FDA and ODAC to get there. Thank you. My final question, great to hear about the ublituximab BLA acceptance of the BLA. Is there expectation to have a panel there or is it just too early to know things like that? I'm gonna say it's too early to know. I'm not gonna opine as to whether a panel would be required or not. Thanks for taking my question, Mike. Thanks, Mayank. Appreciate it. Thank you. Our final question today is coming from Ed White from H.C. Wainwright. Your line is now live. Good morning. Thanks for taking my question. Mike, just can you remind us on the dose modifications seen in UNITY-CLL? Then also, are you getting any feedback in FL and MZL for dose modifications, what the physicians are seeing or are doing in practice? Thanks. Sure. Yes, I mean, we have, I think reasonably clear dose modification rules in the UKONIQ label. We do encourage folks, you know, again, to find the dose that's comfortable for them and, you know, for physicians and their patients. We certainly, if anyone is having a tolerability issue, again, we have the first dose reduction is from 800 down to 600, and if they're still having tolerability issues, we encourage folks, and it's in the guidance to go down to 400. If they can't tolerate 400, then we do recommend they come off of UKONIQ. Again, those have been, you know, dose reduction algorithms that we've used for, you know, throughout the clinical practice. I don't have, you know, in terms of, I'm pretty sure it's in the UNITY-CLL presentation, patients that were subject to dose reductions or dose interruptions. And again, same thing there. You know, I'll just note, I mean, we do encourage folks if, you know, physicians, if the patient is not tolerating the drug, they should give them a drug holiday. I mean, we know the drug has a long half-life. We know that, you know, that they will not lose coverage that quickly, and it's probably just easier to give them a little break. So again, those are dose interruptions are in the label as well. So again, I don't have those numbers, but again, they were in the UNITY-CLL presentation. I'm highly confident of that. Okay. Thanks, Mike, for taking my questions. Yeah, no problem, man. Thank you. Thank you. We have reached the end of our question and answer session. I'd like to turn the floor back over for any further closing comments. Great. So again, just want to conclude by saying thank you to everyone for joining us today. And thank you to the FDA for their continued and thoughtful review of this application. We'll continue to work with them toward the successful completion of the ODAC. Hope everyone has a great day. Thank you. Thank you. That does conclude today's teleconference webcast. You may disconnect your line at this time and have a wonderful day. We thank you for your participation.