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

Hello and welcome to the TG Therapeutics Update Call. [Operator Instructions] 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 umbralisib. 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/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 time frame. 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/refractory chronic lymphocytic leukemia. The trial randomized patients into 4 treatment arms: ublituximab single agent, UKONIQ single agent, U2 and the active control arm of obinutuzumab plus chlorambucil. A prespecified 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. Their criteria for contribution as set out in the protocol was met and accordingly, the UNITY-CLL Phase III trial continued enrollment in a 1:1 ratio into the 2 combination arms. Approximately 420 subjects enrolled in the 2 combination arms and approximately 60% of the patients were treatment-naive and 40% were relapsed/refractory. The primary endpoint for this study was progression-free survival, PFS. And in May of 2020, we announced that the trial met its primary endpoint, with U2 demonstrating a progression-free survival advantage over obinutuzumab chlorambucil, and full results were presented at the American Society of Hematology or ASH Annual Meeting in December of 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/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 for 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 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, so we're -- at this point, at this early stage, we're showing about 1.23 for our ITT population, and of course, as we mentioned, 1.04 for the censored COVID analysis. So again, very similar to what we've 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. So 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. But again -- so 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. And of course, the CLL14 trial was run prior to the COVID era, and so that is something that they do 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 [ v, o ], again, with more time, a follow-up and additional events. So again, I think an interesting analog. Similarly, in the NIH 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 RITUXAN 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 and 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 independently reviewed -- 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. So again, as you can see, we are -- 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 towards this ODAC meeting. We believe in the potential of U2 to fulfill an unmet need in CLL. And 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 would 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 and 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 25, 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 arrive from the same overall survival analysis from the UNITY-CLL trial and to our knowledge, is not related to any overall survival analysis of UKONIQ in follicular marginal zone, for which we haven't even collected such data nor related to any new information specifically related to UKONIQ in marginal zone and follicular. And I will note, to date, the company is not aware of any unexpected safety issues or concerns reported in the post-marketing setting. So 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 nonchemotherapy 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 in 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/refractory marginal 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 e-mail confirmation that our BLA submission has been accepted for filing, and 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 1-hour infusion every 6 months, will represent an attractive option for patients with 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.

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

This is Emily on for Alethia. 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 lastly, how does this impact your guidance for 2022 that you gave previously?

Yes. Thanks for the questions. In terms of guidance, we've always said that guidance was contingent upon approvals on time. So 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. So 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 have to check. But certainly, well past 5 years and possibly approaching 8-plus years of patients on therapy. But I can double check the longest patient. In terms of MS, obviously, we have no idea and we don't think that this will impact MS. It's a separate trial, separate division. It's ublituximab as a single agent. I think it will be viewed on its own merits and not in relation to the U2 combination, where it does appear for the moment that there's a -- that the concern is more focused on UKONIQ, but again, it's hard to fully tell.

Next question is coming from Matt Kaplan from Ladenburg Thalmann.

Mike, could you talk a little bit about the maturity of the OS data that you have right now? And 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?

Yes. So the data are quite immature at this point. In terms of numbers of events, I think overall, where I think combined, the entire ITT population were, 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% to 75% of events. And that would be assuming the study were powered for an endpoint. So for a powered endpoint, you wouldn't want to stop the trial, let's say. As we -- to give some perspective on that, we were looking at the PFS and we were trying to end the trial early because we're 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, we are at a very, very early stage of this analysis, and one would expect that the overall survival would be quite unstable. I've talked to a number of experts, and they would say that you could expect to see -- 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, and so it's very early look. So the -- I think the answer is yes, we're going to -- we're probably going to look at this thing every 3 to 6 months going forward and keep an eye on the trend, and what we're seeing in overall trial. But again, we might expect even early on that it could be pretty unstable.

Okay. That's helpful. And then 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 PI3 kinase inhibitor?

Yes. So again, overall, the toxicity profile was similar between the frontline patients in CLL and the relapsed patients. And again, I think that is a point of differentiation from the other PI3Ks and their inability to be safely dosed in frontline patients. I think -- yes, I mean, we're -- I think generally, we've shown the data where we compare Grade 3/4 AEs and serious adverse events. And again, I think between the frontline and relapsed population, they're pretty similar.

Okay. And then last question kind of 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 in the Grade 3/4 and 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 time frame. I could look into that. I don't have an answer. I don't know if there's any overall inspection in balance other than COVID. I don't -- nothing has been raised to me nor have we looked at that -- like that as a separate analysis. So COVID has been the primary infection that's been of concern.

Our next question is coming from Chris Howerton from Jefferies.

I guess to refer to what you called it, Mike, the derivative of these OS data for follicular and marginal zone, what is the status of the confirmatory study? And what can you tell us about kind of the path towards full approval in those indications?

Yes. So 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. So we're in the process of finalizing that protocol with the FDA before that gets started.

Okay. All right. Sounds good. And then 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? And I just don't recall.

Yes, they -- yes, yes, they did not have an ODAC. So no, no ODAC was required. And yes, again, I think -- yes, no ODAC was required for that and the overall survival was clearly in favor of the GC arm at the time of approval.

Our next question today is coming from Eric Joseph from JPMorgan.

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 2 arms? And 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? A question of whether an imbalance in subsequent or post-progression therapy might be contributing to -- or might be having -- might be contributing to an imbalance in OS?

Yes. So that's a great point, Eric, and 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 -- we kind of put together the overall survival data as a response to a request by the FDA. We did the best we could to gather that data. Again, it was not a primary focus of our efforts. It wasn't in the primary analysis. So again, we did our best to put it all together. We got it to them. And then there was some time between when we got it to them and then they -- saying, well, we're uncomfortable, right? So we want more information. So yes, we're now digging in hard to the data. Again, we looked at the data in context and thought it was an early OS and was not problematic. And then obviously, there was a difference of opinion on that, it's why they want to get this at the ODAC. So again, yes. So 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.

Our next question today is coming from Mayank Mamtani from B. Riley.

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 12-month OS analysis or first-line versus relapsed/refractory? And what I'm trying to gather is like how far we might be from that final hazard ratio number from CLL14, which was, I think, 0.85? Just curious, from a cutoff standpoint, from a follow-up standpoint, where do you think we have with the study and with the events relative to when we learned about the CLL14 hazard ratio earlier this year?

Yes. I mean, again, it's hard to go apples-to-apples since the numbers we've given you are a combined group of patients at frontline and relapsed. [ There is a, surely ], relapsed population. But I think if you look at -- and we -- and so to answer your question, yes, we have looked at frontline versus relapsed. And as many of you know, the benefit, 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. I don't have the exact in my head. But give or take, so there was definitely...

0.48, yes.

Thank you, Mayank. I appreciate that. So 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 relapsed. And 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 [ v, o ], our frontline population is already below 1.

Okay. And then it looks like the UKONIQ incremental...

And that -- Mayank, just to be clear on that, I'm going to say that our -- the hazard ratio for overall survival for the frontline is already below 1. That's, I believe, independent of COVID as well. So it's a pretty solid HR at this point for OS for that frontline population.

Oh, that's great. And maybe actually a good segue would be is there a more refined, labeled population you could kind of target as you think about ODAC? And it looks like this incremental contribution of UKONIQ is sort of top of mind from what I could gather from your prepared remarks. So is there, again, a way you could sort of narrow a particular patient population but make sure that's the best risk benefit that particular patient population gets as you think about discussion at the ODAC?

Yes. I think everything is on the table, Mayank. So yes, if the FDA were to be comfortable with -- in this particular example, one of the patient populations like the frontline and they wanted more information on the relapsed/refractory, I don't think we would be opposed to going down that path. And again, if that were to give you a subject of conversation or [ depth ], again, that would not be a terrible outcome for us either. So yes, I mean, look, we want to make sure that everyone is comfortable with the risk benefit of the U2 regimen in all indications for CLL. And we certainly -- we'll certainly work with the FDA and ODAC to get there.

And my final question, great to hear about the ubli acceptance of BLA. Is there expectation to have a panel there? Or is it just too early to know right now?

I'm going to say it's too early to know. I'm not going to opine as to whether a panel would be required or not.

Our final question today is coming from Ed White from H.C. Wainwright.

So Mike, just -- can you remind us on the dose modifications seen in UNITY-CLL? And then also, are you getting any feedback in FL and MZL for dose modifications, what the physicians are seeing -- are doing in practice?

Sure. Yes, I mean, we have, I think, reasonably clear dose modification rules in the UKONIQ label. We do encourage folks again, to find the dose that's comfortable for them and for physicians and their patients. Certainly, if anyone is having a tolerability issue, again, we have dose -- we have the first dose reductions 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 you can't tolerate 400, then we do recommend they come off of the UKONIQ. So again, those are -- those have been dose reduction algorithms that we've used for -- throughout the clinical practice. I don't have -- in terms of we -- 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, I'll just note, I mean, we do encourage folks if -- 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 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.

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 or closing comments.

Great. So again, I just want to conclude by saying thank you for everyone for joining us today, and thank you to the FDA for their continued and thoughtful review of this application and we'll continue to work with them toward the successful completion of the ODAC. I hope everyone has a great day. Thank you.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.